Clinical Trials

Inclusion Criteria: 

• Signed an IRB/IEC informed consent form (ICF) before any study-specific procedures are performed.
• 18 to 75 years of age.
• Diagnosed with MELAS based on the presence of each of the following criteria:
  • A documented pathogenic variant in a mitochondrial DNA (mtDNA) gene.
  • History of one or more stroke-like episodes (SLEs) with magnetic resonance imaging (MRI) findings consistent with stroke-like lesions.

Note: neurological symptoms consistent with SLE include seizures (focal or generalized) often accompanied by sudden focal neurological deficits; recurrent headaches, sometimes associated with vomiting; and/or encephalopathy with altered level of consciousness with or without acute mental deterioration, which can be slowly progressive and/or reversible.

• Scores >1 standard deviation below normative mean on composite memory score from One Back and One Card Learning tests (Screening Visit criterion only).
• Reports “sometimes,” “often,” or “always” on the “fatigue due to MELAS” PGI-F assessment (Screening Visit criterion only).
• Can complete at least 1 sit-to-stand repetition (with arms crossed against chest) during the 30-second test interval.
• Completed all at-home weekly activities (ie, cognitive performance battery, PFM-SF, and PGI items) for at least the final 3 weeks of the Screening period and at least 1 PCFM-SF during the Screening Period (Day 1 criterion)
  • Note: exception may be granted after consultation with Sponsor for technical difficulties or similar.
  • Note: participant must be able to complete the cognitive performance tests independently; caregiver may help set up tablet, log in, etc. Caregiver may help enter the participant’s responses for the PFM-SF, PGI items, and PCFM-SF.
• Platelet count ≥ 150,000 platelets/μL (Screening Visit criterion only).
• On an optimized, stable dose of Vitamin D supplement per investigator judgment. If NOT on Vitamin D supplement, has Vitamin D > 30 ng/mL (Screening Visit criterion only).
• If diagnosed with a concurrent psychiatric condition (eg, bipolar disorder, anxiety disorder, depression), has been stable and on a consistent treatment regimen for at least 6 months prior to randomization.
• If female, meets 1 of the 2 following criteria:
  • Confirmed as being postmenopausal (no menses for ≥ 1 year or ≥ 12 consecutive months) or surgically sterile (bilateral oophorectomy, hysterectomy, or tubal sterilization [tie, clip, band, or burn]).
  • If of reproductive potential:
    • Is not pregnant or breastfeeding at the time of the Screening Visit and
    • Has negative pregnancy test results at the Screening Visit (serum) and predose on Day 1 (urine)
• Male and female participants of reproductive potential must agree to use 1 of the following effective contraception methods (a or b) from the date of signing the ICF until ≥ 90 days after receiving their final study drug dose:
  • Completely abstain from heterosexual intercourse OR
  • If heterosexually active, adhere to ≥ 1 of the following:
    • Use an intrauterine device and/or a progesterone implant OR
    • Use a combination of 2 highly effective birth control methods (eg, condom with spermicide + diaphragm or cervical cap; hormonal contraceptive [eg, oral or transdermal patch or progesterone implant] + barrier method) OR
    • Maintain a monogamous relationship with a partner who has been surgically sterilized either by vasectomy (conducted ≥ 60 days before the Screening Visit or confirmed via sperm analysis), bilateral oophorectomy, hysterectomy, or tubal sterilization, or is sterile due to postmenopausal status.
• Female participants on hormone replacement therapy must use ≥ 1 nonhormonal highly effective contraception methods listed above.
• Male participants must agree to refrain from donating sperm from the Screening Visit through 90 days after their final dose of study drug.
• Female participants must agree to refrain from egg donation for 30 days after the final dose and from breastfeeding through 90 days after the final dose of study drug.
• Agrees to follow lifestyle restrictions.

Exclusion Criteria:

• Severe visual impairment that precludes participant ability to complete cognitive performance tests independently.
  • Note: a caregiver can provide support for the patient throughout the study (eg, attending and scheduling study visits, facilitating compliance, reading questions, and entering the participant’s responses to questions on the PRIZM study app).
• Systolic blood pressure (BP) < 90 mmHg or diastolic BP < 60 mmHg (average of 2 measures separated by at least 2 minutes).
  • Note: a second set of BP measurements may be taken and the average of those 2 measures may be used to determine eligibility.
• Orthostatic hypotension, defined as a decrease in systolic BP of ≥ 20 mmHg or a decrease in diastolic BP of ≥ 10 mmHg when measured after assuming a standing position from a semi-recumbent/supine position (see Section 7.9.1 for instructions for measurement of orthostatic BP)
  • Note: one additional orthostatic measure may be taken and used to determine eligibility.
• Active malignancy or any other cancer that in the opinion of the investigator is significant enough to confound the results of this study. An active malignancy refers to any unresolved malignancy that warrants treatment or is currently undergoing treatment. Exception may be granted for some active malignancies such as basal cell or squamous epithelial carcinomas of the skin after consultation with the Sponsor.
• Severe gastrointestinal dysmotility that in the opinion of the investigator may impact protocol compliance and/or study drug administration, absorption, and/or tolerance.
• Recent history (within last 6 months) of platelet dysfunction, hemophilia, von Willebrand disease, coagulation disorder, other bleeding diathesis condition(s), or significant, nontraumatic bleeding episodes.
• History of spontaneous fracture(s) that in the investigator’s opinion represents a safety risk for trial participation. 8. Current use of aspirin ≥ 325 mg/day, any P2Y12 inhibitor, any anticoagulant medication, breast cancer resistance protein (BCRP) substrates (ie, lipid-lowering statins, sulfasalazine, tyrosine-kinase inhibitors), BCRP inhibitors (ie, febuxostat, omeprazole), specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of PDE5 (including dipyridamole and theophylline), any supplement for the treatment of erectile dysfunction, riociguat, vericiguat, and/or any nitrate. These medications are prohibited from the Screening Visit through the duration of study participation. Investigators are encouraged to discuss any concerns with the study Medical Monitor.

Note: Arginine and citrulline are allowed.

• Within the 21 days before P1 Day 1, any change in supplements/medications (including in dose and/or frequency).
  • Note: exception may be granted after consultation with Sponsor.
• Clinically significant cardiac involvement that may preclude a patient from safely participating in the study, interfere with study procedures or investigational drug administration in the opinion of the investigator, or an ECG with a corrected QT interval > 450 ms for males or > 480 ms for females using Fridericia’s formula (QTcF interval).
• Any history of a suicidal attempt (actual, interrupted, or aborted) as assessed by the C-SSRS. Exception may be granted in individual cases after consultation with the Sponsor to understand the timeframe and seriousness.
• Any severe acute decompensation, significant disease exacerbation per the investigator, or inpatient hospitalization (eg, SLE) within the 4 weeks prior to the Screening Visit or during the Screening Period.
• Current or prior participation in an interventional clinical trial within 90 days of Day 1 or currently enrolled in a non-interventional clinical trial that, in the opinion of the investigator, may confound the results of the current trial.
• Any medical or other condition that, per investigator judgment, would preclude safe study participation, safe management of study drug, and/or completion of all trial requirements.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 4/29/2024. Questions regarding updates should be directed to the study team contact.