Clinical trial NCT05267574: An Open Label, Long Term Safety Study of REN001 in Primary Mitochondrial Myopathy Patients (Stride Ahead)
Official title: An Open-label, Multi-centre Study to Evaluate the Long-term Safety and Tolerability of REN001 in Subjects With Primary Mitochondrial Myopathy (PMM)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Primary Mitochondrial Myopathy
Lead sponsor: OnKure, Inc.
Sponsor class: INDUSTRY
First posted: 2022-03-04
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the long-term safety and tolerability of REN001 administered once daily to subjects with PMM due to mitochondrial DNA mutations (mtDNA-PMM) or nuclear DNA mutations (nDNA-PMM). Subjects with mtDNA mutations will have previously completed Study REN001-201 or participated in Study REN001-101. Subjects with nDNA mutations who enroll in this study will be REN001- naïve.

Detailed description: This study is designed to evaluate the long-term safety and tolerability of REN001 administered once daily to subjects with PMM due to mitochondrial DNA mutations (mtDNA=PMM) or nuclear DNA mutations (nDNA-PMM). Subjects with mtDNA mutations will have previously completed Study REN001-201 (which is referred to as the STRIDE study) or participated in Study REN001-101. Subjects with nDNA mutations who enroll in this study will be REN001- naïve.

Eligible subjects will be treated with REN001 100mg orally, once daily for 24 months. Following the baseline visit there are planned visits at at defined time points. A final follow-up telephone call will be made by the study centre to the subject approximately 30 days after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

* mtDNA-PMM subjects: Completed treatment in STRIDE or was participating in Study REN001-101 when the study stopped due to the COVID-19 pandemic, and in the opinion of the Investigator and Sponsor had been compliant with the study requirements OR nDNA-PMM subjects: Subjects aged 18 years or older with known nuclear (nDNA) pathogenic variants with a major muscle phenotype consisting of objective myopathy with poor exercise tolerance. Proof of pathogenicity must be provided. Must be able to walk at least 100m in the screening 12MWT and the limitations in walk test must be primarily due to the energy deficit and not due to ataxia or any other condition. For subjects under 25 years old only: confirmation of bone growth plate closure by wrist radiograph.
* Have PMM which continues to be primarily characterized by exercise intolerance or active muscle pain.
* Willing and able to swallow the REN001 gelatin capsules.
* Concomitant medications (including supplements) intended for the treatment of PMM or other co-morbidities likely to remain stable throughout participation in the study where clinically possible.
* Signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
* Females should be either of non-child-bearing potential or must agree to use highly effective methods of contraception from baseline through to approximately 30 days after the last dose of study drug. Males with partners who are women of childbearing potential (WOCBP) must also use contraception from baseline through to 14 weeks after the last dose of study drug.

Exclusion Criteria:

* Anticipated to need a peroxisome proliferator-activated receptor (PPAR) agonist other than REN001 during the study.
* Intent to donate blood, or blood components during the study or within one month after completion of the study.
* Current drug dependency. Use of opiates/cannabis for medical reasons is acceptable with prescription evidence or at the Investigator's discretion.
* Current alcohol dependency.
* Any medical, psychiatric or laboratory condition that may increase the risk associated with study participation or interfere with the interpretation of study results and, in the judgment of the Investigator and Medical Monitor, would make the subject inappropriate for entry into this study.
* Pregnant or nursing female

Subjects with mtDNA mutations can enroll at STRIDE Week 24 visit, STRIDE-FU visit, after exiting from STRIDE or after exiting REN001-101 (UK only). Subjects enrolling after exiting from either of the 2 feeder mtDNA studies and all subjects with nDNA mutations will be required to fulfill additional exclusion criteria during their additional screening visit. This is required for the mtDNA-PMM subjects due to the gap in study drug treatment and period of time without study assessments. The additional exclusion criteria are:

1. Clinically significant kidney disease or impairment calculated as eGFR Grade 2 or above \<60ml/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation at Screening.
2. Clinically significant liver disease or impairment of AST or ALT Grade 2 or above (\>2.5 x ULN), or Total bilirubin \> 1.6 x ULN or \>ULN with other signs and symptoms of hepatotoxicity at Screening.
3. Subjects with uncontrolled diabetes and/or a Screening HbA1c of ≥11%.
4. Evidence of significant concomitant clinical disease that may need a change in management during the study or could interfere with the conduct or safety of this study. (Stable well-controlled chronic conditions such hypercholesterolemia, gastroesophageal reflux, or depression under control with medication (other than tricyclic antidepressants), are acceptable provided the symptoms and medications would not be predicted to compromise safety or interfere with the tests and interpretations of this study.)
5. Subjects with a history of cancer. A history of in situ basal cell carcinoma in the skin is allowed.
6. Clinically significant cardiac disease and/or clinically significant ECG abnormalities such as 2nd degree heart block, symptomatic tachyarrhythmia or unstable arrhythmia (right bundle branch block, left fascicular block and long PR interval are not excluded) that in the opinion of the Investigator should exclude the subject from completing exercise tests.

Primary outcomes:
measure: Number of Participants With Mild, Moderate, Severe TEAEs, TEAEs Leading to Study Discontinuation, All TEAEs and All TESAEs
timeFrame: Baseline through study termination, an average of 12.1 months
Secondary outcomes:
measure: Absolute Values, Changes From Baseline, and Incidence of Potentially Clinically Significant Changes in Laboratory Safety Tests, Electrocardiograms, Supine Vital Signs, and Eye Assessments
timeFrame: Study Termination
measure: Change in Distance Walked During a 12 Minute Walk Test
timeFrame: Baseline to Month 24
measure: Change in Modified Fatigue Impact Scale (MFIS) Score
timeFrame: Baseline to Month 24
measure: Change in Patient Global Impression of Severity (PGIS) Score
timeFrame: Baseline to Month 24
measure: Change in Brief Pain Inventory (BPI) Score
timeFrame: Baseline to Month 24
measure: Change in Patient Reported Outcomes Measurement Information System (PROMIS) Short Form - Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 13a Scores
timeFrame: Baseline to Month 24
measure: Change in 36-Item Short Form Health Survey (SF-36) Score
timeFrame: Baseline to Month 24
measure: Change Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) Score
timeFrame: Baseline to Month 24
measure: Change in Patient Global Impression of Change (PGIC) Score
timeFrame: Baseline to Month 24
Other outcomes:
Locations:
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: PARC Clinical Research
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Calgary
country: Canada
facility: M.A.G.I.C. Clinic (Metabolics and Genetics in Calgary)
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
city: Copenhagen
country: Denmark
facility: Copenhagen Neuromuscular Center
city: Lille
country: France
facility: Hôpital Roger Salengro
state: Hauts De France
city: Angers
country: France
facility: Centre de Référence des Maladies Neuromusculaires
city: Bron
country: France
facility: Hôpital Neurologique
city: Nice
country: France
facility: Nice Teaching Hospital
city: Paris
country: France
facility: Hôpitaux Universitaires Pitié Salpêtrière
city: Strasbourg
country: France
facility: CHU de Strasbourg- Hopital de Hautepierre
city: Bonn
country: Germany
facility: University Hospital Bonn Clinic and Polyclinic for Neurology
city: Munich
country: Germany
facility: Medical Center of the University of Munich Friedrich Baur Institute at the Neurological Clinic and Polyclinic
city: Budapest
country: Hungary
facility: Semmelweis University Insitute of Genomics and Rare Disorders
city: Pécs
country: Hungary
facility: University of Pécs Clinical Centre
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS Neurophysiopathology Unit
state: Lazio
city: Messina
country: Italy
facility: A.O.U Policlinico di Messina U.O.C Neurologia e Malattie Neuromuscolari
state: Sicilia
city: Bologna
country: Italy
facility: IRCCS Institute of Neurological Sciences of Bologna
city: Milan
country: Italy
facility: Istituto Nazionale Neurologico Carlo Besta
city: Pisa
country: Italy
facility: U.O. di Neurologia - Neurofisiopatologia
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
city: Grafton
country: New Zealand
facility: Centre for Brain Research Neurogenetic Clinic
state: Auckland
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: London
country: United Kingdom
facility: Queen Square Centre for Neuromuscular Diseases
state: Greater London
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust
state: Tyne And Wear
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: Newcastle Hospital NHS Foundation Trust
name: Grainne Gorman, MD
role: PRINCIPAL_INVESTIGATOR
References: