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)

NCT06792500 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY00001021UH3TR003897
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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)

Keywords

Mitochondrial Disease; Pathogenic mitochondrial variants; ATP deficiency; Maternal inheritance; Stroke-like episodes; Chronic energy deficit; Deficient oxidative phosphorylation; Seizures; Extreme tiredness; Myopathy; Migraines; Gastrointestinal dysmotility; visual loss; Dystonia; Anxiety; Hearing loss; Tremors; Lactic Acidosis; Cognitive deficit; Neuropathy; m.3243 variant; m.11778 variant

Outcome Measures

Primary Outcomes (2)

• Assessment of Dose Safety for Glycerol Tributyrate

  To assess the dose safety of the investigational drug, glycerol tributyrate, the investigators will measure Incidence of Treatment-Emergent Adverse Events \[Safety and Tolerability\] using the CTCAE version 4.03

  20 months

• Potential Efficacy of Glycerol Tributyrate on the oxidative phsophorylation metabolism

  The investigators will assess whether participant-specific maximum tolerated dose (MTD) of glycerol tributyate results in increase of the participant's bioenergetic parameters for the oxidative phosphorylation pathway and/or mitochondrial ATP rate production above the participant's baseline determined from a dermal fibroblasts derive from a skin biopsy during the two-month-long baseline lead-in phase.

  20 months

Secondary Outcomes (10)

• Shared Secondary MELAS and LHON-Plus Outcome

  20 months

• Shared Secondary MELAS and LHON-Plus Outcome

  20 months

• Shared Secondary MELAS and LHON-Plus Outcome

  20 months

• Shared Secondary MELAS and LHON-Plus Outcome

  20 months

• Shared Secondary MELAS and LHON-Plus Outcome

  20 months

Other Outcomes (5)

• MELAS-Specific Exploratory Outcome

  20 months

• MELAS-Specific Exploratory Outcome

  20 months

• LHON-Plus-Specific Exploratory Outcome

  20 months

Study Arms (2)

MELAS

EXPERIMENTAL

12 MELAS participants will be enrolled in the baseline phase before being given an oral administration of glycerol tributyrate. All participants will undergo a six-month-long non-randomized dose escalation phase to determine each participant-specific maximum tolerated dose (MTD), after which the fixed MTD of glycerol tributyrate will be orally administered during the 12-month-long clinical phase.

Drug: Glycerol Tributyrate

LHON-Plus

EXPERIMENTAL

12 LHON-Plus participants will be enrolled and will be given the interventional drug, glycerol tributyrate. All participants will undergo a six-month-long non-randomized dos escalation phase in order to determine the patient-specific maximum tolerated dose (MTD), after which they will be orally administered this MTD for a period of 12 months.

Drug: Glycerol Tributyrate

Interventions

Glycerol Tributyrate DRUG

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.

LHON-Plus; MELAS

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be aged 18 to 65 years
• A confirmed molecular diagnosis of MELAS or LHON-Plus
• Symptomatic participants with MELAS harboring the m.3243A\>G variant or a mitochondrial pathogenic variant solely mapping in a mitochondrial gene encoding a mitochondrial subunit of Complex I
• Symptomatic participants with LHON-Plus harboring the m.11778G\>A or a mitochondrial pathogenic variant only mapping in a mitochondrial gene encoding a mitochondrial subunit of Complex I
• Normal enzymatic Complex II activity
• Participants able to swallow capsules and comply with the requirements of the study according to the opinion of the investigator
• Able to give written, informed consent
• Participants who are sexually active and/or fertile must use an effective birth control during the study

You may not qualify if:

• History of another primary mitochondrial disorder
• Participants acutely ill
• Positive urine pregnancy test for female subjects of childbearing potential within seven days prior to the first dose of the investigational drug
• Pregnancy and/or breastfeeding
• Participating in another mitochondrial disorder trial
• Participated in another mitochondrial disorder trial within the last six months
• On a current therapy with other investigational agents
• Absence of neurological symptoms, muscle weakness, or exercise intolerance
• Presence of any of the following signs or symptoms in the past six months at grade 3 or higher based on the CTCAE version 4.03: nausea, vomiting, diarrhea, hypoglycemia, hyperglycemia, dizziness, blurred vision, or syncope
• A known hypersensitivity to any excipient contained in the drug formulation
• Current abuse of drugs and/or alcohol
• Unable to consent for themselves
• Participants with an enteral feeding tube
• Inability to travel to the study site

Sponsors & Collaborators

• George Washington University: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator
• Children's National Research Institute: collaborator

Study Sites (1)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

RECRUITING

MeSH Terms

Conditions

MELAS Syndrome; Mitochondrial Diseases; Seizures; Muscular Diseases; Migraine Disorders; Vision Disorders; Dystonia; Anxiety Disorders; Hearing Loss; Tremor; Acidosis, Lactic; Cognition Disorders

Condition Hierarchy (Ancestors)

Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Headache Disorders, Primary; Headache Disorders; Sensation Disorders; Eye Diseases; Dyskinesias; Mental Disorders; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Acidosis; Acid-Base Imbalance; Neurocognitive Disorders

Study Officials

• Debra Regier, M.D., Ph.D.

  Children's National Hospital; Children's National Rare Disease Institute

  PRINCIPAL INVESTIGATOR

• Wei-Liang Chen, M.D.

  Children's National Research Institute

  STUDY CHAIR

• Anne Chiaramello, Ph.D.

  George Washington University School of Medicine and Health Sciences

  STUDY DIRECTOR

Central Study Contacts

Anne Chiaramello, Ph.D.,

CONTACT

(202) 994-2173; achiaram@gwu.edu

Debra Regier, M.D., Ph.D.

CONTACT

(202) 545-2512; dregier@childrensnational.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 15, 2025
• First Posted: January 24, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: February 9, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)