Dr. Anne Chiaramello, Professor of Anatomy and Cell Biology and Director of the Mito-EpiGen Program at GW SMHS, is the sponsor of the Investigational New Drug protocol 171755, which received the FDA letter of “Study May Proceed” for the first basket clinical trial on two rare mitochondrial diseases, MELAS and LHON-Plus. Her clinical studies are funded by the National Center for Advancing Translational Sciences at the National Institutes of Health.
The main objective of this basket clinical trial is to test a novel small molecule-based therapy for discovered by the Chiaramello’s lab on patients affected by MELAS (12) or LHON-Plus (12). This study will be performed at the single site, Children’s National Hospital, located in Washington D.C., to investigate the safety and efficacy of the investigational drug. This study consists three phases: a baseline lead-in phase, a dose-escalation phase (6 months), and a clinical phase at fixed subject-specific maximum tolerated dose (12 months). All enrolled patients will receive the investigational drug. Thus, there is no placebo arm in this clinical trial.
During lead-in-phase, each patient will be scheduled for an on-site visit during which patient-specific baseline for clinical, biochemical, molecular and metabolic biomarkers will be collected so that each patient will serve as their own control. All patients will undergo a skin biopsy from which skin cells are derived to determine their mitochondrial signature and to quantify their load of pathogenic mitochondrial variants. At the end of on-site visit, patients will receive a bottle of capsules containing the investigational drug.
During the six-month-long dose escalation phase, patients will be administered oral doses of the investigational drug taken three times a day. In the absence of toxicity, each oral dose is increased in each subsequent month until determination of the patient-specific maximum tolerated dose (MTD). During this phase, patients are required to travel to Washington, D.C., for monthly visits at the Neuroscience Clinic of Children’s National Hospital until the MTD has been identified. If the MTD is identified before reaching six months, the patient immediately transfers to the clinical phase at fixed MTD and undergoes a skin biopsy.
During the 12-month-long clinical phase at fixed MTD, each patient will undergo a skin biopsy, biochemical tests, and physical and neurological examination at the mid-phase and the end. Thus, patients are required to travel twice to Washington D.C over a period of 12 months. During this clinical phase, we will assess safety of the investigational drug and its potential for efficacy.
INCLUSION CRITERIA
- To meet the two objectives of this small phase 1 investigational parallel arm, non-randomized dose-escalation and open-label basket clinical trial for glycerol tributyrate in subjects with MELAS or LHON-Plus, an individual must meet all the following inclusion criteria to be eligible to participate in this study:
- Subjects must be aged 18 to 65 years
- A confirmed molecular diagnosis of MELAS or LHON-Plus
- Symptomatic subjects 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 subjects 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
- Subjects 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
- Subjects who are sexually active and/or fertile must use an effective birth control during the study
EXCLUSION CRITERIA
- A subject who meets any of the following criteria will be excluded from participation in this study:
- History of another primary mitochondrial disorder
- Subjects 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
- Subjects with an enteral feeding tube
- Inability to travel to the study site