Clinical trial NCT03978832: Safety, Tolerability, Pharmacokinetics and Efficacy of 180 mg Subcutaneous Risperidone From 6 mg Oral Risperidone
Official title: An Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of 180 mg Risperidone Subcutaneous Injection (PERSERIS) Following a Switch From 6 mg Oral Risperidone in Patients With Clinically Stable Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Lead sponsor: Indivior Inc.
Sponsor class: INDUSTRY
First posted: 2019-06-07
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The study will enroll subjects currently on a stable dose of 5 or 6 mg of oral risperidone. After screening, eligible subjects will be admitted to the clinical unit and stabilized on 6 mg daily (3 mg oral risperidone twice a day) for 5 days, followed by an additional 3 days, during which the first injection of PERSERIS will be administered. Subjects will then return to the clinical unit every 28 days for an additional 3 admit periods for subsequent PERSERIS injections (2 injections per visit).
Primary purpose: TREATMENT

Brief summary: This study evaluates PERSERIS at a higher dose than what has been administered in previous clinical trials. Subjects with stable schizophrenia on a dose of 5-6 mg oral risperidone will be switched to PERSERIS at the higher dose, which is believed to be similar to the oral dose

Detailed description: PERSERIS is an extended-release subcutaneous (SC) injectable suspension administered monthly for the treatment of schizophrenia in adults. PERSERIS was approved by the FDA at doses equivalent to 3 mg and 4 mg oral risperidone. Many patients require doses of 5-6 mg oral risperidone and above, and this study will test a higher dose of PERSERIS in order to meet this need.

Eligible subjects will initially be stabilized in the clinical unit on 6 mg oral risperidone for 5 days and transition to an approximate dose of PERSERIS by SC injection. PERSERIS will be administered every 28 days and subjects will be admitted to the clinical unit the day before, and remain in the unit for 3 days after each injection for pharmacokinetics (PK) and safety evaluations (a total of 8 days for the first injection including the stabilization period). Subjects will return to the clinic between injections for additional PK, safety and efficacy assessments at scheduled intervals until the next injection.

A total of 4 doses of PERSERIS will be administered. The 4th dose will evaluate an alternate site for injection, and will be administered in the back of the upper arm.

Subjects will return to the clinical unit for an end of study visit and will receive a follow up phone call to assess for adverse events one week after the end of study visit.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of schizophrenia
* Clinically stable as defined as no hospitalizations for acute exacerbations within 3 months of screening and Screening PANSS score ≤70
* Total body mass index (BMI) between 18 and 35 kg/m2
* Given written informed consent

Exclusion Criteria:

* Received a once-monthly long-acting injectable (LAI) antipsychotic within 60 days of screening and a once every 3 month LAI antipsychotic within 120 days of screening
* Taking the following concurrent or over the counter (OTC) products:

  1. Inducers or inhibitors of CYP2D6 within 14 days or 5 half-lives whichever is greater prior to study screening
  2. Bupropion, chlorpheniramine, cimetidine, clomipramine, doxepin or quinidine within 30 days prior to study screening
  3. Clozapine, phenothiazines, aripiprazole, haloperidol or any other antipsychotic other than oral risperidone within 14 days prior to study screening
  4. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) within 30 days prior to study screening
  5. Opioids or opioid-containing analgesics within 14 days prior to study screening
  6. Medications, in the addition to those listed above which in the opinion of the Investigator in conjunction with the medical monitor, may be expected to significantly interfere with the metabolism or excretion of risperidone and/or 9-hydroxyrisperidone, that may be associated with a significant drug interaction with risperidone, or that may pose a significant risk to subjects' participation in the study. The medical monitor should be contacted with any questions regarding the use of CYP2D6 or 3A4 inducers or inhibitors in particular.
* History of cancer (with the exception of resected basal cell or squamous cell carcinoma of the skin) unless they have been disease free for ≥5 years.
* Another active medical condition or organ disease that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug.
* Evidence or history of a significant hepatic disorder that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug. Individuals with acute or chronic hepatitis (including but not limited to hepatitis B or C); or individuals with 1) total bilirubin \>1.5x the upper limit of normal (ULN) and/or 2) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3x ULN will be excluded.
* A history of renal disease, or a creatinine clearance of less than 60 mL/min (as determined by the Cockcroft-Gault formula).
* A history of orthostatic hypotension, syncope, significant low white blood cell (WBC) count (i.e., based on absolute neutrophil count or drug-induced leukopenia or other medical conditions including, but not limited to, history of heart attack (i.e., myocardial infarction) or brain injury (i.e., traumatic with loss of consciousness and/or cardiovascular accident) within a year of Screening and clinically significant low blood pressure or arrhythmias as interpreted by the principal investigator (PI).
* Corrected QT interval \[Fridericia's calculation (QTcF)\] \>450 msec (male) or \>470 msec (female) at screening or prior to administration of the 1st dose of PERSERIS, or with a known history of Torsades de Points, or family member with sudden unexplained cardiac death.
* Known to have AIDS (acquired immunodeficiency syndrome) or to be HIV (human immunodeficiency virus) positive.
* Suicidal ideation with intent and plan, as assessed by affirmative answers to C-SSRS questions 4 and 5 of the ideation section,or suicide attempts within the last 6 months as noted on the C-SSRS, or subjects with uncontrolled depression in the opinion of the Investigator.
* Known diagnosis of type 1 diabetes or subjects with Haemoglobin A1c (HbA1c) \>8.0% at screening.
* Participated in a clinical trial within 30 days prior to study screening.
* Significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening.
* Meet the criteria for the diagnosis of current moderate or severe substance use disorder.
* Prior allergic reactions, sensitivities, or other known contraindications to any component of PERSERIS.
* Women of childbearing potential who are pregnant or breastfeeding, seeking pregnancy or failing to use adequate contraceptive methods during the study.
* Positive urine drug screen (UDS) anytime through Day -1 for opioids, cocaine, amphetamines, methadone, cannabinoids, barbiturates, benzodiazepines, methamphetamine and phencyclidine, unless the positive screen is determined to be secondary to an allowable concomitant medication. If a positive UDS is possibly the result of a subject's use of OTC or prescription medications, a repeat urine drug screen may be permissible. Study site personnel should contact the medical monitor for approval to retest.
* Tardive dyskinesia as assessed by a score of ≥2 on Item 8 of the Abnormal Involuntary Movement Scale (AIMS) at Screening.
* Epilepsy or other seizure disorders, Parkinson's disease or dementia.
* History of neuroleptic malignant syndrome.
* Previously injected with PERSERIS within 6 months prior to screening.
* Unable, in the opinion of the PI, to comply fully with the study requirements.
* Determined to be poor metabolisers, intermediate metabolisers or ultra-rapid metabolisers for CYP2D6 genotype.

Primary outcomes:
measure: Steady-state Average Plasma Concentration (Cavg,ss) of Risperidone and Total Active Moiety
timeFrame: 0-12 hours post-dose on Day -1, and 0-672 hours after Dose 3
Secondary outcomes:
measure: Assessment of Local Injection Site Tolerability*
timeFrame: First injection at Day 1 until last injection administered at Day 85
measure: The Number of Participants With TEAEs as Assessed by Local Injection Site*
timeFrame: First injection at Day 1 until Day 120
measure: The Number of Participants With TEAEs as Assessed by Changes in Vital Signs
timeFrame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)
measure: The Number of Participants With TEAEs as Assessed by Changes in ECG
timeFrame: Time participants sign the informed consent form throughout the study until EOS (Day 113)
measure: The Number of Participants With TEAEs as Assessed by Changes in Body Weight
timeFrame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)
measure: The Number of Participants With TEAEs as Assessed by Changes in Laboratory Testing
timeFrame: Time subjects sign the informed consent form throughout the study until end of study (EOS) visit (Day 113)
measure: The Number of Participants With TEAEs as Assessed by Extrapyramidal Symptoms (EPS) of Anti-psychotic Drug Treatment
timeFrame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)
measure: Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, defined as last assessment prior to first injection, through Day 113 (EOS)
measure: Clinical Global Impression-Severity of Illness Scale (CGI-S)
timeFrame: Baseline through EOS (Day 113)
measure: Columbia-Suicide Severity Rating Scale (C-SSRS)-Change
timeFrame: Screening through EOS (Day 113)
measure: Safety as Measured by Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
timeFrame: Screening through EOS (Day 113)
measure: Minimum Plasma Concentration Over the Dosing Interval
timeFrame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).
measure: Maximum Plasma Concentration Over the Dosing Interval
timeFrame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4)
measure: Percent Fluctuation in Concentration Over the Dosing Interval
timeFrame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4)
measure: Area Under the Plasma Concentration-time Curve Over the Dosing Interval
timeFrame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).
measure: Average Plasma Concentration (Cavg) Over the Dosing Interval of Risperidone, 9-OH and Total Active Moiety
timeFrame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).
measure: Trough Plasma Concentration
timeFrame: Calculated over the dosing interval (0-672 hours) after Dose 1, 3 or 4.
measure: Time to Occurrence of Maximum Concentration
timeFrame: Calculated over the overall dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).
Other outcomes:
Locations:
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network
state: California
Study officials:
affiliation: Collaborative Neuroscience Network
name: David Walling
role: PRINCIPAL_INVESTIGATOR
References: