Substantial Amendment 01 This amendment relates to two additional documents not previously submitted as part of the initial REC approval process. These documents include: • AIMM Sleep Wake Diary (attached) – This is a diary to be used for the subset of participants who will undergo activity monitoring as part of the trial. It is detailed in the approved trial protocol but was not included in the original application • Pregnancy Follow-up Consent Form - To formally obtain consent for follow-up for trial participants or their partner should a pregnancy occur during their participation in the trial

Substantial Amendment 02 Inclusion criteria updated to include patients (≥ 16 years) with clinician-confirmed, genetically proven mitochondrial myopathy. Protocol, PIS, Brief PIS and Lily wording adverts updated to reflect change Assay analysis of primary outcome measure changed following assay validation work Secondary outcome measure of cycle ergometry made optional due to COVID-19 and access to facilities Frequency of follow-up phone calls reduced from weekly to Weeks 1, 2, 4 and 8, and optional at Week 10 Options for participants wishing to withdraw from trial or from active treatment clarified and refined to withdrawal from active treatment with continued follow-up by trial team, or withdrawal with no further data collection; protocol updated and Participant Withdrawal Form and Discontinuation of Treatment Form created Protocol updated to allow use of routine bloods taken in previous three months period to be used for screening, to minimise visit length participant burden Protocol updated to provide more contraceptive guidance for participants and their partners while on the trial Protocol updated to include signposting of participants via Patient Identifying Centres (PICs) Staffing and contact detail changes: • Protocol, GP letter, Hospital Consultant letter, Thank you letters, invitation letter and consent form - Update of Chief Investigator’s title and role • Protocol updated to include: additional trial management and data management staff, updated Sponsor Pharmacy email and Sponsor address, and to remove Prof Turnbull as a Co-investigator Information sheets created to provide participants with information prior to, and following, muscle biopsy Pregnant Partner Information sheet created to provide information formally to a pregnant partner of a trial participant, prior to obtaining their consent for pregnancy follow-up and to accompany previously approved Consent to Follow up Form

Substantial Amendment 03 Dr Naomi Thomas replaced Professor Gráinne Gorman as Principal Investigator at the single trial site PIC Site Invitation Letter created for PIC sites to give to potential participants Patient Information Sheet, brief Patient Information Sheet, invitation letter and adverts updated to correct timings of follow-up phone calls

Substantial Amendment 04 Change of Trial Manager Transfer of Physical Examination and assessment of Vital Signs from Baseline to Screening Addition of Oxygen saturations to Vital Signs tests ECG only to be performed in patients undergoing exercise testing Removal of laboratory analyses in trial protocol: Investigation of potential molecular markers of mitochondrial biogenesis, and metabolomic analysis to identify novel biomarkers in blood and urine Alteration of laboratory analyses: use of an assay kit forNAD+/NADH ratio via metabolomics in muscle, and quantitative proteomics analysis made optional Correction of typographical errors in protocol Addition of box for witness details to Informed Consent Form, and amendment of wording in Patient Information Sheet and protocol to allow for oral consent, with independent witnessing and signature of the Consent Form, for patients with weakness/ataxia due to their condition Addition of information relating to site procedures to manage potential non-availability of web-based randomisation system Change of individual performing expectedness assessment of SARs, due to change in Sponsor process Avoidance of unblinding during recruitment process, in this cohort of patients Update to Contraception Guidance to include exclusively same-sex relationships Protocol updated to state that eligibility bloods analysed in Newcastle Laboratories in previous three months are acceptable for screening Clarification of which staff members can carry out follow-up phone calls Separation of Chief Investigator (CI) and Principal Investigator (PI) responsibilities Addition of information relating to filing withdrawal forms at site Clarification of: SAE, site pregnancy reporting, and Statistics procedures, and timing of dispensing and fitting of wearable activity monitor, and provision of sleep-wake diary

Substantial Amendment 05 This amendment was submitted for the formal halt of trial recruitment. A temporary recruitment pause was necessary as the trial IMP reached the end of its shelf life as a result of COVID-19 and delays to the second IMP campaign.

Substantial Amendment 06 Change of definition of end of trial, from Last Patient Last Visit (LPLV) date, to date of last data collection for last participant.