Sirolimus for Leigh Syndrome

A Pilot Phase 2 Study With Long-Term Extension to Assess the Safety and Efficacy of Sirolimus in Patients With Leigh Syndrome Caused by Genetically-Confirmed Mitochondrial Respiratory Chain Deficiency

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

Study Overview

• Status: Enrolling by invitation
• Conditions: Leigh Syndrome
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

This is a pilot phase 2 study with long-term extension to evaluate the safety and efficacy of enteral sirolimus in patients with genetically-confirmed Leigh syndrome.

Sirolimus will be given daily at a starting dose of 0.8 to 1.3 mg/m2 depending on subject age, weight, and BSA (body surface area). Dosage will be adjusted as needed based on sirolimus trough level to maintain patients within a range of 5 to10 ng/mL, a level lower than what is targeted in renal transplant recipients. Patients will be followed through this study for up to 24 weeks in the active phase. Participants who are eligible for the long-term extension may choose to stay on drug for up to 2 years thereafter

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Age 6 months to 55 years at the time of enrollment.
3. Weight ≥ 5 kg at the time of enrollment.
4. 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.
5. Adequate renal function as evidenced by glomerular filtration rate (GFR) > 60 mL/min/1.73m2 (cystatin C for pediatric population).

6. Normal hematologic parameters as defined as:

   1. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
   2. Platelet count ≥ 100,000/mm3 (100 x 109/L)
   3. Hemoglobin ≥ 9 g/dL
7. Non-fasting serum triglycerides and cholesterol < 300 mg/dL.
8. Serum amylase and lipase < 2x ULN.

9. Adequate immunoglobulin levels as outlined below that, in the opinion of the investigator, will not place the patient at increased risk of infection.

   1. Immunoglobulin G (IgG) ≥ 200 mg/dL
   2. Immunoglobulin M (IgM) ≥ 30 mg/dL
   3. Immunoglobulin A (IgA) ≥ 10 mg/dL

10. All sexually active participants must agree to use effective contraception:

    1. Females of child-bearing potential must agree to use effective contraception without interruption from 28 days prior to starting Investigational Product (IP) throughout 3 months after last dose of IP and have a negative urine pregnancy test result at screening and agree to ongoing pregnancy testing during the course of the study.
    2. Male patients must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after the last dose of investigational drug.
11. The patient or parent(s)/legal guardian(s) is/are willing and able to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator.
12. The patient or the patient's parent(s)/legal guardian(s) understand(s) and voluntarily sign(s) the informed consent documents(s) prior to any study-related assessments/procedures being conducted.

Exclusion Criteria:

1. 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.
2. Patients with implanted cardiac assist/medical devices (including pacemakers), unless device was implanted prophylactically, and the patient is clinically asymptomatic.
3. In the opinion of the investigator, clinically significant ECG and/or echocardiogram alterations at the time of screening.
4. Myocardial infarction within 6 months prior to enrollment.
5. Symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or unstable coronary artery disease.
6. Prior history of hypersensitivity to sirolimus or other mTOR (Mechanistic Target of Rapamycin inhibitors).
7. Prior history of angioedema requiring treatment or cessation of a presumed causative agent.
8. Planned surgical procedure during the study period.
9. Confirmed or highly suspected immunodeficiency disorder(s), including but not limited to, common variable immune deficiency (CVID), complement deficiency, etc.
10. Clinically significant proteinuria that requires ongoing medical therapy.
11. Any uncontrolled psychiatric or medical condition which, in the opinion of the investigator, would interfere with the patient's participation in the study.
12. Patients who are breastfeeding or are pregnant.
13. History of solid organ transplant (kidney, liver, heart, lung) or bone marrow transplant.
14. 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).
15. Patients with confirmed or suspected increased intracranial pressure, pseudotumor cerebri (PTC)/idiopathic intracranial hypertension, and or papilledema.
16. Currently active malignancy (other than adequately treated non-melanoma skin cancers [i.e., squamous cell and/or basal cell carcinoma], carcinoma in situ of the cervix, or other adequately treated carcinoma in situ) and/or ongoing treatment for malignancy are ineligible. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for ≥ 1 year.
17. Recent infection requiring systemic anti-infective treatment that was completed ≤ 14 days prior to enrollment.
18. Uncontrolled diabetes mellitus, as defined by HbA1c > 8%, despite adequate therapy.
19. History of interstitial lung disease and/or pneumonitis.
20. Use of strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4 (CYP3A4) and/or p-glycoprotein (p-GP) within the 14 days prior to receiving the first dose of study drug. Additionally, use of any known CYP3A4 substrates with a narrow therapeutic window (e.g., fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfenadine) within the 14 days prior to receiving the first dose of study drug.
21. Use of medications with a high risk of angioedema
22. Known human immunodeficiency virus (HIV), active hepatitis B or hepatitis C infection(s).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2A; 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; Sirolimus will be given at a starting dose of 0.8 to 1.3 mg/m2 twice daily, depending on subject age and weight.; Other Names: Rapamycin; Rapamune
Experimental: Long-Term Extension; Eligible participants may continue Sirolimus treatment for up to two (2) years.	Drug: Sirolimus; Sirolimus will be given at a starting dose of 0.8 to 1.3 mg/m2 twice daily, depending on subject age and weight.; Other Names: Rapamycin; Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MM-COAST Score	Mitochondrial Myopathy-Composite Assessment Tool (MM-COAST) is a composite assessment tool used to measure the domains of muscle strength, muscle fatigue, balance, dexterity, and exercise intolerance. Scores are assigned for each domain assessment, based on z-score or % decrement for muscle fatigue, summed and averaged to achieve a domain score. The mean domain score is reported as the MM-COAST Composite Score.	Baseline up to end of study (up to 2.5 years)
Change in GMFM (Gross Motor Function Measure) Score	The GMFM is a clinical tool used assess changes in gross motor functions in 5 dimensions (1. lying and rolling, 2. sitting, 3. crawling and kneeling, 4. standing, and 5. walking, running, and jumping). Each task is scored as 0-does not initiate, 1-initiates, 2-partially completes, and 3-completed. Item scores are summed to calculate raw and percent scores for each of the five dimensions. Dimension percent scores are averaged to obtain an overall total score.	Baseline up to end of study (up to 2.5 years)
Change in Movement Disorder-Childhood Rating Score (MDCRS)	The MDCRS is a scale used to evaluate the impact of movement disorder on patient motor function and daily living activities. Severity of movement disorder in different regions of the body at rest, and during specific tasks, is ranked from 0 (no movement disorder) to 4 (severe movement disorder). Item scores are summed to calculate total score, with a higher total score indicating greater overall impact of movement disorder on daily functioning.	Baseline up to end of study (up to 2.5 years)
CGI Scale	The CGI (Clinical Global Impression Scale) is a 3-item clinician-rated scale used to assess severity of illness, global improvement, and therapeutic response. Degree of global improvement for participants receiving sirolimus will be assessed by the investigator and rated on a scale 7-point scale based on improvement from baseline from 1 (very much improved) to 7 (very much worse). A lower score indicates greater response to treatment.	Baseline up to end of study (up to 2.5 years)
Change in Barry-Albright Dystonia Scale (BADS)	The Barry-Albright Dystonia Scale is used to assess dystonia in 8 bodily regions: eyes, mouth, neck, trunk, and each upper and lower extremity. Each bodily region is scored based on a scale from 0 (absent) to 4 (severe symptoms). Total BADS score ranges from 0 (dystonia absent) to 32 (severe dystonia).	Baseline up to end of study (up to 2.5 years)
Change in Scale for the Assessment and Rating of Ataxia (SARA)	The SARA is an 8-item performance-based scale that assesses ataxia. Patients are evaluated based on their ability to perform a series of tasks with a cumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia).	Baseline up to end of study (up to 2.5 years)
Newcastle Pediatric Mitochondrial Disease Scale (NPMDS)	The NPMDS evaluates the progression of mitochondrial disease in pediatric patients in 4 domains: current function, system specific involvement, current clinical assessment and quality of life. Domain scores are summed for total score with higher scores indicating worse conditions.	Baseline up to end of study (up to 2.5 years)
Newcastle Adult Mitochondrial Disease Scale (NMDAS)	Evaluation of disease progression in adults. Each question in the NMDAS section I-III has a possible score from 0-5. The total score is calculated by summing the scores obtained for each question. The higher the score the more severe the disease.	Baseline up to end of study (up to 2.5 years)
Change in PEDI-CAT Score	Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a test that evaluates daily functional activities. A t-score of 50 represents the function of the general population (SD of 10). A t-score below 30 reflects poor performance compared to the general population. The range for the scores are 20-80.	Baseline up to end of study (up to 2.5 years)
Patient Global Impression of Change (PGIC)	Patients rate their impression of overall change from baseline on a 7-point scale from 0 (no change or condition is worse) to 7 (a great deal better). PGIC indicates a patient's belief of treatment efficacy	Baseline up to end of study (up to 2.5 years)
Change in PedsQL	Pediatric Quality of Life Inventory (PedsQL) is a 23-item questionnaire that evaluates health-related quality of life that is reported as 3 summary scores including Physical Health, Psychosocial Health and School/Work, as well as a total score (sum of summary scores). Total score ranges from 0-100 with a higher score indicating better quality of life.	Baseline up to end of study (up to 2.5 years)
Change in Karnofsky-Lansky	Karnofsky Lansky Scale: 0-100. 0-40: Unable to care for self, requires equivalent of institutional or hospital care; disease may be progressing rapidly. 50-70: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed. 80-100: Able to carry on normal activity and to work; no special care needed.	Baseline up to end of study (up to 2.5 years)
Change in MFIS	The MFIS (Modified Fatigue Impact Scale) evaluates fatigue using a total MFIS score (0-84), where higher scores indicate greater impact of fatigue on an individual's activities and scores above 38 are considered to be indicative of fatigue. The MFIS is calculated from the sum of three subscales: the Physical Subscale (0-36), the Cognitive Subscale (0-40), and the Psychosocial Subscale (0-8), where higher scores indicate a greater impact of fatigue in each domain.	Baseline up to end of study (up to 2.5 years)

Collaborators and Investigators

• Sponsor: Matthew Demczko
• Investigators: Principal Investigator: Matthew Demczko, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 19, 2025
• First Submitted That Met QC Criteria: February 19, 2025
• First Posted (Actual): February 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Carbohydrate Metabolism, Inborn Errors; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Pyruvate Metabolism, Inborn Errors; Mitochondrial Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Leigh Disease; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 24-022433

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No