A Phase 2b Study of Zagociguat in Patients With MELAS

NCT06402123 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: TIS6463-203
• Study Type: interventional
• Target: 43
• Locations: 6 countries
• Sites: 20

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.

Conditions

Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS Syndrome)

Keywords

MELAS

Outcome Measures

Primary Outcomes (2)

• • 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 Outcomes (4)

• Number of repetitions completed during the 30-second sit-to-stand test

  Week 12

• PROMIS Cognitive Function MELAS Short Form (PCFM-SF) score

  Week 12

• Plasma concentrations of GDF-15

  Week 12

• Memory composite scores (One Card Learning and One Back Tests) for Week 9 through 12

  Week 9 through 12

Study Arms (4)

Placebo then Zagociguat 15mg

EXPERIMENTAL

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; Drug: Placebo

Zagociguat 15mg then Placebo

EXPERIMENTAL

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; Drug: Placebo

Placebo then Zagociguat 30mg

EXPERIMENTAL

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: zagociguat 30mg; Drug: Placebo

Zagociguat 30mg then Placebo

EXPERIMENTAL

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: zagociguat 30mg; Drug: Placebo

Interventions

zagociguat 15mg DRUG

Once-daily oral tablets

Also known as: IW-6463, CY6463

Placebo then Zagociguat 15mg; Zagociguat 15mg then Placebo

zagociguat 30mg DRUG

Once-daily oral tablets

Also known as: IW-6463, CY6463

Placebo then Zagociguat 30mg; Zagociguat 30mg then Placebo

Placebo DRUG

Once-daily oral tablets

Placebo then Zagociguat 15mg; Placebo then Zagociguat 30mg; Zagociguat 15mg then Placebo; Zagociguat 30mg then Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed consent form.
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Tisento Therapeutics: lead

Study Sites (20)

UC San Diego - Altman Clinical and Translational Research Institute

La Jolla, California, 92037, United States

Location

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Rare Disease Research

Atlanta, Georgia, 30329, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Columbia University Irving Medical Center

New York, New York, 10027, United States

Location

Mount Sinai - Ichan School of Medicine

New York, New York, 10029, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Texas Medical School at Houston

Houston, Texas, 77030, United States

Location

Neuroscience Research Australia

Sydney, New South Wales, NSW 2031, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3052, Australia

Location

Shared Health/University of Manitoba

Winnipeg, Manitoba, R3A1R9, Canada

Location

McMaster University Medical Center

Hamilton, Ontario, L8N 3Z5, Canada

Location

University Hospital Bonn

Bonn, 53127, Germany

Location

Ludwig-Maximilians-University of Munich

Munich, 80336, Germany

Location

Neurologic Institute Carlo Besta of Milan

Milan, 20133, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli

Roma, 00168, Italy

Location

UCL Queen Square Institute of Neurology

London, WC1N 3BG, United Kingdom

Location

Newcastle University

Newcastle upon Tyne, NE14LP, United Kingdom

Location

MeSH Terms

Conditions

Mitochondrial encephalopathy; Acidosis, Lactic; MELAS Syndrome

Condition Hierarchy (Ancestors)

Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mitochondrial Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This a double-blind study in which investigators, participants/caregivers, Sponsor, and all study personnel will be blinded.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled, 3-treatment, 2-period, incomplete-block, 4-sequence, crossover study. Eligible patients will be randomized to 1 of 4 crossover treatment sequences. Each treatment period will last 12 weeks, separated by a 4-week washout period.

Study Record Dates

• First Submitted: May 2, 2024
• First Posted: May 7, 2024
• Study Start: September 10, 2024
• Primary Completion (Estimated): June 20, 2026
• Study Completion (Estimated): June 20, 2026
• Last Updated: March 25, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

DE (2); IT (2); GB (2); CA (2); US (10); AU (2)