ZAGOCIGUAT for MELAS syndrome | Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

Inclusion criteria

• {"criterion_text":"- Signed an IRB/IEC informed consent form (ICF) before any study-specific procedures are performed.\n- 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.\n- If female, meets 1 of the 2 following criteria: a. 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]) OR b. 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)\n- Male and female participants of reproductive potential must agree to use 1 of the following highly effective contraception methods (a or b) from the date of signing the ICF until ≥90 days after receiving their final study drug dose: a. Completely abstain from heterosexual intercourse OR b. If heterosexually active, adhere to ≥1 of the following: • Use a combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, OR intrauterine hormonereleasing system • Have had a bilateral tubal occlusion • Maintain a monogamous relationship with a partner who is permanently sterilized either by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis), hysterectomy, bilateral salpingectomy, or bilateral oophorectomy or is sterile due to postmenopausal status.\n- Female participants on hormone replacement therapy must use ≥1 nonhormonal highly effective contraception methods listed above.\n- Male participants must agree to refrain from donating sperm from the Screening Visit through 90 days after their final dose of study drug.\n- 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.\n- 18 to 75 years of age.\n- Diagnosed with MELAS based on the presence of each of the following criteria: a. A documented pathogenic variant in a mitochondrial DNA (mtDNA) gene. b. History of one or more stroke-like episodes (SLEs) with magnetic resonance imaging (MRI) findings consistent with stroke-like lesions (cortical/sub-cortical changes consistent with tissue damage; calcifications and diffuse atrophy should not be considered confirmatory findings alone). MRI findings can be on a prior MRI and do not need to be on the most recent MRI. 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.\n- Able to complete iDSST and GMLT and scores (redacted information-dummy placeholder) below normative mean on at least one of the following: iDSST, GMLT. (Screening Visit criterion only).\n- Reports “sometimes,” “often,” or “always” on the “fatigue due to MELAS” PGI-F assessment (Screening Visit criterion only).\n- Is ambulatory with or without an assistive device and can complete at least 1 full or partial sit to stand (with arms crossed against chest) during the 30-second test (retest allowed).\n- 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) a. Note: exception may be granted after consultation with Sponsor (eg, for technical difficulties). b. Note: participant must be able to complete the cognitive performance tests independently and be able to answer the PRO questionnaires independently per investigator judgement; caregiver may help set up device/app, log in, etc.\n- Platelet count ≥150,000 platelets/μL (Screening Visit criterion only).\n- 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)."}

Exclusion criteria

• {"criterion_text":"- 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.\n- Electrolyte abnormalities that cannot be corrected per investigator judgment.\n- Estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 by 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (Inker 2021) at Screening Visit.\n- 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.\n- 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.\n- 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.\n- 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.\n- 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). a.Note: one additional orthostatic measure may be taken and used to determine eligibility.\n- 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.\n- Severe gastrointestinal dysmotility that in the opinion of the investigator may impact protocol compliance and/or study drug administration, absorption, and/or tolerance.\n- 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.\n- History of spontaneous fracture(s) that in the investigator’s opinion represents a safety risk for trial participation.\n- Current use of (redacted information-dummy placeholder) ≥325 mg/day, any (redacted information-dummy placeholder) , any (redacted information-dummy placeholder) medication, (redacted information-dummy placeholder) , specific inhibitors of phosphodiesterase 5 (PDE5), (redacted information-dummy placeholder) 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. (see Appendix 1 Prohibited Medications) Note: Arginine and citrulline are allowed.\n- 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.\n- 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 >460 ms for females using Fridericia’s formula (QTcF interval)."}

Primary endpoints

• {"endpoint_text":"- For Week 9 through 12 • PROMIS Fatigue MELAS Short Form (PFM-SF) scores • Groton Maze Learning Test (GMLT) scores • International Digit Symbol Substitution Test (iDSST) scores These 3 endpoints (with weights of 0.4, 0.3, and 0.3, respectively) will be combined using a global statistical test (GST)","definition_or_measurement_approach":"Three component measures collected Week 9–12: PROMIS Fatigue MELAS Short Form (PFM-SF), Groton Maze Learning Test (GMLT), and International Digit Symbol Substitution Test (iDSST); combined into a single outcome using a weighted global statistical test (weights 0.4, 0.3, 0.3)."}
• {"endpoint_text":"- Incidence of treatment-emergent adverse events (TEAEs) from study drug initiation through the Follow-up Visit or end of treatment if a participant continues to the open-label extension study.","definition_or_measurement_approach":"Collection and tabulation of treatment-emergent adverse events from initiation of study drug through Follow-up Visit or end of treatment for participants who enter the open-label extension; incidence reported as counts/rates."}

Secondary endpoints

• {"endpoint_text":"- Number of repetitions completed during the 30-second sit-to-stand test at Week 12","definition_or_measurement_approach":"Count of repetitions completed during a standardized 30-second sit-to-stand test assessed at Week 12."}
• {"endpoint_text":"- PROMIS Cognitive Function MELAS Short Form (PCFM-SF) score for Week 12","definition_or_measurement_approach":"PROMIS Cognitive Function MELAS Short Form administered and scored at Week 12."}
• {"endpoint_text":"- Concentrations of GDF-15 at Week 12","definition_or_measurement_approach":"Laboratory measurement of circulating GDF-15 concentration at Week 12."}
• {"endpoint_text":"- Memory composite scores (One Card Learning and One Back Tests) for Week 9 through 12","definition_or_measurement_approach":"Composite memory score derived from One Card Learning and One Back cognitive tests collected Week 9–12."}

Methods

• Recruitment documentation present: 'K1_Recruitment procedure_27June2024' (recruitment arrangements document associated with Part II submissions).
• Patient-facing recruitment flyers: 'K2_PRIZM Flyer IT 10May2024' (Italy) and 'K2_PRIZM Flyer DE 10May2024' (Germany).
• Study procedures support remote participation elements: study drug may be provided at clinic and/or shipped to participant’s home; home health support is listed among third-party duties.

Italy

Earliest CTIS Part Ii Submission Date

09-10-2024

Latest Decision Or Authorization Date

30-04-2025

Processing Time Days

203

Number Of Sites

3

Number Of Participants

12

Germany

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

24-10-2025

Processing Time Days

375

Number Of Sites

2

Number Of Participants

8

Primary sponsor

Full Name

Tisento Therapeutics Inc.

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

United States

Contract research organisations

Name

Advanced Clinical GmbH

Name

Professional Case Management Clinical Trials LLC

Responsibilities

Home Health

Third parties

• {"country":"United States","full_name":"Merative US LP","duties_or_roles":"eCRF and IRT","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Thread Research Limited","duties_or_roles":"ePro Platform","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pyxant Labs Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"EPL Pathology Archives LLC","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Professional Case Management Clinical Trials LLC","duties_or_roles":"Home Health","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Australia","full_name":"Cogstate Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Rules Based Medicine Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Netherlands","full_name":"Eurofins Central Laboratory B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Travel support/reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Advanced Clinical GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}