Safety and Effect on Central Retinal Thickness of BI 1026706 in Patients With Diabetic Macular Edema

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02732951
• Collaborator: (none)
• Enrollment: 105
• Locations: 35
• Arms: 2
• Actual Duration (Months): 18.3
• Patients Per Site: 3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a proof of mechanism trial to explore the effect of BI 1026706 on the central retinal thickness and to evaluate safety and tolerability of BI 1026706 administered orally for 12 weeks in patients with mild vision impairment due to center-involved DME

Condition or Disease	Intervention/Treatment	Phase
Macular Edema	Drug: BI 1026706; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-masked, Placebo-controlled Exploratory Study to Evaluate Pharmacodynamics, Safety and Tolerability of Orally Administered BI 1026706 for 12 Weeks in Patients With Mild Visual Impairment Due to Center-involved Diabetic Macular Edema (DME)
• Actual Study Start Date: Apr 14, 2016
• Actual Primary Completion Date: Oct 23, 2017
• Actual Study Completion Date: Oct 24, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 1026706	Drug: BI 1026706
Active Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Central Subfield Foveal Thickness (CSFT) at Week 12 [Baseline and Week 12]

   The change from baseline in CSFT at Week 12 and the BI 1026706 effect was compared between the BI 1026706 treatment group and the placebo group as measured by Spectral-domain Optical Coherence Tomography (SD-OCT). Baseline was defined as the CSFT value measured at the visit when patients were randomised. Mean presented here is an adjusted mean.

Secondary Outcome Measures

1. Number of Subjects With Serious Adverse Events (SAEs), Investigator Defined Drug-related Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [From first drug administration until 4 days after last drug administration, up to 89 days.]

   Number of subjects with serious adverse events (SAEs), Investigator defined drug-related Adverse events (AEs) and adverse events of special interest (AESIs) comparing the BI 1026706 treatment group with the placebo group is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patients 18 years of age and older

• Male patients or female patients of non-childbearing potential

• Diagnosis of Diabetes mellitus type 1 or type 2

• Retinal thickening due to Diabetic macular edema (DME) involving the center of the macula in the study eye as confirmed by the Investigator on clinical exam

• Center-involved DME confirmed on Spectral-Domain Optical Coherence Tomography (SD-OCT) with central subfield thickness (CSFT) of at least 300 µm in the study eye at screening, confirmed by Central Reading Centre

• Best corrected visual acuity ETDRS (Early Treatment Diabetic Retinopathy Study) letter score in the study eye of 84 or below, but at least 70 at screening

• Further inclusion criteria apply

Exclusion criteria:

• Macular edema considered to be due to other causes than DME in the study eye

• Additional eye disease in the study eye that, in the opinion of the Investigator, might affect macular edema or could compromise or alter visual acuity during the course of the trial

• Anterior segment and vitreous abnormalities in the study eye that would compromise the adequate assessment of the best corrected visual acuity or an adequate examination of the posterior pole

• Intraocular surgery in the study eye within 4 months prior to randomization or planned intraocular surgery, including cataract, during the study period

• Proliferative diabetic retinopathy or iris neovascularisation in the study eye

• Aphakia in the study eye

• Any indication that requires immediate treatment or for which treatment is expected in the study eye with anti-Vascular Endothelial Growth Factor (VEGF) or with laser photocoagulation during the period, as per Investigator's judgment

• History of prior laser photocoagulation or other surgical, intravitreal or peribulbar treatment in the study eye within 4 months prior to randomization, either for DME or an ocular condition other than DME

• History of fluocinolone acetonide intravitreal implant in the study eye

• Application of intraocular corticosteroids in the study eye within 2 years prior to randomization in phakic eyes or 9 months in pseudophakic eyes

• History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment in the study eye within 30 days prior to randomization

• Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization

• Initiation of intensive insulin treatment (multiple daily injections or a pump) within 3 months prior to randomization or plans to do so in the next 4 months

• Change in oral antidiabetic medication within 3 months prior to randomization

• Patients with a clinically relevant abnormal screening haematology, blood chemistry, or urinalysis

• Renal impairment with estimated creatinine clearance < 30 mL/min (as calculated by Cockcroft-Gault equation)

• Myocardial infarction or unstable angina pectoris within 3 months before randomization

• Uncontrolled arterial hypertension defined as a single measurement of systolic >180 mmHg, two consecutive measurements of systolic >160 mmHg, or diastolic >100mmHg on optimal medical regimen

• Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brussels-UNIV Brugmann -Horta	Brussel		Belgium	1020
2	Leuven - UNIV UZ Leuven (Sint-Rafaël)	Leuven		Belgium	3000
3	HOP Nord	Marseille		France	13915
4	HOP Hôtel-Dieu	Nantes		France	44093
5	HOP Lariboisière	Paris		France	75010
6	Hosp National 15-20, Ophtalmo, Paris	Paris		France	75012
7	HOP Pierre Paul Riquet	Toulouse		France	31059
8	Universitätsklinikum Aachen, AöR	Aachen		Germany	52074
9	Augen Zentrum Nordwest, Ahaus	Ahaus		Germany	48683
10	Kamppeter Augenzentrum, Bayreuth	Bayreuth		Germany	95444
11	Universitätsmedizin Göttingen, Georg-August-Universität	Göttingen		Germany	37075
12	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
13	Augenarzt Dr. Dunker und Kollegen, Troisdorf	Troisdorf-Sieglar		Germany	53844
14	Universitätsklinikum Tübingen	Tübingen		Germany	72076
15	Universitätsklinikum Ulm	Ulm		Germany	89075
16	Attikon, Panepistimiako Geniko Nosokomeio	Athens		Greece	12462
17	University General Hospital of Heraklion	Herakleion,Crete		Greece	71110
18	University of Patras Medical School	Patras		Greece	26504
19	Uzsoki Street Hospital, Budapest	Budapest		Hungary	1145
20	BAZ County Hospital, Ophtalmology Department, Miskolc	Miskolc		Hungary	3526
21	Univ.Szeged;Szent-Gyorgyi;Albert Heal.Cent.Ophtalmology Dep	Szeged		Hungary	6720
22	Hospital de Braga-Escala Braga	Braga		Portugal	4710-243
23	AIBILI - Association for Innovation and Biomedical Research on Light and Image	Coimbra		Portugal	3000-548
24	Centro Hospitalar São João,EPE	Porto		Portugal	4200-319
25	Hospital de Vila Franca de Xira	Vila Franca de Xira		Portugal	2600-009
26	Hospital Dos de Maig	Barcelona		Spain	08025
27	Hospital Vall d'Hebron	Barcelona		Spain	08035
28	Hospital La Paz	Madrid		Spain	28046
29	Instituto Oftalmológico Gómez-Ulla	Santiago de Compostela		Spain	15706
30	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47005
31	Frimley Park Hospital	Frimley		United Kingdom	GU16 7UJ
32	Royal Surrey County Hospital	Guildford		United Kingdom	GU2 7XX
33	Moorfields Eye Hospital	London		United Kingdom	EC1V 2PD
34	Royal Victoria Infirmary	Newcastle upon Tyne		United Kingdom	NE1 4LP
35	Southampton General Hospital	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 26, 2017
• Study Protocol - Mar 7, 2016

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02732951
• Other Study ID Numbers: 1320.22; 2015-003529-33
• First Posted: Apr 11, 2016
• Last Update Posted: Mar 20, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Macular Edema; Edema

Study Results

Participant Flow

Recruitment Details	This was randomised, double-blind, placebo-controlled, parallel-group trial to evaluate pharmacodynamics, safety and tolerability of orally administered Boehringer Ingelheim (BI) 1026706 for 12 weeks in patients with Diabetic Macular Oedema (DME).
Pre-assignment Detail	All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.

Arm/Group Title	Placebo Matching to BI 1026706	BI 1026706
Arm/Group Description	Patients were administered film-coated tablet of placebo to match 100 mg BI 1026706 twice daily orally for 12 weeks.	Patients were administered film-coated tablet of 100 mg BI 1026706 twice daily orally for 12 weeks.
Period Title: Overall Study
STARTED	53	52
COMPLETED	48	46
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Placebo Matching to BI 1026706	BI 1026706	Total
Arm/Group Description	Patients were administered film-coated tablet of placebo to match 100 mg BI 1026706 twice daily orally for 12 weeks.	Patients were administered film-coated tablet of 100 mg BI 1026706 twice daily orally for 12 weeks.	Total of all reporting groups
Overall Participants	53	52	105
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.2 (9.7)	63.9 (8.7)	63.0 (9.2)
Sex: Female, Male (Count of Participants)
Female	14 26.4%	14 26.9%	28 26.7%
Male	39 73.6%	38 73.1%	77 73.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 7.5%	4 7.7%	8 7.6%
Not Hispanic or Latino	35 66%	43 82.7%	78 74.3%
Unknown or Not Reported	14 26.4%	5 9.6%	19 18.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.9%	0 0%	1 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	38 71.7%	47 90.4%	85 81%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	14 26.4%	5 9.6%	19 18.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Central Subfield Foveal Thickness (CSFT) at Week 12
Description	The change from baseline in CSFT at Week 12 and the BI 1026706 effect was compared between the BI 1026706 treatment group and the placebo group as measured by Spectral-domain Optical Coherence Tomography (SD-OCT). Baseline was defined as the CSFT value measured at the visit when patients were randomised. Mean presented here is an adjusted mean.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): FAS includes all patients who were randomised, treated with at least 1 dose of BI 1026706 or placebo, and with a baseline and at least one post randomisation central subfield foveal thickness (CSFT) measurement.

Arm/Group Title	Placebo Matching to BI 1026706	BI 1026706
Arm/Group Description	Patients were administered film-coated tablet of placebo to match 100 mg BI 1026706 twice daily orally for 12 weeks.	Patients were administered film-coated tablet of 100 mg BI 1026706 twice daily orally for 12 weeks.
Measure Participants	47	47
Mean (Standard Deviation) [Micrometre [μm]]	-6.19 (11.61)	10.26 (11.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching to BI 1026706, BI 1026706
	Comments	Null hypothesis = The CSFT change from baseline at Week 12 is equal in both groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3199
	Comments
	Method	Mixed model for repeated measurements
	Comments	Kenward-Roger approximation was used for denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted Mean
	Estimated Value	16.45
	Confidence Interval	(2-Sided) 95%; -16.23 to 49.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.45
	Estimation Comments	Fixed effects of treatment, prior anti-diabetic macular oedema treatment status, visit, treatment by visit interaction, baseline, baseline by visit interaction; patient as a random effect; unstructured covariance matrix for within patient errors.

2. Secondary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs), Investigator Defined Drug-related Adverse Events (AEs) and Adverse Events of Special Interest (AESIs)
Description	Number of subjects with serious adverse events (SAEs), Investigator defined drug-related Adverse events (AEs) and adverse events of special interest (AESIs) comparing the BI 1026706 treatment group with the placebo group is presented.
Time Frame	From first drug administration until 4 days after last drug administration, up to 89 days.

Outcome Measure Data

Analysis Population Description

Treated set (TS): TS includes all patients who were treated with at least 1 dose of trial drug, either BI 1026706 or placebo.

Arm/Group Title	Placebo Matching to BI 1026706	BI 1026706
Arm/Group Description	Patients were administered film-coated tablet of placebo to match 100 mg BI 1026706 twice daily orally for 12 weeks.	Patients were administered film-coated tablet of 100 mg BI 1026706 twice daily orally for 12 weeks.
Measure Participants	53	52
Total with SAEs	2 3.8%	7 13.5%
Investigator defined drug-related AE	7 13.2%	7 13.5%
AESIs	0 0%	1 1.9%

Adverse Events

Time Frame	From first drug administration until 4 days after last drug administration, up to 89 days.
Arm/Group Title	Placebo Matching to BI 1026706		BI 1026706
Arm/Group Description	Patients were administered film-coated tablet of placebo to match 100 mg BI 1026706 twice daily orally for 12 weeks.		Patients were administered film-coated tablet of 100 mg BI 1026706 twice daily orally for 12 weeks.
All Cause Mortality
	Placebo Matching to BI 1026706		BI 1026706
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/52 (0%)
Serious Adverse Events
	Placebo Matching to BI 1026706		BI 1026706
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/53 (3.8%)		7/52 (13.5%)
Cardiac disorders
Myocardial infarction	0/53 (0%)		1/52 (1.9%)
Gastrointestinal disorders
Inguinal hernia	0/53 (0%)		1/52 (1.9%)
Infections and infestations
Localised infection	1/53 (1.9%)		0/52 (0%)
Pneumonia	0/53 (0%)		1/52 (1.9%)
Investigations
Alanine aminotransferase increased	0/53 (0%)		1/52 (1.9%)
Aspartate aminotransferase increased	0/53 (0%)		1/52 (1.9%)
Haemoglobin decreased	0/53 (0%)		1/52 (1.9%)
Red blood cell count decreased	0/53 (0%)		1/52 (1.9%)
Nervous system disorders
Generalised tonic-clonic seizure	1/53 (1.9%)		0/52 (0%)
Renal and urinary disorders
Glycosuria	0/53 (0%)		1/52 (1.9%)
Skin and subcutaneous tissue disorders
Reactive perforating collagenosis	0/53 (0%)		1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Placebo Matching to BI 1026706		BI 1026706
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/53 (22.6%)		14/52 (26.9%)
Eye disorders
Visual acuity reduced	2/53 (3.8%)		3/52 (5.8%)
Infections and infestations
Nasopharyngitis	4/53 (7.5%)		6/52 (11.5%)
Investigations
Gamma-glutamyltransferase increased	3/53 (5.7%)		0/52 (0%)
Nervous system disorders
Headache	1/53 (1.9%)		4/52 (7.7%)
Somnolence	3/53 (5.7%)		1/52 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.