Sirolimus for Leigh Syndrome

NCT06843811 | Enrolling By Invitation Phase 2 FDA Drug

• 1 other identifier: 24-022433
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of the drug Sirolimus in participants with Leigh syndrome.

Conditions

Leigh Syndrome

Outcome Measures

Primary Outcomes (4)

• Rate of Adverse Events

  Adverse events will be measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Incidence of AEs will be reported.

  Up to 2.5 years

• Rate of Intercurrent Infection and Hospitalization

  Each infection and hospitalization will be reported.

  Up to 2.5 years

• Incidence of abnormal safety lab values

  Count of clinically significant changes from baseline in safety labs

  Up to 2.5 years

• Sirolimus Trough Level

  Measure of Sirolimus level in the blood. Sirolimus dosage will be adjusted as needed in order to maintain a sirolimus trough level within a range of 5 to 10 ng/mL. The number of out-of-range results will be reported.

  Up to 2.5 years

Secondary Outcomes (13)

• Change in MM-COAST Score

  Baseline up to end of study (up to 2.5 years)

• Change in GMFM (Gross Motor Function Measure) Score

  Baseline up to end of study (up to 2.5 years)

• Change in Movement Disorder-Childhood Rating Score (MDCRS)

  Baseline up to end of study (up to 2.5 years)

• CGI Scale

  Baseline up to end of study (up to 2.5 years)

• Change in Barry-Albright Dystonia Scale (BADS)

  Baseline up to end of study (up to 2.5 years)

Study Arms (2)

Phase 2A

EXPERIMENTAL

Participants will receive Sirolimus for at least 24 weeks at a starting dose of 0.8 to 1.3 mg/m2 two (2) times daily.

Drug: Sirolimus

Long-Term Extension

EXPERIMENTAL

Eligible participants may continue Sirolimus treatment for up to two (2) years.

Drug: Sirolimus

Interventions

Sirolimus DRUG

Sirolimus will be given at a starting dose of 0.8 to 1.3 mg/m2 twice daily, depending on subject age and weight.

Also known as: Rapamune, Rapamycin

Long-Term Extension; Phase 2A

Eligibility Criteria

• Age: 6 Months - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Genetically-confirmed diagnosis of Leigh syndrome with neurodevelopmental manifestations, which include documented developmental delay, developmental regression, or abnormal neurologic exam findings including but not limited to hypotonia, hypertonia, dystonia, chorea, nystagmus, ataxia, dysmetria, tremor or muscle weakness.
• Age 6 months to 55 years at the time of enrollment.
• Weight ≥ 5 kg at the time of enrollment.
• Adequate liver function as evidenced by total bilirubin \< 1.5x upper limit of normal (ULN) and liver function tests, alanine transaminase (ALT) and aspartate aminotransferase (AST), \< 3x ULN.
• Adequate renal function as evidenced by glomerular filtration rate (GFR) \> 60 mL/min/1.73m2 (cystatin C for pediatric population).
• Normal hematologic parameters as defined as:
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
• Platelet count ≥ 100,000/mm3 (100 x 109/L)
• Hemoglobin ≥ 9 g/dL
• Non-fasting serum triglycerides and cholesterol \< 300 mg/dL.
• Serum amylase and lipase \< 2x ULN.
• Adequate immunoglobulin levels as outlined below that, in the opinion of the investigator, will not place the patient at increased risk of infection.
• Immunoglobulin G (IgG) ≥ 200 mg/dL
• Immunoglobulin M (IgM) ≥ 30 mg/dL
• Immunoglobulin A (IgA) ≥ 10 mg/dL

You may not qualify if:

• Cardiac ejection fraction ≤ 50 %, shortening fraction ≤ 25% on cardiac echocardiogram within one year of screening and/or severe end-organ hypo-perfusion syndrome (secondary to cardiac failure) resulting in lactic acidosis.
• Patients with implanted cardiac assist/medical devices (including pacemakers), unless device was implanted prophylactically, and the patient is clinically asymptomatic.
• In the opinion of the investigator, clinically significant ECG and/or echocardiogram alterations at the time of screening.
• Myocardial infarction within 6 months prior to enrollment.
• Symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or unstable coronary artery disease.
• Prior history of hypersensitivity to sirolimus or other mTOR (Mechanistic Target of Rapamycin inhibitors).
• Prior history of angioedema requiring treatment or cessation of a presumed causative agent.
• Planned surgical procedure during the study period.
• Confirmed or highly suspected immunodeficiency disorder(s), including but not limited to, common variable immune deficiency (CVID), complement deficiency, etc.
• Clinically significant proteinuria that requires ongoing medical therapy.
• Any uncontrolled psychiatric or medical condition which, in the opinion of the investigator, would interfere with the patient's participation in the study.
• Patients who are breastfeeding or are pregnant.
• History of solid organ transplant (kidney, liver, heart, lung) or bone marrow transplant.
• Treatment with any investigational drug (i.e., a drug for which there is no approved indication), including an investigational drug for mitochondrial disease within 1 month prior to receiving the first dose of study drug (or within 3 months for a trial with an investigational biologic).
• Patients with confirmed or suspected increased intracranial pressure, pseudotumor cerebri (PTC)/idiopathic intracranial hypertension, and or papilledema.

Sponsors & Collaborators

• Matthew Demczko: lead

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19146, United States

Location

Related Publications (4)

• Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter RD, Rabinovitch PS, Morgan PG, Sedensky MM, Kaeberlein M. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013 Dec 20;342(6165):1524-8. doi: 10.1126/science.1244360. Epub 2013 Nov 14.

  PMID: 24231806 BACKGROUND

• Johnson SC, Yanos ME, Bitto A, Castanza A, Gagnidze A, Gonzalez B, Gupta K, Hui J, Jarvie C, Johnson BM, Letexier N, McCanta L, Sangesland M, Tamis O, Uhde L, Van Den Ende A, Rabinovitch PS, Suh Y, Kaeberlein M. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front Genet. 2015 Jul 22;6:247. doi: 10.3389/fgene.2015.00247. eCollection 2015.

  PMID: 26257774 BACKGROUND

• Tinker RJ, Falk MJ, Goldstein A, George-Sankoh I, Xiao R, Adang L, Ganetzky R. Early developmental delay in Leigh syndrome spectrum disorders is associated with poor clinical prognosis. Mol Genet Metab. 2022 Apr;135(4):342-349. doi: 10.1016/j.ymgme.2022.02.006. Epub 2022 Feb 19.

  PMID: 35216885 BACKGROUND

• Zheng X, Boyer L, Jin M, Kim Y, Fan W, Bardy C, Berggren T, Evans RM, Gage FH, Hunter T. Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration. Elife. 2016 Mar 23;5:e13378. doi: 10.7554/eLife.13378.

  PMID: 27008180 BACKGROUND

MeSH Terms

Conditions

Leigh Disease

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Matthew Demczko, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: February 19, 2025
• First Posted: February 25, 2025
• Study Start: February 27, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)