Clinical Trial Results:
A study that tests BI 1467335 in patients with diabetic eye disease (diabetic retinopathy). It looks at the way BI 1467335 is taken up, the effects it has, and how well it is tolerated
|
Summary
|
|
EudraCT number |
2016-002971-91 |
Trial protocol |
NO GR GB ES IT PT |
Global end of trial date |
14 May 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
31 May 2021
|
First version publication date |
31 May 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
1386-0012
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03238963 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Boehringer Ingelheim
|
||
Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
|
||
Public contact |
Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
|
||
Scientific contact |
Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
|
||
|
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 |
14 Jul 2020
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
14 May 2020
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective is to evaluate safety and tolerability of 12 weeks treatment of
oral BI 1467335 compared to placebo in patients with moderately severe to severe
non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic
macular edema (CI-DME) and secondary to explore the efficacy of BI 1467335 on
improvement of diabetic retinopathy.
|
||
Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Nov 2017
|
||
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 |
Austria: 2
|
||
Country: Number of subjects enrolled |
Greece: 5
|
||
Country: Number of subjects enrolled |
Italy: 5
|
||
Country: Number of subjects enrolled |
Norway: 7
|
||
Country: Number of subjects enrolled |
Portugal: 18
|
||
Country: Number of subjects enrolled |
Spain: 9
|
||
Country: Number of subjects enrolled |
United Kingdom: 29
|
||
Country: Number of subjects enrolled |
United States: 213
|
||
Worldwide total number of subjects |
288
|
||
EEA total number of subjects |
46
|
||
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) |
202
|
||
From 65 to 84 years |
86
|
||
85 years and over |
0
|
||
|
||||||||||||||||||||||||||||
|
Recruitment
|
||||||||||||||||||||||||||||
Recruitment details |
A study evaluated safety and tolerability of 12-week treatment of oral BI 1467335 compared to placebo in patients with moderately severe to severe non-proliferative diabetic retinopathy without center-involved diabetic macular edema and explored the efficacy of BI 1467335 on improvement of diabetic retinopathy. | |||||||||||||||||||||||||||
|
Pre-assignment
|
||||||||||||||||||||||||||||
Screening details |
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. | |||||||||||||||||||||||||||
|
Period 1
|
||||||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
|||||||||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Data analyst, Assessor | |||||||||||||||||||||||||||
|
Arms
|
||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||
|
Arm title
|
BI 1467335 10 mg | |||||||||||||||||||||||||||
Arm description |
2 film coated tablets of 5 milligram (mg) BI 1467335 (Total: 10 mg) were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
BI 1467335
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
2 film coated tablets of 5 milligram (mg) BI 1467335 (Total: 10 mg) were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up.
|
|||||||||||||||||||||||||||
|
Arm title
|
Placebo | |||||||||||||||||||||||||||
Arm description |
2 film coated tablets of matching placebo were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
2 film coated tablets of matching placebo were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 1467335 10 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
2 film coated tablets of 5 milligram (mg) BI 1467335 (Total: 10 mg) were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
2 film coated tablets of matching placebo were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
BI 1467335 10 mg
|
||
Reporting group description |
2 film coated tablets of 5 milligram (mg) BI 1467335 (Total: 10 mg) were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
2 film coated tablets of matching placebo were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||
|
|||||||||||||
End point title |
Percentage of participants with any ocular adverse events over the on-treatment period [1] | ||||||||||||
End point description |
Percentage of participants with any ocular adverse events over the on-treatment period was reported. Treated set (TS): the TS consists of all patients who were treated with at least one dose of trial drug (BI 1467335 or placebo).
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
On-treatment period: from first dose of study drug until end of follow-up period, up to 24 weeks.
|
||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of participants with at least 2 steps improvement from baseline in the study eye on the Diabetic Retinopathy Severity Scale (DRSS) at week 12 | ||||||||||||
End point description |
7-field or modified 4-field digital fundus photographs was obtained from both eyes by a qualified person according to the imaging manual to collect all data for the assessment of the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS). The images was sent to the independent central reading center who performs the grading on the basis of the DRSS. The DRSS ranges from level 10 (Diabetic retinopathy absent) to level 85 (advanced proliferative Diabetic retinopathy). Full analysis set (FAS): the FAS consists of all the patients who were randomized, treated with at least one dose of BI 1467335/placebo and have baseline and one on-treatment Diabetic Retinopathy Severity Scale assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At baseline and at Week 12.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Risk difference of BI 1467335 10 milligram (mg) group minus Placebo group was presented. 95% confidence interval was calculating using the Chan and Zhang method.
|
||||||||||||
Comparison groups |
BI 1467335 10 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
69
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
Method |
Chan and Zhang method | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
0.057
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.053 | ||||||||||||
upper limit |
0.192 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.039
|
||||||||||||
|
|||||||||||||
End point title |
Percentage of participants with adverse events other than ocular adverse events over on-treatment period | ||||||||||||
End point description |
Percentage of participants with adverse events other than ocular adverse events over on-treatment period was reported. Treated set (TS): the TS consists of all patients who were treated with at least one dose of trial drug (BI 1467335 or placebo).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
On-treatment period: from first dose of study drug until end of follow-up period, up to 24 weeks.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From first dose of study drug until end of follow-up period, up to 24 weeks.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Treated set (TS): the TS consists of all patients who were treated with at least one dose of trial drug (BI 1467335 or placebo).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 1467335 10 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
2 film coated tablets of 5 milligram (mg) BI 1467335 (Total: 10 mg) were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
2 film coated tablets of matching placebo were taken orally once daily for a treatment period of 12 weeks with 12 weeks of follow-up. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
18 Jan 2018 |
- Descriptive analysis of the secondary efficacy endpoint was added because the number of
patients with at least 2-step improvement in Diabetic retinopathy Screened set (DRSS) by Week 12 could be too small for
adequate statistical modelling (which had been planned in the original clinical trial
protocol).
- Upon request by the health authorities, changes were made to Inclusion Criteria 1 and 3,
Exclusion criteria 1 and 15, the rules for withdrawal from trial treatment, and restrictions
regarding concomitant treatment were made. Furthermore, rescreening of patients based
on the changed inclusion/exclusion criteria was allowed.
- Fasting prior to drug administration and prior to study visits was no longer required, as
data from trail 1386.17 had shown that Bi 1467335 could be given with or without food. |
||
20 Mar 2018 |
- The drug profile, benefit-risk assessment, Exclusion Criterion 7, and restrictions regarding
concomitant treatment and diet/life style were updated, as BI 1467335 had been
demonstrated in vitro to be an irreversible inhibitor of MAO-B.
- Use of the Heidelberg Optical coherence tomography (OCT) device was allowed (as an alternative to the OptoVue device)
and the consistent use of the same device by a given patient throughout the trial was
emphasized.
- The treatment with aflibercept (Eylea®) or ranibizumab (Lucentis®) in the fellow eye was
allowed during the trial. |
||
01 Aug 2018 |
- It was stated that the screening visit should be split into 2 parts, when possible, to account
for the high probability of patients failing screening due to DRSS grading.
- Food and diet precautions were modified.
- Upon request by the healthy authorities, bupropion, triptans, linezolide, tedizolid,
methylene blue, lithium, and pethidine were added as restricted concomitant treatments
and a section regarding gamete donation was introduced. |
||
11 Apr 2019 |
- The number of pharmacokinetic and pharmacodynamic sampling was reduced in order to
reduce the burden on patients.
- A sentence describing a potential sensitivity analysis excluding observations obtained after
the start of rescue medication was removed, as no such rescue medication had been
defined. |
||
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. | |||
| None reported | |||
