Patients suffering Diabetic Macular Edema treated with intravitreous Ranibizumab*

MEDICAL NUTRITION SPECIALISTS

High concentration

DHA

It contributes significantly reducing

Central Macular Thickness (CMT)

It significantly improves

Visual Acuity (VA)

*24 months results

RESULTS IN BCVA

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12 L

8.9 L

RESULTS IN CMT

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Triglyceride

Treatment of Diabetic Macular Edema with Ranibizumab intravitreal injections according to a strict moonthly PRN regimen. Influence of a highly concentrated DHA supplementation. Results at 24 months.

M. Lafuente López-Herrera1, Argente del Castillo1, Guindo Vilchez1, L. Bernal1, L. Ortín1, JC. Domingo3, J. López Román2, J. Lajara2. 1 Hospital Universitario Morales Mesesguer, Murcia. 2Universidad Católica San Antonio de Murcia. 3Universidad de Barcelona.

MAIN OBJECTIVETo evaluate BCVA, CMT, number of injections and sistemic markers of oxidation in type 2 Diabetes Mellitus suffering DME treated with intravitreous Ranibizumab and oral supplementation with highly concentrated DHA, during 24 months.

OTHER OBJECTIVES· Influence of Supplementation on the metabolic control (HbA1c).· Evolution of oxidative stress biochemical markers in serum.· Evaluate any changes in Omega-6 versus Omega-3 concentrations in red blood cell membrane.

OBJECTIVESEvaluate posible changes in VA, CMT and in oxidative sistemical markers after 24 months of DHA supplementation in Diabetic Macular Edema (DME). To find any positive influence of DHA supplementation on the metabolic control.

The trial was onset in December 2012 with the inclusión of 76 eyes (62 patients), all them treated with Ranibizumab IV in a strict monthly PRN regimen; 50% randomized either to receive or not 3 capsules/day of BRUDYRETINA (DHA-triglyceride1g/day).

24 months Follow-up period

A PROSPECTIVE, INTERVENTIONAL, RANDOMIZED, CONTROLLED WITH PARALLEL GROUPS TRIAL, 2 YEARS FOLLOW-UP

DMEaffecting the central Macula

(76 eyes, 62 patients)

Monthly IV 0,5mgRANIBIZUMAB

(Plus DHA 1050mg/day oraly)

Monthly IV 0,5mgRANIBIZUMAB

During the initial 24 months of the follow-up period, a monthly regimen of visits has been stablished, evaluating VA (by EDTRS) and OCT. Compliance of supplementation was also evaluated monthly asking to bring the empty box at each visit, and giving them a new box. A phone call was done every 15 days to remind the need of compliance. At 6, 12, 18 and 24 months there were also performed other investigations as needed: FAG, Biochemistry,…

VISITS REGIMEN DURING 1ST AND 2ND YEARS

21 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

VA (EDTRS)OCT measuring Central Macular Thickness

DHA supplementation control

VA, and OCT macular thickness evolution (all)/ OCT ON (evaluate fibers’ layer)Fundus Oph, FAG/ biochemistry of serum and urine.

BCVA: Best Corrected Visual Acuity I DM: Diabetes Mellitus I DME: Diabetic Macular Edema I CMT: Central Macular Thickness I DHA: Docosahexaenoic Acid I HbA1c: Glicosilated Hemoglobin I OCT: Optical Coherence Tomography I FAG: Fluorescein Angiography.

CMT is significantly improved at 24 months (basal thickness: 447±104 microns), showing average thickness at 24 months: 329±104 microns; (p<0.001), being the reduction significantly larger in the supplemented group (p<0.035). Supplemented patients are showing lower CMT at 24 months, being the average thickness reduction of 145 microns in the supplemented group, against 97 microns in the control group. Difference is detected starting in the first month.

CMT • RESULTSControl Experimental

CMT significant improvement at 24 months (p<0.001) with significant differences in the experimental group compared with the control group (p<0.035). CMT (OCT) is reduced in a stable 97 microns of thickness in the control group, and in a stable sustained 145 microns in

the supplemented group.

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Initial CMT at onset does have influence on the number of injections needed after 24 months. Those patients showing less CMT at onset will need les number of injections tan those with initial larger CMT. If we divide into two groups at arround 450 microns (enough thicknes requiring treatment), we can see that patients having thickness below this figures they can skip at least 2 injections after 2 years of follow-up when compared with those showing initial thickness over 450 microns. Correlation tends to increase with time; injections needed at 18 and 24 months are increasing over those needed during the first 12 months (r=5.1). At 18 months 6.9 injections in those having initial thickness below 450 microns, and 9,4 in those with initial thickness over 450 microns; 7,7 injections in those with initial thickness below at 24 months, and 10,6 injections in those starting at a wider thickness.

NUMBER OF INJECTIONS • RESULTS

Average nº of injections at 12, 18, 24 monthsWhat is the number of injections related with?

Initial VA Metabolic Control Supplementation

Initial CMT

CMT 12 m 18 m 24 m

P<0.004 P<0.0001 P<0.003

< 450 μm 6.5 6.9 7.7

> 450 μm 7.5 9.4 10.6

Relating the metabolic control, it seems not being much influenced by supplementation, but a tendency towards a better metabolic control is seen in the supplemented group of patients. We should wait until the 36 months of follow-up results to get the final conclusion on this variable.

HbA1c • RESULTS

Metabolic control (HbA1c)Tendency to a better metabolic control (<HbA1c) in the supplemented group

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Hb

%

Experimental Control

Basal 6 months 9 months 12 months 24 monthsTime

The percentage of patients gaining more than 15 L is equal for both groups, but those gaining more than 5 L or more than 10 L, the percentage of improvement is significantly larger for the supplemented group than for the controls. Most remarkable is that there exist a significant lower percentage of supplemented patients (15,6%) against controls (35,9%) showing a loss of more than 5 L.

BCVA • RESULTS

How is the evolution of VA along 24 months?Which variables are influencing on the final VA?

• Those gaining more than 15 letters, their percentage of improvement is equivalent for both groups.

• A significant larger percentage of improvement in the supplemented group in those gaining more than 5 L or more than 10 L.

• The percentage of patients loosing more than 5 letters of VA is significantly lower in the supplemented group than in controls.

9080

0

605040302010

70

DHAPlacebo

< 5 letters > 5 letters > 10 letters > 15 letters

15,6

35,9

84,4

64 62,6

55,9

18,8 20,5

MEDICAL NUTRITION SPECIALISTS

One injection a month until reaching stability along 3 consecutive visits. Injecting again when a loss in stability is detected: meaning a loss equal or more than 5 EDTRS letters, or an OCT increase in central macular thickness of more than 100 microns. Should this happen, a new set of two injections were placed going back to stability.

INTRAVITREAL INJECTIONS REGIMEN

TREATMENTWhen there is a VA loss due to DME with central affectation. Monthly Ranibizumab IV injections until reaching VA stability along 3 consecutive visits.

1 2 3 4

BCVA ≠ 5 LCMT > 100 µm

RE-TREATMENTWhen stability is lost (difference in VA loss reading capacity of 5 letters) or an OCT difference ≥ 100 microns.

Considering both groups globally after 2 years, the gain is 10,31 L, but separating both groups, a significant difference can be seen in the last 2 months of the follow-up; 12 L for the supplemented group, and 8,9 L for the control group. Initial VA of both groups are almost equal (31,2 L in the supplemented group, and 30,8 L in the control group, approximately 0.3 in the decimal scale. After 2 years, the average reading of both groups taken globally is 41,36 L, being of 43,28 L in the supplemented group, and of 39,7 L in the control group; 0,5 in the decimal scale.

BCVA • RESULTS

How is the evolution of VA along 24 months?Which variables are influencing on the final VA?

• Initial VA was around 31L. Globally considered both groups, the gain is 10,31 L (12L in the supplemented vs 8,9 in the non supplemented). A significant difference between both groups is detected reaching the last 2 months of the follow-up period.

• Initial VA, Initial Macular Thickness, and supplementation are influencing on the final VA.

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Relating the PUFA concentration variation into the red blood cell membranes, only in the supplemented group is seen a significant reduction in Arachidonic acid (AA) concentration (Omega-6; p<0.05), also a significant increase in the DHA concentration (Omega-3; p<0.01), and a significant reduction in the Omega-6/Omega-3 Index (p<0.01). No changes were detected in the control group.

RED BLOOD CELL MEMBRANE PUFA CONCENTRATION

*p<0,05 Intragroup differences. Final vs Initial.

**p<0.01 Intragroup differences. Final vs Initial.

#p<0,05 Intergroup differences between evolution of experimental and control groups.

##p<0,01 Intergroup differences between evolution of experimental and control groups.

There are significant differences (p<0.05) between supplemented and non supplementedInitial FinalTime:

SIGNIFICANT REDUCTION IN ARACHIDONIC A. (p<0.05)

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% n

-6

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*#

SIGNIFICANT n-6/n-3 INDEX REDUCTION

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/ n-3

ControlExperimental

**

##

SIGNIFICANT DHA INCREASE (p<0.01)

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At ocular level one episode of endophthalmitis due to an enterococcus faecalis, but also subconjuctival hemorrages or cataracts. Most adverse events seen are related with the prolonged follow-up period of observation in the trial. There are 3 deceased patients, 4 Cardiovascular events, and 1 Miocardial infarction all of them related with their advanced metabolic disease (Diabetes) but had no relation with any of the implemented treatments.

ADVERSE EVENTS

AE Patients n=62

Ocular 1 endoftalmitis

Systemic (deceased) 3

Cardiovascular events 4

Miocardial infarction 1

Dizziness 1

Gastrointestinal 1

There is a significant TAC increase found in the experimental group versus that found in the control group (p<0.034). There is only TAC significance in the supplemented group, but not in the control group (p=0.056). A increase in total serum antioxidant protection is offered by the supplementation product.

OXIDATION MARKERS • RESULTS

SERUM TOTAL ANTIOXIDANT CAPACITY (TAC)· Significant TAC improvement in the supplemented group, but not in the control group.

· Significant difference in the TAC values of supplemented group vs control group.

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TAC

Experimental Control

BasalFinalP<0.034P<0.000012

P<0.056

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The information content is exclusively addressed to healthcare professionals

Conclusions

Relating to supplementation

Supplemented patients are reaching less CMT from the very first month of supplementation comparing with the control group. This difference is maintained during the complete follow-up period of 24 months.

Supplemented patients show a significant better VA starting in the last two months than in controls.

Supplemented patients show lower CMT, and larger gain in letters reading after 2 years compared with controls.

Relating to other studied variables

Initial VA is a variable influencing on the VA at 24 months, having a predictive value. The better is the VA at onset, the better will be the VA recovery finally.

The lower is the initial CMT the larger will be the reduction in the number of injections at 12, 18, and 24 months.

Total serum antioxidant capacity profile and PUFA balance in red blood cell membrane is only improved in supplemented patients.

All in all, supplementation is showing as a benefit for patients suffering DME.

COMPOSITION 1 cap. %RDA* 3 cap. %RDA*

Oil concentrated inOmega-3 fatty acids22:6ω3, DHA (mg) 350 - 1050 -20:5ω3, EPA (mg) 42,5 - 127 -22:5ω3, DPA (mg) 30 - 90 -VitaminsVitamin B1 (mg) 0,37 33 1,1 100Vitamin B2 (mg) 0,47 33 1,4 100Vitamin B3 (mgNE) 5,3 33 16 100Vitamin B6 (mg) 0,47 33 1,4 100Vitamin B9 (µg) 66,7 33 200 100Vitamin B12 (µg) 0,83 33 2,5 100Vitamin C (mg) 26,7 33 80 100Vitamin E (mg α-TE) 4 33 12 100MineralsZinc (mg) 1,66 16,66 5 50Copper (mg) 0,16 16,66 0,5 50Selenium (µg) 9,16 16,66 27,5 50Manganese (mg) 0,33 16,66 1 50Other nutrientsLutein (mg) 3 - 9 -Zeaxanthin (mg) 0,3 - 0,9 -Glutathione (mg) 2 - 6 -

3 capsules/day = 1050 mg DHA

B R U D Y R E T I N A

COMPOSITION In 1 capsule %RDA*

Oil concentrated inOmega-3 fatty acids22:6ω3, DHA (mg) 350 -20:5ω3, EPA (mg) 42,5 -22:5ω3, DPA (mg) 30 -VitaminsVitamin C (mg) 80 100Vitamin E (mg α-ET) 12 100MineralsZinc (mg) 10 100Copper (mg) 1 100Other nutrientsLutein (mg) 5 -Zeaxanthin (mg) 1,4 -

1 capsule/day = 350 mg DHA

B R U D Y M Á C U L A

*RDA= Recommended Daily Allowances

2015

-03