18F-Dihydroxyphenylalanine (DOPA) Positron Emission Tomography (PET) Study to Explore Dopamine Synthesis Capacity in the Whole Striatum After 2 Weeks of Treatment With Ralmitaront or Placebo in Participants With Schizophrenia

Phase 1

Completed

• Conditions: Schizophrenia
• Interventions: Drug: Ralmitaront; Other: Radiolabeled PET tracer [18F]-DOPA; Drug: Placebo

• Registration Number: NCT06880328
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This study is an exploratory proof of mechanism (POM) study using PET/functional magnetic resonance imaging (fMRI) in a 2-period, 2-sequence, crossover design. The aim of the study is to confirm the potential of Ralmitaront to decrease dopamine synthesis capacity (DSC) - as measured by levels of F-DOPA - in the striatum of participants with schizophrenia.

Detailed Description

Not available

Study Timeline

• Study Start: 2018-11-07
• Primary Completion: 2019-09-04
• Study Completion: 2019-09-04
• Status Verified: 2025-03
• Study First Submitted: 2025-03-11
• Study First Submitted QC: 2025-03-11
• Last Update Submitted: 2025-03-11
• Study First Posted: 2025-03-17
• Last Update Posted: 2025-03-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 35

Inclusion Criteria

• Male patients with non-acute schizophrenia defined by DSM-5 diagnosis of schizophrenia as established by the mini-international neuropsychiatric interview (MINI)
• Medically stable over 1 month and psychiatrically stable for at least 3 months prior to the screening visit
• Patients with evidence of clear treatment response to antipsychotics as documented by chart information or reported by the patient or an informant considered reliable by the Investigator
• Outpatient with no hospitalization for worsening of schizophrenia within 3 months prior to screening (hospitalization for social management within this time was acceptable)
• At least one positive and negative syndrome scale (PANSS) positive subscale item from P1 (delusion), P3 (hallucination), P5 (grandiosity), or P6 (suspiciousness/persecution) of mild or greater severity (score .3), but below 7 (extreme severity)
• Body mass index (BMI) between 18 and 35 kg/m2 inclusive

Exclusion Criteria

• Diagnosis for bipolar disorder, schizoaffective disorder or major depressive disorder based on DSM-5
• A prior or current general medical condition that might be impairing central nervous system (CNS) functioning (e.g., head trauma with persistent clinically significant neurological or cognitive sequelae, dementia, seizure disorder, stroke, neurodegenerative, inflammatory, infectious, neoplastic, toxic, metabolic or endocrine disorders)
• Average triplicate QTcF interval greater than 450 msec or other clinically significant abnormality on screening electrocardiogram (ECG) as assessed by the Investigator or deputy based on centralized reading
• Clinically significant abnormalities in laboratory safety test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis)
• Positive result at screening for hepatitis B (HBV), hepatitis C (HCV, untreated), or human immunodeficiency virus (HIV)-1 and HIV-2. HCV patients who had been successfully treated and who tested negative for HCV ribonucleic acid (RNA), could be considered eligible for entry into the study
• Patient at current significant risk of suicide or harming him or others according to the Investigator's judgment
• Patients with a history of violent/suicidal/homicidal behavior or history of suicidal/homicidal command hallucinations in the past 10 years
• Patients who have had 3 or more exacerbations associated with violent/suicidal/homicidal behavior or suicidal/homicidal command hallucinations (regardless of time)
• History of electroconvulsive treatment (ECT)
• Patients treated with long-acting injectable antipsychotic drugs or cariprazine
• Patients with known history of treatment resistance or having received clozapine within 3 months of screening
• Treatment with prohibited medication taken within 4 weeks (or within 5 times the elimination half-life of the medication) before the first study drug administration (whichever is longer). This included medications with known effects on cerebral blood flow.
• Use of grapefruit, Seville orange or star fruit containing products within 1 week before the first study drug administration
• Receipt of an investigational drug within 90 days or 5 times the half-life of the investigational drug, whatever was longer, prior to baseline visit
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per Investigator assessment)
• Moderate-to-severe substance use disorder within 6 months of screening (excluding caffeine) as defined by DSM-5
• Heavy smokers as defined by a high dependence score in the Fagerstrom Tolerance Scale (score ≥ 6)
• Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, methadone, cannabinoids, cocaine and barbiturates after informed consent and prior to randomization
• Any sensorial impairment such as deafness and reduced visual acuity, which could not be corrected in the MRI scanner
• Clinically significant abnormal findings on the baseline MRI images such as stroke, infarction, space-occupying lesion such as tumor, structural abnormalities, or vascular pathology
• Known exposure to radiation in the last year that would mean the total exposure to radiation with participation in the study was likely to exceed 30 mSv
• Donation of blood over 400 mL within 3 months prior to screening

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 1: Ralmitaront then Placebo	Ralmitaront	Participants were given a daily dose of Ralmitaront during the treatment period of 14 days, followed by a 7 day washout period, and then a daily dose for 14 days with the placebo.
Sequence 1: Ralmitaront then Placebo	Radiolabeled PET tracer [18F]-DOPA	Participants were given a daily dose of Ralmitaront during the treatment period of 14 days, followed by a 7 day washout period, and then a daily dose for 14 days with the placebo.
Sequence 1: Ralmitaront then Placebo	Placebo	Participants were given a daily dose of Ralmitaront during the treatment period of 14 days, followed by a 7 day washout period, and then a daily dose for 14 days with the placebo.
Sequence 2: Placebo then Ralmitaront	Ralmitaront	Participants were given a daily dose of the placebo during the 14 day period, followed by a 7 day washout, and then a daily dose of Ralmitaront for 14 days.
Sequence 2: Placebo then Ralmitaront	Radiolabeled PET tracer [18F]-DOPA	Participants were given a daily dose of the placebo during the 14 day period, followed by a 7 day washout, and then a daily dose of Ralmitaront for 14 days.
Sequence 2: Placebo then Ralmitaront	Placebo	Participants were given a daily dose of the placebo during the 14 day period, followed by a 7 day washout, and then a daily dose of Ralmitaront for 14 days.

Primary Outcome Measures

Name	Time	Method
Influx Rate Constant (Ki) Value of [18F]-DOPA in the Whole Striatum, as Measured Using [18F]-DOPA PET Imaging	Baseline, and on Days 13-14 and Days 34-35

Secondary Outcome Measures

Name	Time	Method
Bilateral Ventral Striatum Eigenvariates From the T-Contrast of Rewarded vs. Non-reward Expectation During the Monetary Incentive Delay (MID) Task, as Assessed Using fMRI	Baseline, and on Days 13-14 and Days 34-35
Percentage of High Effort Choices Under Deterministic Reward Condition for High Reward in the Effort-Choice Benefit Task	Baseline, and on Days 13-14 and Days 34-35
Mean Cerebral Blood Flow (CBF) in Different Brain Regions, as Measured by fMRI	Baseline, and on Days 13-14 and Days 34-35
Bilateral Eigenvariate From Dorsolateral Prefrontal Regions Defined Based on the 2-back >0-back Contrast in the N-back Working Memory Task, as Assessed Using fMRI	Baseline, and on Days 13-14 and Days 34-35
Incidence and Severity of Adverse Events (AEs)	From first dose until 14 days after the last dose of study treatment (up to 49 days)
Incidence of Treatment Discontinuations Due to AEs	From first dose until 14 days after the last dose of study treatment (up to 49 days)
Incidence of Vitals Sign Abnormalities (Resting and Orthostatic)	From first dose until 14 days after the last dose of study treatment (up to 49 days)
Change From Baseline in ECG Intervals: PQ (PR), QRS, QT, RR and QTcF	Baseline, Days 13-14, 21, 34-35, and during the follow-up visit (14-18 days after last dose)
Incidence of Laboratory Abnormalities, Based on Hematology, Clinical Chemistry, and Urinalysis Test Results	From first dose until 14 days after the last dose of study treatment (up to 49 days)
Concentration of Ralmitaront and Ralmitaront-derived Metabolite(s) Per Time-point	Days 2, 7, 13-14, 23, 28, 34-35, and during the follow up visit (14-18 days after last dose)
Area Under the Curve (AUCss) of Ralmitaront and Ralmitaront-derived Metabolite(s)	Days 2, 7, 13-14, 23, 28, 34-35, and during the follow up visit (14-18 days after last dose)
Cmax of Ralmitaront and Ralmitaront-derived Metabolite(s)	Days 2, 7, 13-14, 23, 28, 34-35, and during the follow up visit (14-18 days after last dose)

Trial Locations

Locations (4)

Parexel California Clinical Trials Medical Group; 🇺🇸 Glendale, California, United States

Collaborative Neuroscience Network Inc.; 🇺🇸 Torrance, California, United States

CBH Health; 🇺🇸 Gaithersburg, Maryland, United States

St Louis Clinical Trials; 🇺🇸 Saint Louis, Missouri, United States