A Study of Safety and Tolerability in Subjects With Schizophrenia

Denovo Biopharma

Status and phase: Completed; Phase 1

Conditions: Schizophrenia

Treatments: Drug: LY2140023; Drug: Aripiprazole

Study type: Interventional

Funder types: Industry

Identifiers

NCT01354353

13565

H8Y-MC-HBDB (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 75 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Participants on Aripiprazole prior to study entry must:

• On a stable dose of aripiprazole within the approved range in product labeling (less than or equal to 30 milligrams [mg]/day) for at least 60 days prior to Day 1 and with no anticipation of changes to dose, regimen (except as required for this study) or treatment within the next 1 month

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
• Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (Text Revision) (DSM-IV-TR) diagnosis of substance dependence or substance abuse (except nicotine and caffeine) within the 6 months prior to admission
• Diagnosis of substance-induced psychosis by DSM-IV-TR criteria within 7 days of admission (or at any time during the dosing period)
• Have a history of one or more seizures except for either of the following 2 situations: a single simple febrile seizure between ages 6 months and 5 years or a single seizure with an identifiable etiology, which has been completely resolved
• Have a screening electroencephalogram (EEG) with paroxysmal (epileptiform) activity, for example, one that demonstrates 3 or more focal sharp or spike waves, any sharp and slow wave complex, or any epileptiform discharge that is rhythmic, sustained, or generalized, or as locally defined
• Participants who have had electroconvulsive therapy (ECT) within 3 months of observation period or who are expected to have ECT at any time during the live phase of this study
• A diagnosis of Parkinson's disease, dementia-related psychosis, or related disorders
• Participant with untreated hyperthyroidism or hypothyroidism needing a thyroid hormone supplement who have not been on a stable dose of medication for at least 2 months prior to screening
• Have leukopenia or history of leukopenia during the participant's lifetime
• Participants with alanine aminotransferase (ALT/SGPT) or aspartate aminotransferase (AST/SGOT) values >2 times the upper limit of normal (ULN) of the performing laboratory, or total bilirubin values >1.5 times the ULN of the performing laboratory at screening
• Participants with corrected QT interval (Bazett's); QTcB >450 milliseconds (msec) (male) or >470 msec (female) at admission
• Have acute, serious or unstable medical conditions, including (but not limited to) inadequately controlled diabetes (hemoglobin A1c [HgbA1c] >8%), severe hypertriglyceridemia (fasting triglycerides greater than or equal to 500 milligrams/deciliter (mg/dL) or 5.65 micromoles/liter [umol/L]), hepatic insufficiency (specifically any degree of jaundice), recent cerebrovascular accidents, seizure disorders, serious acute systemic infection or immunology disease, unstable cardiovascular disorders (including ischemic heart disease), renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases
• Prolactin level of >200 nanograms/milliliter (ng/mL) (200 micrograms/liter [ug/L], or 4228 milli international units/liter [mIU/L]) at screening with the exception of participants treated with risperidone. Participants treated with risperidone are excluded if the prolactin level is >300 ng/mL (300 ug/L, or 6342 mIU/L) at screening
• Participants with known medical history of Human Immunodeficiency Virus positive (HIV+) status
• Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody. Participants with positive Hepatitis B core antibody test and negative HBsAg may be included in the study if ALT/SGPT and AST/SGOT levels are less than 2 times the ULN and total bilirubin does not exceed the ULN of the central laboratory

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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75 participants in 7 patient groups

Aripiprazole

Active Comparator group

Description:

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)

Treatment:

Drug: Aripiprazole

Part A: 160 mg LY2140023

Experimental group

Description:

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)

Treatment:

Drug: LY2140023

Part A: 240 mg LY2140023

Experimental group

Description:

Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)

Treatment:

Drug: LY2140023

Part A: 320 mg LY2140023

Experimental group

Description:

Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)

Treatment:

Drug: LY2140023

Part A: 400 mg LY2140023

Experimental group

Description:

Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)

Treatment:

Drug: LY2140023

Part A: 480 mg LY2140023

Experimental group

Description:

Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16)

Treatment:

Drug: LY2140023

Part B: LY2140023

Experimental group

Description:

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.

Treatment:

Drug: LY2140023