Efficacy and Safety Evaluation of Zagociguat in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) Patients
- Trial ID
- 2024-515389-15-00
- Protocol
- TIS6463-203
- Sponsor
- Tisento Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2b randomized, double-blind, placebo-controlled crossover study is to evaluate the **efficacy** of zagociguat on fatigue and cognition in patients with **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)**. Additionally, the study aims to assess the **safety** and tolerability of zagociguat, which is crucial for determining its potential as a therapeutic option for this condition. The secondary objectives include evaluating the effect of zagociguat on exercise intolerance and muscle weakness, cognition, disease progression, and memory. These secondary endpoints are significant as they address various aspects of the disease that impact patient quality of life and functional capacity.
Participants
The clinical trial involves a total of **24 participants** diagnosed with **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on specific criteria, including a documented pathogenic variant in mitochondrial DNA and a history of stroke-like episodes with corresponding MRI findings. The trial population is characterized by individuals who are ambulatory, with or without assistive devices, and capable of completing cognitive performance tests independently. Participants are required to be on an optimized, stable dose of Vitamin D supplement or have a Vitamin D level greater than 30 ng/mL. The study also considers lifestyle factors such as the ability to complete at-home weekly activities related to cognitive performance and fatigue assessments. The trial includes a vulnerable population, ensuring comprehensive evaluation of the effects of zagociguat on fatigue and cognition in patients with MELAS, while also assessing the safety and tolerability of the treatment.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled crossover study** designed to evaluate the efficacy and safety of **zagociguat** in participants diagnosed with **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)**. The trial aims to assess the effects of zagociguat on fatigue and cognition, as well as its safety and tolerability. The study involves the administration of zagociguat in tablet form, with doses of 7.5 mg and 15 mg, and matching placebos. The trial is expected to last for approximately 12 months, with an estimated end date in March 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis of MELAS, and stable psychiatric conditions if present. Following the screening, participants will be randomized to receive either zagociguat or placebo in a crossover design, ensuring that each participant receives both the active drug and placebo at different periods. The trial includes follow-up visits to monitor the participants' response to the treatment and to collect data on primary endpoints, such as PROMIS Fatigue MELAS Short Form scores, Groton Maze Learning Test scores, and International Digit Symbol Substitution Test scores. Secondary endpoints include the number of repetitions in a 30-second sit-to-stand test and concentrations of GDF-15 at Week 12.
The expected length of participant involvement is approximately 12 months, with conditions for early termination including the occurrence of treatment-emergent adverse events or non-compliance with study protocols. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall outcomes of the treatment. Participants are required to adhere to specific contraceptive measures and refrain from donating sperm or eggs during and after the study period to ensure safety and compliance with the trial's requirements.
Treatment
The clinical trial involves the administration of **zagociguat**, a chemical compound, in two different dosages. The first experimental medication is **zagociguat 15 mg**, provided in tablet form. The active substance, **zagociguat**, is chemically synthesized and is also known by its synonyms IW-6463 and 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine. The tablets are administered orally, with a maximum daily dose of 30 mg and a total maximum dose of 2520 mg over a treatment period of 12 weeks. The pharmaceutical product is manufactured by Tisento Therapeutics Inc.
The second experimental medication is **zagociguat 7.5 mg**, also in tablet form. This formulation contains the same active substance, **zagociguat**, and is administered orally. The maximum daily dose for this formulation is 7.5 mg, with a total maximum dose of 630 mg over the same 12-week treatment period. This product is also produced by Tisento Therapeutics Inc.
In addition to the experimental medications, the study includes the use of placebo tablets designed to match the appearance of the **zagociguat** tablets. The placebo-to-match (ptm) tablets are available in two forms: one corresponding to the 7.5 mg **zagociguat** tablets and the other to the 15 mg **zagociguat** tablets. These placebo tablets are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments.
Efficacy
The efficacy of zagociguat in participants with **MELAS** will be assessed using a combination of primary and secondary endpoints. The primary endpoints include scores from the PROMIS Fatigue MELAS Short Form (PFM-SF), Groton Maze Learning Test (GMLT), and International Digit Symbol Substitution Test (iDSST) measured from Week 9 through Week 12. These endpoints will be combined using a global statistical test (GST) with respective weights of 0.4, 0.3, and 0.3. Additionally, the incidence of treatment-emergent adverse events (TEAEs) will be monitored from the initiation of the study drug through the Follow-up Visit or end of treatment if participants continue to the open-label extension study.
Secondary endpoints will be evaluated at Week 12 and include the number of repetitions completed during the 30-second sit-to-stand test, PROMIS Cognitive Function MELAS Short Form (PCFM-SF) scores, concentrations of GDF-15, and memory composite scores from the One Card Learning and One Back Tests for Week 9 through Week 12. These efficacy parameters will be collected and analyzed at specified timepoints to determine the impact of zagociguat on fatigue and cognition in patients with MELAS.
Inclusion and Exclusion Criteria
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. 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.
- 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).
- Reports “sometimes,” “often,” or “always” on the “fatigue due to MELAS” PGI-F assessment (Screening Visit criterion only).
- 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).
- 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.
- 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: 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)
- 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.
- 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.
Exclusion Criteria
- 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). a.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.
- 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.
- 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 >460 ms for females using Fridericia’s formula (QTcF interval).
- Electrolyte abnormalities that cannot be corrected per investigator judgment.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 12 Nov 2024 | 8 |
 Italy | Not Recruiting | 12 Nov 2024 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
zagociguat 7.5 mg | Test | TABLET | ORAL USE | 7.5 | 12 | PRD11289962 |
zagociguat 15 mg | Test | TABLET | ORAL USE | 30 | 12 | PRD11291263 |
Placebo-to-match (ptm) zagociguat 15mg tablets | Placebo | N/A | — | — | — | N/A |
Placebo-to-match (ptm) zagociguat 7.5mg tablets | Placebo | N/A | — | — | — | N/A |