A Phase 2b Study of Zagociguat in Patients With MELAS
- Conditions
- Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS Syndrome)
- Interventions
- Registration Number
- NCT06402123
- Lead Sponsor
- Tisento Therapeutics
- Brief Summary
PRIZM is a Phase 2b randomized, double-blind, placebo-controlled, 3-treatment, 2-period, crossover study evaluating the efficacy and safety of oral zagociguat 15 and 30 mg vs. placebo when administered daily for 12 weeks in participants with genetically and phenotypically defined MELAS.
- Detailed Description
The goal of this clinical trial is to learn about the effectiveness of zagociguat in patients with MELAS. The main questions it aims to answer are:
* Does zagociguat improve fatigue in patients with MELAS?
* Does zagociguat improve cognitive performance in patients with MELAS?
* What is the safety and tolerability profile of zagociguat?
The PRIZM study is evaluating 2 dose levels of zagociguat in a crossover design consisting of two 12-week treatment periods separated by a 4-week washout. Patients will be screened and if eligible, randomly assigned either to receive placebo in period 1 followed by active drug in period 2 OR to receive active drug in period 1 followed by placebo in period 2. Study medication is a once daily oral tablet and will be provided at the clinic and/or shipped to the participant's home. Clinic visits will occur at screening and Week 1 and Week 12 of each treatment period. Visits at Week 4 and Week 8 of both crossover periods will either be in clinic or optionally at the participant's home. Study assessments will be conducted weekly on a phone app and a separate tablet and additional assessments will be conducted during visits. Patients who complete the study will be eligible for an open label extension study.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 44
-
Signed consent form.
-
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.
-
Scores below normal average on the iDSST and GMLT.
-
Reports fatigue due to MELAS.
-
Can complete at least 1 sit-to-stand in the 30-second test interval.
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Completes all at-home weekly activities independently during the Screening Period (caregiver may help set up device/app, log-in, etc.).
-
Other criteria per the protocol.
- Systolic blood pressure (BP) 90 mmHg or diastolic BP 60 mmHg.
- Orthostatic hypotension when measured after standing from a semi-recumbent/supine position.
- Active cancer significant enough to confound the results of this study.
- Severe gastrointestinal dysmotility that may impact participation.
- 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 prohibited medication (reviewed by investigator).
- Any medical or other condition that the investigator thinks would preclude study participation.
- Other exclusion criteria per protocol.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Placebo then Zagociguat 15mg zagociguat 15mg Participants first receive placebo once a day for 12 weeks. Then after a 4 week washout, they receive zagociguat 15 mg once a day for 12 weeks. Placebo then Zagociguat 15mg Placebo Participants first receive placebo once a day for 12 weeks. Then after a 4 week washout, they receive zagociguat 15 mg once a day for 12 weeks. Zagociguat 15mg then Placebo Placebo Participants first receive zagociguat 15 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks. Placebo then Zagociguat 30mg Placebo Participants first receive placebo once a day for 12 weeks. Then after a 4-week washout, they receive zagociguat 30 mg once a day for 12 weeks. Zagociguat 30mg then Placebo Placebo Participants first receive zagociguat 30 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks. Zagociguat 15mg then Placebo zagociguat 15mg Participants first receive zagociguat 15 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks. Placebo then Zagociguat 30mg zagociguat 30mg Participants first receive placebo once a day for 12 weeks. Then after a 4-week washout, they receive zagociguat 30 mg once a day for 12 weeks. Zagociguat 30mg then Placebo zagociguat 30mg Participants first receive zagociguat 30 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks.
- Primary Outcome Measures
Name Time Method • PROMIS Fatigue MELAS Short Form scores• Groton Maze Learning Test scores • International Digit Symbol Substitution Test scores Weeks 9 through 12 of each treatment period These measures are a patient reported questionnaire on MELAS-specific fatigue and 2 cognitive performance tests. These 3 outcome measures will be combined using a global statistical test.
Incidence of Treatment-emergend Adverse Events (TEAEs) Weeks 1 through washout for treatment period 1 and Weeks 1 through follow-up for treatment period 2 TEAEs are any untoward event that may or may not be related to study medication.
- Secondary Outcome Measures
Name Time Method Plasma concentrations of GDF-15 Week 12 Measure of disease pathophysiology
Number of repetitions completed during the 30-second sit-to-stand test Week 12 Leg strength and exercise intolerance
PROMIS Cognitive Function MELAS Short Form (PCFM-SF) score Week 12 Patient-reported questionnaire on MELAS-specific cognitive function
Memory composite scores (One Card Learning and One Back Tests) for Week 9 through 12 Week 9 through 12 Test of memory
Trial Locations
- Locations (25)
UC San Diego - Altman Clinical and Translational Research Institute
🇺🇸La Jolla, California, United States
Children's Hospital of Colorado
🇺🇸Aurora, Colorado, United States
Children's National
🇺🇸Washington, District of Columbia, United States
Rare Disease Research
🇺🇸Atlanta, Georgia, United States
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
Mount Sinai - Ichan School of Medicine
🇺🇸New York, New York, United States
Akron Children's Hospital
🇺🇸Akron, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Texas Medical School at Houston
🇺🇸Houston, Texas, United States
Neuroscience Research Australia
🇦🇺Sydney, New South Wales, Australia
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Shared Health/University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
McMaster University Medical Center
🇨🇦Hamilton, Ontario, Canada
University Hospital Bonn
🇩🇪Bonn, Germany
Ludwig-Maximilians-University of Munich
🇩🇪Munich, Germany
Neurologic Institute Carlo Besta of Milan
🇮🇹Milan, Italy
University of Pisa Neurological Clinic
🇮🇹Pisa, Italy
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Italy
UCL Queen Square Institute of Neurology
🇬🇧London, United Kingdom
Newcastle University
🇬🇧Newcastle Upon Tyne, United Kingdom