Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kröger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. Lancet 2016; published online Sept 12. http://dx.doi.org/10.1016/S0140-6736(16)31535-5.

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Supplementary appendix

Figure S1: Study design

SMBG=self-monitoring of blood glucose.

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Figure S2: Difference in groups for glycaemic measures at 6 months during the day time (06:00–23:00) and night time (23:00–06:00)

Re-scaled CIs are CIs for the difference in the intervention group from the control group at 6 months expressed as a percentage of the control group adjusted mean.

AUC=area under the curve; CI=confidence interval.

Day:

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Night:

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Figure S3: Nocturnal time in hypoglycaemic range during baseline and treatment phase (days 1–208), intervention group (per protocol)

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Table S1: Hyperglycaemic measures*

Intervention (n=119)

Control (n=119)

Baseline (days 1–15)

Mean (SD)

Final (days 194–208)

Mean (SD)

Change from baseline-adjusted mean (SE) % difference vs.

control

P-value vs.

control

Measure and sensor glucose

level

Intervention Control Intervention Control Intervention Control Difference

Time >10·0 mmol/L (180 mg/dL)†

5·62 (2·48) 5·80 (3·11) 6·16 (3·05) 6·08 (3·20) 0·37 (0·251) 0·18 (0·253) 0·19 (0·329) 3·2 0·5623

Time >13·3 mmol/L

(240 mg/dL)†

1·85 (1·44) 1·91 (1·70) 1·67 (1·36) 2·06 (1·61) −0·31 (0·124) 0·06 (0·126) −0·37 (0·163) −19·1 0·0247

Time >16·7 mmol/L (300 mg/dL)†

0·48 (0·58) 0·49 (0·69) 0·34 (0·46) 0·44 (0·54) −0·20 (0·05) −0·09 (0·05) −0·11 (0·06) −27·7 0·0684

*Analysis based on ANCOVA model with treatment group, insulin administration method, and study centre (pooled per country for <5 subjects/centre) as fixed effects and the baseline measurement as covariate. †Hours/day.

n=number of subjects with non-missing 14-day baseline and 14-day treatment-phase values; NA=not available; SD=standard deviation; SE=standard error.

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Table S2: Details of glycaemic measures at 3 months including hyperglycaemia, time in range, hypoglycaemia, and glucose variability

Intervention (n=119)

Control (n=120)

Intervention

(n=119)

Control

(n=119) Intervention (n=119)

Control

(n=119)

Difference in adjusted means

vs. control (SE)

P-value vs.

control

Glycaemic measure Baseline mean (SD) 3-month mean (SD)

HbA1c (mmol/mol) 50·7 (5·7) 50·6 (7·0) 51·4 (7·1) 52·1 (7·3) −0·7 (0·59) 0·2329

HbA1c (%) 6·79 (0·52) 6·78 (0·64) 6·85 (0·65) 6·92 (0·67) −0·06 (0·054) 0·2322

Glucose 3·9–10·0 mmol/L (70–180 mg/dL) time,

hours 15·0 (2·5) 14·8 (2·8) 16·0 (2·8) 14·3 (3·1) 1·6 (0·30) <0·0001

Glucose

<3·9 mmol/L

(70 mg/dL)

24 hours

Events 1·81 (0·90) 1·67 (0·80) 1·30 (0·77) 1·59 (0·83) −0·35 (0·085) <0·0001

Time, hours 3·38 (2·31) 3·44 (2·62) 1·91 (1·42) 3·03 (2·21) −1·09 (0·183) <0·0001

Night

(23:00–06:00)

7 hours

Events 0·47 (0·32) 0·46 (0·29) 0·31 (0·28) 0·42 (0·28) −0·11 (0·032) 0·0010

Time, hours 1·32 (1·07) 1·48 (1·29) 0·72 (0·70) 1·26 (0·99) −0·48 (0·095) <0·0001

Glucose

<3·1 mmol/L

(55 mg/dL)

24 hours

Events 0·96 (0·65) 0·92 (0·73) 0·51 (0·42) 0·82 (0·67) −0·33 (0·057) <0·0001

Time, hours 1·59 (1·42) 1·77 (1·86) 0·74 (0·75) 1·48 (1·57) −0·68 (0·132) <0·0001

Glucose

<2·2 mmol/L Events 0·39 (0·43) 0·44 (0·51) 0·17 (0·23) 0·36 (0·50) −0·18 (0·045) <0·0001

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(40 mg/dL)

24 hours Time, hours 0·59 (0·85) 0·75 (1·11) 0·23 (0·34) 0·60 (1·02) −0·33 (0·091) 0·0003

Glucose

>13·3 mmol/L (240 mg/dL)

24 hours

Time, hours 1·85 (1·44) 1·91 (1·70) 1·73 (1·41) 2·36 (2·06) −0·60 (0·187) 0·0016

BGRI 8·2 (2·3) 8·3 (2·7) 7·3 (2·4) 8·8 (3·1) −1·4 (0·29) <0·0001

LBGI 2·7 (1·5) 2·7 (1·7) 1·7 (1·1) 2·4 (1·4) −0·7 (0·12) <0·0001

MAGE mg/dL (average) 142 (29) 144 (31) 133 (27) 145 (33) −11 (3.0) 0·0003

Mean glucose mg/dL 141 (19) 142 (23) 146 (20) 148 (26) −1 (2·3) 0·5649

CONGA

2 hours (mg/dL)

56 (13) 56 (14) 49 (12) 59 (14) −10 (1·3) <0·0001

6 hours (mg/dL)

70 (24) 69 (26) 55 (23) 71 (28) −17 (3·3) <0·0001

BGRI=blood glucose risk index; CONGA=continuous overall net glycaemic action; CV=coefficient of variation; LBGI=low blood glucose index; MAGE=mean amplitude of glycaemic excursions; SE=standard error;

SD=standard deviation.

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Figure S4: Glycaemic variability after 6 months

BGRI=blood glucose risk index; CI=confidence interval; CONGA=Continuous Overall Net Glycaemic Action; CONGAx=Continuous Overall Net Glycaemic Action x hours;

CV=coefficient of variation; HBGI=high blood glucose index; LBGI=low blood glucose index; MAGE=mean amplitude of glycaemic excursions; MODD=mean of daily

differences; SE=standard error; SD=standard deviation. Re-scaled confidence intervals are confidence intervals for the difference from control at 6 months expressed as a percentage of the control group adjusted mean

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Table S3: Details of primary endpoint by age group

Intervention (n=119)

Control (n=120)

Intervention

Control

Intervention Control

Difference in adjusted means

vs. control (SE)

P-value vs.

control

Glycaemic measure Baseline mean (SD) Study end mean (SD)

Glucose

<3·9 mmol/L

(70 mg/dL)

24 hours

time, hours/day

<45 years 3·51 (2·57)

n=65

3·95 (2·90)

n=60

2·11 (2·21)

n=65

2·95 (2·07)

n=60 −0·61 (0·29) 0·0372

≥45 years 3·23 (1·96)

n=54

2·93 (2·20)

n=59

1·94 (1·55)

n=54

3·60 (3·00)

n=59 −1·87 (0·37) <0·0001

Glucose

>13·3 mmol/L

(240 mg/dL)

24 hours

time, hours/day

<45 years 2·20 (1·55)

n=65

1·90 (1·57)

n=60

1·74 (1·38)

n=65

2·30 (1·60)

n=60 −0·70 (0·24) 0·0041

≥45 years 1·43 (1·17)

n=54

1·91 (1·84)

n=59

1·58 (1·34)

n=54

1·80 (1·59)

n=59 0·07 (0·21) 0·7547

SD=standard deviation.

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Figure S5: Scores from A) DTSQ, B) DQoL C) Hypoglycemia Fear Survey, and D) Diabetes Distress Scale questionnaires – per protocol population

Error bars show 95% CIs. DTSQ treatment satisfaction scores range from –18 to 18; high scores indicate much more satisfied, convenient, flexible, or likely to recommend treatment

now. DTSQ perceived frequency scores range from –3 to 3; high scores indicate much more of the time now. DQoL scores range from 1 to 5; high scores indicate dissatisfaction,

frequent impact, or frequent worry. HFS behaviour score ranges from 0 to 60. High scores indicate high frequency of behaviours to avoid low blood sugar. HFS worry score ranges

from 0 to 72. High scores indicate high frequency of worries related to low blood sugar. DDS scores range from 1 to 6. High scores indicate a very serious problem.

CI=confidence interval; DQoL=Diabetes Quality of Life Questionnaire; DTSQ=Diabetes Treatment Satisfaction Questionnaire; DDS=Diabetes Distress Scale; HFS=Hypoglycemia

Fear Survey.

a)

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b)

12

c)

13

d)

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Figure S6: A) Hypoglycemia Fear Survey and B) Diabetes Distress Scale

HFS behaviour score ranges from 0 to 60. High scores indicate high frequency of behaviours to avoid low blood sugar. HFS worry score ranges from 0 to 72. High scores indicate

high frequency of worries related to low blood sugar. DDS scores range from 1 to 6. High scores indicate a very serious problem.

CI=confidence interval; DDS=Diabetes Distress Scale; HFS=Hypoglycemia Fear Survey.

a)

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b)

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Table S4: Device-related AEs

Subject AE term* Severity** Action taken Discontinuation from study?

1 Allergic reaction at sensor insertion site Severe Drug therapy No

2 Sensor-site reaction Moderate Drug therapy No

3 Itching at sensor insertion site Mild Drug therapy Yes

4 Rash Mild Drug therapy Yes

5 SISS (erythema and itching) Severe Not stated Yes

5 SISS (erythema) Severe None No

5 SISS (erythema) Severe None No

6 SISS (rash, erythema, pain, itching) Severe Drug therapy Yes

7 Erythema Mild Drug therapy No

8 Oedema Moderate Drug therapy No

9 Erythema Severe None No

10 Allergy (itching, redness, pustules) Moderate Drug therapy No

10 Allergy (redness, weeps) Moderate Drug therapy Yes

*All adverse events (AEs) were categorised as ‘medical device site reaction’; **none of the AEs were listed as serious adverse events (SAEs).

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Table S5: Observed anticipated sensor insertion-site symptoms (non-adverse events)

Intervention

(6-month system use)

Control

(4-week masked system use)

Not-randomised

(up to 2-week masked system use)

Severity

Patients (n) Events (n) Patients (n) Events (n)

Patients

(n) Events (n)

Mild Moderate Severe Unspecified

Total 47 (39·5%) 215 15 (12·5%) 27 3 6

Erythema 30 (25·2%) 79 4 (3·3%) 5 1 1 39 44 2 0

Itching 20 (16·8%) 42 5(4·2%) 6 2 3 25 24 1 1

Rash 12 (10·1%) 29 2(1·7%) 2 0 0 9 21 1 0

Pain 19 (16·0%) 29 7(5·8%) 8 1 1 14 22 2 0

Bleeding 12 (10·1%) 19 5(4·2%) 5 1 1 17 7 1 0

Bruising 4 (3·4%) 4 1(0·8%) 11 0 0 3 2 0 0

Oedema 5 (4·2%) 8 0 0 0 0 3 5 0 0

Induration 3 (2·5%) 5 0 0 0 0 1 4 0 0

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Table S6: Hypoglycaemia status assessment at baseline: to what extent can you tell by your symptoms that your blood glucose is LOW?

Intervention (n=119)

Control (n=120)

Intervention

Control

Number (%)

n 111 (93·3%) 109 (90·8%)

Never 1 (0·8%) 0 (0·0%)

Rarely 6 (5·0%) 4 (3·3%)

Sometimes 17 (14·3%) 10 (8·3%)

Often 41 (34·5%) 46 (38·3%)

Always 46 (38·7%) 49 (40·8%)

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List of study centres

23 study centres (three in Sweden, six in Austria, five in Germany, three in Spain, and six in the Netherlands).

Chief Investigator (Sweden): Prof. Jan Bolinder, Karolinska Universitetssjukhuset Huddinge, Stockholm

Other Swedish investigators:

Dr Michael Alvarsson, Karolinska Universitetssjukhuset Solna, Stockholm

Dr Peter Hallgren, Falu Lasarett, Falun

Country Lead Principal Investigator (Austria): Dr Raimund Weitgasser, Diakonissen-Krankenhaus Salzburg, Abteilung für Innere Medizin, Salzburg

Other Austrian investigators:

Prof. Thomas Pieber, Medizinische Universität Graz, Graz

Prof. Peter Fasching, Wilhelminenspital Medizin, Wien

Prof. Heinz Drexel, VIVIT-Institut am Akad. Lehrkrankenhaus Feldkirch, Feldkirch

Prof. Anton Luger, Medizinische Universität Wien, Wien

Dr Markus Laimer/Dr Christoph Ebenbichler, Universitätsklinik für Innere Medizin I, Innsbruck

Country Lead Principal Investigator (Germany): Prof. Stephan Matthaei, Christliches Krankenhaus Quakenbrück gemeinnützige GmbH, Quakenbrück

Other German investigators:

Dr Ralph Geldmacher, Diabetes-Zentrum Hannover-Nord, Hannover

Dr Jens Kröger, Zentrum für Diabetologie Hamburg-Bergedorf, Hamburg

Prof. Thomas Haak, Diabetes Zentrum Mergentheim, Bad Mergentheim

Dr Ulrich Aigner, Versdias GmbH, Sulzbach-Rosenberg

Country Lead Principal Investigator (Spain): Dr Ramiro Antuna, Clinica Diabetologica, Gijon

Other Spanish investigators:

Dr Eva Aguilera, Hospital Universari Germans Trias i Pujol, Badalona

Dr Sonia Gaztambide Sáenz, Servicio de Endocrinología Hospital Unversitario Cruces, Cruces-Barakaldo (Vizcaya)

Country Lead Principal Investigator (Netherlands): Dr Nel Geelhoed, Medisch Centrum Haaglanden, Den Haag

Other Dutch investigators:

Dr Sjoerd van Thiel, Amphia Ziekenhuis, Breda

Dr Fred Storms, St. Antonius, Utrecht

Dr Teri Brouwer, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam

Dr Erik Serne, Vanderbilt University Medical Center, Amsterdam

Dr Adriaan Kooy, Bethesda Diabetes Research Center, Hoogeveen