Safety and Tolerability of Multiple Ascending Doses of LY2140023 in Subjects With Schizophrenia
Overview
- Phase
- Phase 1
- Intervention
- Aripiprazole
- Conditions
- Schizophrenia
- Sponsor
- Denovo Biopharma LLC
- Enrollment
- 75
- Locations
- 1
- Primary Endpoint
- Number of Participants With Clinically Significant Events (Physical Assessments and Clinical Lab Tests)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an inpatient, open-label, multiple-dose, multicenter study to evaluate the safety and tolerability of LY2140023 given at doses expected to reflect multiples of the anticipated therapeutic exposure under clinical investigation. In the event of poor tolerability in Part A of this study Part B may be conducted to explore higher doses using titration. Participants in both Parts A and B will participate in a 9 day wash-out period of current medication (Study Days 1-9); participants coming into the study on aripiprazole will remain on their current therapy throughout.
Detailed Description
The primary objective of this study was to evaluate the safety and tolerability of escalating doses of LY2140023 in subjects with schizophrenia. The secondary objectives of this study were: * to characterize the pharmacokinetic (PK) parameters of LY2140023 and its active moiety - LY404039 in subjects with schizophrenia * to explore higher doses of LY2140023 in subjects with schizophrenia for use in further regulatory studies * to compare safety of LY2140023 to aripiprazole (ARP) * to access changes in pharmacodynamic (PD) measures (Clinical Global Impression-Severity Scale \[CGI-S\], Extrapyramidal Symptoms \[EPS\], and Brief Psychiatric Rating Scale \[BPRS\]) This was an inpatient, open-label, multiple-dose, multi-center study to evaluate the safety and tolerability of LY2140023 given at doses expected to reflect multiples of the anticipated maximum therapeutic exposure under investigation.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have a diagnosis of schizophrenic disorder
- •Female participants who test negative for pregnancy at screening and agree to use a reliable method of birth control for the duration of the study and for at least 3 months after the last LY2140023 dose or are postmenopausal
- •Not have been hospitalized for psychiatric illness for at least 12 weeks prior to Day 1 of washout period and have a Clinical Global Impression -Severity (CGI-S) scale score of \<4
- •Be willing and able as determined by the investigator to be hospitalized from the beginning of the washout period to the end of the study
- •In the opinion of the investigator, the participant can be washed out of their Standard of Care (SOC) therapy (other than aripiprazole for the aripiprazole participants) for the duration of the study without detrimental effect to the participant's mental health (CGI-S \<4 after completion of the washout period)
- •Be considered reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures
- •Be able to understand the nature of the study and have given their own informed consent
- •Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
- •Have venous access sufficient to allow blood sampling
- •Clinically acceptable sitting blood pressure and pulse rate, as determined by the investigator
Exclusion Criteria
- •Currently enrolled in, or discontinued within the 30 days prior to screening from, a clinical trial involving an investigational drug or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
- •Have known allergies to LY2140023, LY404039, aripiprazole, or related compounds
- •Participants with moderate to severe renal impairment as defined by creatinine clearance (CrCl) \<60 milliliters (mL)/minute (min)
- •Have previously completed this study or have discontinued from any study investigating LY2140023 after having received at least 1 dose of LY2140023
- •Participants for whom treatment with LY2140023 or aripiprazole as specified in this protocol, is relatively or absolutely clinically contraindicated
- •Participants who have received treatment with clozapine
- •Participants who have a diagnosis of schizophrenia who are taking either thioridazine or thiothixene
- •Participants receiving treatment with depot antipsychotic medication within 12 weeks, prior to screening
- •Participants who are taking any of medications that are specifically excluded
- •Participants who have answered 'yes' to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the Columbia suicide severity rating scale (C-SSRS), or answer "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior" portion of the C-SSRS; and the ideation or behavior occurred within the past 3 months
Arms & Interventions
Aripiprazole
Part A: Continue current prescribed dosing regimen -- Study Day 1 to discharge (Study Day 21). Part B: Continue current prescribed dosing regimen (≤ 30 milligrams \[mg\]/day ) -- Study Day 1 to discharge (Study Day 23, 25 or 28 based on adaptive design)
Intervention: Aripiprazole
Part A: 160 mg LY2140023
Administered orally, twice daily (BID) for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)
Intervention: LY2140023
Part A: 400 mg LY2140023
Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)
Intervention: LY2140023
Part A: 240 mg LY2140023
Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)
Intervention: LY2140023
Part A: 320 mg LY2140023
Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)
Intervention: LY2140023
Part A: 480 mg LY2140023
Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)
Intervention: LY2140023
Part B: LY2140023
If doses up to or equal to 400 mg BID are not tolerated, Part B of the study may be started. The dose of LY2140023 will be titrated in the same participant from highest dose that was tolerated in Part A, with the intention to reach a dose of 480 mg LY2140023.
Intervention: LY2140023
Outcomes
Primary Outcomes
Number of Participants With Clinically Significant Events (Physical Assessments and Clinical Lab Tests)
Time Frame: Baseline up to Day 21 for Part A
Participants with at least 1 postdose (Day 10 through the end of study visit \[Day 21\]) treatment emergent adverse event (TEAE) were counted by dose cohort. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Secondary Outcomes
- Part A: Pharmacokinetics, Maximum Concentration (Cmax)(Pre-dose and post-dose on Day 10 and Day 16)
- Part B: Pharmacokinetics, Maximum Concentration (Cmax)(Pre-dose and post-dose on Days 12, 15, 18, 21, and 24)
- Part B: Pharmacokinetics, Area Under the Concentration - Time Curve (AUC)(Pre-dose and post-dose on Days 12, 15, 18, 21, and 24)
- Percentage of Participants With Increased Severity From Baseline to Day 17 in Clinical Global Impression- Severity Scale (CGI-S)(Baseline through Day 17 for Part A)
- Part A: Pharmacokinetics, Area Under the Concentration - Time Curve (AUC)(Pre-dose and post-dose on Day 10 and Day 16)
- Percentage of Participants With Worsening Symptoms From Baseline to Day 17 in Brief Psychiatric Rating Scale (BPRS)(Baseline through Day 17 for Part A)
- Percentage of Participants With Worsening Severity From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Abnormal Involuntary Movement Scale (AIMS)(Baseline through Day 17 for Part A)
- Percentage of Participants With Increasing Impairment From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Simpson-Angus Scale (SAS)(Baseline through Day 17 for Part A)
- Percentage of Participants With Worsening Symptoms From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Barnes Akathisia Scale (BAS)(Baseline through Day 17 for Part A)