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).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Thiogenesis Therapeutics

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Nervous System Diseases [C10]

Trial duration

20 Mar 2025 → 12 Jan 2026

Decision date (initial)

2024-12-09

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-506723-28-00

WHO UTN

U1111-1292-1105

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Safety, Efficacy

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 objectives 1

1. 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.

Conditions and MedDRA coding

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. 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.
2. 2. Males and females between 16 and 60 years of age at screening.
3. 3. 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.
4. 4. Moderate disease severity defined as Newcastle Mitochondrial Disease Adult Scale (NMDAS) score between 15 to 45 inclusive.
5. 5. 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.
6. 6. 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).
7. 7. 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.
8. 8. Willing and able to comply with study drug dosing requirements, i.e., able to ingest study drug solution orally.
9. 9. 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.
10. 10. 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.
11. 11. Have suitable venous access for blood sampling.
12. 12. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion criteria 23

1. 1. Documented diagnosis of concurrent inborn errors of metabolism.
2. 2. Non-elective hospitalization related to their mitochondrial disease or direct complication of disease within 60 days prior to the Screening Visit.
3. 3. 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.
4. 4. Treatment with taurine during the previous month (28 days), and not willing to discontinue for the duration of the trial.
5. 5. 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.
6. 6. Hepatic insufficiency with liver enzyme tests (alkaline phosphatase, AST or ALT) greater than 2.5 times to upper limit of normal (ULN) at screening.
7. 7. Bilirubin > 1.2 mg/dL at screening.
8. 8. Renal insufficiency, defined as 1) a requirement for chronic dialysis or 2) serum creatinine ≥1.2 mg/dl or creatinine clearance <60 ml/min
9. 9. Severe gastrointestinal disease including gastroparesis
10. 10. 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.
11. 11. Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis.
12. 12. Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema.
13. 13. History of angina, myocardial infarction, or cardiac surgery within 2 years prior to screening.
14. 14. History of drug or alcohol abuse.
15. 15. History of pancreatitis.
16. 16. Known or suspected hypersensitivity to cysteamine.
17. 17. Allergy to any medicine containing mercaptamine, penicillamine or known hypersensitivity to any of the study drug ingredients.
18. 18. Evidence of or verbal attestation of Helicobacter pylori infection, presently, or within the last 90 days prior to Screening.
19. 19. 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).
20. 20. For women of childbearing potential, a positive urine pregnancy test and confirmatory positive serum test at screening. Must not be currently breastfeeding.
21. 21. 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.
22. 22. Participation in another investigational clinical trial within 30 days if a drug, or 90 days for a biologic or device, prior to screening.
23. 23. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary outcome measure will be “change in functional capacity” based upon the 12-minute walking test (12-MWT) from Day 1/Baseline to Week 24/Study Exit
2. Safety and tolerability endpoints include the incidence, severity and relationship of adverse events; change in clinical laboratory parameters, physical exam findings, vital signs, 12-lead electrocardiography and seizure activity.

Secondary endpoints 3

1. Efficacy: Change over time as measured at Day 1/Baseline, Weeks 4, 8, 12, 16, 20 and Week 24/Study Exit: - Fatigue Severity Scale (FSS); - Quality of Life (WHOQOL-BREF)
2. PK parameters will be determined for cysteamine, pantothenic acid (vitamin B5) and taurine
3. PD: Change over time as measured at Day 1/Baseline, Weeks 4, 8, 12, 16, 20 and Week 24/Study Exit for pharmacodynamic biomarkers: glutathione, glutathione disulfide, lactate, pyruvate, GDF-15, FGF21, amino acid panel (including alanine).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Thiogenesis Therapeutics

Sponsor organisation

Thiogenesis Therapeutics

Address

66 Avenue Des Champs Elysees

City

Paris

Postcode

75008

Country

France

Scientific contact point

Organisation

Thiogenesis Therapeutics

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Thiogenesis Therapeutics

Contact name

Clinical Trial Information Desk

Third parties 5

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications