Clinical Trial Results:
Prospective, randomized, multicenter, open label phase II study to access efficacy and safety of Lucentis monotherapy (ranibizumab 0.5 mg intravitreal injections) compared with Lucentis plus panretinal photocoagulation (PRP) and PRP (monotherapy) in the treatment of patients with high risk proliferative diabetic retinopathy.

Trial information Top of page
Trial identification
Sponsor protocol code	CRFB002DPT04T
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01280929
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	AIBILI
Sponsor organisation address	Azinhaga de Santa Comba, Celas , Coimbra, Portugal, 3000-548
Public contact	President of Board of AIBILI and Coordinating Investigator, Prof. José Cunha Vaz, 351 239480131, lcarvalho@aibili.pt
Scientific contact	President of Board of AIBILI and Coordinating Investigator, Prof. José Cunha Vaz, 351 239480131, lcarvalho@aibili.pt
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	30 Oct 2015
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	02 Dec 2013
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The purpose of this trial is to evaluate safety and to compare the efficacy of intravitreous injection of ranibizumab alone (0.5 mg), versus combination of intravitreous injection of ranibizumab (0.5 mg) plus PRP, versus PRP alone in the regression of retinal neovascularization in eyes with high-risk PDR.
Protection of trial subjects	Informed consent was obtained from each subject in writing before any study procedures. The study was described by a study coordinator and/or investigator, who answered any questions, and written information was also provided. Samples of the written information were given to each subject.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	11 Nov 2010
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Portugal: 35
Worldwide total number of subjects	35
EEA total number of subjects	35
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	35
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The recruitment period was extended from November 2010 to November 2012 (2 years). Even though, only 35 patients were recruited from the 54 initially planned.
Pre-assignment
Screening details	Type I, or Type II diabetic subjects as defined by the WHO criteria of either, and aged ≥ 18 years. HR-PDR eyes. Best corrected Visual Acuity (BCVA) at screening > 20/320 (25 letters in the ETDRS Chart) in the study eye. Clear ocular media and adequate pupillary dilatation to permit good quality fundus photography. Intraocular pressure < 21 mmH
Pre-assignment period milestones
Number of subjects started	35
Number of subjects completed	35
Period 1
Period 1 title	baseline (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Single blind
Roles blinded	Subject
Arms
Are arms mutually exclusive	Yes
Arm title	Active Comparator: Panretinal Photocoagulation (PRP)
Arm description	Group 1: Panretinal photocoagulation treatment (PRP) at month-0 that can be repeated after month-3.
Arm type	Comparator - Surgical Procedure
Investigational medicinal product name	No investigational medicinal product assigned in this arm
Arm title	Experimental: Ranibizumab
Arm description	Group 2: Intravitreous injections of ranibizumab every 4 weeks at month-0, month-1 and month-2 that can be repeated after month-3.
Arm type	Experimental
Investigational medicinal product name	Ranibizumab
Investigational medicinal product code
Other name
Pharmaceutical forms	Dispersion for injection
Routes of administration	Intravitreal use
Dosage and administration details	Intravitreous injections of ranibizumab every 4 weeks at month-0, month-1 and month-2 that can be repeated after month-3.
Arm title	Experimental: Ranibizumab + Panretinal Photocoagulation (PRP)
Arm description	Group 3: Combination treatment of ranibizumab intravitreous injections plus PRP (2 weeks +/- 1 week after injection), at month-0, month-1 and month-2 that can be repeated after month-3.
Arm type	Combination
Investigational medicinal product name	Panretinal Photocoagulation (PRP) Drug: Intravitreous injection of ranibizumab
Investigational medicinal product code
Other name
Pharmaceutical forms	Injection
Routes of administration	Intravitreal use, Ocular use
Dosage and administration details	Combination treatment of ranibizumab intravitreous injections plus PRP (2 weeks +/- 1 week after injection), at month-0, month-1 and month-2 that can be repeated after month-3.
Number of subjects in period 1 Active Comparator: Panretinal Photocoagulation (PRP) Experimental: Ranibizumab Experimental: Ranibizumab + Panretinal Photocoagulation (PRP) Started 13 10 12 Completed 11 9 10 Not completed 2 1 2      Adverse event, non-fatal 2 1 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Active Comparator: Panretinal Photocoagulation (PRP)
Reporting group description	Group 1: Panretinal photocoagulation treatment (PRP) at month-0 that can be repeated after month-3.
Reporting group title	Experimental: Ranibizumab
Reporting group description	Group 2: Intravitreous injections of ranibizumab every 4 weeks at month-0, month-1 and month-2 that can be repeated after month-3.
Reporting group title	Experimental: Ranibizumab + Panretinal Photocoagulation (PRP)
Reporting group description	Group 3: Combination treatment of ranibizumab intravitreous injections plus PRP (2 weeks +/- 1 week after injection), at month-0, month-1 and month-2 that can be repeated after month-3.
Reporting group values Active Comparator: Panretinal Photocoagulation (PRP) Experimental: Ranibizumab Experimental: Ranibizumab + Panretinal Photocoagulation (PRP) Total Number of subjects 13 10 12 35 Age categorical Age over 18 Units: Subjects     Adults age over 18 13 10 12 35 Age continuous Age at screening Units: years     arithmetic mean (standard deviation) 52.7 ( 13.6 ) 59.9 ( 6.2 ) 55.1 ( 10.6 ) - Gender categorical Units: Subjects     Female 3 4 2 9     Male 10 6 10 26
Subject analysis sets
Subject analysis set title	ITT population
Subject analysis set type	Intention-to-treat
Subject analysis set description	All patients included in the study were used for the Intent to Treat (ITT) population analysis.
Subject analysis set title	PP population
Subject analysis set type	Per protocol
Subject analysis set description	All patients which concluded the study were used for Per Protocol (PP) population analysis.
Subject analysis set title	Safety Population
Subject analysis set type	Safety analysis
Subject analysis set description	All patients with at least 1 evaluation.
Subject analysis sets values ITT population PP population Safety Population Number of subjects 35 30 35 Age categorical Age over 18 Units: Subjects     Adults age over 18 35 30 35 Age continuous Age at screening Units: years     arithmetic mean (standard deviation) 55.6 ( 11.3 ) 54.8 ( 11.7 ) 55.6 ( 11.3 ) Gender categorical Units: Subjects     Female 9 9 9     Male 26 21 26

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Active Comparator: Panretinal Photocoagulation (PRP)
Reporting group description	Group 1: Panretinal photocoagulation treatment (PRP) at month-0 that can be repeated after month-3.
Reporting group title	Experimental: Ranibizumab
Reporting group description	Group 2: Intravitreous injections of ranibizumab every 4 weeks at month-0, month-1 and month-2 that can be repeated after month-3.
Reporting group title	Experimental: Ranibizumab + Panretinal Photocoagulation (PRP)
Reporting group description	Group 3: Combination treatment of ranibizumab intravitreous injections plus PRP (2 weeks +/- 1 week after injection), at month-0, month-1 and month-2 that can be repeated after month-3.
Subject analysis set title	ITT population
Subject analysis set type	Intention-to-treat
Subject analysis set description	All patients included in the study were used for the Intent to Treat (ITT) population analysis.
Subject analysis set title	PP population
Subject analysis set type	Per protocol
Subject analysis set description	All patients which concluded the study were used for Per Protocol (PP) population analysis.
Subject analysis set title	Safety Population
Subject analysis set type	Safety analysis
Subject analysis set description	All patients with at least 1 evaluation.

End points Top of page

Primary: Regression of NV Top of page
End point title	Regression of NV
End point description	Regression of NV from screening to the 12 months visit (primary endpoint), was measured by an independent reading center in disc area (DA) units (decimal DA units), based on CFP (retinography) and FA. Regression of NV was defined as any decrease in the area of NV.
End point type	Primary
End point timeframe	From screening to 12-months visit
End point values Active Comparator: Panretinal Photocoagulation (PRP) Experimental: Ranibizumab Experimental: Ranibizumab + Panretinal Photocoagulation (PRP) ITT population PP population Number of subjects analysed 13 9 10 35 30 Units: number     Without Regression 5 3 0 8 6     With Regression 8 6 10 24 24
Statistical analysis title	Primary Objective
Statistical analysis description	The hypothesis was tested using the Exact Fisher test with a statistical adjustment for multiple between-treatment comparisons (i.e., PRP vs. Ranibizumab and Ranibizumab+PRP). An alpha level of 0.05 was considered (corrected to 0.016 for the 3 groups under analysis).
Comparison groups	Active Comparator: Panretinal Photocoagulation (PRP) v Experimental: Ranibizumab v Experimental: Ranibizumab + Panretinal Photocoagulation (PRP)
Number of subjects included in analysis	32
Analysis specification	Pre-specified
Analysis type	superiority [1]
P-value	= 0.075
Method	Fisher exact
Parameter type	proportion
Point estimate	0.6
Confidence interval
level	90%
sides	2-sided
lower limit	0.5
upper limit	0.7
Notes [1] - The primary objective of this study was to demonstrate superiority of one of the treatment groups: ranibizumab 0.5 mg monotherapy, PRP monotherapy or combination therapy (ranibizumab 0.5 mg plus PRP) over a 12-month treatment period in the following: 1. Regression of NV.

Primary: Regression of NV Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From Screening up to 24-months (12-months of study follow-up plus 12-months post-study).
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	18.0
Reporting groups
Reporting group title	Safety Population
Reporting group description	Safety population safety reporting
Reporting group title	Group 1
Reporting group description	Safety reporting for Group 1
Reporting group title	Group 2
Reporting group description	Safety reporting for Group 2
Reporting group title	Group 3
Reporting group description	Safety reporting for Group 3
Serious adverse events Safety Population Group 1 Group 2 Group 3 Total subjects affected by serious adverse events      subjects affected / exposed 4 / 35 (11.43%) 0 / 13 (0.00%) 2 / 10 (20.00%) 2 / 12 (16.67%)      number of deaths (all causes) 0 0 0 0      number of deaths resulting from adverse events 0 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign neoplasm of adrenal gland      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac disorders Angina unstable      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 1 / 10 (10.00%) 0 / 12 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Benign prostatic hyperplasia      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Erysipelas      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 3%
Non-serious adverse events Safety Population Group 1 Group 2 Group 3 Total subjects affected by non serious adverse events      subjects affected / exposed 20 / 35 (57.14%) 8 / 13 (61.54%) 3 / 10 (30.00%) 7 / 12 (58.33%) Vascular disorders Hypertension      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Cardiac disorders Cardiac valve disease      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Ischaemic cardiomyopathy      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Surgical and medical procedures Vitrectomy      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 1 / 10 (10.00%) 0 / 12 (0.00%)      occurrences all number 1 0 1 0 Ear and labyrinth disorders Preauricular cyst      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Eye disorders Conjunctivitis      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Diabetic retinopathy      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Eye pain      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Ocular hypertension      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Retinal detachment      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 1 / 10 (10.00%) 0 / 12 (0.00%)      occurrences all number 1 0 1 0 Retinal neovascularisation      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Ulcerative keratitis      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Vitreous haemorrhage      subjects affected / exposed 10 / 35 (28.57%) 7 / 13 (53.85%) 2 / 10 (20.00%) 1 / 12 (8.33%)      occurrences all number 10 7 2 1 Gastrointestinal disorders Oral mucosal blistering      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Psychiatric disorders Anxiety      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Depression      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Renal and urinary disorders Renal impairment      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Infections and infestations Cystitis      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Influenza      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Rhinitis      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1 Metabolism and nutrition disorders Hyperuricaemia      subjects affected / exposed 1 / 35 (2.86%) 1 / 13 (7.69%) 0 / 10 (0.00%) 0 / 12 (0.00%)      occurrences all number 1 1 0 0 Hypoglycaemia      subjects affected / exposed 1 / 35 (2.86%) 0 / 13 (0.00%) 0 / 10 (0.00%) 1 / 12 (8.33%)      occurrences all number 1 0 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
The main limitations of this trial are the follow-up period and the reduced number of patients included in the study.
Online references
http://www.ncbi.nlm.nih.gov/pubmed/26630400

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