A Phase 2b Study of Zagociguat in Patients With MELAS (PRIZM)

Phase 2b Randomized, Double-blind, Placebo-controlled Crossover Study Evaluating the Efficacy and Safety of Zagociguat in Participants With MELAS (PRIZM)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS Syndrome)
• Intervention / Treatment: Drug: zagociguat 15mg; Drug: Placebo; Drug: zagociguat 30mg

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.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, NSW 2031
      • Neuroscience Research Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Royal Melbourne Hospital
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A1R9
      • Shared Health/University of Manitoba
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Center
• Germany
  • Bonn, Germany, 53127
    • University Hospital Bonn
  • Munich, Germany, 80336
    • Ludwig-Maximilians-University of Munich
• Italy
  • Milan, Italy, 20133
    • Neurologic Institute Carlo Besta of Milan
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • UCL Queen Square Institute of Neurology
  • Newcastle upon Tyne, United Kingdom, NE14LP
    • Newcastle University
• United States
  • California
    • La Jolla, California, United States, 92037
      • UC San Diego - Altman Clinical and Translational Research Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Rare Disease Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10027
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai - Ichan School of Medicine
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • University of Texas Medical School at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed consent form.
2. 18 to 75 years of age.

3. Diagnosed with MELAS based on the presence of each of the following criteria:

   1. A documented pathogenic variant in a mitochondrial DNA (mtDNA) gene.
   2. History of one or more stroke-like episodes (SLEs) with magnetic resonance imaging (MRI) findings consistent with stroke-like lesions.
4. Scores below normal average on the iDSST and GMLT.
5. Reports fatigue due to MELAS.
6. Can complete at least 1 sit-to-stand in the 30-second test interval.
7. Completes all at-home weekly activities independently during the Screening Period (caregiver may help set up device/app, log-in, etc.).
8. Other criteria per the protocol.

Exclusion Criteria:

1. Systolic blood pressure (BP) 90 mmHg or diastolic BP 60 mmHg.
2. Orthostatic hypotension when measured after standing from a semi-recumbent/supine position.
3. Active cancer significant enough to confound the results of this study.
4. Severe gastrointestinal dysmotility that may impact participation.
5. 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.
6. History of spontaneous fracture(s) that in the investigator's opinion represents a safety risk for trial participation.
7. Current use of prohibited medication (reviewed by investigator).
8. Any medical or other condition that the investigator thinks would preclude study participation.
9. Other exclusion criteria per protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo then 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.	Drug: zagociguat 15mg; Once-daily oral tablets; Other Names: CY6463; IW-6463; Drug: Placebo; Once-daily oral tablets
Experimental: Zagociguat 15mg then 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.	Drug: zagociguat 15mg; Once-daily oral tablets; Other Names: CY6463; IW-6463; Drug: Placebo; Once-daily oral tablets
Experimental: Placebo then 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.	Drug: Placebo; Once-daily oral tablets; Drug: zagociguat 30mg; Once-daily oral tablets; Other Names: CY6463; IW-6463
Experimental: Zagociguat 30mg then 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.	Drug: Placebo; Once-daily oral tablets; Drug: zagociguat 30mg; Once-daily oral tablets; Other Names: CY6463; IW-6463

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• PROMIS Fatigue MELAS Short Form scores• Groton Maze Learning Test scores • International Digit Symbol Substitution Test scores	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.	Weeks 9 through 12 of each treatment period
Incidence of Treatment-emergent Adverse Events (TEAEs)	TEAEs are any untoward event that may or may not be related to study medication.	Weeks 1 through washout for treatment period 1 and Weeks 1 through follow-up for treatment period 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of repetitions completed during the 30-second sit-to-stand test	Leg strength and exercise intolerance	Week 12
PROMIS Cognitive Function MELAS Short Form (PCFM-SF) score	Patient-reported questionnaire on MELAS-specific cognitive function	Week 12
Plasma concentrations of GDF-15	Measure of disease pathophysiology	Week 12
Memory composite scores (One Card Learning and One Back Tests) for Week 9 through 12	Test of memory	Week 9 through 12

Collaborators and Investigators

• Sponsor: Tisento Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2024
• Primary Completion (Estimated): June 20, 2026
• Study Completion (Estimated): June 20, 2026

Study Registration Dates

• First Submitted: May 2, 2024
• First Submitted That Met QC Criteria: May 2, 2024
• First Posted (Actual): May 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: MELAS
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Mitochondrial Diseases; Acid-Base Imbalance; Cerebral Small Vessel Diseases; Acidosis; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; MELAS Syndrome; Acidosis, Lactic; Mitochondrial encephalopathy
• Other Study ID Numbers: TIS6463-203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No