Pilot Study of a Combination Drug Product for Treatment of Short-term Insomnia

The purpose of this study is to evaluate the effect of a combination drug product containing 50 mg diphenhydramine, 5 mg zolpidem and 0.5 mg lorazepam on total sleep time, and to determine the contribution of diphenhydramine to the combination, using a 5-hour Phase Advance model of sleep challenge. This is a 3-arm cross-over study; each participant will receive 3 single-dose treatments on consecutive visits. The 3 arms are: investigational combination product, placebo, and a 2-drug comparator containing the zolpidem and lorazepam components but not diphenhydramine. Participants will be adults who sometimes have difficulty falling asleep or staying asleep, but who are generally healthy and do not have chronic insomnia or sleep apnea.

A total of 39 subjects are being recruited. Subjects who qualify for participation will be asked to keep a sleep diary to document their sleep times leading up to and during the study, and will be asked to spend 7-8 hours in bed at a regular bedtime during the study. Qualifying participants also will not anticipate significant disruptions in their sleep schedules, for example by traveling across timezones or changing shifts at work, during the study. The study requires 3 one-night stays in a sleep center in New York City, for administration of the study treatments and EEG measurements. Qualifying subjects will anticipate being able to return to the sleep center, located in Manhattan, for a total of 4 visits, including initial screening and 3 treatment times.

During each sleep center visit, subjects will be given their study treatment and be put to bed 5 hours before their usual bedtime, and sleep time will be monitored for 8 hours. Each subject will receive all 3 treatments, although the sequence of the 3 treatments will be randomized. Both subjects and study personnel monitoring the subjects will be blinded to the identity of the treatment administered at each visit.

Inclusion criteria

• Body mass index (BMI) between 19 and 32 kg/m2, inclusive;
• Report occasional difficulty falling asleep or staying asleep;
• Report a regular, habitual bedtime between 21:00 and 24:00, routinely spend at least 7.5 and no more than 9.0 hours in bed each night and observe a bedtime that does not vary by more than 2 hours over the course of the week. Subjects will be required to complete at least 5 days of sleep information in a diary provided at the screening visit and returned to study personnel no later than 24 hours prior to check-in for the first overnight visit.
• Be in good general health as determined by a thorough medical history and physical examination including vital signs and clinical laboratory tests;
• Females of childbearing potential must be using an acceptable method of contraception, have a negative serum pregnancy test at screening and have a negative urine pregnancy test before randomization and prior to each Treatment Period. Acceptable methods of contraception include oral, intrauterine and injectable contraceptives or double barrier methods. After screening, subjects using oral contraceptives must agree to add a double barrier method until 30 days following the last dose of study medication. Female subjects relying on oral contraceptives must have been using them for at least one month prior to screening;
• Female subjects who have been surgically sterilized are eligible if they have a negative serum pregnancy test at screening and negative urine pregnancy test at check-in for Visits 2 and 3, or are post-menopausal as defined by the cessation of menses for a period of at least 2 years prior to screening or have had a complete hysterectomy;
• Male subjects must use an acceptable method of contraception during the course of the study and for the 30 days following the last dose of study medication. Acceptable methods of contraception include:

• Abstinence
• A condom and one of the following:

i. Vasectomy for more than 6 months. ii. Female partner who meets one of the following conditions:

• Uses a spermicidal gel or foam; or
• Has had a tubal ligation, hysterectomy or bilateral oophorectomy; or
• Is post-menopausal (menopause is defined as over the age of 60 years, or between 45 and 60 years being amenorrheic for at least 2 years with plasma follicle stimulating hormone (FSH) level > 30 UI/L); or
• Be able to read, understand, and provide written/dated informed consent before enrolling in the study and must be willing to comply with all study procedures;
• Be willing and able to be confined to the clinical research site for one night in each of 3 treatment periods as required by the protocol.
• Refrain from alcohol on PSG days;
• On the days of check-in for each of the study's two treatment periods, refrain from the use of alcohol and from napping, defined as any sleep episode occurring outside of the subject's main sleep episode of the day;
• Report a recent history of napping of no more than once per week.
• An Epworth Sleepiness Scale score ≤8 at screening.

Exclusion criteria

• Clinically significant, acute illness within 14 days prior to screening (Visit 1).
• Clinically significant, unstable medical illness;
• Evidence or history of clinically significant allergic (except for untreated, asymptomatic, seasonal allergies at time of dosing), hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic or neurological disease;
• History of cancer or diabetes;
• A supine blood pressure > 140/90 millimeters mercury (mm/Hg) at screening;
• Heart rate > 100 beats per minute (BPM) at screening;
• Clinically significant psychiatric illness, including chronic psychiatric illness or the history or presence of any Axis I condition;
• History or presence of chronic pain;
• Lifetime history of seizure disorder or serious head injury;
• Clinically significant sleep disorder, including insomnia, sleep apnea, narcolepsy, parasomnia, restless leg syndrome or circadian rhythm disorder;
• Any condition that may affect drug absorption;
• Travel across more than three time zones, an expected change in sleep schedule or involvement in night shift work within one month prior to screening or during the study period;
• Any clinically significant abnormal finding on physical examination, vital signs or clinical laboratory tests, as determined by the Investigator;
• History of allergies, or known sensitivity, hypersensitivity, or adverse reaction to any drug similar to diphenhydramine, zolpidem or lorazepam;
• Pregnant or lactating females;
• Positive serum pregnancy test at Visit 1 or positive urine pregnancy test at check-in for Visit 2 or 3;
• Positive urine drug screen at the Visit 1;
• Recent history (≤ one year) of alcohol or drug abuse, or current evidence of substance dependence or abuse as defined by DSM-V criteria;
• Regular consumption of "large amounts" of xanthine-containing substances (i.e., more than 500 mg of caffeine per day or equivalent amounts of xanthine-containing substances);
• Self-report of a usual consumption of more than 14 units of alcohol per week. One unit of alcohol is equivalent to 12 ounces of beer, 4 ounces of wine or 1 ounce of liquor;
• Use of more than 10 products containing nicotine per day or routinely smokes during sleep period
• Discontinuation of smoking or participation in a smoking cessation program within 90 days of screening;
• Any use with the six months prior to screening of restricted concomitant medications including prescription hypnotics, antidepressants, anxiolytics, anticonvulsants or narcotics;
• Use of any prescription drug, OTC medication, grapefruit juice, herbal preparation or food supplement, excluding vitamins, acetaminophen or hormonal contraceptives within two weeks of randomization;
• Use of any investigational drug within 30 days prior to screening or any prior exposure to the study drugs diphenhydramine, zolpidem or lorazepam or other drugs of the same pharmaceutical classes;
• Positive alcohol breathalyzer test at the time of screening or prior to dosing at Visit 2, 3 or 4.