Clinical trial NCT06402123: A Phase 2b Study of Zagociguat in Patients With MELAS
Official title: Phase 2b Randomized, Double-blind, Placebo-controlled Crossover Study Evaluating the Efficacy and Safety of Zagociguat in Participants With MELAS (PRIZM)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS Syndrome)
Keywords: MELAS
Lead sponsor: Tisento Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-05-07
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: • PROMIS Fatigue MELAS Short Form scores• Groton Maze Learning Test scores • International Digit Symbol Substitution Test scores
timeFrame: Weeks 9 through 12 of each treatment period
measure: Incidence of Treatment-emergend Adverse Events (TEAEs)
timeFrame: Weeks 1 through washout for treatment period 1 and Weeks 1 through follow-up for treatment period 2
Secondary outcomes:
measure: Number of repetitions completed during the 30-second sit-to-stand test
timeFrame: Week 12
measure: PROMIS Cognitive Function MELAS Short Form (PCFM-SF) score
timeFrame: Week 12
measure: Plasma concentrations of GDF-15
timeFrame: Week 12
measure: Memory composite scores (One Card Learning and One Back Tests) for Week 9 through 12
timeFrame: Week 9 through 12
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego - Altman Clinical and Translational Research Institute
state: California
city: Aurora
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National
state: District of Columbia
city: Atlanta
country: United States
facility: Rare Disease Research
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai - Ichan School of Medicine
state: New York
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas Medical School at Houston
state: Texas
city: Sydney
country: Australia
facility: Neuroscience Research Australia
state: New South Wales
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Winnipeg
country: Canada
facility: Shared Health/University of Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: McMaster University Medical Center
state: Ontario
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Munich
country: Germany
facility: Ludwig-Maximilians-University of Munich
city: Milan
country: Italy
facility: Neurologic Institute Carlo Besta of Milan
city: Pisa
country: Italy
facility: University of Pisa Neurological Clinic
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: London
country: United Kingdom
facility: UCL Queen Square Institute of Neurology
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle University
Study officials:
References: