JCHR

Title

A Phase 2 Evaluation of Tonabersat for Diabetic Macular Edema (DME)

Précis

This randomized clinical trial will evaluate the effect of tonabersat compared with placebo on central subfield thickness (CST) in eyes with center-involved DME and good visual acuity. 

Investigational Drug

Tonabersat (SB-220453, Xiflam)

Objectives

The primary objective is to assess the effects of tonabersat, an orally administered Connexin43 hemichannel inhibitor, on CST (mean change) compared with placebo in eyes with center-involved DME and good visual acuity at 6 months.

Exploratory objectives will evaluate biomarkers of kidney function for potential benefit.  Furthermore, this phase 2 study is being conducted to determine whether the conduct of a phase 3 trial has merit and provide information on outcome measures needed to design a phase 3 trial.

Study Design

Randomized, double-masked, placebo-controlled clinical trial

Number of Sites

About 25

Outcome

Primary Outcome:

·         Mean change in central subfield thickness at 6 months*

Secondary Outcomes:

·         Mean change in retinal volume from baseline at 6 months

·         Percentage of eyes with CST below OCT machine- and gender-specific threshold for DME and at least a 10% decrease from baseline at 6 months

·         Mean change in ETDRS BCVA from baseline at 6 months

·         Percentage of eyes receiving other treatment for DME

·         Percentage of eyes with =5 letter loss at the final two consecutive visits or =10 letter loss at the final visit in ETDRS BCVA

Exploratory Outcomes:

·         Percent of eyes with worsening or improvement of diabetic retinopathy on fundus photographs

·         Mean change in eGFR from baseline to 6 months

·         Mean change in CRP from baseline to 6 months

·         Mean change in HbA1c from baseline to 6 months

·         Mean change in Cystatin C from baseline to 6 months

·         Mean change in TSH from baseline to 6 months

·         Mean change in Galectin 3 from baseline to 6 months

·         Mean change in IL-1 ß from baseline to 6 months

·         Mean change in IL-6 from baseline to 6 months

·         Mean change in TNFa  from baseline to 6 months

·         Mean change in urine creatinine from baseline to 6 months

·         Mean change in urine albumin from baseline to 6 months

·         Mean change in urine MCP1 from baseline to 6 months

·         Mean change in urine osteopontin from baseline to 6 months

·         Mean change in urine IL-18 from baseline to 6 months

·         Mean changes in OCTA vessel density and nonperfusion area

·         Change in CST from 6 to 12 months

·         Change in retinal volume from 6 to 12 months

·         CST below the OCT machine- and gender-specific threshold for DME at 12 months and a 10% or more decrease in CST from 6 to 12 months

·         Change in ETDRS BCVA from 6 to 12 monthsReceiving other treatment for DME between the 6 and 12-month visit

·         Changes in blood and urine samples from 6 to 12 months

Safety Outcomes of Interest:

Headache, drowsiness, dizziness, effect on renal function (change in eGFR) and liver function, effect on blood counts and metabolic panel.

* Change in CST will not be used to definitively establish efficacy.  If an anatomical difference is observed in this phase 2 trial compared to placebo the results would suggest that this medication merits further investigation in a definitive, phase 3 trial.

Population

Key Inclusion Criteria

·         Adults with type 1 or 2 diabetes mellitus

·         At least one eye with:

1.      Best corrected E-ETDRS visual acuity letter score = 79 (i.e., 20/25 or better)

2.      Ophthalmoscopic evidence of center-involved DME in study eye confirmed by central subfield thickness on spectral domain OCT

·         Zeiss Cirrus: = 290 µm in females, = 305 µm in males

·         Heidelberg Spectralis: = 305 µm in females, = 320 µm in males

Recruitment will be monitored with a goal to have equal proportions in the following categories above the CI-DME thresholds:     <75 µm, 75 µm to <175 µm, =175 µm

3.      Media clarity, pupillary dilation, and study participant cooperation sufficient for adequate OCT

Key Exclusion Criteria

·         Macular edema is considered to be due to a cause other than DME

·         Major ocular surgery within prior 4 months, or anticipated after randomization

·         History of focal/grid laser or other ocular surgical, intravitreal, or peribulbar treatment for DR or DME within prior 1 year, and no more than 4 prior anti-VEGF injections total

·         Anticipated need to treat DME or DR during the first 6 months, or anticipated need for cataract surgery during study period

·         Any history of vitrectomy

·         Systemic anti-VEGF or pro-VEGF treatment within 12 months prior to randomization

·         History of chronic renal failure requiring dialysis or kidney transplant

·         History of moderate to severe hepatic impairment, including known liver function test (LFT) values > 3x's the upper limit of normal

Sample Size

128

Phase

Phase 2

Treatment Groups

Random assignment (1:1) to tonabersat or placebo

Participant Duration

12 months (6 months on study drug, followed by 6 months not on study drug for each participant)

Study Duration (planned)

Anticipated 24 months total duration, from first enrollment until last participant visit.

Protocol Overview/Synopsis

1.      Informed consent will be obtained.

2.      Study eligibility will be assessed.

3.      Prior to randomization, the participant’s willingness to proceed into the randomized trial will be confirmed.

4.      Eligible participants will be randomly assigned 1:1 to tonabersat or placebo for a duration of 6 months.

5.      A follow-up phone call is performed at 1 week.

6.      Participants will return for monthly follow-up visits for the first 6 months, then one final follow-up visit at 12 months.

7.      Participation in the study will be considered completed upon completion of the 12-month visit.