A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral TTI-0102 for Treatment of Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS)
This is a randomized, double-blind, placebo-controlled study. Prior to treatment, patients will undergo a screening visit. If eligible, each subject will return for a Day 1 visit and will receive their first dose of investigational product (TTI-0102 or placebo). At the end of the first week of treatment, subjects will return for a Week 1/Day 8 study visit to assess study drug dosing/tolerance and instruct on dosing for the upcoming second week of treatment. For the first 8 weeks of treatment, subjects will alternate between returning to the clinic for detailed assessments (Weeks 4 and 8) and receiving a telephone call from the Investigator team to assess safety and TTI-0102 dose (Weeks 2 and 6) and the potential need for an immediate unscheduled study visit. After the first 8 weeks of treatment, subjects will continue to return to the clinic for monthly assessments at Weeks 12, 16, 20. The Study Exit visit will occur at Week 24, and subjects will be offered to continue on an open-label extension study of TTI-0102. If a subject does not complete the study, they will be asked to return for a Study Exit visit 4 weeks after last study drug dose. Primary Objective The primary objective of this study is to assess the efficacy, safety and tolerability of oral TTI 0102 compared to placebo, for up to 6 months in patients with MELAS. Secondary Objective The secondary objectives of this study are to assess the efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of cysteamine after oral administration of TTI-0102 at steady state, in patients with MELAS on a stable dose of TTI-0102. This is a randomized, double-blind, placebo-controlled study. Prior to treatment, patients will undergo a screening visit. If eligible, each subject will return for a Day 1 visit and will receive their first dose of investigational product (TTI-0102 or placebo). At the end of the first week of treatment, subjects will return for a Week 1/Day 8 study visit to assess study drug dosing/tolerance and instruct on dosing for the upcoming second week of treatment. For the first 8 weeks of treatment, subjects will alternate between returning to the clinic for detailed assessments (Weeks 4 and 8) and receiving a telephone call from the Investigator team to assess safety and TTI-0102 dose (Weeks 2 and 6) and the potential need for an immediate unscheduled study visit. After the first 8 weeks of treatment, subjects will continue to return to the clinic for monthly assessments at Weeks 12, 16, 20. The Study Exit visit will occur at Week 24, and subjects will be offered to continue on an open-label extension study of TTI-0102. If a subject does not complete the study, they will be asked to return for a Study Exit visit 4 weeks after last study drug dose. Study Drug Dosing To prevent any manifestation of intolerance at the initiation of drug treatment, only half a dose (2.75 grams) will be given once a day for the first week of treatment. During the following weeks of treatment, patients will be given a full dose of 5.5 grams once a day. Interim Data Review After nine (9) patients have completed three months of treatment (the Week 12 visit) an interim data cut will take place to assess safety and potential efficacy signals. Even if no indications of efficacy are detected at this early stage, the trial itself will not be terminated unless there is a serious safety concern (i.e., protocol-defined Stopping Criteria are met).
• Patient or Patient's legally designated representative has given written informed consent before any study-related activities are carried out and is able to understand the full nature and purpose of the trial, including possible risks and adverse effects. Patient has provided assent according to local/institutional requirements.
• Males and females between 16 and 60 years of age at screening.
• Diagnosis of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defined as:
• \- mtDNA mutation known to be associated with MELAS and MELAS phenotype (Emmanuele et al., 2022) including but not limited to: m.3243A\>G, m.13513G\>A, m.10191T\>C, m. 3271T\>C, m. 13136\_15374del, m. 8363G\>A. Mutation must have heteroplasmy \>50% characterized by mutation load in urinary epithelium or blood.
• AND
• \- two or more of the following clinical symptoms indicative of MELAS phenotype: diabetes, myopathy, seizures, at least one historic stroke-like episode, and exercise intolerance.
• Moderate disease severity defined as Newcastle Mitochondrial Disease Adult Scale (NMDAS) score between 15 to 45 inclusive.
• Able to complete a 12-minute walk test (12-MWT) distance of at least 150 meters and no more than 1000 meters within 30 days prior to, or at time of screening.
• Subjects regularly taking dietary supplements including but not limited to creatine, alpha-lipoic acid, CoQ10, B vitamins, levocarnitine shall have been taking them for at least 3 months pre-study and will agree to continue taking them throughout the study (from the Screening Visit to Study Exit).
• With respect to concomitant medications, the subject must:
∙ Be willing to abstain from initiating new dietary supplements and non-prescribed medications, except as permitted by the Investigator throughout the study.
‣ Be on a stable dose of medications prescribed for seizure management and prevention. Stable dose in this context means unchanged for at least 30 days prior to the Screening Visit.
• Willing and able to comply with study drug dosing requirements, i.e., able to ingest study drug solution orally.
• Female participants:
‣ Must be of nonchildbearing potential (i.e., surgically sterilized \[hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit\]) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone \[FSH\] level \>40 IU/L at the screening visit), or
⁃ If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to the use of acceptable forms of highly effective contraception (refer to protocol Section 19.2) from the time of signing the consent form until at least 30 days after the last dose of the study drug.
⁃ Male participants:
∙ Engaging in any sexual intercourse, including those who are infertile and do not produce sperm (e.g. post-vasectomy), must abstain from unprotected sex until the Study Exit visit.
‣ Must agree to abstain from sperm donation, and if engaging in sexual intercourse with a female of child bearing potential must agree to the use of an acceptable form of highly effective contraception (refer to protocol Section 19.2) from the time of signing the consent form until at least 30 days after the last dose of study drug.
⁃ Have suitable venous access for blood sampling.
⁃ Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.