A Basket Clinical Study to Assess Glycerol Tributyrate in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like Episodes (MELAS) or Leber's Hereditary Optic Neuropathy-Plus (LHON-Plus)

Summary

This is a parallel arm non-randomized dose-escalation, open-label basket exploratory phase 1 clinical trial where Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS) and Leber's hereditary optic neuropathy-Plus (LHON-Plus) participants will undergo simultaneous enrollment in two disease-based arms and receive daily oral doses of glycerol tributyrate to assess its safety and potential for efficacy using clinical, biochemical, and molecular evidence.

This study will utilize a two-month baseline lead-in phase to establish and document the clinical baseline for each participant in both arms in order to compare the molecular and clinical parameters. This is clinically relevant in light of the high clinical heterogeneity among subjects affected by the same mitochondrial disease (MELAS or LHON-Plus). For ethical concerns prompted by the lack of treatment for these two intractable and progressive mitochondrial diseases, there will not be a placebo control group. Thus, each participant will act as their own control and receive oral doses of glycerol tributyrate, eliminating the need for a placebo. Considering the high clinical heterogeneity among participants affected by MELAS or LHON-Plus and some clinical divergence between MELAS and LHON-Plus, this strategy is beneficial to every enrolled participants, as each will receive the investigational drug, glycerol tributyrate. In addition, this approach will determine the subject-specific maximal optimized dose in a personalized medicine-based approach.

After approval of the IRB protocol from the Institutional Review Board Data and signed consent form from all participants, this investigational basket clinical trial has three phases spanning over 20 months:

* A baseline lead-in phase (2 months) to collect participant-specific baseline for clinical, biochemical, molecular and metabolic biomarkers that will be monitored throughout the subsequent dose-escalation and clinical phases.
* A dose-escalation phase (6 months) to determine the participant-specific maximum tolerated dose (MTD) during which participant-specific clinical and biochemical biomarkers are collected every month.
* A clinical phase at a fixed subject-specific MTD dose (12 months) to collect participant-specific clinical, biochemical, molecular and metabolic biomarkers and to perform three scheduled skin biopsies: at the outset, mid-point, and the end of this clinucal phase. We have planned for a 12-month-long clinical phase at a fixed participant-specific MTD considering the absence of reliable predictors that makes idiosyncratic disease-specific symptoms for MELAS and LHON-Plus impossible to forecast among participant for assessing the potential efficacy of glycerol tributyrate by monitoring clinical symptoms specific for each disease. During the 12-month-long time-frame, disease-specific clinical symptoms will be collected as preliminary evidence of efficacy of glycerol tributyrate using disease-specific biomarkers.

Finally, discharge procedure during which the clinical investigator will record non-serious adverse events or serious adverse events for 7 or 30 days, respectively, after the last day of study participation.

Conditions

• MELAS Syndrome
• Lebers Hereditory Optic Neuropathy With Extra Ocular Symptoms (LHON-Plus)

Interventions

DRUG

Glycerol Tributyrate

Participants will be administered orally three times a day enteric hard capsules containing 500 mg of glycerol tributyrate with an 8-ounce glass of water on an empty stomach: morning, noon, and evening during the dose-escalation phase. Each MELAS participant will undergo a six-month dose escalation phase of glycerol tributyrate, starting at a dose of 1,000 mg (tid) per day during the first month followed by a monthly increase of 500 mg (tid) per dose of glycerol tributyrate with the maximal oral dose of glycerol tributyrate 3,500 mg (tid) per dose at the end of six-month-long dose escalation phase. Once the participant-specific fixed maximum tolerated dose (MTD) is determined, MELAS participants will take an oral administration of this MTD three times a day during the 12-month-long clinical phase.

Sponsors & Collaborators

• National Center for Advancing Translational Sciences (NCATS)

  collaborator NIH

• Children's National Research Institute

  collaborator OTHER

• George Washington University

  lead OTHER

Principal Investigators

• Debra Regier, M.D., Ph.D. · Children's National Hospital; Children's National Rare Disease Institute

• Wei-Liang Chen, M.D. · Children's National Research Institute

• Anne Chiaramello, Ph.D. · George Washington University School of Medicine and Health Sciences

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-04-30

Primary Completion

2027-10-31

Completion

2027-10-31

FDA Drug

Yes

Countries

• United States

Study Locations