A RANDOMIZED CONTROLLED TRIAL COMPARING (FGMS) …repository-tnmgrmu.ac.in/9253/2/200701118vinod_kumar.pdf · 2018-08-14 · 3 CERTIFICATE This is to certify that the dissertation

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A RANDOMIZED CONTROLLED TRIAL COMPARING (FGMS) FLASH

GLUCOSE MONITORING SYSTEM + SMBG VS SMBG (SELF

MONITORING OF BLOOD GLUCOSE) ALONE FOR GLYCEMIC

CONTROL IN ADOLESCENTS OF 12- 18 YEARS OF AGE WITH TYPE 1

DIABETS MELLITUS

A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REGULATION FOR THE

AWARD OF THE DEGREE OF MD PAEDIATRICS (BRANCH VII)

THE TAMIL NADU DR. MGR MEDICAL UNIVERSITY

CHENNAI, TAMIL NADU

MAY -2018

2

CERTIFICATE

This is to certify that the dissertation titled “A RANDOMIZED CONTROLLED

TRIAL COMPARING (FGMS) FLASH GLUCOSE MONITORING

SYSTEM + SMBG VS SMBG (SELF MONITORING OF BLOOD

GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN ADOLESCENTS OF

12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS” is the bona

fide work done by Dr. VINOD KUMAR.P. under my supervision in the

Department of Pediatrics, Christian Medical College and Hospital, Vellore, in

partial fulfilment of the requirements for the degree of MD Pediatrics of The Tamil

Nadu MGR Medical University, Chennai, to be held in April 2018.

Dr. Anna Simon MD, DCH, FRCP (Edin)

Professor and head,

Division of Child Health, Unit – 1,

Christian Medical College,

Vellore, Tamil Nadu,

India- 632004.

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CERTIFICATE






fide work done by Dr. VINOD KUMAR. P in the Department of Paediatrics,

Christian Medical College and Hospital, Vellore in partial fulfilment of the

requirements for the degree of MD Paediatrics Examination of The Tamil Nadu

MGR Medical University, Chennai, to be held in April 2018. This work was

carried out under the guidance of Dr. Anna Simon, Professor and head, Division of

Child Health, Unit-1, Christian Medical College, Vellore.

Dr. Indira Agarwal MD FISN

Professor and Head,

Department of Paediatrics,


Vellore, Tamil Nadu,

India- 632004.

4

CERTIFICATE






fide work done by Dr. VINOD KUMAR P. in the Department of Paediatrics,

Christian Medical College and Hospital, Vellore in partial fulfilment of the

requirements for the degree of MD Paediatrics Examination of The Tamil Nadu

MGR Medical University, Chennai , to be held in April 2018.

Dr. Anna B. Pulimood MD

Principal

Christian Medical College

Vellore, Tamil Nadu

India, 632004

5

DECLARATION CERTIFICATE





12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS”, submitted in

partial fulfilment towards the MD Paediatrics examination of The Tamil Nadu Dr

MGR Medical University, Chennai to be held in April, 2018, comprises my

original work and due acknowledgements have been made in the text for all the

materials used.

Dr. VINOD KUMAR.P

PG Registrar, Department of Paediatrics,


Vellore, 632004

India

6

7

CERTIFICATE -II

This is to certify that this dissertation work titled “A RANDOMIZED

CONTROLLED TRIAL COMPARING (FGMS) FLASH GLUCOSE

MONITORING SYSTEM + SMBG VS SMBG (SELF MONITORING OF

BLOOD GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN

ADOLESCENTS OF 12- 18 YEARS OF AGE WITH TYPE 1 DIABETS

MELLITUS” by Dr Vinod Kumar. P with the registration number 201617458 for

the award of Degree of MD Paediatrics. I personally verified the urkund.com

website for the purpose of plagiarism Check. I found that the uploaded thesis file

contains from introduction to conclusion pages and result shows ONE percentage

of plagiarism in the dissertation.

Guide & Supervisor sign with Seal.

8

ACKNOWLEDGEMENTS

I thank God Almighty for giving me the opportunity to do this study and giving me the

grace to complete it successfully.

In the selection of topic and preparation of this dissertation I am deeply indebted to my

guide Dr Anna Simon, professor and head, Division of Child Health, Unit- 1, who guided

me with grace and truth. She gave me suggestions for improvement and made alterations

in the presentation. Without her help, I would not have been able to complete this

assignment in time.

Dr Sophy Korula, Associate Professor, Child Health, Unit -1 who as co-investigator

brought valuable insights into the study.

I am grateful to the nursing staff of department of endocrinology for their

cooperation and help.

I am thankful to Mrs.Hepsy, Department of Biostatistics for her help and advice.

I thank my parents for this life and my in laws for their loving and sacrificial support in

taking care of my children.

I owe thanks to my wife Annie and children Liza and Jamy who bore the pain of my

absence yet showered me with their love.

I thank the children who were part of this study.

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TABLE OF CONTENTS

1. INTRODUCTION 11

2. AIMS AND OBJECTIVES 14

3. MATERIALS AND METHODS 16

4. LITERATURE REVIEW 25

5. RESULTS 49

6. DISCUSSION 76

7. CONCLUSION 89

8. LIMITATIONS 92

9 BIBLIOGRAPHY 95

10 ANNEXURES 101

10

INTRODUCTION

11

INTRODUCTION

Type 1 diabetes is a most common endocrine disorder of childhood. Strict glycemic

control was proven to improve the quality of life and prevent the long term complications.

Self monitoring of blood glucose by finger prick method is commonly practiced to

monitor blood sugars and glycemic control is assessed by HbA1c once in 3months.

However self monitoring of blood glucose can miss the glucose excursions that vary

according to activity and food intake. Continuous glucose monitoring in achieving the

better glycemic control is well established. However cost and need for finger pricks for

machine calibration is cumbersome. FGMS is a novel method of continuous glucose

monitoring which is cost effective and did not require finger pricks. We propose that

FGMS in addition to SMBG will improve the glycemic control compared to self

monitoring of blood glucose alone and will also help in better identifying the

hypoglycemic events which otherwise might go unnoticed with SMBG alone.

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RESEARCH QUESTION

Comparing FGMS (Flash Glucose Monitoring System) + SMBG Vs SMBG (Self

Monitoring of Blood Glucose) alone for glycemic control in adolescents of 12-18years

age with Type 1 diabetes mellitus.

HYPOTHESIS

1) Flash glucose monitoring system offers continuous and frequent monitoring of

glucose once in 15minutes for 14days. Therefore it will allow the clinician for more

appropriate insulin dosing schedule and thereby help in reduction of HbA1c.

2) FGMS helps in improved detection of hypoglycemic episodes when compared to

self monitoring of blood glucose alone in children (12-18years) with type 1

diabetes mellitus.

13

AIMS & OBJECTIVES

14

AIMS AND OBJECTIVES

PRIMARY OUTCOMES

1) To compare the flash glucose monitoring system + self monitoring of blood glucose

with self monitoring of blood glucose alone in terms of glycemic control as assessed by

reduction in HbA1c in adolescents with type 1 diabetes.

2) To identify the hypoglycemic events not identified with self monitoring of blood

glucose alone.

SECONDARY OUTCOMES

1. To assess the correlation of FGMS interstitial glucose recordings with

glucometer capillary recordings.

2. To assess the feasibility and acceptability of FGMS

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METHODOLOGY

16

MATERIALS AND METHODS

Setting

Paediatric endocrinology- division of Child Health Unit-I, Christian Medical

College, Vellore which is a tertiary care centre which caters to an average of 7000

children with endocrine and metabolic issues per year.

Study period: 1 year January 2017 till December 2017

Study design: Prospective, Open label randomized control study

Participants

Inclusion Criteria:

1) Adolescents of 12-18years age with type 1 diabetes for at least 1 year who are

registered in pediatric endocrinology department

2) Residing in and around Vellore.

3) Patients on basal bolus or split mix regimen insulin with 3-4 injections per day

and doing SMBG at least 3-4 times per day for 3 consecutive days once in every 2

weeks.

4) Hba1c >8% and <14%.

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Exclusion Criteria:

1) Patients age less than 12 and more than 18years.

2) Patients residing far from Vellore.

3) New onset Type 1 diabetics for less than 1 year duration.

4) Patients with HbA1c <8% and >14%.

5) Patients on corticosteroid therapy or any other major systemic illness.

Sample size calculation

Sample size was calculated with 1:1 randomization ratio based on assumption of a

common SD of 1% and an absolute difference of 1% in HbA1c between study

groups. This can be detected with an alpha error of 0.05(two sided) and beta error

of 0.20. So by using the formula n=2 x {Z (1-α/2) + Z (1-β)}2

xσ2/d

2. Sample size of

15.68 participants in each in the intervention and control group was required. For

convenience 15 was chosen.

Randomization

Participants were randomized to intervention (FGMS + SMBG) or control (SMBG

alone) arms. Randomization was done by using computer generated random

number list.

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Allocation concealment

Group allocation was concealed from the investigator and participants with opaque

sealed envelopes prepared by a third person from biostatistics department who was

not part of the design and analysis of study.

Blinding

Randomization and allocation was concealed from the subjects and the

investigator. Post allocation blinding was not possible because the study design

was open label randomized study.

Definition of hypoglycemia

Cut off for hypoglycemia in all subjects was taken as any value less than 70mg/dl.

However for FGMS recordings, this cut off was reduced to 60mg/dl allowing for

the difference of 10-15mg/dl between interstitial and blood glucose values.

Asymptomatic hypoglycemia is defined as blood glucose value less than 70mg/dl

presenting without symptoms of hypoglycemia. Symptomatic hypoglycemia is

defined as blood glucose value less than 70mg/dl associated with clinical

symptoms viz headache, palpitation, dizziness, sweating, abdominal pain and

mood changes. Severe hypoglycemia is defined as when the patient has altered

sensorium (coma or convulsions) with concomitant blood glucose value less than

70mg/dl.

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Implementation

The primary investigator had distributed envelopes to the subjects after obtaining

consent. Subjects were asked to open the covers and were allotted to respective

groups. After the sealed cover was opened neither the primary investigator nor the

patient were blinded to further interventions.

As per the protocol followed in the endocrinology unit self monitoring of blood

glucose was done throughout the study period for all the participants in both

groups for 4 consecutive days at two weekly intervals. At the end of every 2 weeks

of home blood glucose monitoring, insulin adjustment and dietary recommendation

were done by the treating physician over phone or in person.

FGMS apparatus installation and monitoring

Flash glucose monitoring sensor was placed for 14 days for participants in

intervention (FGMS+SMBG) group at the beginning of the study period and at

end of 2nd

and 4th

month. The FGMS sensor was placed by the diabetes nurse

educator in the presence of the primary investigator. The participants were sent

home after giving all the necessary precautions about the sensor and advised to

continue the usual way of monitoring of blood glucose by finger pricks as

followed in the unit. Patients were encouraged to follow their regular lifestyle and

treatment during this monitoring period. Participants were not asked to come in

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between 14days of sensor placement. Patients were given contact phone number

available 24 hours throughout the study period to ask and resolve queries about

FGMS maintenance at home. At the end of 14 days, the FGMS sensor was

collected from patients and the information from sensor was downloaded to the

computer using FGMS sensor reader. Insulin adjustments were done as per the

FGMS and SMBG readings. Patients were informed about the changes in insulin

adjustments at the time of sensor removal or over phone.

Hba1c was done at the beginning of the study and at end of 3rd

and 6th

month.

Control group

All other procedures were same except that control group was not placed

intermittent FGMS for glucose monitoring. Treatment modifications were solely

based on SMBG records.

Statistical methods

Statistical analysis was performed using SPSS statistical software. Categorical

variables were summarized using counts and percentages. Quantitative variables

were summarized using mean and standard deviation or median and IQR. Chi

square test was used to compare the proportions between the groups and two

sample t tests were used to compare means between the two groups. For all the

analysis, 5% level of significance was considered to be significant.

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Ethical clearance & Funding

The institutional review board of Christian Medical College, Vellore had reviewed

and accepted the study design (See annexure).The study was registered with

clinical trials registry of India with registration number CTRI/2017/05/008628.

Funds for procuring FGMS sensors were released from the Office of Research,

Institutional Review Board, Christian Medical College, Vellore. Study was

monitored by data safety monitoring board and an interim report was presented to

DSMB.

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LITERATURE REVIEW

23

LITERATURE REVIEW

EPIDEMIOLOGY OF TYPE 1 DIABETES MELLITUS

Type 1 diabetes mellitus is one of the commonest metabolic and endocrine

disorders of childhood. Earlier, because of poor socio-economic status of the

communities’ infectious diseases like viral infections, pneumonia, diarrhea, and

nutritional deficiencies resulted in significant childhood morbidity and mortality.

In the present postmodern era these communicable diseases are replaced by non-

communicable diseases like diabetes, overweight and obesity. (1–3)

Type 1diabetes is often diagnosed in children and adolescents. Unlike type 2

diabetes which can be managed primarily with oral hypoglycemic agents T1DM

requires lifelong requirement of exogenous insulin. The incidence of childhood

T1DM is rising all over the world, with reported increases of 2 to 5% per year in

Europe, the Middle East, and Australia.(4–7) T1DM is on a rising trend in

Finland, India, Sweden, Colorado and Germany. There has been an increase in

incidence of almost 10/100,000 children to 60/100,000 children in Finland in the

last five decades. Around 78,000 children under the age of 15 years are estimated

to develop T1DM yearly worldwide. Of the existing 49lakh children living with

T1DM, 24% are from European region and 23% from the South‑East Asian

region. In South‑East Asia India have most of the children with T1DM. According

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to 6th edition of the IDF diabetes atlas, India has 3 new cases of T1DM/1lakh

children of 0–14 years.(8) The prevalence of diabetes in India as a whole is not

available, data available from hospital based studies showed variable prevalence.

Three studies from metropolitan cities of India showed, 3.2 cases/100,000 children

in Chennai, 17.93 cases/100,000 children in Karnataka and 10.2 cases/100,000

children in Karnal (Haryana).(9–11)

DEFINITION AND TYPES OF DIABETES

As per American diabetic association criteria 2011 diabetes is diagnosed when

fasting plasma glucose is more than 126mg/dl (or) HbA1c >6.5% (or) in a patient

with symptoms of hyperglycemia , a random plasma glucose >200 mg/dl.(12)

T1DM is the most common cause of diabetes in childhood and adolescence. Other

types include Type 2 diabetes and monogenic forms. T1DM often presents with

poydipsia, polyuria and weight loss. It is characterized by the lifelong dependence

on exogenous insulin.(13)

COMPLICATIONS

Chronic hyperglycemia results in multiple complications which includes

microvascular complications (Neuropathy, nephropathy and retinopathy) &

macrovascular complications (cerebrovascular disease, peripheral vascular disease

and coronary artery disease).(14,15) Impaired performance of mathematical tasks

can also occur during periods of hyperglycemia(16)

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Other serious and potentially life threatening complication of diabetes is

hypoglycemia. Hypoglycemia is often a result of intensive insulin therapy.

Children and their caretakers may not be able to identify low blood glucose levels

solely based on symptoms. Gonder et al compared glucometer results with self-

reporting of hypoglycemia. They found >50% of parents and >40% of children

failed to recognize hypoglycemic events.(17) Hence, regular and frequent blood

glucose monitoring is necessary to prevent hypoglycemic episodes and to optimize

glycemic control. In children with T1DM, blood glucose level <70 mg/dl is used as

a threshold for identifying and initiating intervention for hypoglycemia. (18,19) A

lower level <65 mg/dl defined as hypoglycemia. Normal physiologic responses to

hypoglycemia include release glucagon, growth hormone, epinephrine and cortisol

which are counter regulatory hormones. Counter regulatory hormone response

often becomes blunted over time in individuals with T1DM. In these individuals

glucagon response is impaired and the epinephrine rise decreased. This blunting of

responses increases the risk of hypoglycemia.30% of children and adolescents have

impaired epinephrine response in whom diabetes is well controlled.(20)

“Hypoglycemic unawareness” is a state defined by a lack of alarming symptoms of

hypoglycemia because of blunting of counter regulatory hormone response.

Hypoglycemic unawareness is commonly seen in children &adolescents with long

duration of diabetes. This increases the risk of recurrent and severe hypoglycemia.

26

Any event of hypoglycemia can further lower the glucose threshold at which

counter regulatory hormone discharge and symptoms occur, increasing the risk for

further severe hypoglycemia. Hypoglycemia when prevented for few weeks can

lead to restoration of hypoglycemia awareness. Night time hypoglycemia is

common to occur in children. The incidence of nocturnal hypoglycemia in children

at any given night is up to 47 percent. (21,22)

Symptoms of hypoglycemia can be non specific which include behavioral changes

nightmares, disturbed sleep, headache and confusion. Blunted counter regulatory

hormone response to hypoglycemia can result in nocturnal hypoglycemia.(23)

MANAGEMENT

Successful management of T1DM in children and adolescents includes maintaining

a balance of strict glycemic control, which minimizes the risk of chronic

hyperglycemic complications, avoid severe hypoglycemia which can happen with

strict glycemic control, to achieve the recommended goals of glycemic control and

to identify & treat hypoglycemia by educating the patient and care takers to

provide necessary care and to maintain normal growth, and emotional

development, and self-care of diabetes as the adolescent enters into adulthood.(24–

26) American Diabetes Association (ADA) set higher targets in the past for

HbA1C for young children as compared with adolescents and adults. This is of the

concern that strict glycemic control can increase the risk for hypoglycemic

27

episodes. (27) However, ADA and ISPAD in 2014 stated that it is possible to

improve glycemic control by stringent HbA1C targets without much increase in the

risk for severe hypoglycemia. For this reason ADA and ISPAD currently

recommend HbA1C of <7.5 percent for all children. Pre meal level of 90-130mg/dl

and overnight glucose level of 90-150mg/dl are to be maintained to achieve

recommended target of HbA1c <7.5%.(24)

Self monitoring of blood glucose

Daily blood glucose levels are used to monitor glycemic control and adjust insulin

accordingly. Irrespective of age group of the patient, the goal of management in

diabetes is to maintain glucose control as near to normal as possible so as to

balance the risks of long-term complications of hyperglycemia and hypoglycemia.

The lower the HbA1c value, the lower the risk for development of long term

hyperglycemic complications. However, the risk of hypoglycemia is more.

Diabetes is a chronic disease state which requires regular and frequent monitoring

of sugars and insulin adjustment. Regular and frequent monitoring of blood sugars

not only improves glycemic control in children but also decrease the frequency of

serious hypoglycemic events(28–30). Hence self monitoring of blood glucose

monitoring daily is very much needed for management and decreasing the

complications. As per American diabetes association and International society for

pediatric and adolescent diabetes consensus guidelines (ISPAD) self monitoring of

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blood glucose should be done a minimum of four times a day (Early morning

fasting, pre lunch, pre dinner and at bedtime). More frequent monitoring is

recommended during times of increased physical activity and sick days.(21,22)For

self monitoring the most widely used investigation to evaluate long-term glycemic

control is blood glycosylated hemoglobin (Hemoglobin A1C). Newly formed red

blood cells are released into circulation with minimal glucose attached to them. As

red blood cells are permeable to glucose, glucose continues to get attached to

hemoglobin depending on the availability in the blood. Temporary elevation in

glucose in blood forms large amounts of aldamines. This reaction is reversible

because when the glucose concentration of body falls. Another reaction by which

glucose gets attached to hemoglobin leads to formation of ketoamines. Formation

of ketoamines is an irreversible reaction unless the protein to which glucose

attached is metabolized. Majority of commercially available HbA1c assays test for

ketoamines and not aldamines. Hence it reflects long term glycemic control and

mostly unaltered by acute fluctuations in sugar levels.(33,34)

Three useful ways for defining glycemic control includes, firstly estimation of

mean of different values obtained by measuring blood sugars 6 times a day. The

simpler way of doing this is measurement of HbA1c. Second way is to measure

mean daily differences which estimates fluctuation of glucose concentrations day

29

to day. Thirdly measurement of mean amplitude of glycemic excursions to

estimate glucose fluctuations occurs within a day. (35,36)

Estimation of mean blood glucose received much importance in clinical trials.

However at a given mean blood glucose value there may be day to day and within

a day fluctuations. The limitation of Hba1c is that it cannot give any information

about day to day and within a fluctuation in glucose levels. Though frequent self

monitoring of blood glucose monitoring is recommended very few perform it that

frequently.

Continuous glucose monitoring (CGMS)

A new landmark in glucose monitoring called CGMS received FDA approval in

1999. In children who are at increased risk of hypoglycemia and in individuals on

intensive therapy who have multiple snacks and meals in a day and require glucose

measurements before administration of insulin needs frequent monitoring of blood

glucose values. Monitoring at expected peaks of insulin action and during times of

exercise is needed to safeguard against hypoglycemia. In case of nocturnal

hypoglycemia there is no other way to identify a low sugar value except to check

glucose by finger prick. Solely depending on finger prick method for estimation of

hyper and hypoglycemic episodes puts enormous emotional, financial stress upon

families. In addition either home monitoring of blood glucose or Hba1c cannot

30

correctly identify day to day or within a day glucose fluctuations. Intermittent

glucose monitoring by finger prick method of blood glucose provides only limited

information about glycemic profile and often misses asymptomatic hypoglycemia

and overnight glycemic excursions. These limitations led to the development of

continuous blood glucose monitoring (CGM) systems. In a motivated patient and

also patients with hypoglycemic unawareness continuous glucose monitoring

system was found useful to optimize glycemic control. (24)

In a retrospective study Frederico et al studied CGMS utility, accuracy and

complications in children and adolescents with T1DM. They found CGMS is a safe

and well tolerated by all the study participants. CGMS measurements were also

found to be accurate and procedure had low complications.(37) Invasive and

noninvasive CGMS are available for clinical use. Non invasive CGMS uses a

technology of measuring the blood glucose without breaching skin barrier. Non

invasive CGMS is worn like a wrist watch which extracts glucose by reverse

ionotophoresis.(38)

Invasive CGMS measures interstitial blood glucose via an indwelling sensor

placed in subcutaneous tissue. CGMS machine needs calibration by at least three to

four finger stick glucose values every day. Real time CGMS are also available

commercially which provide a continuous information about glucose levels, these

can be accessed by patients so as to make a change in meal and insulin dosage.

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Real time CGMS are also available with alarms to indicate hyper and

hypoglycemic events.(39,40)

Many systematic reviews and metanalysis published till date proved that real time

CGMS with good compliance improves glycemic control by reduction of HbA1c

and helps in identifying hypoglycemic events when compared to self monitoring of

blood glucose alone.

In a systematic review and metanalysis, Golicki et al studied the effectiveness of

CGMS compared to self monitoring of blood glucose on glycemic control in type 1

diabetic children. This study included 5 randomized controlled trials involving 131

children with type 1 diabetes. Data from these studies showed no significant

reduction in HbA1c in CGMS group as compared to SMBG group. They

concluded that CGMS is not superior to SMBG in glycemic control among

Children with type 1 diabetes. (41)

Gunjan Y Gandhi et al conducted a systematic review and meta-analysis to assess

the efficacy of CGMS in improving glycemic control and hypoglycemia reduction

compared to self monitoring of blood glucose. 19 randomized controlled trials

were included in the study. CGMS has resulted in significant reduction in mean

Hba1c reduction in adults with both type 1 and type diabetes [WMD – 0.50%(95%

CI -0.69 to -0.30) and -0.70 (95% CI, -1.14 to -0.27) respectively]. In children and

adolescents there was no significant effect observed. The study concluded that

32

CGMS helps in improving the glycemic control in type 1 and type 2 diabetic

adults, however the effect of CGMS on identification of hypoglycemia is

unclear.(42)

The usefulness of real time continuous glucose monitoring system compared to self

monitoring of blood glucose on glycemic control in patients with type1 diabetes

was studied by A.szypowskai et al in a systematic review and metanalysis.7

randomized controlled studies involving 948 subjects were included in the study.

This study showed that reduction in HbA1c in subjects using RT-CGM compared

with SMBG (MD –0.25; 95% CI: – 0.34 to – 0.17; p<0.001). Subjects used Real

time CGMS with insulin pump had lower HbA1c levels when compared with

subjects on insulin pump and self monitoring of blood glucose. RCTs, n=497; MD

– 0.26; 95% CI: – 0.43 to – 0.10; p=0.002). Real time continuous glucose

monitoring was not associated with a heightened rate of major hypoglycemic

episodes. Subjects who used CGMS for more than 60-70 percent of time had

significantly lowered HbA1c levels.(43)

Nalinee Poolsup et al conducted a systematic review and metanalysis to study the

effects of continuous glucose monitoring system on glycemic control in Type 1

diabetic children and Type 2 diabetic adults compared to self monitoring of blood

glucose. 10 RCTs involving 817 children with type 1diabetes, 5 RCTs involving

161 adults with type 2 diabetes was studied. They found, in children with type 1

33

diabetes, CGMS use was not superior to SMBG in HbA1c reduction [mean

difference – 0.13% (95% CI -0.38% to 0.11%,].Within group analysis showed that

retrospective CGMS was not beneficial than SMBG [mean difference -0.05%

(95% CI -0.46% to 0.35%)]. However real-time CGMS resulted in reduction of

HbA1c level when compared with SMBG [mean difference -0.18% (95% CI -

0.35% to -0.02%, p = 0.02)]. In adults with type 2 diabetes, significant lowering of

HbA1c level was noticed with CGMS as against self monitoring of blood glucose

[mean difference – 0.31% (95% CI -0.6% to -0.02%, p = 0.04)]. They concluded

that real-time CGMS will be more effective than SMBG in children with type

1diabtes, but not retrospective CGMS. In adults with type 2 diabetes CGMS results

in better glycemic control compared to SMBG.(44)

Another systematic review and metanalysis by VT Chetty et al studied effect of

CGMS and SMBG on HbA1c levels in patients with type 1 diabetes. 7 randomized

controlled trials were included involving 335 patients with type 1 diabetes. This

study found CGMS resulted in reduction of HbA1c, however the difference was

not statistically significant (0.22%, 95% CI -0.439 to 0.004). In pediatric patients

they observed a significant decrease in HbA1c associated with continuous glucose

monitoring system (0.37% (95% CI -0.71 to -0.02). With respect to nocturnal

hypoglycemia, patients on CGMS showed reduced number of such episodes.(45)

34

Cochrane data base of systematic reviews by Miranda Langendam et al, studied 22

randomized control trials published till June 2011. They found that the patients on

CGMS compared to SMBG had reduction in HbA1c after 6 months period. Mean

difference in HbA1c level was -0.7%, 95% (CI) -0.8% to -0.5%, 2 RCTs, 562

patients, I2=84%). Most improvement in glycemic control was seen in patients on

sensor-augmented insulin pump therapy. The severe hypoglycemia risk was not

increased significantly in CGMS patients. This study also found that higher

compliance of wearing the CGMS results in reduction of HbA1c. (46)

35

Table 1 Systematic reviews and metanalysis done on continuous glucose monitoring system in Type 1 and Type 2 diabetics

AUTHOR STUDY

TYPE

DATA BASE TIME

PERIOD

No

Of

RCT

Study

population

Age

group

Study question Conclusion Limitation

D. T.

Golicki

Systematic

review and

metanalysis

MEDLINE

EMBASE

CENTRAL

1966-2007 5 Type 1 DM Children CGMS Vs SMBG on

glycemic

Control

CGMS is not superior

to SMBG for glycemic

control

Small number of study

population, methodological

limitations of studies involved.

V T

Chetty

Systematic

review and

metanalysis

MEDLINE

EMBASE

CENTRAL

1996 to

March

2007

7 Type 1 DM Children

Adults

CGMS Vs SMBG on Hba1c

levels CGMS might be

beneficial in children,

It Improves detection

of night time

hypoglycemia

Small number of trials

Gunjan Y Systematic

review and

metanalysis

MEDLINE

EMBASE

CENTRAL

Web Ofscience

SCOPUS

1996-2010 19 Type1 DM

Type 2 DM

Children

Adults

CGMS vs. SMBG in

improving glycemic control

and reducing hypoglycemia

CGMS improves

glycemic control in

adults with T1DM and

T2DM.The effect on

hypoglycemia

incidence is unclear

Heterogeneous documentation

of hypoglycemia

Small number of studies

ASzypow

ska

Systematic

review and

metanalysis

MEDLINE

EMBASE

CENTRAL

1996-2011 7 Type 1 DM Children

Adults

RT CGM Vs SMBG in type

1 DM

RT CGM is more

beneficial in Hba1c

reduction

Heterogenous documentation

of hypoglycemia


Nalinee

Poolsup

Systematic

review and

metanalysis

MEDLINE

SCOPUS

CINAHL

CENTRAL

Web ofScience

Till may

2013


Adults

Effects of CGMS in Type1

DM pediatrics, Type 2 DM

adults

RT CGM is more

effective than SMBG

in pediatric population


Miranda

Langenda

m1a

Cochrane

data base of

systematic

reviews

MEDLINE

CINAHL

CENTRAL

EMBASE

Till June

2011


Adults

Effects of CGM compared

to (SMBG) in patients with

Type 1 DM.

Higher compliance of

wearing the CGM

device improves

Hba1c

Limited details on quality of

life assessment

36

Challenges with adolescents

Adolescence is a unique period where an individual journey from semi dependency

to fully independent adult. Physical and physiological changes of adolescence pose

significant challenge for the management of T1DM. As diabetes is a chronic

condition it places great deal of demands on psychology of adolescent. Minimal or

no intervention by care takers results in poor glycemic control if sole responsibility

of diabetes management is on adolescent. Responsibility shared among care takers

and adolescents result in a better glycemic control. (24,31) Apart from the

management issues other factors that influence glycemic control are risk taking

attitude ( Alcohol, substance abuse), behavioral and eating disorders which can

happen during transition from adolescence to adult.

Limitations of SMBG and CGMS

Though self monitoring of blood glucose by finger prick method is widely

practiced the main disadvantages in using them is the cost of the glucometer and

reagent strips. Commercially available strip cost ranges from Rs 15 to 35 per strip.

If an individual has to do 4-6 readings per day then the cost would be ranging from

Rs90-210 per day which is a major financial burden on families. The other limiting

factor of finger prick method is pain. Pain caused by finger pricks is underrated

and overlooked. There is paucity of literature regarding self monitoring of blood

glucose and pain. Development of thin and sharp lancets has considerably reduced

37

the pain of the procedure but not completely eliminated it. (47) In a child with

difficult to treat diabetes with night time hypoglycemia monitoring of blood sugars

in the night would not only cause stress and sleep disturbance for child or

adolescent but also to the care takers. Apart from these there is a chance of

infection secondary to use of strips from multi use vials with highly virulent

organisms. Chance of infection is less with strips from individually packed

vials.(48)

To overcome the limitations of self monitoring of blood glucose novel continuous

glucose monitoring system is developed. CGMS also needs a minimum of 4 finger

prick glucose recordings for calibration of the machine. Another major limiting

factor for use of CGMS is high cost. CGMS sensor, monitor and battery together

cost around $ 2000.

Flash glucose monitoring system (FGMS)

When initially introduced in the year 2013 free style libre pro flash glucose

monitoring system by Abbott’s is a glucose-monitoring device indicated for

detecting trends and tracking glucose patterns in diabetics who are aged above 18

years. In the year 2016 Abbott received CE Mark approval for use of the system

in children aged above four years. (49)

38

Alike continuous glucose monitoring system, flash glucose monitoring system

collects glucose data continuously from interstitial fluid. Glucose data thus

collected is generated as an advanced software report called the ambulatory

glucose profile (Fig 1&2). The FGMS sensor is placed over the back of the

patient's arm and an adhesive applied over it. Sensor is left in place for up to 14

days. Sensor measures glucose from interstitial fluid every 15 minutes through a

small filament that is inserted in subcutaneous tissue. Patients activities like

outdoor games, bathing and swimming are unhindered by the presence of devise.

After 14days, the sensor is removed and data from the sensor is scanned by

practice-owned reader, thereby downloading the glucose data and generating a

report.

Unlike CGMS sensor, Flash Glucose Monitoring system will be calibrated at the

factory, which means users need not to enter any glucose values by fingerstick for

sensor calibration. This is a major difference between CGMS and FGMS in that

CGMS needs four fingerstick glucose values a day for sensor calibration. Other

difference is FGMS device will not have alarms, reason being data is not

continuously sent to the reader device. To avail the data from the sensor the user

has to scan the reader over the sensor patch to obtain real-time glucose data. The

flash glucose monitoring system is designed as an improvement over traditional

blood glucose monitoring.

39

Figure: 1. How the FGMS system works

Figure: 2. Ambulatory glucose profile obtained from FGMS sensor (Sample)

40

It also overcomes some of the limitations of continuous glucose monitoring system

viz need for calibration and cost. The Flash glucose monitoring system can be

particularly valuable for children, who experience the pain of fingersticks more

than adults. (50)

(Direcnet) Diabetes research in children network study group studied the accuracy

of FGMS with home glucose recordings from venous blood samples. It concluded

that FGMS achieved high percentage of accuracy when compared with laboratory

reference over wider range of concentrations of glucose in T1DM children.(51)

FGMS sensor measures blood glucose from interstitial fluid. Interstitial fluid is a

reasonable alternative for blood. Glucose can be measured in the interstitial fluid

where freely diffusion of glucose occurs from capillaries into interstitial space.

Rebrin et al studied the feasibility of replacing interstitial fluid as a replacement for

plasma blood glucose and concluded that glucose differences between interstitial

fluid and plasma are not significant.(52)

In Italy a study performed by Corradinin et al studied clinical and analytical

accuracy of FGMS in dogs with diabetes and found flash glucose monitoring

system was 93, 99, and 99% precise at low, normal, and high concentrations of

blood glucose. (53)

41

So far many studies were conducted in adults with diabetes demonstrating the

utility feasibility and accuracy of flash glucose monitoring system. But similar

studies in children were sparse. One reason for this was till year 2016 FGMS was

not licensed for use in children.(54–56)

Arndis et al studied the accuracy and treatment experience of the FGMS in Fifty-

eight adults with type 1 diabetes mellitus. All these patients did 6times of home

blood glucose monitoring simultaneously with along FGMS. Mean absolute

relative difference calculated was 13.6% (95% CI 12.1%–15.4%) in 1st week and

12.7% (95% CI 11.5%–13.9%) in 2nd

week. The mean absolute difference was

19.8mg/dl (95% CI 17.8–21.8 mg/dl).Correlation coefficient was 0.96. For sugar

values <72, 72–180, and >180mg/dl, the mean absolute relative difference was

20.3% (95% CI17.7%–23.1%), 14.7% (95% CI 13.4%–16%), and 9.6% (95% CI

8.5%–10.8%). Mean absolute difference values were 12.3, 17.8, and 23.6 mg/dl.

They concluded that flash glucose monitoring system had similar overall MARD

when compared to other CGMS when studied in same at home conditions.(54)

Larry A. Distiller et all studied characterization of glycemic control by using

ambulatory glucose profile (AGP) with flash glucose monitoring system. Amongst

50 adult patients with type 1 and Type 2 diabetes included in the study they found

similar HbA1c values among both groups (8.4 ± 2 Vs 8.6 ± 1.7%) however

patients with type 2 diabetes had low mean glucose levels (166 ± 54 Vs 185

42

mg/dl]) and reduced indices of glucose fluctuations (54 ± 27 vs 90 ± 34.2 mg/dl]).

This study concluded that without much input from either provider or patient much

data was obtained from AGP regarding glucose exposure, fluctuations, and

information regarding incidence and risk of hypoglycemia.(57)

Maya Ish-Shalom et al conducted a study in 31 adults with type 1 and type 2

diabetes with difficult to control diabetes who were treated with multiple daily

insulin injections with an HbA1C ≥7.5% .They studied the beneficial effects of

FGMS in achieving desired target glucose levels and minimizing episodes of

hypoglycemia. FGMS resulted in major improvement in glycemic control in both

type 1 and type 2 diabetic patients. HbA1C was reduced 1.33 ± 0.29% at 8 weeks

(mean ± SE respectively, P < .0001) and then plateaued. But those patients who

continued to use device (n = 27), the change in HbA1c was maintained for 24

weeks,–1.21 ± 0.42% (P =.009) .No events of major hypoglycemia was noticed. At

the end of 3-6 months of follow-up all patients (n = 31) were greatly satisfied and

reported that they would like to use FGMS in future. All the patients reported that

use of FGMS was easy and painless.(58)

An open label randomized controlled study by Thomas Haak et al studied FGMS

as a replacement for SMBG in adults with type 2 diabetes mellitus on intensive

insulin therapy. Intervention group only used FGMS for glucose monitoring where

as control group used self monitoring of blood glucose for the same for initial 6

43

months. Next 6 months period was open access phase. At end of open-access

period (12months), time spent in hypoglycemia [sensor glucose 70 mg/dl] was

reduced by 50% compared to baseline [-0.70 ± 1.85/24 h (mean ± SD); p =

0.0002]. Night time hypoglycemia [2300 to 0600 hours, (70 mg/dl)] was reduced

by 52%; p = 0.0002. SMBG testing fell from a mean of 3.9 times/day at baseline to

0.2, with an average frequency of sensor scanning of 7.1 times/day at 12 month.. 9

patients reported 16 events of sensor-related adverse events and 28 patients

experienced 134 events of erythema, itching and rash. This study concluded that

use of FGMS in patients with type 2 DM on intensive insulin therapy over 1 year

period resulted in sustained reduction in hypoglycemic events and replaced

conventional SMBG effectively and safely(56).

44

Table 2 - Studies previously done on FLASH GLUCOSE MONITORING SYSTEM in adults with Type 1 and Type 2 diabetes

First author,

year

Study

Group

Sample

size

Type of

study

Aim of study Results Conclusion

Arndı´s F. et

al 2017

Adults with

Type 1 DM

58 Clinical

experience

study

To evaluate the

accuracy and

treatment experience

FGMS

MARD was 13.6% (95% CI 12.1%–

15.4%) during week 1 and

12.7% (95% CI 11.5%–13.9%)

during week 2.

overall correlation coefficient was

0.96

FGMS had similar MARD as CGMS in

earlier studies( Studies done at home

conditions)

Larry A.

Distiller et al

2016

Adults with

Type 1 & Type 2

DM

50 Clinical

experience

study

Glycemic Control

with Ambulatory

Glucose Profile by

FGMS

Type 2 DM pts had lower mean

glucose levels (9.2 ± 3 vs 10.3 mmol/l

[166 ± 54 vs 185 mg/dl]) & low

glucose variability (3.0 ± 1.5 vs 5.0 ±

1.9 mmol/l [54 ± 27 vs 90 ± 34.2

mg/dl])

With in short period AGP provides

information regarding glucose exposure,

variability, & risk of hypoglycemia risk and

incidence with minimal patient input.

Maya Ish-

Shalom et al

2016

Adults, Type 2

DM

31 Clinical

experience

study

Reduction in HbA1c

in Difficult-to-

Control -Diabetes

Using FGMS

HbA1C reduced by −1.33 ± 0.29% at

8 weeks (mean ± SE respectively, P <

.0001) & plateaued thereafter.

Continued use of device change in

Hba1c was maintained for 24 weeks,–

1.21 ± 0.42% (P =

.009)

FGMS use greatly

improved glucose control in difficult-

to-control diabetes

Thomas Haak et al 2017

Adults, Type 2

DM

139 Open

labeled RCT

Impact of FGMS

as a replacement for

SMBG

After 12 months , time in

hypoglycemia [sensor glucose (70

mg/dl)] was reduced by 50%

compared to baseline [-0.70 ± 1.85/24

h (mean ± standard

deviation); p = 0.0002]

FGMS use was associated

with reduction in hypoglycemia and

safely and effectively replaced SMBG

45

Identification of night time hypoglycemia is more convenient with FGMS than

with self monitoring of blood glucose. Jan Bolinder et al studied the effect of

FGMS on reduction of time spent in hypoglycemia in adults with well controlled

diabetes. They found mean time of hypoglycemia changed from 3.38 hours at the

beginning of study to 2.03 hours after 6 months of study period when compared to

3.44 hours to 3.27 hours in control group. They concluded that glucose monitoring

by FGMS reduced the time spent in hypoglycemia in adults with type 1 diabetes

mellitus.(59)

Another study by Al Agha et al studied the effect of flash glucose monitoring

system in children and adolescents with T1DM during Ramadan fasting. They

found patients were able to maintain fast for 67.0% of the total days meant for

fasting. They concluded that the risk of serious complications of severe

hypoglycemia during Ramadan fast could be avoided in T1dm children and

adolescents with the use of FGMS. (60)

Julie Edge et al conducted a prospective single arm study to assess the accuracy,

safety and acceptability of the FGMS in the pediatric age group. 89 participants

between 4-17 years of age with type 1 diabetes were included in the study. Glucose

recordings from the sensor were compared with self monitoring of blood glucose

recordings. Participants were blinded to glucose recordings from sensor. All the

study participants were followed up for 2 times after sensor placement. Overall

46

mean absolute relative difference was found to be13.9%. Accuracy of the sensor

was unaffected by body weight, age, gender, method of insulin administration and

time of insulin use. All the study participants were found to be in target glucose

range for 50% of the time (mean 12.1 hours/day). Average duration of

hypoglycemia and hyperglycemia was 2.2 hours/day and 9.5 hours/day

respectively. Application of sensor and use of devise was rated favorable by both

caregivers and participants. This study reported five device related adverse

events(61). Till date there is no published data available from India regarding

effectiveness of flash glucose monitoring in children and adolescents with T1DM.

Advantage of FGMS over CGMS

It is proven beyond doubt that continuous glucose monitoring system will help in

better glycemic control and helps in identifying life threatening hypoglycemia.

However CGMS sensors because of their high cost are not practically feasible for

developing nations like India. Cost of FGMS sensor is Rs 2000 for 14days. If self

monitoring of blood glucose is done daily for four times with currently available

glucose strips the cost ranges from Rs 840-1960 which is almost the same. But the

amount of data on glycemic fluctuations with meals and activity and night time

continuous monitoring by FGMS is cost effective. In addition to these FGMS

needs no calibration unlike CGMS sensor. CGMS sensor records glucose values

47

for 3-4days where as FGMS can record glucose values once every 15 minutes for

14days.

Hence we aimed to study the effectiveness of FGMS in T1DM adolescents in

terms of glycemic control and identification of hypoglycemic episodes.

48

RESULTS

49

RESULTS

A total of 330 children with type 1 DM, on treatment and follow-up from pediatric

endocrinology clinic were screened for eligibility from January – March 2017. Out

of 330 subjects screened, 202 subjects did not meet pre-defined inclusion criteria.

81 subjects who met exclusion criteria were excluded. Remaining 47 subjects who

met eligibility criteria were eligible for enrollment in the study. Among the

subjects eligible to participate in the study, 24 subjects declined to participate in

the study. So, a total of 23 patients were enrolled in the study with 12 in

intervention and 11 in control group.

50

Figure3. STUDY FLOW DIAGRAM

ASSESSED FOR ELIGIBILITY n=330

2) Change in insulin dosage from baseline to 6 months in both groups. ( Epidata file only has total dose of insulin..but in excel sheet i made it for UNITS/ KG/DAY

3)In FGMS group what is the inference on hypoglycemic events

Total duration of hypoglycemia

No of hypoglycemic episodes

duration of daytime and night time hypoglycemia

Effect of BMI, age ,sex and socioeconomic status on hypoglycemia IN FGMS group( with in group analysis)

MY PRIMARY AIM

IS EFFECT OF FGMS ON Hba1c ( whether its use reducing Hba1c in type1 diabteics or not), and ITS EFFECT IN IDENTIFYING HYPOGLYCEMIA

For this i have taken 2 groups 1 group who does conventional finger prick glucose checking alone Once in every 2weeks for 6 months period....and other group along with conventional finger prick + FGMS machine ( which i placed for 14 days at the begining, 2 months and 4 months later).

Is there any better way of reporting the data.

If you need any clarification please call

RANDOMIZED n = 23

Excluded n = 307

Not meeting inclusion

criteria-202

Meeting exclusion

criteria-81

Declines participation-

24

Allocated to control group

n= 11

Received standard care

(SMBG) only

Allocated to intervention

group n= 12

Received intervention

(FGMS) + standard care

(SMBG)

ALLOCATION

Excluded = 2

[1.Withdrew consent for academic reason

2. Sensor failure]

Lost to follow up = 0

Excluded = 0 FOLLOW UP

Total analyzed - 10 Total analyzed - 11 ANALYSIS

51

Base line characteristics

There were 12 participants enrolled in the intervention group of which only 10

were included in the final analysis. Of the 2 patients who were excluded from

intervention group one had withdrew consent and lost to follow up and the other

missed the FGMS sensor for second time and the 3rd

FGMS sensor data was

incomplete for analysis.

Of the 10 children who were included in the final analysis 2 participants missed the

2nd

FGMS placement but they were included in the study to retain the strength of

the sample size. Of the 10 participants 4 were boys and 6 were girls.

There were 11 children in the control group who were included in the final

analysis. Of which 5 were boys and 6 were girls.

The age at the time of diagnosis in intervention and control groups was 8.3±3.6

(Mean ± SD) years and 12.1 ± 2.1(Mean ± SD) years respectively. The mean

duration of diabetes in intervention cohort was 5.1 ± 3 years (Mean ± SD) and the

mean duration of diabetes in control cohort was 3.2 ± 1.5 years (Mean ± SD).

Of the 10 children in intervention group 6 and of 11 children in control group 8

had previous episodes of diabetic ketoacidosis. All the children in both groups

reported to have hypoglycemic awareness as experienced by sweating, dizziness,

reeling, weakness, palpitation. 1 child in intervention group had eventful

52

hypoglycemia in the form of seizures requiring admission for 5 times at 5, 6, 7, 9,

11 years respectively. None of the other participants in either group had similar

events. None of the children in both the cohorts had documented end organ

involvement (Eye, kidney and CNS)

Anti islet antibody was positive in 2 children from control and 3 children from

intervention group. Anti GAD antibody was positive in 3 and 6 children from

control and intervention group respectively. 2children in control group were

positive for anti thyroid antibodies whilst none from intervention group.

Hypovitaminosis D was present in 1child in control and 4 children in intervention

group. One patient in control group had nephrotic syndrome in the past treated

with steroids and levamisole and was off medications for more than one year at th

e time of beginning of study. Anti TTG antibody was positive in 1 child in control

group and 2 children in intervention group.

Average HbA1c 6 months prior to study was 10.2% ± 1.58 (Mean ± SD) in control

group and 10.74% ± 1.7(Mean ± SD) in intervention group. Baseline HbA1c was

10.3% ± 1.9 and 10.32 ±1.27 (Mean ± SD) in control and intervention groups

respectively.

Baseline average insulin intake was1.29 ± 0.44 units/ kg/day in control group and

1.32 ± 0.34 units/kg/day in intervention group. All the baseline characteristics were

53

comparable between control and intervention groups except age of the patient and

age at the time of diagnosis as mentions in table3. More number of younger

children was present in intervention group.

Figure: 4. Gender and group distribution in control and intervention cohorts

0

1

2

3

4

5

6

SMBG FGMS + SMBG

Male 5 4

Female 6 6

Gender & group distribution

Male Female

54

Table: 3. Baseline parameters of the participants in control (SMBG) and

intervention (FGMS+SMBG) groups

S. No Baseline parameter FGMS+ SMBG

N= 10

n (%)

SMBG alone

N = 11

n (%)

P value

1 Age ( years), Mean ± SD 13.1 ± 1.12 15.4 ± 1.8 0.003

2

Gender

Male 4 (40.0) 5 (45.5)

0.80 Female 6 (60.0) 6 (54.5)

3 BMI 17.94 ± 1.46 18.83 ± 4.5 0.56

4 Socio

economic

state

Upper 2 (20.0) 1 (9.1)

Upper middle 3 (30.0) 3 (27.3)

Lower Middle 5 (50.0) 6 (54.6) 0.71

Upper Lower 0 (0) 1 (9.1)

Lower 0 (0) 0

5 Age at diagnosis(years) Mean

± SD

8.3 ± 3.6 12.1 ± 2.1 0.007

6 Duration of illness, Median

(IQR)

5 (3-8) 4 (1-4) 0.16

7 Previous DKA present (n) 6 (60.0) 8 (81.8) 0.27

9 Hypoglycemia awareness 10 (100.0) 11 (100.0) -

10 GAD antibody positive (n) 3 (30.0) 6 (54.6) 0.27

11 IA2 antibody positive (n) 2 (20.0) 3 (27.3) 0.70

12 Thyroid Ab positive (n) 0 (0.0) 2 (18.2) 0.16

13 Anti TTG positive (n) 2 (20.0) 1 (9.1) 0.48

14 Hypovitaminosis D (n) 4 (40.0) 1 (9.1) 0.09

15 Nephrotic syndrome in past 0 (0.0) 1 (9.1) 0.34

16 End organ damage present(n)

)

0 (0) 0 (0) -

17 HbA1c 6 months prior),

Mean ± SD

10.7 (1.7) 10.2 (1.6) 0.46

18 HbA1c Baseline),

Mean ± SD

10.3 (1.3) 10.3 (1.9) 0.99

19 Baseline total insulin

(U/kg/day) ), Mean ± SD

1.3 ± 0.3 1.2 ± 0.4 0.87

Note: Values are reported as n(%) for categorical variables, Mean ± SD for continuous normally

distributed variables, Median (IQR) for skewed variables.

55

FGMS FINDINGS IN INTERVENTION (FGMS + SMBG) GROUP

In our trail, we enrolled 12 patients into intervention group. Of the 12 one patient

withdrew consent after 1st FGMS sensor and were lost to follow up for rest of the

study period, other patient missed FGMS placement for second time and the 3rd

time sensor recording was incomplete (only 6 hours of glucose recordings) for

analysis and hence was excluded from the final analysis.

2 other patients missed FGMS sensor placement for second time. Both of them

were included in the final analysis. Finally a total of 10 patients were analyzed in

intervention group.

FGMS sensor was removed after 14 days of insertion and the data was downloaded

on to the computer using the reader device. Interstitial glucose values recorded for

every 15 minutes for a period of 14days (average of 96 glucose recordings per day

{1344 recordings /14days}) was shown as ambulatory glucose profile. Glucose

patterns over 14days period were depicted as within range (70mg/dl -180mg/dl),

below the range (<70mg/dl) and above the range (>180mg/dl).

Individual recordings of FGMS sensor data done at baseline, end of second month

and at the end of 4th month for 10 participants in the intervention group is shown in

table 4.

56

Table: 4. FGMS data in each individual in intervention group (n=10)

Patient

S no Time in range (%) GRBS - 70-180mg/dl

Time below range

(%) GRBS - < 70mg/dl

Time above range

(%) GRBS - >180mg/dl

FGMS 1 FGMS 2 FGMS 3 FGMS 1 FGMS 2 FGMS 3 FGMS 1 FGMS 2 FGMS 3

1 35 21 19 34 4 14 31 75 67

2 13 14 4 3 3 3 84 83 93

3 10 13 2 3 3 1 87 84 97

4 27 * 27 15 * 26 58 * 57

5 10 30 8 2 12 3 88 58 89

6 11 26 19 8 9 7 81 65 74

7 18 * 21 25 * 19 57 * 60

8 1 22 3 1 6 0 98 72 97

9 17 27 14 5 17 9 78 56 77

10 21 30 17 13 19 9 66 51 74

*Missed 2nd

FGMS sensor placement

From baseline to third sensor placement the percentage of glucose values within

the range was decreased in 7, increased in 2 and unchanged in one participant.

Percentage of glucose values below the range was decreased in 7 participants

where as increased in 2 and unchanged in 1 participant. Percentage of glucose

values above the range increased in 5 participants, decreased in 1 and unchanged in

4 participants.

All the participants in intervention group had hypoglycemic recordings while on 1st

and 2nd

FGMS. During 3rd

FGMS of the 10 participants 9 had hypoglycemic

recordings. Only one participant had no recorded hypoglycemia however the same

57

participant had hyperglycemic recordings above 97% and had within range glucose

values only for 3% of time.

Comparison of FGMS and SMBG data in intervention group

All the participants in intervention group had performed self monitoring of blood

glucose once in 2 weeks all throughout the study period even while on FGMS

sensor. SMBG data was also calculated as within range and below range and above

range. When compared to FGMS data obtained for 14days, SMBG data over 3-4

days showed no major difference in glucose ranges

Table: 5. Simultaneous individual SMBG recordings (For 3days) during

FGMS sensor placement in intervention group

Patient

S no

Time in range (%) Time below range (%) Time above range (%)

SMBG 1 SMBG 2 SMBG 3 SMBG 1 SMBG 2 SMBG 3 SMBG 1 SMBG 2 SMBG 3

1 27 30 30 0 0 0 73 70 70

2 78 53 47 0 0 0 22 47 53

3 16 72 66 2 22 16 72 5 16

4 39 45 32 5 0 0 56 55 68

5 27 27 30 0 0 5 73 73 65

6 47 33 60 5 5 10 38 61 30

7 14 16 71 0 0 0 86 84 29

8 39 45 28 0 0 0 61 55 72

9 55 50 61 0 0 0 45 50 39

10 47 15 24 0 5 0 53 80 76

58

While all the participants during 1st and 2

nd FGMS sensor placement and 9 of 10

participants during 3rd

FGMS sensor placement showed hypoglycemic recordings,

simultaneous glucose monitoring by SMBG showed hypoglycemic recordings only

in 3 participants. During the 3rd

FGMS sensor placement one participant did not

had any hypoglycemic recordings, SMBG data also showed no hypoglycemic

recording in this participant. Simultaneous SMBG data for intervention group

while on FGMS sensor is shown in table 5.

For the 10 participants in intervention group mean percentage of glucose values

within the range (GRBS-70-180mg/dl) below the range (GRBS- <70mg/dl) and

above the range (GRBS- >180mg/dl) for 1st, 2

nd and 3

rd FGMS and simultaneous

SMBG is depicted in tables 6 and 7.

Table: 6. Average time in different ranges by FGMS sensor data {each sensor

for 14days (n=10)}

Parameter FGMS 1 FGMS 2 FGMS 3

Within range 14.8% 22.8% 13.4%

Below range 10.9% 9.1% 9.1%

Above range 72.8% 68% 78.5%

59

Table: 7. Average time in different ranges by SMBG data in intervention

group (3days) n=10

Parameter SMBG 1 SMBG 2 SMBG 3

Within range 38.9% 38.6% 44.9

Below range 1.2% 3.2% 3.2%

Above range 57.9% 58% 51.8%

Hypoglycemia description in intervention group by FGMS report

Hypoglycemic recordings

FGMS sensor considers glucose value <70mg/dl as hypoglycemia and gives the

ambulatory glucose profile which comes as a graph. However FGMS sensor also

gives continuous report of glucose values as a separate report (Annexure). FGMS

sensor records glucose from the interstitial fluid. Because of 10-15mg/dl difference

in glucose value from blood to interstitial fluid, glucose value of less than 60mg/dl

was taken as hypoglycemia when manual evaluation of recording was done. The

total number of hypoglycemic recordings in FGMS data (GRBS less than 60mg/dl)

for individual patients is shown in table 8.

60

Table: 8. Individual Hypoglycemic recordings in intervention group (GRBS

<60mg/dl) during FGMS sensor for 14days

Patient S. No FGMS 1 FGMS 2 FGMS 3

1 30 33 120

2 18 11 17

3 15 4 0

4 136 * 125

5 2 73 9

6 44 53 34

7 143 * 196

8 0 34 0

9 18 160 56

10 75 127 75

*Patient missed FGMS sensor

Compared to the hypoglycemic recordings recorded during 1st and 2

nd FGMS the

number of hypoglycemic recordings in FGMS 3 reduced in 8 patients. While in 2

patients there were increased number of hypoglycemic recordings.

The mean number of hypoglycemic recordings among all 10 participants in the

intervention group during the placement of FGMS sensor for first time was 48

(range 0-143), during second and third FGMS sensor placement the mean number

of hypoglycemic events were 62 (4-160) and 63(0-196) respectively.

61

Table: 9. Mean of hypoglycemic recordings during each time of sensor

placement (14days) in intervention group

FGMS timing Hypoglycemic recordings (Mean) Range

FGMS 1 48 0-143

FGMS 2 62 4-160

FGMS 2 63 0-196

No of hypoglycemic recordings during daytime (6am-6pm) and night time (6pm-

6am) was calculated and shown in table 10.

Table: 10. No of hypoglycemic recordings during daytime (6am-6pm) and

night time (6pm-6am) over 14 days

Patient

s.no

FGMS 1 FGMS 2 FGMS 3

Day

time

Night

time

Day

time

Night

time

Day

time

Night

time

1 4 31 4 30 29 90

2 6 12 7 6 8 9

3 0 15 1 3 0 0

4 57 72 * * 56 59

5 2 0 30 43 19 0

6 28 16 5 40 9 26

7 47 98 * * 36 158

8 0 4 4 30 0 0

9 12 6 71 88 34 25

10 16 53 38 109 7 68

62

*Patient missed 2nd FGMS sensor

Except for 1 patient during the 1st FGMS sensor all the other patients had more

number of hypoglycemic recordings in the night than day. During 2nd

and 3rd

FGMS sensor placement also hypoglycemic recordings were more during the night

than day time.

Day time and night time hypoglycemia

Total time spent in hypoglycemia was calculated. This total time spent in

hypoglycemia was divided into day time hypoglycemia (6am-6pm) and night time

hypoglycemia (6pm-6am). Individual duration of day time and night time

hypoglycemia over 14 days of sensor placement and average time of hypoglycemia

over 24 hours during day time and night time separately is shown in table 11.

Mean of average day time hypoglycemia was 18.36 minutes, 21.36minutes and

21.14 minutes during 1st, 2

nd and 3

rd FGMS respectively.

Mean average of night time hypoglycemia was 32.63minutes, 46.51minutes and

46.48 minutes during 1st, 2

nd and 3

rd FGMS respectively.

63

Table 11 Total day and night time (minutes) hypoglycemia over 14days and average day and night time

hypoglycemia in minutes/ 24 hours during 3 FGMS sensor placement (n=10)

Patient missed 2

nd FGMS sensor

FGMS 1 FGMS 2 FGMS 3

Patient

S.No

Day

time

Avg time in

min/24hours

Night

time

Avg time in

min/24hours

Day

time

Avg time in

min/24hours

Night

time

Avg time in

min/24hours

Day

time

Avg time in

min/24hours

Night

time

Avg time in

min/24hours

1 60 4.2 465 33.2 60 4.2 450 32.1 435 31 1350 96.4

2 90 6.4 180 12.8 105 7.5 90 5 120 8.5 135 9.6

3 0 0 225 16 15 1 45 3.2 0 0 0 0

4 855 61 1080 77.1 * * * * 840 60 885 63

5 30 2.1 0 0 450 32 645 46 285 20.3 0 0

6 420 30 240 17 75 5.3 600 42.8 135 9.6 390 27.8

7 705 50 1470 105 * * * * 540 38.5 2370 169.2

8 0 0 60 4.2 60 4.2 450 32.1 0 0 0 0

9 180 12.8 90 5 1065 76 1320 94.2 510 36 375 26

10 240 17.1 795 56 570 40.7 1635 116.7 105 7.5 1020 72.8

64

With In Group Analysis of Baseline and Follow Up Parameters

Baseline and follow up parameters in intervention group (FGMS + SMBG)

HbA1c and insulin intake (units/kg/day) at baseline,3 months and 6months was

compared in intervention group. Of the 10 participants in intervention group 4 had

shown a decrease in HbA1c from baseline to 6 months while remaining 6

participants had an increase in HbA1c. Values are shown in table 12.

Table: 12. HbA1c and Insulin requirement (units/kg/day) comparison in

intervention group (n=10)

Patient

S.No

HbA1c

Baseline

Insulin

Unit/kg/day

HbA1c

3 months

Insulin

Unit/kg/day

HbA1c

6 months

Insulin

Unit/kg/day

1 10.1 1.8 10.2 2.4 10.1 2.4

2 10.3 1.1 11.2 1.75 10.6 1.73

3 10.8 1.9 10.3 1.9 11 1.5

4 9.1 0.9 7.8 0.7 7 0.8

5 9.5 1.5 8.7 1.7 10.2 1.7

6 10.5 1.1 9 1.4 9 1.4

7 9.5 0.9 10.4 1 10.6 1

8 13.1 1.3 11.7 2.1 13.5 1.1

9 11.5 1.5 9.9 1.8 10.6 1.8

10 8.8 1.2 9.2 2.1 9.4 2.1

Median HbA1c 6 months prior to study was 10.55% (IQR; 10.1 -11.72) with range

8.1-13.8 in intervention group. Baseline median Hba1c was a10.2% (IQR; 9.5-

10.8) with range 8.8-13.1. Insulin intake at baseline was 1.32 ± 0.35 (Mean ± SD)

65

units/kg/day. In intervention group changes of outcome variables within a cohort at

different study points (Baseline, 3rd

and 6 months) were analyzed with pared t test

for normally distributed data and non parametric Wilcoxon- rank sum test was

used for rest of the data. Table 13&14

Table: 13. Baseline and 3 month follow up parameters in intervention group

(n=10)

S.No Parameter Baseline 3 months Change

1 HbA1c

Median(IQR)

Range

10.2%(9.5-10.8)

(8.8-13.1)

10.05%(9-10.4)

(7.8-11.7)

0.65%( - 0.4 -1.4)

(-0.9 – 1.6)

2 Insulin

(units/kg/day)

Mean± SD

1.32 ± 0.35 1.68 ± 0.52 -0.36 ± 0.36

Table: 14.Baseline and 6 month follow up parameters in intervention group

(n=10)


1 HbA1c

Median(IQR)

Range

10.2%(9.5-10.8)

(8.8-13.1)

10.6%(9.75-10.8)

(9-13.5)

- 0.25%(-0.5 - 0.45)

(-1.1 – 1.5)

2 Insulin

(units/kg/day)

Mean± SD

1.32 ± 0.35 1.55 ± 0.5 -0.23 ± 0.40

66

Baseline and follow up parameters in control group (SMBG alone)

Individual values of HbA1c and insulin requirement in control group at baseline

and change of the same at 3months and 6 months are shown in table 15.

Of 11 participants in control group 10participnats had shown a decrease in HbA1c

at the end of 6months from baseline.

Table: 15. HbA1c and Insulin requirement (unit/kg/day) comparison in

control group (n =11)

Patient

S.No

HbA1c

baseline

Insulin

Unit/kg/day

HbA1c

3 months

Insulin

Unit/kg/day

HbA1c

6 months

Insulin

Unit/kg/day

1 10.3 2.1 7.7 2.2 8.6 2.2

2 10.4 1.4 12.5 1.7 10.7 1.7

3 13.8 2.1 12.5 1.2 13.1 1.4

4 9.8 0.8 9.4 0.9 7.4 0.9

5 7.3 1.2 7.7 1.2 5.8 1.2

6 8.9 1.3 7.3 1.3 6.9 1.4

7 9.6 1 9.6 1.2 9 1

8 10.1 1.3 8 1.1 8 1.2

9 13.5 0.8 11.8 1.5 9.5 1.5

10 9 1.2 9.8 1.4 8.3 1.4

11 10.9 1 10.1 1.3 9.9 1.2

67

Median HbA1c 6 months prior to study was 9.7% (IQR; 9.4 – 10) with range 7.3-

12.8 and baseline median hba1c was 10.1% (IQR; 9.0- 10.9) with range 7.3-13.8 in

SMBG group. Baseline total insulin intake was 1.29 ± 0.45 units (Mean ± SD).

Change in HbA1c and insulin intake at the end of 3 months and 6 months is

depicted in table 16 & 17

Table: 16. Baseline and 3 month follow up parameters in control (SMBG) group

(n=11)


1 HbA1c

Median(IQR)

Range

10.1%(9.4-10.9)

(7.3-13.8)

9.6%(7.7-10.1)

(6.7-12.5)

0.8%(0.4 -1.7)

(-0.8 – 2.6)

2 Insulin

(units/kg/day)

Mean± SD

1.29 ± 0.45 1.35 ± 0.36 -0.05 ± 0.39

In control group changes of outcome variables within a cohort at different study

points (Baseline, 3rd

and 6 months) were analyzed with pared t test for normally

distributed data and non parametric Wilcoxon- rank sum test was used for rest of

the data.

68

Table: 17. Baseline and 6 month follow up parameters in control (SMBG) group

(n=11)


1 HbA1c

Median(IQR)

Range

10.1%(9.4-10.9)

(7.3-13.8)

8.6%(7.4-9.9)

(5.8-13.3)

1.5%( 0.7 -2.1)

(0.3 – 4)

2 Insulin

(units/kg/day)

Mean± SD

1.29 ± 0.45 1.37 ± 0.36 -0.08 ± 0.33

COMPARISON OF CHANGE IN OUTCOME PARAMETERS BETWEEN

TWO GROUPS

Table: 18. Comparison of change in outcome parameters at 3 months between

two groups

S.No Parameter FGMS +SMBG SMBG P value

1 HbA1c

Median(IQR)

Range

0.65%( -0.4 -1.4)

(-0.9 – 1.6)

0.8%(0.4 -1.7)

(-0.8 – 2.6)

0.2904

2 Insulin

(units/kg/day)

Mean± SD

1.68 ± 0.52 1.35 ± 0.36 0.1115

69

Change in HbA1c and insulin requirement from baseline to 3 months in both

intervention groups and control group is shown in table 18. P value for both the

parameters is not significant

Table: 19. Comparison of change in outcome parameters at 6 months between

two groups

S.No Parameter FGMS +SMBG SMBG P value

1 HbA1c

Median(IQR)

Range

-0.25%(-05-0.45)

(-1.1 – 1.5

1.5%( 0.7 -2.1)

(0.3 – 4)

0.0081

2 Insulin

(units/kg/day)

Mean± SD

-0.23 ± 0.40

-0.08 ± 0.33

0.4380

Change in HbA1c from baseline to 6 months showed a significant reduction in

control group but no such change observed in intervention group P value was

0.0081. Change in Insulin requirement in both groups was not statistically

significant. Table 19

70

Hypoglycemic recording by SMBG in both groups

Hypoglycemic recordings by SMBG in intervention group

In the intervention group participants had done SMBG once in 2 weeks. While

FGMS sensor was placed 3 times during the study period simultaneous SMBG was

continued. While all the participants during 1st and 2

nd FGMS sensor placement

and 9 of 10 participants during 3rd

FGMS sensor placement showed hypoglycemic

recordings, simultaneous glucose monitoring by SMBG showed hypoglycemic

recordings only in 3 participants. Refer to table 5 for individual SMBG recordings

during FGMS sensor placement.

Hypoglycemic recordings done by SMBG (for 3days) simultaneously during 14

days of FGMS sensor placement showed 1.2%, 3.2% and 3.2% of hypoglycemic

recordings.

Hypoglycemic recordings by SMBG in control group

SMBG values at baseline and 3 months and 6 months were recorded for 11

participants in control group. Hypoglycemic recordings were present in 4, 4 and 5

participants at baseline, 3months and 6 months respectively.

Average percentage of glucose recordings below the range (<70mg/dl) was 5%,

71

2.9% and 7% at baseline, 3 months and 6 months respectively.

FGMS and SMBG glucose values correlation

FGMS measures interstitial blood glucose and SMBG measures capillary blood

glucose. Participants in intervention group (FGMS + SMBG) performed SMBG for

3-4 consecutive days once in 2 weeks like control group. Glucose values of both

FGMS and SMBG were compared for the days on which both values were

available. Table20 describes the comparison of FGMS and SMBG values. The

difference between FGMS and SMBG values were calculated. The mean of

differences between FGMS and SMBG glucose values was 14± 3.5 mg/dl (Mean ±

SD) was within the variability described in previous studies.(54)

72

Table: 20. Simultaneous FGMS (interstitial glucose in mg/dl) and SMBG (capillary glucose in mg/dl) glucose

values and the difference between both during FGMS1 (VALUES for 1day)

FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff

1 180 196 4 301 324 23 295 308 13 311 329 18 378 398 20 133 143 10

2 233 255 22 90 115 25 111 123 12 119 127 8 383 423 40 233 245 12

3 244 262 18 121 140 19 171 182 11 442 479 37 50 66 16 467 499 22

4 231 253 22 290 303 13 135 147 12 53 61 8 266 278 12 198 214 16

5 211 226 15 155 179 24 107 112 5 158 162 4 311 333 22 211 225 14

6 151 169 18 66 70 16 156 164 8 87 91 4 266 279 13 297 303 6

7 99 108 9 199 204 5 226 233 7 99 103 4 119 127 8 169 174 5

8 287 291 4 299 308 9 456 471 15 134 148 14 211 224 13 166 173 7

9 166 185 19 75 88 13 89 93 4 244 277 33 269 297 28 151 162 11

10 440 454 14 90 104 14 88 96 8 197 208 11 150 177 27 400 420 20

3.00 am6:00 AM 9.00am 12.00noon 6.00pm 9.00 pm

FGMS- Flash Glucose Monitoring System, SMBG- Self Monitoring of Blood Glucose, Diff- Difference between SMBG and FGMS

values

73

Adverse events and technical problems with FGMS sensor

Serious adverse events like infection, swelling at the site of sensor

placement were not noticed in any of the 10 patients analyzed.

For total of 10 patients included in intervention arm total of 30 sensors were

used.

8 patients completed 3 sensor placements during the study period

(24sensors). Of these for 1 participant FGMS sensor was repeated during 2nd

time because FGMS sensor read only 6 hours.

2 participants had sensor placement for 2 times only, of these for one

participant during 1st FGMS placement, sensor was damaged and it could

not be inserted properly and fell off from insertion site. For this patient a

new sensor was placed and secured with regular measures.

Accidental premature removal of sensor was noticed in one participant on

day 11 after sensor placement.

One participant had minimal bleeding at the time of insertion which was

controlled with manual pressure. The same participant had pain at insertion

site which was controlled with single dose of analgesic.

All the participants found sensor socially acceptable and not interfering with

privacy and daily activities.

74

Table: 21. Description of sensor count in intervention group

Description No of patients No of sensors

Completed 3 sensor

placements

8 24

Completed 2 senor

placements

2 4

Sensor repeated 1 1

Failed sensor insertion 1 1

Total 10 30

75

DISCUSSION

76

DISCUSSION

Design and setting of the study

In this prospective open label randomized controlled trial, a total of 30 patients

were intended to be enrolled however we could enroll only 23 patients. Of these 23

patients 12 participants received the intervention (FGMS) along with standard care

(SMBG). Other 11 patients received only standard care (SMBG). Study period

was from January 2017 till December 2107. Patients were enrolled from February

2017 to April 2017. Participants were enrolled from pediatric endocrinology clinic,

Christian medical college, Vellore.

Demographic details

A total of 23 patients were enrolled as against 30 as per protocol. Of 23 only 21

patients (10 in the intervention group and 11 in control group) were included in

final analysis. 2 were excluded from study. Of these 9 were male, 5 (45%) in

control group and 4 (40%) in intervention group. There were 12 female

participants of which 6 (55%) in control group and 6 (60%) in intervention group.

Justification for the study

Type 1 diabetes is a most common endocrine disorder of child hood. Strict

glycemic control was proven to improve the quality of life and prevent the long

term complications. Self monitoring of blood glucose (SMBG) by finger prick

77

method is commonly practiced to monitor blood sugars and glycemic control is

assessed by SMBG records and HbA1c done once in 3months. However self

monitoring of blood glucose can miss the glucose excursions that vary according to

activity and food intake. Continuous glucose monitoring (CGMS) helps in

achieving the better glycemic control and this has been established by systematic

reviews and metanalysis. However cost and need for finger pricks for machine

calibration is cumbersome. FGMS is a novel method of continuous glucose

monitoring which is cost effective and does not require finger pricks for

calibration. Till date many trials done in adults have proven effectiveness of FGMS

in glycemic control and identifying hypoglycemic events. Use of FGMS in

children with type 1 diabetes is sparse. To the best of our knowledge, till date only

few studies assessed the use of FGMS in children and none form India. The

current study was planned with the idea that FGMS in addition to SMBG in

children with type 1 diabetes will improve the glycemic control when compared to

self monitoring of blood glucose alone and will also help in identifying the hypo

and hyperglycemic changes which otherwise might go unnoticed with SMBG

alone. This open label randomized control study was done in type 1 diabetics with

the primary objective of assessing the effectiveness of FGMS in glycemic control

and in identifying hypoglycemia events. The secondary outcomes of our study

were to assess the correlation of FGMS interstitial glucose recordings with

78

glucometer capillary recordings and to assess the feasibility and acceptability of

FGMS.

FGMS – DESCRIPTION AND DATA ANALYSIS

Intervention group (FGMS + SMBG) had 12 participants. But only 10 participants

were included in final analysis. Of the 2 who were excluded from the final analysis

one patient withdrew consent and lost to follow up after 1st FGMS ,the other

patient missed 2nd

FGMS sensor and the 3rd

FGMS sensor recording was

inadequate( recorded only for 6hours) .

Total of 30 sensors were used during the study period. A total of 8 patients

completed 3 sensor placements. Of the 8 participants who completed 3 sensor

placements, for one patient 2nd

FGMS sensor had to be repeated as it recorded

glucose values only for 6 hours. 2 participants completed only 1st and 3

rd sensors,

but were included in final analysis to retain the strength of sample size.

All patients had tolerated FGMS sensors well with minimal side effects. With the

exception of FGMS data recorded for only 6 hours in 2 participants all the other

sensor recordings were enough for therapeutic decisions.

Limitations of FGMS

1) One of the limitations in FGMS data was non availability of real time data to

patient and absence of alarms unlike in CGMS (39,40). Patients had to visit

79

the hospital for the sensor to be read and avail the glucose readings. Device

to read the sensor recording is currently not available for patient use in India,

but is available to patients in some countries.

2) Another limitation of FGMS found in our study was the need for patient to

come to hospital to insert and to check the working condition of sensor. Julie

et al studied the effectiveness of FGMS as a replacement to SMBG in type 1

diabetic children. In their study patients had three hospital visits. After the

sensor placement patient had their second visit between 5-8days and a final

visit between 12-15 days (61). In resource poor countries like India calling

the patient multiple times to hospital for ensuring the working condition of

sensor is practically difficult. This was overcome by Al Algha et al in a

study done in type 1 diabetic children during Ramadan fasting, all the

participants were given a scanning devise to avail the glucose values(60).

3) FGMS gives retrospective data for 14days. We found that patients were not

able to recollect the nature of symptoms and activity at which time FGMS

showed hypoglycemic and hyperglycemic results.

During 3 times of sensor placement over 6 month duration, we found all the

children had episodes of hypoglycemia. 100% of children had night time

hypoglycemia. The interstitial glucose value measured by FGMS sensor is usually

10-15% lower than blood glucose was a well recognized physiology.

80

Although the data was analyzed retrospectively FGMS sensor gives data similar to

CGMS devise. The major difference to currently available CGMS is no need for

calibration for FGMS. Data over 14 days can be collected with minimal effort from

the caregiver or patient.

In our study FGMS data obtained helped to identify patterns of glycemic

excursions like pre and post meal hypoglycemia and hyperglycemia and nocturnal

hypo and hyperglycemia. We found identification of asymptomatic nocturnal

hypoglycemia was much beneficial which was not at all possible with standard

SMBG done 4 times a day (in our study population 4days / 2weeks). Identification

of nocturnal hypoglycemia detected in all the subjects in intervention group affirms

the presence of unrecognized nocturnal hypoglycemia in children with type 1

diabetes.

Unlike CGMS cost of FGMS is very economical and gives data for14 days as

compared to 3days data by CGMS. Each FGMS senor cost is Rs. 2000. As per

American diabetes association and International society for pediatric and

adolescent diabetes consensus guidelines (ISPAD) self monitoring of blood

glucose should be done a minimum of four times a day (24, 32) . If self monitoring

of blood glucose is done daily for four times with currently available glucose strips

the cost ranges from Rs 840-1960 ( for 14days) which is almost the same as FGMS

sensor. But the amount of data on glycemic fluctuations with meals and activity

81

and night time continuous monitoring by FGMS is cost effective. Because of this

reason in a motivated and affordable patient FGMS can replace self monitoring of

blood glucose by conventional finger prick method. Study by Julie et al compared

FGMS as an alternative method to capillary blood sugar values. They found FGMS

data was found to be accurate, safe and user acceptable. (61)

Outcome of study

In our study we analyzed the effectiveness of FGMS in addition to SMBG in

glycemic control assessed by reduction in HbA1c and identification of

hypoglycemic episodes when compared to SMBG alone. We also analyzed the

correlation of FGMS and SMBG glucose values and feasibility and acceptability of

FGMS.

Although this was a computer generated randomization, we noted that age of the

patient at diagnosis and age at inclusion into study were both significantly different

in both groups, with all other baseline demography well matched. Children in

intervention group were younger and diagnosed at a younger age with type 1

diabetes compared to control group.

Children and adolescents of 12-18 years of age with type 1 diabetes for more than

1 year period with HbA1c between 8-14% were included in the study. All the

82

subjects are on basal bolus or split mix regimen and doing self monitoring of blood

glucose for 4 days once in 2 weeks.

The reason to include the children and adolescents of 12-18 years of age was that

FGMS was not at all studied in younger children and was recently only licensed

for use in children. Other reason was adolescence is a challenging period with

more physical activity hence feasibility of the device is better studied in this group.

The reason to include children with diabetes over a year was to exclude

honeymoon period which is transient and could have fluctuating blood glucose

levels.

We planned to enroll 30 patients in our 6months study. However at the end of

enrollment period we could get only 21 patients.

Randomized controlled design was planned so as to exclude the selection bias.

However because the intervention is not blinded to participants, we planned for

open label study design. Hence in our study the primary investigator and

participants were blinded till the allocation which was concealed by use of opaque

envelopes. Randomization was done by using computer generated random number

list. The allotment was revealed to participants after the written consent was

obtained for the study.

83

The ideal outcome of this study would require daily self monitoring of blood

glucose and a follow up period of at least one year. Though the recommendation

for home monitoring is at least 4 recordings daily, in our institution and various

other health centers the clinical practice has been that home blood glucose

monitoring are done once in 2 weeks for 3-4 consecutive days because of the poor

economic status of the families and not being able to afford the cost of glucose test

strips.

Also a large sample size would have been ideal. Till now there are no published

data available from India comparing SMBG and FGMS in children with type 1

diabetes. Hence we conducted this pilot study. Performing HbA1c once in 3

months is a proven indicator for monitoring good glycemic control however it

gives no information regarding the glucose excursions that happen during the day.

FGMS gives data for every 15minutes for 14days.

Primary outcome

The change in HbA1c was not significant in intervention group compared to

control group. We expected that FGMS would result in significant reduction

HbA1c because of longer duration (14days) and frequent measurement (once in

15minutes) of glucose. The possible explanations as to why FGMS did not achieve

better glycemic control could be,

84

1) Baseline characters like age of the patient and age at the time of diagnosis

was unmatched (P values were 0.003 and 0.007 respectively).

2) Randomization was done using computer generated random numbers hence

resulted in statistically significant difference between control and

intervention groups and could have influenced the final outcome of study.

3) 5 patients in intervention group missed regular diabetes clinic visits but

continued to inform SMBG data over phone for insulin tailoring. This was

because all the patients in intervention group had to come twice to hospital

for insertion and removal of FGMS sensor apart from regular clinic visits.

At the time of insertion each individual had to wait for 2-3 hours to ensure

working condition of the sensor. Study done by Al Algha et al gave 3

separate pre educational sessions (20minutes each) to participants and

parents in their one month study period. We could not give a separate

educational session apart from explaining about the devise and adherence to

routine follow up at the beginning of the study and at the time of sensor

insertion. Responsibility shared among care takers and adolescents result in

a better glycemic control. (24) Multidisciplinary management in type 1

diabetes helps to achieve better glycemic control. However non compliance

to treatment protocols was also been observed as the patient has to consult

multiple health professionals.

85

4) FGMS data evaluation and insulin adjustment in our study was done by

different treating endocrinologists resulting in non uniformity of

interpretation of complex FGMS data.

We observed a significant change in HbA1c in control group. One possible reason

for this could be participation in study itself and participants knowing that they

were not given FGMS sensor (a special machine) which could have made this

group more compliant to multidisciplinary management.

In intervention group all the patients had hypoglycemia recordings documented by

FGMS during each time of sensor placement. While simultaneous glucose values

by SMBG had shown hypoglycemic recording only in 3 patients. Remaining 7

patients there was no documented hypoglycemia by SMBG.

In addition to identification of hypoglycemic values which were missed by SMBG

FGMS data also helped in identifying the time at which hypoglycemia happened

(day time or night time). There is no other way to identify a low sugar value except

to check glucose by finger prick. Use of CGMS to identify this asymptomatic

hypoglycemia and nocturnal hypoglycemia was proved in studies done by Golicki

et al, Gandhi et al and Chetty et al.

86

Superiority of FGMS in identification and reduction in time spent in hypoglycemia

was proved in clinical experience trial by Larry et al and open label randomized

control trial by Thomas et al in adult population.

In our study we found that hypoglycemic recordings identified by FGMS were

more than SMBG confirming the results of other similar studies.

Secondary outcome

FGMS (interstitial fluid glucose) and SMBG (capillary blood glucose) values were

compared in intervention group. The normal difference between capillary blood

glucose and interstitial fluid glucose is 10-15mg/dl. In our study we found the

difference between FGMS and SMBG values was 14 ± 3.5mg/dl.

All the participants found sensor socially acceptable and not interfering with

privacy and daily activities. None of the participants had major side effects. Of the

33 sensors used during study period 2 sensors fell from the site at the time of

insertion. And 2 sensors recorded data only for 6 hours.

Power of the study

Difference in HbA1c from baseline to 6 months in intervention and control groups

were -0.02 ± 0.84 and 1.49 ± 1.15 (mean± SD). Estimated power for a 2 sample

87

mean test by Satterthwaite’s test assuming unequal variances with (alpha error=

0.0500, N=23 and delta error of=3.5166) was 0.8.

88

CONCLUSION

89

CONCLUSION

1) Use of FGMS in improving glycemic control with reduction of Hba1c was

not noted in our study. Rather than reading the sensor at the end of 14days, a

change in the study design allowing the clinician to read FGMS at interval of

4-5days during each sensor placement for insulin modification needs to be

explored.

2) The primary benefit as seen in our study for the use of FGMS is in

identifying hypoglycemic events. FGMS is a good tool to identify

hypoglycemia compared to SMBG. We found all the participants in

intervention group (n=10) had hypoglycemic recordings by FGMS but such

episodes were identified in only 3 participants by SMBG.

3) FGMS helps in identifying asymptomatic glycemic variations which affects

the long term outcome of disease. Adjusting insulin depending on glycemic

excursion helps in better glycemic control by avoiding rebound

hyperglycemia after episodes of hypoglycemia.

4) FGMS values were comparable with SMBG values. The mean difference of

14 ± 3.5mg /dl was found in our study.

5) FGMS is feasible and acceptable for use in children and adolescents with

type 1 diabetes mellitus.

90

6) FGMS sensor for 14days almost cost the same as SMBG if done daily.

Hence it is in a way cost effective and gives much frequent and larger

number of glucose values than SMBG.

91

LIMITATIONS

92

LIMITATIONS

Our study has various limitations

1) Being an open label randomized study intervention was not blinded to

participants and the primary investigator after allocation.

2) Small sample size.

3) Randomization technique used was computer generated random sequence of

number. Hence baseline characteristics like age and duration of illness were

not matched between the study groups.

4) We could not meet the estimated sample size within the study period

because the study group is in school going age and not willing for multiple

visits.

5) As FGMS data obtained was retrospective, and there were no alarms

available for abnormal glucose recordings patients and clinicians were

unaware of real time data and no clinical intervention was possible close to

the event.

6) FGMS data interpretation and insulin adjustments were done by different

clinicians which could have bearing effect on the outcome of study.

7) FGMS had shown an improving HbA1c during FGMS 2 but this declined

during FGMS 3. This clearly demonstrated the need for regular clinic visits

93

in tandem with FGMS monitoring was necessary for complete diabetes

management.

Further randomized studies with larger sample size and long term follow up period

comparing the FGMS with daily SMBG monitoring can show the effect of FGMS

on reduction of HbA1c. In between visits while the patient is on FGMS sensor will

help in assessing the working condition of sensor.

94

BIBILIOGRAPHY

95

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5. Tuomilehto J. The Emerging Global Epidemic of Type 1 Diabetes. Curr Diab Rep. 2013 Sep 27;13(6):795–804.

6. Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G, EURODIAB Study Group. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet Lond Engl. 2009 Jun 13;373(9680):2027–33.

7. The Onset Age of Type 1 Diabetes in Finnish Children Has Become Younger. The Finnish Childhood Diabetes Registry Group [Internet]. PubMed Journals. [cited 2017 Jul 21]. Available from: https://ncbi.nlm.nih.gov/labs/articles/10388969/

8. Aguiree F, Brown A, Cho NH, Dahlquist G, Dodd S, Dunning T, et al. International diabetes federation Diabetes Atlas. 6th Edition:160.

9. Ramachandran A, Snehalatha C, Krishnaswamy CV. Incidence of IDDM in children in urban population in southern India. Madras IDDM Registry Group Madras, South India. Diabetes Res Clin Pract. 1996 Oct;34(2):79–82.

10. Prasanna Kumar K. Incidence trends for childhood type 1 diabetes in India. Indian J Endocrinol Metab. 2015;19(7):34.

11. Kalra S, Kalra B, Sharma A. Prevalence of type 1 diabetes mellitus in Karnal district, Haryana state, India. Diabetol Metab Syndr. 2010;2(1):14.

12. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2010 Jan;33(Suppl 1):S62–9.

13. Type 1 diabetes in children and adolescents in india. CLinical practice guidelines 2011. 1st ed. Sanjay Gandhi Postgraduate Institute of Medical Sciences;

14. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003 Oct 22;290(16):2159–67.

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16. Gonder-Frederick LA, Zrebiec JF, Bauchowitz AU, Ritterband LM, Magee JC, Cox DJ, et al. Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study. Diabetes Care. 2009 Jun;32(6):1001–6.

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18. Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A, Jones TW. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15(S20):180–92.

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23. Jones TW, Porter P, Sherwin RS, Davis EA, O’Leary P, Frazer F, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998 Jun 4;338(23):1657–62.

24. Chiang JL, Kirkman MS, Laffel LMB, Peters AL. Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association. Diabetes Care. 2014 Jul 1;37(7):2034–54.

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26. Association AD. Standards of Medical Care in Diabetes—2014. Diabetes Care. 2014 Jan 1;37(Supplement 1):S14–80.

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31. Association AD. 12. Children and Adolescents. Diabetes Care. 2017 Jan 1;40(Supplement 1):S105–13.

32. Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15 Suppl 20:102–14.

33. Larsen ML, Hørder M, Mogensen EF. Effect of Long-Term Monitoring of Glycosylated Hemoglobin Levels in Insulin-Dependent Diabetes Mellitus. N Engl J Med. 1990 Oct 11;323(15):1021–5.

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39. Monsod TP, Flanagan DE, Rife F, Saenz R, Caprio S, Sherwin RS, et al. Do sensor glucose levels accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia? Diabetes Care. 2002 May;25(5):889–93.

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45. Chetty VT, Almulla A, Odueyungbo A, Thabane L. The effect of continuous subcutaneous glucose monitoring (CGMS) versus intermittent whole blood finger-stick glucose monitoring (SBGM) on hemoglobin A1c (HBA1c) levels in Type I diabetic patients: a systematic review. Diabetes Res Clin Pract. 2008 Jul;81(1):79–87.

46. Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJPM. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008101.

47. Heinemann L. Finger Pricking and Pain: A Never Ending Story. J Diabetes Sci Technol Online. 2008 Sep;2(5):919–21.

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49. FDA Approves Abbott’s FreeStyle Libre Pro System for Diabetes [Internet]. Medscape. [cited 2017 Aug 4]. Available from: http://www.medscape.com/viewarticle/869386

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52. Rebrin K, Steil GM. Can interstitial glucose assessment replace blood glucose measurements? Diabetes Technol Ther. 2000;2(3):461–72.

53. Corradini S, Pilosio B, Dondi F, Linari G, Testa S, Brugnoli F, et al. Accuracy of a Flash Glucose Monitoring System in Diabetic Dogs. J Vet Intern Med. 2016 Jul;30(4):983–8.

54. Ólafsdóttir AF, Attvall S, Sandgren U, Dahlqvist S, Pivodic A, Skrtic S, et al. A Clinical Trial of the Accuracy and Treatment Experience of the Flash Glucose Monitor FreeStyle Libre in Adults with Type 1 Diabetes. Diabetes Technol Ther. 2017 Mar;19(3):164–72.

55. A Multicenter Evaluation of the Performance and Usability of a Novel Glucose Monitoring System in Chinese Adults With Diabetes. - PubMed - NCBI [Internet]. [cited 2017 Aug 4]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27559031

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100

ANNEXURES

101

ANNEXURE 1

STUDY PROFORMA

Name DATE -

Hospital id-

Unique ID

DOB- DD/MM/YYYY

Age YY/MM

SEX - Male 1 Female 2

Phone number-

Place-

Socio economic status

102

Weight kg Height cm BMI-

Age at the time of diagnosis - - year/months

Duration of illness- - year/months

Insulin Storage

1Fridge 2 Mud pot 3 Wraps in cloth 4 Open place

Previous episode of DKA Yes 1 No2

Hypoglycemic awareness 1Yes 2 No

Previous episodes of hypoglycemia 1yes 2 No

End organ involvement Kidney Yes 1 No 2

Eye Yes 1 No 2

CNS Yes 1 No 2

Other associated conditions

GAD

TSH

T3

TTG T4

Thy Ab

Any other conditions

Insulin intake at base line

Type of insulin NAME Units Timings

103

Ultra short

1.

2.

3.

Long acting 4.

Drugs other than Insulin for glycemic control

1 Yes 2 No

HbA1c

Date HbA1c 6-12 months prior

Base line 3 months

6 months

Insulin intake during study period

Type of insulin Baseline 2months 4months 6months

Short acting

Long acting

Hospitalization during study period-

104

SMBG sugar levels

WEEK

No of hypoglycemic episodes

105

ANNEXURE 2

PARENT INFORMATION SHEET

A randomized trial comparing (FGMS) Flash Glucose Monitoring System + SMBG Vs

(SMBG) self monitoring of blood glucose alone for glycemic control in adolescents of

12-18years age with Type 1 diabetes mellitus.

Dear Parent, your child is currently under treatment for Type 1 diabetes mellitus in the

endocrinology division under Child health Unit 1. Your child is on insulin for the control of

sugar levels.

Type 1 diabetes is a condition in which strict control of sugars prevents the damage to vital

organs of body (Kidney, Eyes, Nervous system). However a low sugar level which can occur

due to excess activity or high dose of insulin can be harmful.self monitoring of blood glucose

(SMBG) by finger pricks is the most commonly used method to monitor sugars at home. HbA1c

is the test which gives an average sugar control of past 3 months which we consider as the test of

choice.

What is Flash glucose monitoring system?

FLASH glucose monitoring system (FGMS) is a recent advance in which a small device will

collect continuous sugar levels from the fluid around the body cells (Interstitial fluid). FGMS has

a sensor with a needle. Sensor is 5mm height and 35mm wide with a needle. Needle is of 0.4mm

thickness placed 5millimeters under the skin surface.

Does FGMS has any side effects?

Usually you will not feel the discomfort of the filament under the skin. Your child may

experience minimal pain at the time of insertion of needle. Sensor can be worn while bathing,

swimming and exercise.

If you take part what will you have to do?

If you allow your child to participate in this study, your child’s sugars will be monitored either

by FGMS+ SMBG or SMBG alone. Irrespective of the group your child assigned to you will

have to do SMBG once in every 14days (4times/day) as you have been routinely doing as per

protocol in the unit.In addition to this if your child belong to (SMBG + FGMS group) along with

SMBG, FGMS Sensor is to be worn for total of 14days for 3 times in next 6 months. ( At

beginning ,2 months and at 4 months).

While on FGMS device, parent/care giver will have to keep record of all meals, exercise,

symptoms of low/high sugars and any other time which the patient/caregiver feel could affect the

sugar level. Neither you nor your doctor will have any choice in whether you will get

FGMS+SMBG or SMBG as this will be decided by a computer program; this is like tossing a

coin and you have an equal chance of getting either method.

106

You will be expected to come for a review to the hospital 2 months after starting the test and

again after 2 months and finally after a further 2 months.HbA1c will be done at the beginning of

the study and at 3rd

and 6months. At each visit you will be given a sheet to document the meals

taken, insulin requirement, any symptoms related to low/high sugars. Difficulties (In-

convenience / interference with daily activities) encountered during the time of FGMS is to be

recorded. No additional procedures or blood tests will be conducted routinely for this study.

If at any time you experience any problems, you will be expected to report this to the doctor.

You will also be contacted by telephone at least once in between the monthly visits by the

doctors in this study who will ask you about any side effects you are experiencing.

Purpose of this study

We assume that continuous sugar monitoring by FGMS can achieve better glycemic control and

there by helps in adjusting the insulin for reduction in HbA1c.

What will happen if you develop any study related injury?

We do not expect any injury to happen to you but if you do develop any side effects or problems due to the study, these will be treated at no cost to you. How will it help you?

This study may or may not help you. At the end of this study if use of FGMS has resulted in

reduction if HbA1c levels and helped in identifying low sugar levels which SMBG missed. Your

doctor may prescribe it for further use.

Will it benefit other people?

The results of the study may provide benefit to other children with Type 1 diabetes for better

management.

Do I have to allow my child/ myself to be part of the study?

No, you are free to refuse the inclusion of your child in the study.

Even if you choose for your child not to be included in the study your child will be treated as per

the protocol followed in endocrinology unit.

If you allow your child to be part of the study you can still withdraw your child from the study at

anytime.

Do i need to pay for the cost of FGMS?

There is no extra cost incurred to the patient. FGMS are provided free of cost to you.

Instructions to caregiver/ patient

1) You have to wear the sensor continuously for 14days

2) Document the details in the sheet provided to you

3) Test finger prick blood glucose 4 times a day once in every 2weeks using the blood

glucose monitoring device

4) Protect the sensor from accidental removal from insertion site

107

ANNEXURE 3

CONSENT TO TAKE PART IN A CLINICAL TRIAL

Study Title: A randomized trial comparing (FGMS) Flash Glucose Monitoring System+ SMBG Vs

(SMBG) self monitoring of blood glucose for glycemic control in adolescents of 12-18years age

with Type 1 diabetes mellitus.

Participant’s name:

Date of Birth / Age (in years):

I_____________________________________________________________

___________, son/daughter of ___________________________________

(Please tick boxes)

Declare that I have read the information sheet provide to me regarding this study and have

clarified any doubts that I had. [ ]

I also understand that my participation in this study is entirely voluntary and that I am free to

withdraw permission to continue to participate at any time without affecting my usual

treatment or my legal rights [ ]

I also understand that neither I, nor my doctors, will have any choice or knowledge of whether I

will get FGMS +SMBG or SMBG alone [ ]

I also understand that during study period, FGMS will be provided free, but after this, if FGMS is

needed, I may have to pay for it [ ]

I understand that I will receive free treatment for any study related injury or adverse event but I

will not receive and other financial compensation [ ]

I understand that the study staff and institutional ethics committee members will not need my

permission to look at my health records even if I withdraw from the trial. I agree to this access [

]

I understand that my identity will not be revealed in any information released to third parties or

published [ ]

108

I voluntarily agree to take part in this study [ ]

Signature (or Thumb impression) of the Subject/Legally Acceptable

Date: _____/_____/______

Signatory’s Name: _________________________________ Signature:

Or

Guardian's name & signature: ………………………………………..

Or

109

ANNEXURE 4 CHILD INFORMATION SHEET

A randomized trial comparing (FGMS) Flash Glucose Monitoring System + SMBG Vs

(SMBG) self monitoring of blood glucose alone for glycemic control in adolescents of

12-18years age with Type 1 diabetes mellitus.

Dear child, you are currently under treatment for Type 1 diabetes mellitus in the endocrinology

division under Child health Unit 1. Your are on insulin for the control of sugar levels.

Type 1 diabetes is a condition in which strict control of sugars prevents the damage to vital

organs of body (Kidney, Eyes, Nervous system). However a low sugar level which can occur

due to excess activity or high dose of insulin can be harmful.

Self monitoring of blood glucose (SMBG) by finger pricks is the most commonly used method

to monitor sugars at home. HbA1c is the test which gives an average sugar control of past 3

months which we consider as the test of choice.

What is Flash glucose monitoring system?

FLASH glucose monitoring system (FGMS) is a recent advance in which a small device will

collect continuous sugar levels from the fluid around the body cells (Interstitial fluid). FGMS has

a sensor with a needle. Sensor is 5mm height and 35mm wide with a needle. Needle is of 0.4mm

thickness placed 5millimeters under the skin surface.

Does FGMS has any side effects?

Usually you will not feel the discomfort of the filament under the skin. Your child may

experience minimal pain at the time of insertion of needle. Sensor can be worn while bathing,

swimming and exercise.

If you take part what will you have to do?

If you agree to participate in this study, your sugars will be monitored either by FGMS+ SMBG

or SMBG alone.

Irrespective of the group you assigned to you will have to do SMBG once in every 14days

(4times/day) as you have been routinely doing as per protocol in the unit.

In addition to this if you belong to (SMBG + FGMS group) along with SMBG, FGMS Sensor is

to be worn for total of 14days for 3 times in next 6 months. ( At beginning ,2 months and at 4

months).

While on FGMS device, you/care giver will have to keep record of all meals, exercise, symptoms

of low/high sugars and any other time which the patient/caregiver feel could affect the sugar

level. Neither you nor your doctor will have any choice in whether you will get FGMS+SMBG

or SMBG as this will be decided by a computer program; this is like tossing a coin and you have

an equal chance of getting either method.

You will be expected to come for a review to the hospital 2 months after starting the test and

again after 2 months and finally after a further 2 months.HbA1c will be done at the beginning of

110

the study and at 3rd

and 6months. At each visit you will be given a sheet to document the meals

taken, insulin requirement, any symptoms related to low/high sugars. Difficulties (In-

convenience / interference with daily activities) encountered during the time of FGMS is to be

recorded. No additional procedures or blood tests will be conducted routinely for this study.

If at any time you experience any problems, you will be expected to report this to the doctor.

You will also be contacted by telephone at least once in between the monthly visits by the

doctors in this study who will ask you about any side effects you are experiencing.

Purpose of this study

We assume that continuous sugar monitoring by FGMS can achieve better glycemic control and

there by helps in adjusting the insulin for reduction in HbA1c.

What will happen if you develop any study related injury?

We do not expect any injury to happen to you but if you do develop any side effects or

problems due to the study, these will be treated at no cost to you.

How will it help you?

This study may or may not help you. At the end of this study if use of FGMS has resulted in

reduction if HbA1c levels and helped in identifying low sugar levels which SMBG missed. Your

doctor may prescribe it for further use at which point you need to buy the devise at your own

expense.

Will it benefit other people?

The results of the study may provide benefit to other children with Type 1 diabetes for better

management.

Do I have to be part of the study?

No, you are free to refuse to be included in the study.

Even if you choose for your child not to be included in the study you will be treated as per the

protocol followed in endocrinology unit.If you are willing to be part of the study you can still

withdraw your child from the study at anytime.

Do i need to pay for the cost of FGMS?

There is no extra cost incurred to the patient. FGMS are provided free of cost to you.

Instructions to caregiver/ patient

1) You have to wear the sensor continuously for 14days

2) Document the details in the sheet provided to you

3) Test finger prick blood glucose 4 times a day once in every 2weeks using the blood

glucose monitoring device

4) Protect the sensor from accidental removal from insertion site.

111

ANNEXURE 5 CONSENT TO TAKE PART IN A CLINICAL TRIAL

Study Title: A randomized trial comparing (FGMS) Flash Glucose Monitoring System+ SMBG Vs

(SMBG) self monitoring of blood glucose for glycemic control in adolescents of 12-18years age

with Type 1 diabetes mellitus.

Participant’s name:

Date of Birth / Age (in years):

I_____________________________________________________________

___________, son/daughter of ___________________________________

(Please tick boxes)

Declare that I have read the information sheet provide to me regarding this study and have

clarified any doubts that I had. [ ]

I also understand that my participation in this study is entirely voluntary and that I am free to

withdraw permission to continue to participate at any time without affecting my usual

treatment or my legal rights [ ]

I also understand that neither I, nor my doctors, will have any choice or knowledge of whether I

will get FGMS +SMBG or SMBG alone [ ]

I also understand that during study period, FGMS will be provided free, but after this, if FGMS is

needed, I may have to pay for it [ ]

I understand that I will receive free treatment for any study related injury or adverse event but I

will not receive and other financial compensation [ ]

I understand that the study staff and institutional ethics committee members will not need my

permission to look at my health records even if I withdraw from the trial. I agree to this access [

]

I understand that my identity will not be revealed in any information released to third parties or

published [ ]

I voluntarily agree to take part in this study [ ]

112

Signature (or Thumb impression) of the Subject/Legally Acceptable

Date: _____/_____/______

Signatory’s Name: _________________________________ Signature:

Or

Guardian's name & signature: ………………………………………..

Or

113

ANNEXURE 6

114

115

116

117

118

ANNEXURE 7

119

ANNEXURE 8

FGMS DATA

Documents

A RANDOMIZED CONTROLLED TRIAL COMPARING (FGMS) …repository-tnmgrmu.ac.in/9253/2/200701118vinod_kumar.pdf · 2018-08-14 · 3 CERTIFICATE This is to certify that the dissertation