Efficacy and Safety of Oral TTI-0102 in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-506723-28-00
- Protocol
- TTI-MITO-001
- Sponsor
- Thiogenesis Therapeutics
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy**, safety, and tolerability of oral TTI-0102 compared to placebo over a period of up to 6 months in patients diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This objective is clinically relevant as it aims to determine the potential therapeutic benefits and safety profile of TTI-0102, which could offer a new treatment option for individuals affected by this rare and debilitating condition.
The secondary objectives of the study are to assess the efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of cysteamine following oral administration of TTI-0102 at steady state in patients with MELAS who are on a stable dose of TTI-0102. These assessments are crucial for understanding the drug's behavior in the body and its mechanism of action, which can inform dosing strategies and optimize therapeutic outcomes.
Participants
The clinical trial involves participants diagnosed with **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)**. The study population includes both male and female subjects aged between 16 and 60 years. Participants are required to have a moderate disease severity, as indicated by a Newcastle Mitochondrial Disease Adult Scale (NMDAS) score ranging from 15 to 45. The trial population was selected based on specific genetic mutations associated with MELAS and the presence of clinical symptoms such as diabetes, myopathy, seizures, historic stroke-like episodes, and exercise intolerance. Participants must be able to complete a 12-minute walk test covering a distance of at least 150 meters but not exceeding 1000 meters. Lifestyle considerations include the regular intake of dietary supplements like creatine, alpha-lipoic acid, CoQ10, B vitamins, and levocarnitine, which must have been consistently taken for at least three months prior to the study and continued throughout its duration. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of oral TTI-0102 in patients diagnosed with **mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)**. The trial will span a period of up to 6 months, with the primary objective being the assessment of the efficacy, safety, and tolerability of TTI-0102 compared to a placebo. Participants will be randomly assigned to receive either the investigational product or a placebo, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.
The trial will commence with an inclusion (screening) visit, where potential participants will be evaluated against the inclusion criteria, such as age between 16 and 60 years, a confirmed diagnosis of MELAS, and the ability to complete a 12-minute walk test. Following successful screening, eligible participants will be enrolled in the study. The study will include several follow-up visits at Weeks 4, 8, 12, 16, and 20, with the final end-of-study visit occurring at Week 24. These visits are designed to monitor the participants' health, assess the primary and secondary endpoints, and ensure adherence to the study protocol.
The expected length of participant involvement is approximately 6 months, from the screening visit to the end-of-study visit. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The primary outcome measure will be the change in functional capacity, assessed by the 12-minute walking test from baseline to Week 24. Secondary endpoints will include changes in fatigue severity, quality of life, and various pharmacodynamic biomarkers. The study will also evaluate the pharmacokinetic parameters of cysteamine, pantothenic acid, and taurine.
Treatment
The clinical trial involves the administration of **TTI-0102**, an experimental medication formulated as an **oral solution**. The active substance in TTI-0102 is **mercaptamine-pantetheine disulfide acetate**, a prodrug derivative of the existing and approved active moiety cysteamine, known commercially as Cystagon®. The medication is administered orally, with a maximum daily dose of 5.5 grams and a total maximum dose of 924 grams over a treatment period of up to 24 weeks. The study aims to evaluate the efficacy, safety, and tolerability of TTI-0102 in patients diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance and administration route, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This design helps to maintain the integrity of the study by minimizing bias and allowing for a more accurate assessment of the experimental medication's effects.
Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. This monitoring is crucial for maintaining the validity of the trial results and for assessing the true efficacy and safety profile of TTI-0102. The study is conducted over multiple centers, with a focus on maintaining consistent administration and monitoring practices across all sites.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the **change in functional capacity** as measured by the 12-minute walking test (12-MWT), comparing results from Day 1/Baseline to Week 24/Study Exit. This test will provide quantitative data on the improvement or decline in patients' physical capabilities over the course of the trial.
Secondary endpoints will evaluate additional efficacy parameters, including changes over time in the Fatigue Severity Scale (FSS) and Quality of Life as measured by the WHOQOL-BREF. These assessments will be conducted at multiple timepoints: Day 1/Baseline, Weeks 4, 8, 12, 16, 20, and Week 24/Study Exit. Furthermore, pharmacokinetic (PK) parameters for cysteamine, pantothenic acid (vitamin B5), and taurine will be determined, alongside pharmacodynamic (PD) biomarkers such as glutathione, glutathione disulfide, lactate, pyruvate, GDF-15, FGF21, and an amino acid panel including alanine. These measurements will provide a comprehensive evaluation of the drug's efficacy in treating patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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: a. Be willing to abstain from initiating new dietary supplements and nonprescribed medications, except as permitted by the Investigator throughout the study. b. 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.
Exclusion Criteria
- Documented diagnosis of concurrent inborn errors of metabolism.
- Non-elective hospitalization related to their mitochondrial disease or direct complication of disease within 60 days prior to the Screening Visit.
- Overt comorbidity preventing them from safely performing an exercise. In particular, patients suffering from cardiovascular, neurological disorders (e.g. ataxia, sequel blindness from pseudostroke, peripheral neuropathy) or advanced osteo-arthrosis.
- Treatment with taurine during the previous month (28 days), and not willing to discontinue for the duration of the trial.
- Platelet count, lymphocyte count or hemoglobin level below the lower limit of normal (LLN) and considered to be clinically significant by the Investigator at screening.
- Hepatic insufficiency with liver enzyme tests (alkaline phosphatase, AST or ALT) greater than 2.5 times to upper limit of normal (ULN) at screening.
- Bilirubin > 1.2 mg/dL at screening.
- Renal insufficiency, defined as 1) a requirement for chronic dialysis or 2) serum creatinine ≥1.2 mg/dl or creatinine clearance <60 ml/min
- Severe gastrointestinal disease including gastroparesis
- Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Examples: malabsorption requiring TPN, chronic diarrhea, bouts of pseudo obstruction.
- Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis.
- Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema.
- History of angina, myocardial infarction, or cardiac surgery within 2 years prior to screening.
- History of drug or alcohol abuse.
- History of pancreatitis.
- Known or suspected hypersensitivity to cysteamine.
- Allergy to any medicine containing mercaptamine, penicillamine or known hypersensitivity to any of the study drug ingredients.
- Evidence of or verbal attestation of Helicobacter pylori infection, presently, or within the last 90 days prior to Screening.
- Use of any live vaccinations within 30 days prior to the first study drug administration except for the influenza vaccine (note that COVID-19 vaccine is permitted).
- For women of childbearing potential, a positive urine pregnancy test and confirmatory positive serum test at screening. Must not be currently breastfeeding.
- Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration.
- Participation in another investigational clinical trial within 30 days if a drug, or 90 days for a biologic or device, prior to screening.
- Any other condition or prior therapy that in the opinion of the Investigator would make the subject unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 22 Jan 2024 | 6 |
 The Netherlands | Not Recruiting | 22 Jan 2024 | — |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TTI-0102 | Test | ORAL SOLUTION | ORAL | 5.5 | 24 | PRD10427286 |
Pearlitol® 100 SDmannitol | Placebo | N/A | — | — | — | N/A |