Download PDF

Clinical Trial Results:
Neurodegeneration as an early event in the pathogenesis of Diabetic Retinopathy: A multicentric, prospective, phase II-III, randomized controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest Diabetic Retinopathy.

Summary
EudraCT number	2012-001200-38
Trial protocol	DE GB PT DK
Global end of trial date	03 Nov 2015

Results information
Results version number	v1(current)
This version publication date	29 Dec 2019
First version publication date	29 Dec 2019
Other versions
Summary report(s)	Synopsis of the Clinical Study Report

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

4C-2011-02

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

BCN Peptides SA

Sponsor organisation address

Poligon Industrial Els Vinyets-Els Fogars II, Sant Quintí de Mediona, Spain, 08777

Public contact

Clinical Trial Info Desk, BCN Peptides SA, 0034 938191399, ctinfodesk@bcnpeptides.com

Scientific contact

Clinical Trial Info Desk, BCN Peptides SA, 0034 938191399, ctinfodesk@bcnpeptides.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Mar 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Nov 2015

Global end of trial reached?

Yes

Global end of trial date

03 Nov 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate whether Somatostatin 0.1% and Brimonidine tartrate 0.2% eye drops, administered twice a day for 2 years to type 2 diabetes patients with early-stage diabetic retinopathy (DR), were able to prevent or arrest the development and progression of DR.

Protection of trial subjects

This study was designed, implemented and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labour, and Welfare), and with the latest revision of the Declaration of Helsinki as adopted by the World Medical Association the Declaration of Helsinki. The Investigator ensured that each patient was fully informed about the nature and objective of the study and possible risks associated with participation. Patient indicated assent to participate in the study by personally signing and dating the written informed consent form. The process of obtaining informed consent was documented in the patient’s source documents. The informed consent form used in this study, and any changes made during the course of the study, was prospectively approved by both the IRB/IEC/REB and the EUROCONDOR Ethics Committee before used.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Portugal: 78

Country: Number of subjects enrolled

Spain: 49

Country: Number of subjects enrolled

United Kingdom: 141

Country: Number of subjects enrolled

Denmark: 47

Country: Number of subjects enrolled

Germany: 35

Country: Number of subjects enrolled

Italy: 79

Country: Number of subjects enrolled

France: 20

Worldwide total number of subjects

449

EEA total number of subjects

449

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

250

From 65 to 84 years

199

85 years and over

Subject disposition

Top of page

Recruitment details

Eligible participants at screening and baseline visits were randomized 1:1:1 to Somatostatin 0.1%, Brimonidine tartrate 0.2% or Placebo and were treated and followed for 96 weeks. The randomisation was stratified by ETDRS level < 20 (MAs absent) (50% of enrolled patients) and ETDRS levels 20 or 35 with presence of at least 1 MA in the study eye.

Screening details

A total of 569 adult patients were screened out of which 450 patients were randomized. 449 patients received at least one dose of study medication and were included in the Safety population.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

The treatment was double-blind for Somatostatin and Placebo. The 3 treatment groups were masked to the Central Reading Centre to reduce bias in the assessment of the study outcomes.

Are arms mutually exclusive

Yes

Somatostatin 0.1%

Arm description

Primary efficacy (PE) population patients who received Somatostatin 0.1% as eye drops, 1 drop in each eye twice a day.

Arm type

Experimental

Investigational medicinal product name

COLIRIOBCN070660

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution in single-dose container

Routes of administration

Ophthalmic use

Dosage and administration details

Somatostatin 0.1% was administered as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening.

Placebo

Arm description

Primary efficacy (PE) population patients who received Placebo as eye drops, 1 drop in each eye twice a day.

Arm type

Placebo

Investigational medicinal product name

Placebo eye drops

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution in single-dose container

Routes of administration

Ophthalmic use

Dosage and administration details

Placebo was administered as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening.

Brimonidine tartrate 0.2%

Arm description

Primary efficacy (PE) population patients who received Brimonidine tartrate 0.2% as eye drops, 1 drop in each eye twice a day.

Arm type

Experimental

Investigational medicinal product name

Brimonidine tartrate 0.2%

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ophthalmic use

Dosage and administration details

Brimonidine tartrate 0.2% was administered as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening.

Number of subjects in period 1	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Started	145	152	152
Completed	120	124	97
Not completed	25	28	55
Consent withdrawn by subject	13	11	7
Intraocular pressure higher than 22 mmHg	-	-	2
Development of allergic reactions to study drug	-	1	15
Adverse event, non-fatal	-	1	9
Other	7	10	10
Development of DR complications	1	-	-
Interruption of treatment for more than 1 month	3	4	12
Protocol deviation	1	1	-

Baseline characteristics

Top of page

Reporting group title

Somatostatin 0.1%

Reporting group description

Primary efficacy (PE) population patients who received Somatostatin 0.1% as eye drops, 1 drop in each eye twice a day.

Reporting group title

Placebo

Reporting group description

Primary efficacy (PE) population patients who received Placebo as eye drops, 1 drop in each eye twice a day.

Reporting group title

Brimonidine tartrate 0.2%

Reporting group description

Primary efficacy (PE) population patients who received Brimonidine tartrate 0.2% as eye drops, 1 drop in each eye twice a day.

Reporting group values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%	Total
Number of subjects	145	152	152	449
Age categorical
The age range of all patients at baseline was 45-80 years.
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	63.2 ( 6.8 )	63.2 ( 7.0 )	63.5 ( 6.3 )	-
Gender categorical
Units: Subjects
Female	52	48	53	153
Male	93	104	99	296
Body Mass Index (BMI)
Units: Kg/m2
arithmetic mean (standard deviation)	31.0 ( 5.2 )	30.6 ( 5.5 )	30.7 ( 5.8 )	-

End points

Top of page

Reporting group title

Somatostatin 0.1%

Reporting group description

Primary efficacy (PE) population patients who received Somatostatin 0.1% as eye drops, 1 drop in each eye twice a day.

Reporting group title

Placebo

Reporting group description

Primary efficacy (PE) population patients who received Placebo as eye drops, 1 drop in each eye twice a day.

Reporting group title

Brimonidine tartrate 0.2%

Reporting group description

Primary efficacy (PE) population patients who received Brimonidine tartrate 0.2% as eye drops, 1 drop in each eye twice a day.

Subject analysis set title

MA>1 at screening subpopulation - Somatostatin 0.1%

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subset of the Primary efficacy (PE) population with more than 1 microaneurysm (MA) at screening treated with Somatostatin 0.1%. Placebo-treated patients of the PE did not show disease progression during the 2 years of the clinical trial on the different efficacy variables analysed, making it unfeasible to evaluate the neuroprotective role of Somatostatin and Brimonidine eye drops in the PE (see endpoints named as A). For this reason, complementary analyses were performed focused on retinal microaneurysms (MAs), a classical macroscopic parameter commonly used for diagnosis of DR (see endpoints named as B). A subpopulation of patients more affected in terms of MAs was selected since the presence of 1 or 2 of MAs is associated with disease worsening in the early stages of DR. Specifically, the efficacy of Somatostatin and Brimonidine eye drops in a subpopulation of the PE with early microvascular effects, i.e. >1 MA at screening, was evaluated.

Subject analysis set title

MA>1 at screening subpopulation - Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subset of the Primary efficacy (PE) population with more than 1 microaneurysm (MA) at screening treated with Placebo.

Subject analysis set title

MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subset of the Primary efficacy (PE) population with more than 1 microaneurysm (MA) at screening treated with Brimonidine tartrate 0.2%.

Primary: A.1. Change in total number of abnormal hexagons with respect to Implicit Time (IT): success (no increase) versus failure (increase)

Top of page

End point title

A.1. Change in total number of abnormal hexagons with respect to Implicit Time (IT): success (no increase) versus failure (increase)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Implicit Time values from healthy volunteers.

End point type

Primary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[1]	123 ^[2]	96 ^[3]
Units: Subjects
Success	55	69	47
Failure	65	54	49

Notes
[1] - Primary efficacy (PE) population with data at 24 months
[2] - Primary efficacy (PE) population with data at 24 months
[3] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Statistical analysis description

Chi-square test was performed to analyse the rate of success in the primary efficacy endpoint between Somatostatin and Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Statistical analysis description

Chi-square test was performed to analyse the rate of success in the primary efficacy endpoint between Brimonidine and Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.294

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.1. Change in total number of abnormal hexagons with respect to Amplitude: success (no increase) versus failure (increase)

Top of page

End point title

A.1.1. Change in total number of abnormal hexagons with respect to Amplitude: success (no increase) versus failure (increase)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Amplitude values from healthy volunteers.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[4]	123 ^[5]	96 ^[6]
Units: Subjects
Success	69	67	61
Failure	51	56	35

Notes
[4] - Primary efficacy (PE) population with data at 24 months
[5] - Primary efficacy (PE) population with data at 24 months
[6] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.634

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.177

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.2. Primary efficacy related endpoint 1 (Prevention) - Implicit Time (IT)

Top of page

End point title

A.1.2. Primary efficacy related endpoint 1 (Prevention) - Implicit Time (IT)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference IT values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 1 was assessed on a subset of patients that were identified as normal with respect to IT at Baseline (less than 6 abnormal hexagons). "Prevention" was defined as follows: an eye remained normal with respect to IT at 24 months. "No prevention" was defined as follows: a normal eye turned to be abnormal with respect to IT at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	79 ^[7]	84 ^[8]	57 ^[9]
Units: Subjects
Prevention	54	66	38
No prevention	25	18	19

Notes
[7] - Subset of the PE identified as normal with respect to IT at Baseline
[8] - Subset of the PE identified as normal with respect to IT at Baseline
[9] - Subset of the PE identified as normal with respect to IT at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

163

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.157

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.124

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.3. Primary efficacy related endpoint 1 (Prevention) - Amplitude

Top of page

End point title

A.1.3. Primary efficacy related endpoint 1 (Prevention) - Amplitude

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Amplitude values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 1 was assessed on a subset of patients that were identified as normal with respect to Amplitude at Baseline (less than 6 abnormal hexagons). "Prevention" was defined as follows: an eye remained normal with respect to Amplitude at 24 months. "No prevention" was defined as follows: a normal eye turned to be abnormal with respect to Amplitude at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	91 ^[10]	94 ^[11]	70 ^[12]
Units: Subjects
Prevention	78	81	63
No prevention	13	13	7

Notes
[10] - Subset of the PE identified as normal with respect to Amplitude at Baseline
[11] - Subset of the PE identified as normal with respect to Amplitude at Baseline
[12] - Subset of the PE identified as normal with respect to Amplitude at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

164

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.63

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.4. Primary efficacy related endpoint 2 (Progression arrest) - Implicit Time (IT)

Top of page

End point title

A.1.4. Primary efficacy related endpoint 2 (Progression arrest) - Implicit Time (IT)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference IT values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 2 was assessed on a subset of patients that were identified as abnormal with respect to IT at Baseline (6 or more abnormal hexagons). "No Progression" was defined as follows: the number of abnormal hexagons with respect to IT at 24 months did not increase compared to Baseline. "Progression" was defined as follows: number of abnormal hexagons with respect to IT at 24 months increased compared to Baseline.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	41 ^[13]	39 ^[14]	39 ^[15]
Units: Subjects
No progression	21	19	25
Progression	20	20	14

Notes
[13] - Subset of the PE identified as abnormal with respect to IT at Baseline
[14] - Subset of the PE identified as abnormal with respect to IT at Baseline
[15] - Subset of the PE identified as abnormal with respect to IT at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Placebo v Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.253

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.5. Primary efficacy related endpoint 2 (Progression arrest) - Amplitude

Top of page

End point title

A.1.5. Primary efficacy related endpoint 2 (Progression arrest) - Amplitude

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Amplitude values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 2 was assessed on a subset of patients that were identified as abnormal with respect to Amplitude at Baseline (6 or more abnormal hexagons). "Progression arrest" was defined as follows: the number of abnormal hexagons with respect to Amplitude at 24 months did not increase compared to Baseline. "Progression" was defined as follows: number of abnormal hexagons with respect to Amplitude at 24 months increased compared to Baseline.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	29 ^[16]	29 ^[17]	26 ^[18]
Units: Subjects
No progression	19	21	18
Progression	10	8	8

Notes
[16] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline
[17] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline
[18] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.777

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.6. Primary efficacy related endpoint 3 (Regression) - Implicit Time (IT)

Top of page

End point title

A.1.6. Primary efficacy related endpoint 3 (Regression) - Implicit Time (IT)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference IT values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 3 was assessed on a subset of patients that were identified as abnormal with respect to IT at Baseline (6 or more abnormal hexagons). "Regression" was defined as follows: a subject turned to be normal at 24 months. "No regression" was defined as follows: a subject remained to be abnormal at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	41 ^[19]	39 ^[20]	39 ^[21]
Units: Subjects
Regression	13	9	15
No regression	28	30	24

Notes
[19] - Subset of the PE identified as abnormal with respect to IT at Baseline
[20] - Subset of the PE identified as abnormal with respect to IT at Baseline
[21] - Subset of the PE identified as abnormal with respect to IT at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.457

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.22

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.7. Primary efficacy related endpoint 3 (Regression) - Amplitude

Top of page

End point title

A.1.7. Primary efficacy related endpoint 3 (Regression) - Amplitude

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Amplitude values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 3 was assessed on a subset of patients that were identified as abnormal with respect to Amplitude at Baseline (6 or more abnormal hexagons) at Baseline. "Regression" was defined as follows: a subject turned to be normal with respect to Amplitude at 24 months. "No regression" was defined as follows: a subject remained to be abnormal with respect to Amplitude at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	29 ^[22]	29 ^[23]	26 ^[24]
Units: Subjects
Regression	11	19	10
No regression	18	10	16

Notes
[22] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline
[23] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline
[24] - Subset of the PE identified as abnormal with respect to Amplitude at Baseline

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.065

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.06

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.8. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Implicit time (IT)

Top of page

End point title

A.1.8. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Implicit time (IT)

End point description

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[25]	123 ^[26]	96 ^[27]
Units: Change in number of abnormal hexagons
arithmetic mean (standard deviation)	2.2 ( 10.1 )	0.9 ( 8.9 )	1.2 ( 9.8 )

Notes
[25] - Primary efficacy (PE) population with data at 24 months
[26] - Primary efficacy (PE) population with data at 24 months
[27] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.347

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.819

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.9. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Amplitude

Top of page

End point title

A.1.9. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Amplitude

End point description

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[28]	123 ^[29]	96 ^[30]
Units: Change in number of abnormal hexagons
arithmetic mean (standard deviation)	1.3 ( 7.6 )	0.1 ( 8.1 )	-0.3 ( 7.0 )

Notes
[28] - Primary efficacy (PE) population with data at 24 months
[29] - Primary efficacy (PE) population with data at 24 months
[30] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.733

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.365

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.10. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Implicit Time (IT)

Top of page

End point title

A.1.10. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Implicit Time (IT)

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference IT values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 5 was defined to test prevention in normal subjects together with progression arrest in abnormal subjects. "Success" was defined as follows: subject was Normal at Baseline and remained Normal at 24 months or subject was Abnormal at Baseline and the number of abnormal hexagons decreased or remain unchanged at 24 months. "Failure" was defined as follows: subject was Normal at Baseline and became Abnormal at 24 months or subject was Abnormal at Baseline and the number of abnormal hexagons increased at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[31]	123 ^[32]	96 ^[33]
Units: Subjects
Success	75	85	63
Failure	45	38	33

Notes
[31] - Primary efficacy (PE) population with data at 24 months
[32] - Primary efficacy (PE) population with data at 24 months
[33] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Placebo v Somatostatin 0.1%

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.278

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.585

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.1.11. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Amplitude

Top of page

End point title

A.1.11. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Amplitude

End point description

For mfERG analysis, the study eye was divided into 103 hexagons and each hexagon was classified as normal or abnormal based on reference Amplitude values from healthy volunteers. An eye was considered normal if less than 6 pathological hexagons were found, otherwise an eye was considered abnormal. Primary efficacy related endpoint 5 was defined to test prevention in normal subjects together with progression arrest in abnormal subjects. "Success" was defined as follows: subject was Normal at Baseline and remained Normal at 24 months or subject was Abnormal at Baseline and the number of abnormal hexagons decreased or remain unchanged at 24 months. "Failure" was defined as follows: subject was Normal at Baseline and became Abnormal at 24 months or subject was Abnormal at Baseline and the number of abnormal hexagons increased at 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	120 ^[34]	123 ^[35]	96 ^[36]
Units: Subjects
Success	97	102	81
Failure	23	21	15

Notes
[34] - Primary efficacy (PE) population with data at 24 months
[35] - Primary efficacy (PE) population with data at 24 months
[36] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.672

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.774

Method

Chi-squared

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.2. CFP 30º/35º eye progression assessed by ETDRS

Top of page

End point title

A.2. CFP 30º/35º eye progression assessed by ETDRS

End point description

"Eye progression" was defined as follows: ETDRS at 24 months increased by at least two steps (on classification) as compared to screening. Otherwise "No eye progression" was defined as follows: ETDRS at 24 months decreased as compared to screening, did not change or increased by one step.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	119 ^[37]	123 ^[38]	96 ^[39]
Units: Subjects
Eye progression	4	6	6
No eye progression	115	117	90

Notes
[37] - Primary efficacy (PE) population with data at 24 months
[38] - Primary efficacy (PE) population with data at 24 months
[39] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Somatostatin v Placebo

Comparison groups

Placebo v Somatostatin 0.1%

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.749

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Brimonidine v Placebo

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.768

Method

Fisher exact

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: A.3. Best Corrected Visual Acuity (BCVA) score

Top of page

End point title

A.3. Best Corrected Visual Acuity (BCVA) score

End point description

Best Corrected Visual Acuity (BCVA) was mesured according to the ETDRS protocol and is presented as descriptive statistics.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	135 ^[40]	136 ^[41]	139 ^[42]
Units: score
arithmetic mean (standard deviation)
BCVA score (Baseline)	86.0 ( 5.0 )	86.2 ( 4.9 )	86.2 ( 5.3 )
BCVA score (24 months)	86.2 ( 5.5 )	86.7 ( 4.4 )	85.7 ( 6.1 )

Notes
[40] - Primary efficacy (PE) population: 135 (Baseline); 120 (24 months)
[41] - Primary efficacy (PE) population: 136 (Baseline); 124 (24 months)
[42] - Primary efficacy (PE) population: 139 (Baseline); 97 (24 months)

No statistical analyses for this end point

Secondary: A.4. Visual field test

Top of page

End point title

A.4. Visual field test

End point description

Visual Fields defects assessed by Visual Fields Test. Descriptive statistics for global mean deviation and pattern mean deviation are presented.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	133 ^[43]	134 ^[44]	139 ^[45]
Units: dB
arithmetic mean (standard deviation)
Global mean deviation (Baseline)	-1.36 ( 2.25 )	-1.43 ( 3.31 )	-1.41 ( 3.58 )
Global mean deviation (24 months)	-1.30 ( 2.60 )	-1.22 ( 3.06 )	-1.63 ( 3.00 )
Pattern deviation (Baseline)	2.10 ( 1.30 )	2.07 ( 1.45 )	2.18 ( 1.64 )
Pattern deviation (24 months)	2.08 ( 1.30 )	1.82 ( 1.12 )	2.38 ( 1.60 )

Notes
[43] - Primary efficacy (PE) population: 133 (Baseline); 120 (24 months)
[44] - Primary efficacy (PE) population: 134 (Baseline); 122 (24 months)
[45] - Primary efficacy (PE) population: 139 (Baseline); 97 (24 months)

No statistical analyses for this end point

Secondary: A.5. Visual Function Questionnaire (VFQ-25)

Top of page

End point title

A.5. Visual Function Questionnaire (VFQ-25)

End point description

Overall composite score for the Visual Function Questionnaire (VFQ-25) is presented as descriptive statistics. Overall composite score is defined as mean of each sub-scale item excluding question on general health.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	103 ^[46]	106 ^[47]	105 ^[48]
Units: score
arithmetic mean (standard deviation)
Overall composite score (Baseline)	92.91 ( 5.89 )	92.49 ( 5.70 )	90.72 ( 7.67 )
Overall composite score (24 months)	92.87 ( 7.25 )	92.80 ( 5.64 )	91.48 ( 6.91 )

Notes
[46] - Primary efficacy (PE) population: 103 (Baseline); 92 (24 months)
[47] - Primary efficacy (PE) population: 106 (Baseline); 90 (24 months)
[48] - Primary efficacy (PE) population: 105 (Baseline); 70 (24 months)

No statistical analyses for this end point

Secondary: B.1. Mean Microaneurysm (MA) number. PE population

Top of page

End point title

B.1. Mean Microaneurysm (MA) number. PE population

End point description

Number of microaneurysms (mean) at screening and 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	119 ^[49]	122 ^[50]	96 ^[51]
Units: Number of microaneurysms
arithmetic mean (standard deviation)
MA number screening	0.9 ( 1.9 )	0.8 ( 1.0 )	0.8 ( 1.4 )
MA number 24 months	1.0 ( 1.6 )	1.1 ( 1.8 )	1.2 ( 2.0 )

Notes
[49] - Primary efficacy (PE) population with data at 24 months
[50] - Primary efficacy (PE) population with data at 24 months
[51] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_MA number_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.4079 (Somatostatin). Arrest in the appearance of microaneurysms. P-value=0.0608 (Placebo). Almost statistically significant increase in the number of microaneurysms. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare number of MAs at 24 months between treatments has been performed:

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

241

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.8178

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_MA number_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.0158* (Brimonidine). Statistically significant increase in the number of microaneurysms. P-value=0.0608 (Placebo). Almost statistically significant increase in the number of microaneurysms. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare number of MAs at 24 months between treatments has been performed:

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

218

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.8519

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.1.1. Mean Microaneurysm (MA) number. MA>1 at screening subpopulation

Top of page

End point title

B.1.1. Mean Microaneurysm (MA) number. MA>1 at screening subpopulation

End point description

Number of microaneurysms (mean) at screening and 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[52]	21 ^[53]	14 ^[54]
Units: number of MA
arithmetic mean (standard deviation)
MA number screening	3.8 ( 2.9 )	2.7 ( 0.9 )	3.6 ( 1.7 )
MA number 24 months	2.3 ( 2.2 )	2.2 ( 3.1 )	3.1 ( 3.6 )

Notes
[52] - Subset of PE with more than 1 microaneurysm (MA) at screening
[53] - Subset of PE with more than 1 microaneurysm (MA) at screening
[54] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1_MA number_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.0089* (Somatostatin). Statistically significant reduction in the number of microaneurysms. P-value=0.1630 (Placebo). Not statistically significant. Number of microaneurysms was not reduced. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare number of MAs at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Somatostatin 0.1% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4252

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_MA number_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.5852 (Brimonidine). Not statistically significant. P-value=0.1630 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare number of MAs at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Brimonidine tartrate 0.2% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4919

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.1.2. Mean Microaneurysm (MA) formation rate. PE population

Top of page

End point title

B.1.2. Mean Microaneurysm (MA) formation rate. PE population

End point description

Mean Microaneurysm formation rate (new MA/year) at 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	118 ^[55]	122 ^[56]	96 ^[57]
Units: new MA/year
arithmetic mean (standard deviation)
arithmetic mean (standard deviation)	0.22 ( 0.47 )	0.31 ( 0.69 )	0.27 ( 0.52 )

Notes
[55] - Primary efficacy (PE) population with data at 24 months
[56] - Primary efficacy (PE) population with data at 24 months
[57] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

240

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.3743

Method

Wilcoxon (Mann-Whitney)

Confidence interval

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

218

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.7956

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.1.3. Mean Microaneurysm (MA) formation rate. MA>1 at screening subpopulation

Top of page

End point title

B.1.3. Mean Microaneurysm (MA) formation rate. MA>1 at screening subpopulation

End point description

Microaneurysm formation rate (new MA/year) at 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[58]	21 ^[59]	14 ^[60]
Units: new MA/year
arithmetic mean (standard deviation)
arithmetic mean (standard deviation)	0.23 ( 0.39 )	0.51 ( 1.17 )	0.67 ( 0.86 )

Notes
[58] - Subset of PE with more than 1 microaneurysm (MA) at screening
[59] - Subset of PE with more than 1 microaneurysm (MA) at screening
[60] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1

Comparison groups

MA>1 at screening subpopulation - Somatostatin 0.1% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4413

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.3622

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.1.4. Mean Microaneurysm (MA) disappearance rate. PE population

Top of page

End point title

B.1.4. Mean Microaneurysm (MA) disappearance rate. PE population

End point description

Mean microaneurysm disappearance rate (disappeared MA/year) at 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	118 ^[61]	122 ^[62]	96 ^[63]
Units: Disappeared MA/year
arithmetic mean (standard deviation)
arithmetic mean (standard deviation)	0.29 ( 0.68 )	0.23 ( 0.42 )	0.20 ( 0.40 )

Notes
[61] - Primary efficacy (PE) population with data at 24 months
[62] - Primary efficacy (PE) population with data at 24 months
[63] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

240

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.7513

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

218

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4631

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.1.5. Mean Microaneurysm (MA) disappearance rate. MA>1 at screening subpopulation

Top of page

End point title

B.1.5. Mean Microaneurysm (MA) disappearance rate. MA>1 at screening subpopulation

End point description

Mean microaneurysm disappearance rate (disappeared MA/year) at 24 months.

End point type

Secondary

End point timeframe

Screening and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[64]	21 ^[65]	14 ^[66]
Units: Disappeared MA/year
arithmetic mean (standard deviation)
arithmetic mean (standard deviation)	1.17 ( 1.15 )	0.89 ( 0.56 )	0.90 ( 0.59 )

Notes
[64] - Subset of PE with more than 1 microaneurysm (MA) at screening
[65] - Subset of PE with more than 1 microaneurysm (MA) at screening
[66] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.8151

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.7253

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.2. Mean Implicit Time (IT) (ms). MA>1 at screening subpopulation

Top of page

End point title

B.2. Mean Implicit Time (IT) (ms). MA>1 at screening subpopulation

End point description

Mean Implicit Time (ms) at baseline and 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[67]	21 ^[68]	14 ^[69]
Units: ms
arithmetic mean (standard deviation)
IT (mean +-SD) Baseline	35.0 ( 1.6 )	35.3 ( 1.1 )	34.8 ( 1.2 )
IT (mean+- SD) 24 months	35.1 ( 1.8 )	35.2 ( 1.6 )	34.8 ( 1.4 )

Notes
[67] - Subset of PE with more than 1 microaneurysm (MA) at screening
[68] - Subset of PE with more than 1 microaneurysm (MA) at screening
[69] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1_IT_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.5642 (Somatostatin). Not statistically significant. P-value=0.6902 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare mean IT values at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Somatostatin 0.1% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.831

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_IT_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired Wilcoxon test afforded: P-value=0.5313 (Brimonidine). Not statistically significant. P-value=0.6902 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare mean IT values at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4452

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.3. Mean Amplitude (nV/deg2). MA>1 at screening subpopulation

Top of page

End point title

B.3. Mean Amplitude (nV/deg2). MA>1 at screening subpopulation

End point description

Mean Amplitude (nV/deg2) at baseline and 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[70]	21 ^[71]	14 ^[72]
Units: nV/deg2
arithmetic mean (standard deviation)
Amplitude (mean +- SD) Baseline	17.2 ( 6.0 )	18.8 ( 6.2 )	20.1 ( 5.1 )
Amplitude (mean +- SD) 24 months	20.0 ( 7.4 )	19.1 ( 5.4 )	18.9 ( 6.0 )

Notes
[70] - Subset of PE with more than 1 microaneurysm (MA) at screening
[71] - Subset of PE with more than 1 microaneurysm (MA) at screening
[72] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1_Amplitude_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.0203* (Somatostatin). Statistically significant increase (improvement) of Amplitude. P-value=0.8178 (Placebo). Not statistically significant increase of Amplitude. INTERGROUP ANALYSIS. Unpaired t-test to compare mean Amplitude values at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Somatostatin 0.1% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.6484

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_Amplitude_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.4079 (Brimonidine). Not statistically significant. P-value=0.8178 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare mean Amplitude values at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.9095

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.4. Mean Retinal thickness (RT). MA>1 at screening subpopulation

Top of page

End point title

B.4. Mean Retinal thickness (RT). MA>1 at screening subpopulation

End point description

Mean Retinal thickness at Central Subfield (CSF), Inner Ring (IR) and Outer Ring (OR) at baseline and 24 months.

End point type

Secondary

End point timeframe

Baseline and 24 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	23 ^[73]	21 ^[74]	14 ^[75]
Units: micra
arithmetic mean (standard deviation)
Mean CSF thickness (Baseline)	269.3 ( 32.0 )	261.2 ( 19.3 )	259.6 ( 26.2 )
Mean CSF thickness (24 months)	270.8 ( 34.8 )	260.8 ( 20.5 )	256.2 ( 24.7 )
Mean IR thickness (Baseline)	323.1 ( 24.8 )	317.7 ( 18.4 )	328.3 ( 17.4 )
Mean IR thickness (24 months)	322.6 ( 25.9 )	315.8 ( 19.0 )	325.8 ( 15.7 )
Mean OR thickness (Baseline)	278.8 ( 22.9 )	276.4 ( 14.3 )	284.9 ( 18.1 )
Mean OR thickness (24 months)	278.2 ( 23.1 )	274.4 ( 13.8 )	283.5 ( 17.1 )

Notes
[73] - Subset of PE with more than 1 microaneurysm (MA) at screening
[74] - Subset of PE with more than 1 microaneurysm (MA) at screening
[75] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1_CSF thickness_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test test afforded: P-value=0.2773 (Somatostatin). Not statistically significant. P-value=0.8060 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare Mean CSF Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.3202

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2_CSF thickness_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.0601 (Brimonidine). Not statistically significant. P-value=0.8060 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare Mean CSF Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.551

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3_IR thickness_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.6295 (Somatostatin). Not statistically significant. Somatostatin arrested the thinning of the inner ring (IR) of the retina. P-value=0.0477* (Placebo). Statistically significant thinning of the inner ring (IR) of the retina. INTERGROUP ANALYSIS. Unpaired t-test to compare Mean IR Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.3316

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 4_IR thickness_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.0587 (Brimonidine). Almost significant thinning of the inner ring (IR) of the retina. P-value=0.0477* (Placebo). Statistically significant thinning of the inner ring (IR) of the retina. INTERGROUP ANALYSIS. unpaired t-test to compare Mean IR Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.1124

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 5_OR thickness_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.5189 (Somatostatin). Not statistically significant. Somatostatin arrested the thinning of the outer ring (OR) of the retina. P-value=0.0349* (Placebo). Statistically significant thinning of the outer ring (OR) of the retina. INTERGROUP ANALYSIS. Unpaired t-test to compare Mean OR Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.519

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 6_OR thickness_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (baseline) and final (24 months) values by using a paired t-test afforded: P-value=0.1337 (Brimonidine). Not statistically significant. P-value=0.0349* (Placebo). Statistically significant thinning of the outer ring (OR) of the retina. INTERGROUP ANALYSIS. Unpaired t-test to compare mean OR Retinal Thickness at 24 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0932

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.5. Blood biomarkers: Laminin, ADMA and CML. PE population

Top of page

End point title

B.5. Blood biomarkers: Laminin, ADMA and CML. PE population

End point description

Blood levels of Laminin, ADMA (Asymmetric Dimethylarginine) and CML (N-carboxymethyl-lysine) (3 biomarkers associated with Diabetic Retinopathy) at screening and 12 months.

End point type

Secondary

End point timeframe

Screening and 12 months

End point values	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Number of subjects analysed	108 ^[76]	118 ^[77]	90 ^[78]
Units: ng/mL
arithmetic mean (standard deviation)
Laminin concentration (screening)	423.1 ( 399.6 )	492.9 ( 534.4 )	467.1 ( 383.9 )
Laminin concentration (12 months)	398.2 ( 408.1 )	474.2 ( 481.9 )	488.4 ( 507.6 )
ADMA concentration (screening)	103.8 ( 59.8 )	94.6 ( 53.2 )	98.8 ( 67.8 )
ADMA concentration (12 months)	103.5 ( 61.9 )	113.1 ( 70.5 )	107.9 ( 69.6 )
CML concentration (Screening)	276.8 ( 154.0 )	277.6 ( 183.8 )	262.8 ( 160.4 )
CML concentration (12 months)	265.6 ( 150.5 )	295.7 ( 206.2 )	287.3 ( 170.0 )

Notes
[76] - Primary efficacy (PE) population with data at 24 months
[77] - Primary efficacy (PE) population with data at 24 months
[78] - Primary efficacy (PE) population with data at 24 months

Statistical analysis 1_Laminin_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired Wilcoxon test afforded: P-value=0.1757 (Somatostatin). Not statistically significant. P-value=0.2816 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare Laminin values at 12 months between treatments has been performed:

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

226

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2113

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2 _Laminin_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired Wilcoxon test afforded: P-value=0.9873 (Brimonidine). Not statistically significant. P-value=0.2816 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare Laminin values at 12 months between treatments has been performed:

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

208

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.8209

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3 _ADMA_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.9715 (Somatostatin). Not statistically significant. Somatostatin-treated patients did not show an increase of ADMA levels. P-value=0.0082* (Placebo). Statistically significant increase of ADMA Levels (Diabetic Retinopathy progression). INTERGROUP ANALYSIS. Unpaired t-test to compare ADMA values at 12 months between treatments has been performed:

Comparison groups

Somatostatin 0.1% v Placebo

Number of subjects included in analysis

226

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2799

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 4 _ADMA_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.1807 (Brimonidine). Not statistically significant. P-value=0.0082* (Placebo). Statistically significant increase of ADMA levels (Diabetic Retinopathy progression) INTERGROUP ANALYSIS. Unpaired t-test to compare ADMA values at 12 months between treatments has been performed:

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

208

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.5951

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 5 _CML_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.4103 (Somatostatin). Not statistically significant. P-value=0.2192 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare CML values at 12 months between treatments has been performed:

Comparison groups

Placebo v Somatostatin 0.1%

Number of subjects included in analysis

226

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2155

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 6_CML_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.1265 (Brimonidine). Not statistically significant. P-value=0.2192 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare CML values at 12 months between treatments has been performed:

Comparison groups

Placebo v Brimonidine tartrate 0.2%

Number of subjects included in analysis

208

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.756

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: B.5.1. Blood biomarkers: Laminin, ADMA and CML. MA>1 at screening subpopulation

Top of page

End point title

B.5.1. Blood biomarkers: Laminin, ADMA and CML. MA>1 at screening subpopulation

End point description

Blood levels of Laminin, ADMA (Asymmetric Dimethylarginine) and CML (N-carboxymethyl-lysine) (3 biomarkers associated with Diabetic Retinopathy) at screening and 12 months.

End point type

Secondary

End point timeframe

Screening and 12 months

End point values	MA>1 at screening subpopulation - Somatostatin 0.1%	MA>1 at screening subpopulation - Placebo	MA>1 at screening subpopulation - Brimonidine tartrate 0.2%
Number of subjects analysed	19 ^[79]	21 ^[80]	14 ^[81]
Units: ng/mL
arithmetic mean (standard deviation)
Laminin concentration (screening)	461.2 ( 381.3 )	649.9 ( 667.4 )	449.2 ( 383.2 )
Laminin concentration (12 months)	382.3 ( 390.3 )	679.6 ( 591.2 )	562.6 ( 660.1 )
ADMA concentration (screening)	114.6 ( 63.0 )	73.4 ( 34.0 )	106.6 ( 74.2 )
ADMA concentration (12 months)	116.0 ( 61.4 )	96.3 ( 57.2 )	114.4 ( 70.4 )
CML concentration (Screening)	287.9 ( 110.5 )	262.5 ( 155.4 )	338.6 ( 196.2 )
CML concentration (12 months)	277.4 ( 128.9 )	251.7 ( 162.0 )	346.5 ( 244.9 )

Notes
[79] - Subset of PE with more than 1 microaneurysm (MA) at screening
[80] - Subset of PE with more than 1 microaneurysm (MA) at screening
[81] - Subset of PE with more than 1 microaneurysm (MA) at screening

Statistical analysis 1_Laminin_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired Wilcoxon test afforded: P-value=0.2935 (Somatostatin). Not statistically significant. P-value=0.3339 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare Laminin values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Somatostatin 0.1% v MA>1 at screening subpopulation - Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0551 ^[82]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[82] - Laminin levels of Somatostatin-treated patients were almost significantly lower than Laminin levels of placebo-treated patients at 12 months, indicating an arrest of Diabetic Retinopathy progression in Somatostatin group.

Statistical analysis 2_Laminin_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired Wilcoxon test afforded: P-value=0.7148 (Brimonidine). Not statistically significant. P-value=0.3339 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired Wilcoxon test to compare Laminin values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2153

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3_ADMA_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.9208 (Somatostatin). Not statistically significant. Somatostatin-treated patients did not show an increase of ADMA levels. P-value=0.0176* (Placebo). Statistically significant increase of ADMA levels (Diabetic Retinopathy progression). INTERGROUP ANALYSIS. Unpaired t-test to compare ADMA values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2986

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 4_ADMA_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.4803 (Brimonidine). Not statistically significant. P-value=0.0176* (Placebo). Statistically significant increase of ADMA levels (Diabetic Retinopathy progression). INTERGROUP ANALYSIS. Unpaired t-test to compare ADMA values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.409

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 5_CML_Somatostatin

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.5705 (Somatostatin). Not statistically significant. P-value=0.6848 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare CML values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Somatostatin 0.1%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.584

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 6_CML_Brimonidine

Statistical analysis description

INTRAGROUP ANALYSIS between initial (screening) and final (12 months) values by using a paired t-test afforded: P-value=0.9023 (Brimonidine). Not statistically significant. P-value=0.6848 (Placebo). Not statistically significant. INTERGROUP ANALYSIS. Unpaired t-test to compare CML values at 12 months between treatments has been performed:

Comparison groups

MA>1 at screening subpopulation - Placebo v MA>1 at screening subpopulation - Brimonidine tartrate 0.2%

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.1761

Method

t-test, 2-sided

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse Events (AEs) were reported from baseline visit to end of study visit (24 months).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Somatostatin 0.1%

Reporting group description

Patients received Somatostatin 0.1% as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening.

Reporting group title

Placebo

Reporting group description

Patients received Placebo as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening.

Reporting group title

Brimonidine tartrate 0.2%

Reporting group description

Patients received Brimonidine tartrate 0.2% as eye drops, 1 drop in each eye twice a day; once in the morning and once in the evening

Serious adverse events	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 145 (8.28%)	23 / 152 (15.13%)	21 / 152 (13.82%)
number of deaths (all causes)	0	2	1
number of deaths resulting from adverse events	0	2	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	2 / 152 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma stage I
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	0 / 145 (0.00%)	2 / 152 (1.32%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Breast operation
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac pacemaker insertion
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin neoplasm excision
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgery
Additional description: Planned spondylolistese operation.
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transurethral prostatectomy
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia repair
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Condition aggravated
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 145 (0.69%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Priapism
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diaphragmatic paralysis
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obliterative bronchiolitis
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 145 (0.00%)	2 / 152 (1.32%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 145 (0.69%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Atrioventricular block complete
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	2 / 145 (1.38%)	1 / 152 (0.66%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	2 / 152 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Basilar migraine
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radicular pain
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radiculitis
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Glaucoma
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ocular hyperaemia
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ischaemic
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis norovirus
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	0 / 152 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 145 (0.00%)	0 / 152 (0.00%)	1 / 152 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Somatostatin 0.1%	Placebo	Brimonidine tartrate 0.2%
Total subjects affected by non serious adverse events
subjects affected / exposed	107 / 145 (73.79%)	120 / 152 (78.95%)	133 / 152 (87.50%)
Investigations
Blood triglycerides increased
subjects affected / exposed	6 / 145 (4.14%)	9 / 152 (5.92%)	11 / 152 (7.24%)
occurrences all number	7	10	11
Nervous system disorders
Headache
subjects affected / exposed	3 / 145 (2.07%)	7 / 152 (4.61%)	6 / 152 (3.95%)
occurrences all number	3	7	6
Sciatica
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	7 / 152 (4.61%)
occurrences all number	0	1	7
Eye disorders
Anterior chamber disorder
subjects affected / exposed	10 / 145 (6.90%)	14 / 152 (9.21%)	8 / 152 (5.26%)
occurrences all number	10	14	8
Conjunctival follicles
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	15 / 152 (9.87%)
occurrences all number	1	0	16
Conjunctival hyperaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 152 (0.00%)	8 / 152 (5.26%)
occurrences all number	1	0	9
Conjunctivitis allergic
subjects affected / exposed	2 / 145 (1.38%)	1 / 152 (0.66%)	9 / 152 (5.92%)
occurrences all number	2	1	10
Dry eye
subjects affected / exposed	7 / 145 (4.83%)	9 / 152 (5.92%)	8 / 152 (5.26%)
occurrences all number	10	9	9
Eye discharge
subjects affected / exposed	9 / 145 (6.21%)	7 / 152 (4.61%)	3 / 152 (1.97%)
occurrences all number	12	8	3
Eye pain
subjects affected / exposed	16 / 145 (11.03%)	16 / 152 (10.53%)	32 / 152 (21.05%)
occurrences all number	18	21	41
Eye pruritus
subjects affected / exposed	11 / 145 (7.59%)	14 / 152 (9.21%)	13 / 152 (8.55%)
occurrences all number	12	14	14
Eyelid oedema
subjects affected / exposed	0 / 145 (0.00%)	1 / 152 (0.66%)	9 / 152 (5.92%)
occurrences all number	0	1	12
Foreign body sensation in eyes
subjects affected / exposed	6 / 145 (4.14%)	4 / 152 (2.63%)	12 / 152 (7.89%)
occurrences all number	6	7	17
Lacrimation increased
subjects affected / exposed	4 / 145 (2.76%)	6 / 152 (3.95%)	11 / 152 (7.24%)
occurrences all number	4	7	13
Ocular hyperaemia
subjects affected / exposed	12 / 145 (8.28%)	4 / 152 (2.63%)	33 / 152 (21.71%)
occurrences all number	14	4	49
Vision blurred
subjects affected / exposed	11 / 145 (7.59%)	1 / 152 (0.66%)	6 / 152 (3.95%)
occurrences all number	14	2	7
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 145 (4.83%)	7 / 152 (4.61%)	4 / 152 (2.63%)
occurrences all number	8	8	5
Back pain
subjects affected / exposed	12 / 145 (8.28%)	10 / 152 (6.58%)	9 / 152 (5.92%)
occurrences all number	14	11	9
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	8 / 145 (5.52%)	10 / 152 (6.58%)	5 / 152 (3.29%)
occurrences all number	8	11	5
Nasopharyngitis
subjects affected / exposed	26 / 145 (17.93%)	31 / 152 (20.39%)	24 / 152 (15.79%)
occurrences all number	38	49	30
Urinary tract infection
subjects affected / exposed	7 / 145 (4.83%)	4 / 152 (2.63%)	3 / 152 (1.97%)
occurrences all number	9	8	3

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

19 Jun 2012

Protocol Amendment 1 (only applicable to France). A description of how travel expenses incurred by patients were to be reimbursed.

24 Oct 2012

Protocol Amendment 2 (All Countries). Change of party responsible for clinical operations. Biochemistry and urine samples were to be analysed locally instead of in a central laboratory.

20 Feb 2013

Protocol Amendment 3 (All countries). As an alternative to albumin excretion rate, albumin/creatinine ratio could be used to evaluate diabetic nephropathy.

03 Sep 2013

Protocol amendment 4 (All countries). The permitted window for scheduled follow-up visits and the discharge/early termination visit was widened from ± 5 days to ± 14 days.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: Neurodegeneration as an early event in the pathogenesis of Diabetic Retinopathy: A multicentric, prospective, phase II-III, randomized controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest Diabetic Retinopathy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: A.1. Change in total number of abnormal hexagons with respect to Implicit Time (IT): success (no increase) versus failure (increase)

Primary: A.1. Change in total number of abnormal hexagons with respect to Implicit Time (IT): success (no increase) versus failure (increase)

Secondary: A.1.1. Change in total number of abnormal hexagons with respect to Amplitude: success (no increase) versus failure (increase)

Secondary: A.1.1. Change in total number of abnormal hexagons with respect to Amplitude: success (no increase) versus failure (increase)

Secondary: A.1.2. Primary efficacy related endpoint 1 (Prevention) - Implicit Time (IT)

Secondary: A.1.2. Primary efficacy related endpoint 1 (Prevention) - Implicit Time (IT)

Secondary: A.1.3. Primary efficacy related endpoint 1 (Prevention) - Amplitude

Secondary: A.1.3. Primary efficacy related endpoint 1 (Prevention) - Amplitude

Secondary: A.1.4. Primary efficacy related endpoint 2 (Progression arrest) - Implicit Time (IT)

Secondary: A.1.4. Primary efficacy related endpoint 2 (Progression arrest) - Implicit Time (IT)

Secondary: A.1.5. Primary efficacy related endpoint 2 (Progression arrest) - Amplitude

Secondary: A.1.5. Primary efficacy related endpoint 2 (Progression arrest) - Amplitude

Secondary: A.1.6. Primary efficacy related endpoint 3 (Regression) - Implicit Time (IT)

Secondary: A.1.6. Primary efficacy related endpoint 3 (Regression) - Implicit Time (IT)

Secondary: A.1.7. Primary efficacy related endpoint 3 (Regression) - Amplitude

Secondary: A.1.7. Primary efficacy related endpoint 3 (Regression) - Amplitude

Secondary: A.1.8. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Implicit time (IT)

Secondary: A.1.8. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Implicit time (IT)

Secondary: A.1.9. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Amplitude

Secondary: A.1.9. Primary efficacy related endpoint 4. Change in total number of abnormal hexagons (mean) - Amplitude

Secondary: A.1.10. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Implicit Time (IT)

Secondary: A.1.10. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Implicit Time (IT)

Secondary: A.1.11. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Amplitude

Secondary: A.1.11. Primary efficacy related endpoint 5 (Prevention and Progression Arrest) - Amplitude

Secondary: A.2. CFP 30º/35º eye progression assessed by ETDRS

Secondary: A.2. CFP 30º/35º eye progression assessed by ETDRS

Secondary: A.3. Best Corrected Visual Acuity (BCVA) score

Secondary: A.3. Best Corrected Visual Acuity (BCVA) score

Secondary: A.4. Visual field test

Secondary: A.4. Visual field test

Secondary: A.5. Visual Function Questionnaire (VFQ-25)

Secondary: A.5. Visual Function Questionnaire (VFQ-25)

Secondary: B.1. Mean Microaneurysm (MA) number. PE population

Secondary: B.1. Mean Microaneurysm (MA) number. PE population

Secondary: B.1.1. Mean Microaneurysm (MA) number. MA>1 at screening subpopulation

Secondary: B.1.1. Mean Microaneurysm (MA) number. MA>1 at screening subpopulation

Secondary: B.1.2. Mean Microaneurysm (MA) formation rate. PE population

Secondary: B.1.2. Mean Microaneurysm (MA) formation rate. PE population

Secondary: B.1.3. Mean Microaneurysm (MA) formation rate. MA>1 at screening subpopulation

Secondary: B.1.3. Mean Microaneurysm (MA) formation rate. MA>1 at screening subpopulation

Secondary: B.1.4. Mean Microaneurysm (MA) disappearance rate. PE population

Secondary: B.1.4. Mean Microaneurysm (MA) disappearance rate. PE population

Secondary: B.1.5. Mean Microaneurysm (MA) disappearance rate. MA>1 at screening subpopulation

Secondary: B.1.5. Mean Microaneurysm (MA) disappearance rate. MA>1 at screening subpopulation

Secondary: B.2. Mean Implicit Time (IT) (ms). MA>1 at screening subpopulation

Secondary: B.2. Mean Implicit Time (IT) (ms). MA>1 at screening subpopulation

Secondary: B.3. Mean Amplitude (nV/deg2). MA>1 at screening subpopulation

Secondary: B.3. Mean Amplitude (nV/deg2). MA>1 at screening subpopulation

Secondary: B.4. Mean Retinal thickness (RT). MA>1 at screening subpopulation

Secondary: B.4. Mean Retinal thickness (RT). MA>1 at screening subpopulation

Secondary: B.5. Blood biomarkers: Laminin, ADMA and CML. PE population

Secondary: B.5. Blood biomarkers: Laminin, ADMA and CML. PE population

Secondary: B.5.1. Blood biomarkers: Laminin, ADMA and CML. MA>1 at screening subpopulation

Secondary: B.5.1. Blood biomarkers: Laminin, ADMA and CML. MA>1 at screening subpopulation

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Neurodegeneration as an early event in the pathogenesis of Diabetic Retinopathy: A multicentric, prospective, phase II-III, randomized controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest Diabetic Retinopathy.