An Open Label, Long Term Safety Study of REN001 in Primary Mitochondrial Myopathy Patients (Stride Ahead)

An Open-label, Multi-centre Study to Evaluate the Long-term Safety and Tolerability of REN001 in Subjects With Primary Mitochondrial Myopathy (PMM)

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.

Study Overview

• Status: Terminated
• Conditions: Primary Mitochondrial Myopathy
• Intervention / Treatment: Drug: REN001

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.

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Study Clinical Trial Coordinator; Phone Number: +44 (0) 1304 809360; Email: clintrialinfo@reneopharma.com

Study Locations

• Australia
  • New South Wales
    • St. Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • PARC Clinical Research
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
• Belgium
  • Leuven, Belgium, 3000
    • University Hospital Leuven
• Canada
  • Vancouver, Canada, V5Z 1M9
    • Vancouver General Hospital
  • Alberta
    • Calgary, Alberta, Canada, T2E 7Z4
      • M.A.G.I.C. Clinic (Metabolics and Genetics in Calgary)
• Denmark
  • Copenhagen, Denmark, 2100
    • Copenhagen Neuromuscular Center
• France
  • Angers, France, 49933
    • Centre de Référence des Maladies Neuromusculaires
  • Bron, France, 69599
    • Hôpital Neurologique
  • Nice, France
    • Nice Teaching Hospital
  • Paris, France, 75013
    • Hôpitaux Universitaires Pitié Salpêtrière
  • Strasbourg, France, 6700
    • CHU de Strasbourg- Hopital de Hautepierre
  • Hauts De France
    • Lille, Hauts De France, France, 59037
      • Hopital Roger Salengro
• Germany
  • Bonn, Germany, 53127
    • University Hospital Bonn Clinic and Polyclinic for Neurology
  • Munich, Germany, 80336
    • Medical Center of the University of Munich Friedrich Baur Institute at the Neurological Clinic and Polyclinic
• Hungary
  • Budapest, Hungary, 1082
    • Semmelweis University Insitute of Genomics and Rare Disorders
  • Pécs, Hungary, 7624
    • University of Pécs Clinical Centre
• Italy
  • Bologna, Italy, 40139
    • IRCCS Institute of Neurological Sciences of Bologna
  • Milan, Italy, 20100
    • Istituto Nazionale Neurologico Carlo Besta
  • Pisa, Italy, 56100
    • U.O. di Neurologia - Neurofisiopatologia
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS Neurophysiopathology Unit
  • Sicilia
    • Messina, Sicilia, Italy, 98125
      • A.O.U Policlinico di Messina U.O.C Neurologia e Malattie Neuromuscolari
• Netherlands
  • Nijmegen, Netherlands, 6525EX
    • Radboud Universitair Medisch Centrum
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1042
      • Centre for Brain Research Neurogenetic Clinic
• Spain
  • Madrid, Spain, 20841
    • Hospital Universitario 12 de octubre
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe
• United Kingdom
  • Salford, United Kingdom, M5 5AP
    • Salford Royal NHS Foundation Trust
  • Greater London
    • London, Greater London, United Kingdom, WC1N 3BG
      • Queen Square Centre for Neuromuscular Diseases
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE1 4LP
      • The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: REN001; 100 mg once daily	Drug: REN001; Once daily dosing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events, serious adverse events, and withdrawals due to adverse events	Number and Severity	Baseline to Study Termination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in distance walked during a 12 Minute Walk Test	Distance walked in meters	Baseline to Month 24
Change in Modified Fatigue Impact Scale (MFIS) score	The MFIS is a 21-item scale to describe the impact of fatigue on physical, cognitive, and psychosocial functioning. The questionnaire includes 9 physical, 10 cognitive, and 2 psychosocial items with each item scored between 0=Never and 4=Almost Always	Baseline to Month 24
Change in Patient Global Impression of Severity (PGIS) score	The PGIS is a 2-item questionnaire to describe the severity of fatigue and muscle symptoms. Each item is scored as Absent, Mild, Moderate, Severe, or Very Severe	Baseline to Month 24
Change in Brief Pain Inventory (BPI) score	The BPI is a 15-item questionnaire to describe severity of pain and its interference on functioning. The questionnaire includes 4 pain severity items each scored between 0=No Pain and 10= Pain, and 7 pain interference items each scored between 0=Does not Interfere and 10=Completely Interferes	Baseline to Month 24
Change in Patient Reported Outcomes Measurement Information System (PROMIS) Short Form - Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 13a scores	The PROMIS Short Form - FACIT Fatigue 13a is a 13-item questionnaire to describe fatigue and its impact upon daily activities and function. Each item is scored between 1=Not At All and 5=Very Much	Baseline to Month 24
Change in 36-Item Short Form Health Survey (SF-36) score	The SF-36 is a 36-item questionnaire to describe health status and quality of life. The questionnaire includes 8 domains (physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions). Items are scored, summed into domains, and transformed into a scale of 0-100	Baseline to Month 24
Change Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) score	The WPAI:SHP is a 6-item questionnaire to describe impairment in work and activities due to a certain disease. Items are scored, summed, and transformed into a scale of 0-100%	Baseline to Month 24
Change in Patient Global Impression of Change (PGIC) score	The PGIC is a 2-item questionnaire to describe the change in fatigue and muscle symptoms since starting the study. Each item is scored as Very Much Worse, Moderately Worse, Minimally Worse, No Change, Minimally Improved, Moderately Improved, or Very Much Improved	Baseline to Month 24
Absolute values, changes from baseline, and incidence of potentially clinically significant changes in laboratory safety tests, electrocardiograms, supine vital signs, and eye assessments	Number of participants	Study Termination

Collaborators and Investigators

• Sponsor: Reneo Pharma Ltd
• Investigators: Principal Investigator: Grainne Gorman, MD, Newcastle Hospital NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): December 14, 2023
• Study Completion (Actual): January 31, 2024

Study Registration Dates

• First Submitted: February 24, 2022
• First Submitted That Met QC Criteria: March 3, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Mitochondrial Diseases; Muscular Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: REN001-202

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.: Yes