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

Primary Mitochondrial Myopathy Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05267574
• Other study ID #: REN001-202
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: February 1, 2022
• Est. completion date: January 31, 2024

Study information

• Verified date: June 2023
• Source: Reneo Pharma Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 155
• Est. completion date: January 31, 2024
• Est. primary completion date: December 14, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Mitochondrial Myopathies
• Muscular Diseases
• Primary Mitochondrial Myopathy

Intervention

Drug:
• REN001
Once daily dosing

Locations

Country	Name	City	State
Australia	PARC Clinical Research	Adelaide	South Australia
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Belgium	University Hospital Leuven	Leuven
Canada	M.A.G.I.C. Clinic (Metabolics and Genetics in Calgary)	Calgary	Alberta
Canada	Vancouver General Hospital	Vancouver
Denmark	Copenhagen Neuromuscular Center	Copenhagen
France	Centre de Référence des Maladies Neuromusculaires	Angers
France	Hôpital Neurologique	Bron
France	Hôpital Roger Salengro	Lille	Hauts De France
France	Nice Teaching Hospital	Nice
France	Hôpitaux Universitaires Pitié Salpêtrière	Paris
France	CHU de Strasbourg- Hopital de Hautepierre	Strasbourg
Germany	University Hospital Bonn Clinic and Polyclinic for Neurology	Bonn
Germany	Medical Center of the University of Munich Friedrich Baur Institute at the Neurological Clinic and Polyclinic	Munich
Hungary	Semmelweis University Insitute of Genomics and Rare Disorders	Budapest
Hungary	University of Pécs Clinical Centre	Pécs
Italy	IRCCS Institute of Neurological Sciences of Bologna	Bologna
Italy	A.O.U Policlinico di Messina U.O.C Neurologia e Malattie Neuromuscolari	Messina	Sicilia
Italy	Istituto Nazionale Neurologico Carlo Besta	Milan
Italy	U.O. di Neurologia - Neurofisiopatologia	Pisa
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS Neurophysiopathology Unit	Roma	Lazio
Netherlands	Radboud Universitair Medisch Centrum	Nijmegen
New Zealand	Centre for Brain Research Neurogenetic Clinic	Grafton	Auckland
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitari i Politècnic La Fe	Valencia
United Kingdom	Queen Square Centre for Neuromuscular Diseases	London	Greater London
United Kingdom	The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne	Tyne And Wear
United Kingdom	Salford Royal NHS Foundation Trust	Salford

Sponsors (1)

Lead Sponsor	Collaborator
Reneo Pharma Ltd

Countries where clinical trial is conducted

Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Hungary,  Italy,  Netherlands,  New Zealand,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of adverse events, serious adverse events, and withdrawals due to adverse events	Number and Severity	Baseline to Study Termination
Secondary	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
Secondary	Change in distance walked during a 12 Minute Walk Test	Distance walked in meters	Baseline to Month 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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