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Efficacy and safety of roluperidone versus drug combination in adults with schizophrenia with negative symptoms

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults who have schizophrenia with prominent negative symptoms, which are aspects such as reduced motivation, limited emotional expression, and social withdrawal. The experimental medication being tested is roluperidone, an oral tablet taken once daily. For comparison, the trial also includes commonly used antipsychotic drugs such as olanzapine, fluoxetine hydrochloride, risperidone and aripiprazole, as well as a placebo that looks the same but contains no active drug. The main aim is to see whether roluperidone can improve the negative symptoms more than placebo, measured with a rating system called the Marder Negative Symptoms Factor Scores.

Participants are randomly assigned to receive either the test drug or placebo for about three months, and neither the participants nor the study staff know which treatment is given, a design known as double-blind. After the initial 12‑week period, the study continues for an additional 40 weeks in a phase where participants may switch to other antipsychotic medications or continue the study drug, using a “double‑dummy” approach to keep the blind intact. Throughout the trial, safety checks and simple questionnaires are performed at regular visits to monitor how participants feel and whether any problems develop.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and start of double‑blind 12‑week treatment

    After you join the study, a computer program assigns you to receive either roluperidone or a matching placebo without knowing which one you receive.

    The study is double‑blind, meaning neither you nor the study staff know which medication you are taking during this period.

  2. Step 2

    Daily medication intake during the first 12 weeks

    If you are assigned to roluperidone, you take one tablet containing 64 mg once each day for 12 weeks.

    If you are assigned to placebo, you take a tablet that looks identical to the roluperidone tablet once each day for 12 weeks.

  3. Step 3

    Regular study visits for assessments in the first 12 weeks

    You attend visits at the clinic according to the schedule given by the study team.

    At each visit, you complete questionnaires that measure negative symptoms of schizophrenia and safety checks such as blood pressure and lab tests.

  4. Step 4

    Completion of the 12‑week double‑blind period and transition

    After 12 weeks, the initial treatment period ends and you move directly into the next phase of the study.

    The study staff informs you that you will continue taking study medication, but the specific drugs may change according to a new randomization.

  5. Step 5

    Randomization to the 40‑week double‑dummy phase

    You are randomly assigned to one of two options:

    Option a: continue taking roluperidone 64 mg daily and also take a matching placebo tablet that looks like an antipsychotic medication.

    Option b: stop roluperidone and start one of the following antipsychotic medications, each taken once daily, together with a matching placebo tablet that looks like roluperidone:

    - olanzapine 10 mg

    - risperidone 4 mg

    - aripiprazole 10 mg

  6. Step 6

    Daily medication intake during the 40‑week phase

    You take two tablets each day: one active tablet (either roluperidone or the assigned antipsychotic) and one placebo tablet that matches the other type of medication.

    The active tablet is taken once daily at the same time each day for the entire 40‑week period.

  7. Step 7

    Ongoing study visits for safety and relapse monitoring

    Throughout the 40‑week phase, you attend scheduled clinic visits to assess whether schizophrenia symptoms return and to monitor any side effects.

    At each visit, the same questionnaires and safety checks used in the first phase are repeated.

  8. Step 8

    Final study completion

    After the 40‑week period ends, the study concludes for you.

    You have a final assessment that records the overall outcome of the trial and any remaining safety information.

Who can join the trial?

10 criteria

  • Informed consent must be given by you (and by a legal representative if required), and the doctor must judge that you understand what the study involves.
  • You need a score higher than 20 on the PANSS negative subscale (a questionnaire that measures the severity of negative symptoms of schizophrenia) at both the screening visit and the baseline visit, and the score must not change by more than 4 points between those two visits.
  • You must be between 18 and 55 years old, any gender, and have a body weight to height ratio (BMI) of 35.0 kg/m² or lower at the screening visit.
  • You must meet the diagnostic criteria for schizophrenia according to the DSM‑5 (a manual doctors use to diagnose mental disorders) and this must be confirmed by a full psychiatric interview and the Mini International Neuropsychiatric Interview (MINI), which is a short structured interview.
  • You need a caregiver, family member, or health‑care person who can give information to the study team and help you follow the study plan. This person must have regular contact with you and remain the same throughout the trial.
  • Your diagnosis of schizophrenia must be documented for at least one year before you are screened for the study.
  • Your positive (e.g., hallucinations, delusions) and negative (e.g., lack of motivation, reduced emotional expression) symptoms must have been stable for the past six months, as shown by your doctor’s notes or reliable caregiver information. Having stable positive symptoms is allowed.
  • You must be an outpatient (not staying in a hospital) and have not been hospitalized for an acute worsening of your condition in the past six months.
  • You must have had a stable living situation (your residence) for the past six months.
  • You must not have been hospitalized for any reason in the six months before screening, unless special approval is obtained and the reason for hospitalization is properly documented.

Who cannot join the trial?

10 criteria

  • Having a current diagnosis of major depressive disorder, bipolar disorder, panic disorder, obsessive‑compulsive disorder, an intellectual disability (identified by age 14), or an addiction to drugs or alcohol means you cannot join the study.
  • If you have taken the medication clozapine in the past six months, you are excluded, unless it was a low dose (100 mg or less per day) used only for trouble sleeping.
  • Scoring higher than 4 on any of the following items of the PANSS (a symptom rating scale) excludes you: feeling overly excited or hyperactive, feeling suspicious or persecuted, feeling hostile, being uncooperative, or having poor control over impulses.
  • A total score greater than 6 on the Calgary Depression Scale for Schizophrenia (CDSS) (a questionnaire that measures depression in people with schizophrenia) means you cannot take part.
  • Having a score of 2 or more on two of the first three items, or a score of 3 or more on the fourth item of the Barnes Akathisia Rating Scale (BARS) (which measures restlessness and an urge to move) excludes you.
  • If your symptoms are caused directly by a substance (such as an illegal drug or a medication) or by another medical illness, you cannot participate.
  • Any recent serious suicide attempts or behavior within the past year makes you ineligible.
  • A history of a substance use disorder (excluding caffeine and cigarette smoking) within three months before screening prevents participation.
  • A positive urine test for any illegal drug (including cocaine, methadone, amphetamines, cannabinoids, opiates, benzodiazepines, or barbiturates), tricyclic antidepressants, or alcohol (except prescribed benzodiazepines) means you cannot join.
  • If you are unable to stop taking your current psychiatric medicines (psychotropics), you are not eligible for the trial.
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Investigated drugs

  • Olanzapine

    is an antipsychotic medication that is often used to treat symptoms of schizophrenia. In this study it was given to one group of participants as a standard treatment so that the researchers could compare its effects with the new drug being tested. The goal was to see how well olanzapine improves symptoms compared with the test medication.

  • Risperidone

    is another commonly prescribed antipsychotic for schizophrenia. Participants in the trial received risperidone as a comparison treatment. By using risperidone, the study could evaluate whether the new medication works as well as, or better than, an established therapy for managing the illness.

  • Aripiprazole

    is a different type of antipsychotic that helps control both positive and negative symptoms of schizophrenia. In the trial, aripiprazole served as an additional comparator drug. This allowed the researchers to assess the new treatment’s effectiveness relative to several existing options.

  • Roluperidone

    is the experimental medication being studied for the first time as a single‑drug (monotherapy) treatment for schizophrenia. It is taken by mouth and is being tested to see if it can reduce the negative symptoms of the disorder, such as lack of motivation or reduced emotional expression, over a 12‑week period. After the initial phase, the study also looks at whether roluperidone can help prevent relapse when participants continue on the medication for a longer time.

What is already known about the treatment

  • Olanzapine

    This medication is taken as an oral tablet. It is an approved drug that has been used for many years in the treatment of schizophrenia and bipolar disorder. It works by blocking the action of dopamine and serotonin in the brain, which helps reduce psychotic symptoms. Olanzapine belongs to the class of atypical antipsychotics.

  • Risperidone

    This drug is administered as an oral tablet. It is a widely approved medication for schizophrenia, bipolar disorder, and irritability associated with autism. It reduces symptoms by blocking dopamine and serotonin receptors in the brain. Risperidone is classified as an atypical antipsychotic.

  • Aripiprazole

    This medication comes in oral tablet form. It is an approved treatment for schizophrenia, bipolar disorder, and as an add‑on for major depression. It works by partially stimulating dopamine receptors while also blocking certain serotonin receptors, which balances brain signaling. Aripiprazole is an atypical antipsychotic.

  • Roluperidone

    This investigational drug is given as a coated oral tablet. It is not yet approved but is being studied for its potential to improve negative symptoms of schizophrenia. It is thought to act by blocking specific serotonin and sigma receptors, helping to normalize brain activity linked to motivation and emotional expression. Roluperidone is considered a novel, experimental antipsychotic agent.

Investigated diseases

Schizophrenia with negative symptoms - Schizophrenia is a long‑lasting brain disorder that affects thinking, feeling, and behavior. Negative symptoms include reduced emotional expression, lack of motivation, social withdrawal, and limited speech. These features often appear early in the illness or persist throughout its course. They tend to develop gradually and may become more noticeable as other symptoms improve. The condition usually follows a slowly progressive pattern with periods of relative stability and worsening.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-525925-19-00Protocol codeMIN-101C19Estimated enrolment380 patients

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