Aerobic exercise added to olanzapine‑samidorphan treatment

A Proof of Concept Study of Time Limited Exercise Plus Olanzapine-samidorphan for the Prevention of Early Weight Gain

This trial will try whether adding four weeks of supervised aerobic exercise to olanzapine‑samidorphan reduces antipsychotic-related weight gain in adults with schizophrenia or bipolar disorders.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: New York State Psychiatric Institute (other)
• Locations: 1 site (New York, New York)
• Trial ID: NCT06740890 on ClinicalTrials.gov

What this trial studies

This single-site, open-label pilot enrolls 30 adults with schizophrenia, schizoaffective disorder, or bipolar I/II/NOS and delivers eight weeks of olanzapine plus fixed-dose samidorphan (10 mg). Olanzapine is flexibly dosed and all participants complete supervised aerobic exercise for the first four weeks (2–4 sessions/week). Weight, metabolic, and symptom measures are collected at baseline, four weeks, and eight weeks, with cognitive testing at baseline and study end. The study tests whether the combination produces less weight gain at four weeks than historical data for olanzapine‑samidorphan alone.

Who should consider this trial

Good fit: Adults 18–65 with schizophrenia, schizoaffective disorder, or bipolar I/II/NOS who are medically and psychiatrically stable, have BMI 18–40, and are willing to switch to olanzapine‑samidorphan and do supervised aerobic exercise.

Not a fit: Patients who are unstable, on clozapine, unwilling or unable to perform aerobic exercise, outside the 18–65 age or BMI 18–40 range, or unable to attend the single New York site are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, this approach could reduce olanzapine-associated weight gain and related metabolic risks while maintaining psychiatric symptom control.

How similar studies have performed: Prior trials showed olanzapine combined with samidorphan reduces olanzapine-related weight gain and exercise alone can reduce weight, but the specific combination of olanzapine‑samidorphan plus structured aerobic exercise has been only lightly studied.

Eligibility criteria

Inclusion Criteria:

1. Age between 18-65, inclusive at Visit 1.
2. DSM-V diagnosis of schizophrenia or schizoaffective or Bipolar I/II/NOS disorder at Visit 1.
3. Body Mass Index (BMI) of 18.0-40.0 kg/m2, inclusive, at Visits 1 and 2.
4. Willing to provide informed consent at Visit 1.
5. Medically and psychiatrically stable for study participation at Visit 1.
6. Responsive to an antipsychotic treatment (other than clozapine) in the past 5 years prior to Visit 1.
7. Can benefit from participation in this study and has a reason to participate, such as inadequate efficacy on current treatment, side effects on current treatment, desire to start olanzapine-samidorphan or try structured exercise program (assessed at Visit 1).
8. Maintained a stable body weight (change \< 5%) for at least 3 months prior to Visit 1.
9. Willing to use qualified methods of contraception (listed in section 5.3) for the study duration (for women of childbearing potential only) (assessed at Visit 1 and Visit 2).

Exclusion Criteria:

1. Positive drug screen for opioids, phencyclidine, amphetamine/ methamphetamine, or cocaine at Visit 1 or Visit 2.
2. Diagnosis of moderate or severe substance use disorder, anorexia nervosa, bulimia, binge eating disorder or any other clinically significant eating disorder at Visit 1.
3. EKG abnormality that is clinically significant including a QT interval \> 450 msec for men and \> 470 msec for women, as corrected by the Fridericia formula (QTcF) at Visit 1.
4. Use of olanzapine+samidorphan for any reason in the last six months prior to Visit 1, any history of poor or inadequate response to treatment with olanzapine or no justifiable reason to expect improvement on olanzapine as assessed at Visit 1.
5. Taken opioid agonists (e.g., codeine, oxycodone, tramadol, or morphine) within the 14 days prior to Visit 1 and/or anticipates a need to take opioid medication during the study period (e.g., planned surgery), or has taken opioid antagonists including naltrexone (any formulations) or naloxone within 60 days prior to Visit 1.
6. Pregnant or breast feeding women. Women of child-bearing potential must have a negative serum beta-hCG pregnancy test at Visit 1 and a negative urine pregnancy test at Visit 2.
7. Any clinically significant or unstable medical illness, condition, or disorder that is anticipated to potentially compromise subject safety on study medication or exercise, or adversely affect the evaluation of efficacy, including (but not necessarily limited to) the following (as assessed at Visit 1):

   1. Clinically significant hypotension or hypertension not stabilized on medical therapy.
   2. Unstable thyroid dysfunction in the past 6 months (e.g., hypothyroidism, hyperthyroidism, or thyroiditis that was untreated, or discovered and treatment was initiated within the 6 months prior to screening).
   3. Personal or family history of neuroleptic malignant syndrome, has a history of clinically significant extrapyramidal symptoms when taking olanzapine, or has had clinically significant tardive dyskinesia.
   4. Neurological conditions include the following:

      * History of seizure disorder or a condition associated with seizures (except history of febrile seizures).
      * History of brain tumor, subdural hematoma, stroke or any other clinically significant neurological condition within the 12 months prior to Visit 1.
      * Head trauma with loss of consciousness within the 12 months prior to Visit 1.
      * Active, acute or chronic CNS infection.
   5. Cardiac condition that might confound study results, pose additional risk when administering the study drug or exercise regimen to the subject, or preclude successful completion of the study. Conditions include the following:

      * Clinically significant cardiac arrhythmia, cardiomyopathy, a cardiac conduction defect, or a history of myocardial infarction or unstable angina within 6 months prior to Visit 1.
8. Currently taking any contraindicated medications as per the approved labeling for Olz-Sam (see section 6.5 for details) at Visit 1 and Visit 2.
9. Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 3 months prior to Visit 1 or current at Visit 2
10. Inflammatory bowel disease or any other gastrointestinal disorder associated with weight loss at Visit 1.
11. Joined a weight management program or had significant changes in diet or exercise regimen within 6 weeks prior to Visit 1 or plans to join a weight management program during the study as assessed at Visit 1.
12. History of diabetes (assessed at Visit 1).
13. Laboratory abnormality that would compromise the well-being of the subject, or any of the following specific laboratory results at Visit 1:

    1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value \> 2 times the upper limit of the laboratory normal reference range
    2. Absolute neutrophil count (ANC) \<1.5 x 10\^3 μL
    3. Platelet count \< 75 x 10\^3 uL
    4. Serum creatinine \> 1.5 mg/dL
    5. Dyslipidemia, defined for this study as total fasting cholesterol \> 280 mg/dL or fasting triglycerides \> 500 mg/dL
    6. Hemoglobin A1c (HbA1c) \> 6.0%
    7. Fasting plasma glucose \> 126 mg/dL (7.0 mmol/L)
14. Is not fit for the trial in the opinion of the investigator at Visit 1 and Visit 2.

Where this trial is running

New York, New York

• New York State Psychiatric Institute — New York, New York, United States (RECRUITING)

Study contacts

• Study coordinator: Megan Mayer, BA

Conditions: Schizophenia Disorder, Schizoaffective Disorder, Bipolar Disorder I or II, Bipolar Disorder NOS, Exercise, Antipsychotic induced weight gain, olanzapine-samidorphan