A Study to Evaluate the Phase-Shifting Effects of Repeated Daily Dosing of TAK-375 in Healthy Subjects

Condition(s) targeted: Sleep Disorder

Intervention: TAK-375 (Drug); TAK-375 (Drug); TAK-375 (Drug); TAK-375 (Drug); Placebo (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Takeda Global Research & Development Center, Inc.

Official(s) and/or principal investigator(s):
Stephen Sainati, MD, PhD, Study Director, Affiliation: Takeda Global Research & Development Center, Inc.

This was a Dose-Ranging Study to Evaluate TAK-375 at 1 mg, 2 mg, 4 mg, or 8 mg versus a placebo taken once daily for five days.

Official title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging Study to Evaluate the Phase-Shifting Effects of Repeated Daily Dosing of TAK-375 in Healthy Subjects

Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety Study

Primary outcome: To evaluate TAK-375 at various doses vs. placebo to facilitate restoration of normal circadian phase relationships in healthy subjects after imposition of a 5-hour phase advance, measured by dim light salivary melatonin offset time.

Secondary outcome:

To evaluate the continued impact of repeated doses of TAK-375 on measures of sleep latency and sleep quality, as determined both objectively by polysomnography (PSG), and subjectively by subject-assessed questionnaires.

To evaluate the safety in this study based on adverse events, clinical laboratory results, ECG findings, vital signs, and physical examination findings.

Detailed description: Eligible subjects were randomized to one of 5 treatments: TAK-375 1, 2, 4, or 8 mg, or placebo taken once daily, and were confined to the sleep laboratory for the Treatment Period (Day 1 to Day 5), where they received their assigned study medication and went to bed 5 hours earlier than their habitual bedtime—undergoing an 8-hour, PSG-recorded sleep each night. Upon awakening, subjects provided a salivary melatonin sample (within 5 minutes), and filled out a post-sleep questionnaire. Melatonin samples were collected every hour for 10 hours after awakening. On Day 5, subjects underwent end-of-study procedures and were discharged from the sleep laboratory.

Minimum age: 18 Years. Maximum age: 45 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Female subjects of childbearing potential were nonpregnant and nonlactating; had a

negative serum human chorionic gonadotropin (HCG) pregnancy test result prior to dosing; had a negative urine HCG test result on the evening of PSG screening; and used an acceptable method of contraception (see the protocol, Appendix 16. 1.1)

- Had a habitual bedtime between 10: 00 p. m. and 1: 00 a. m. as determined by a sleep

diary.

- Had a median sSL of <30 minutes and a median sTST >6. 5 but <9 hours as determined by a

sleep diary.

Exclusion Criteria:

- Known hypersensitivity to TAK-375 or related compounds, including melatonin, and

melatonin related compounds.

- Previously participated in a study involving TAK-375.

- Participated in any other investigational study and/or taken any investigational drug

within 30 days or 5 half-lives of the investigational drug, whichever is longer, prior to the first dose of single-blind study medication.

- Sleep schedule changes required by employment (eg, shift worker) within 3 months prior

to the administration of single-blind study medication.

- Flew across more than 3 time zones within 21 days prior to or during screening.

- Participated in a weight loss program or substantially altered exercise routine within

30 days prior to the administration of single-blind study medication.

- History of seizures, sleep apnea, restless leg syndrome, periodic limb movement

disorder, COPD, schizophrenia, bipolar disorder, mental retardation, or cognitive disorder.

- History of primary sleep disorders as defined in the DSM-IV-TR TM within the past 6

months.

- History of psychiatric disorder (including anxiety or depression) within the past 12

months.

- History of alcohol abuse within the past 12 months as defined in DSM-IV-TR TM;

regularly consumed more than 14 alcoholic drinks per week; consumed any alcoholic drinks 2 hours prior to bedtime; or consumed any alcoholic drinks within 24 hours of Screening Visit 2.

- History of drug abuse within the past 12 months, as defined in DSM-IV-TR TM.

- Current neurological (including cognitive), hepatic, renal, endocrine, cardiovascular,

gastrointestinal, pulmonary, hematologic, or metabolic disease.

- Apnea hypopnea index (per hour of sleep) >10 as seen on the PSG screening night

(Screening Visit 2).

- Periodic limb movement syndrome with arousal index (per hour of sleep) >10 as seen on

the PSG screening night (Screening Visit 2).

- Smoked >3 cigarettes per day or used tobacco products during nightly awakenings.

- High caffeine consumption (>500 mg daily).

- Use of any central nervous system medication within 1 week (or 5 half lives of the

drug, whichever is longer) prior to the administration of single-blind study medication. These medications must not have been used to treat psychiatric disorders.

- Use of prescription or over-the-counter (OTC) hypnotic medication (including

melatonin) within 6 months of the screening visit.

- Intended to continue taking any disallowed medication or any prescription medication

or OTC medication that was known to affect the sleep/wake function or otherwise interfere with evaluation of the study medication (subjects were required to report all prescription and OTC medications taken during the 3 weeks prior to screening).

- Had any clinically important abnormal finding as determined by a medical history,

physical examination, ECG, or clinical laboratory tests, as determined by the investigator (subjects with clinically significant abnormal laboratory values being considered for the study must have been approved by both TGRD or its designee and the Principal Investigator).

- Positive hepatitis panel including anti-HAV (only IgM is exclusionary), HBsAg, or

anti-HCV.

- Any additional condition(s) that in the Investigator's opinion would have: (a)

affected sleep/wake function, (b) prohibited the subject from completing the study, or (c) not been in the best interest of the subject.

Hot Springs, Arkansas, United States

San Diego, California, United States

Los Angeles, California, United States

Miami, Florida, United States

Atlanta, Georgia, United States

Macon, Georgia, United States

Danville, Indiana, United States

Overland Park, Kansas, United States

Metairie, Louisiana, United States

Chevy Chase, Maryland, United States

Las Vegas, Nevada, United States

Dublin, Ohio, United States

Columbia, South Carolina, United States

Starting date: March 2005
Ending date: May 2005
Last updated: May 1, 2008