Evaluation of Safety, Drug-Drug Interactions and Pharmacokinetic Profiles of Co-Administration of Betahistine With Olanzapine in Healthy Female Subjects

This will be a phase I, randomized, two-arm, double-blind, placebo-controlled, sequential study in up to 50 healthy female subjects. The study will be comprised of three treatment periods for a total of 4 weeks treatment duration:

Period I 1 week (Days 1-7) administration of betahistine daily (three times per day; 144 mg/day total) or matching placebo.

Period II 1 week (Days 8-14) titration of olanzapine once daily (2.5 to 10 mg) and continuation of betahistine or matching placebo administration (daily; three times per day) Period III 2 weeks (Days 15-28) of continued co-administration of betahistine/matching placebo, three times per day, and olanzapine once daily (7.5 to 10 mg/day)

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Betahistine

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• Romania
  • Arad, Romania
    • IFE Human Pharmacology
  • Timisoara, Romania
    • IFE Human Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Healthy female subjects 18 to 45 years of age.
2. Signed written informed consent.
3. Willing and able to comply with study procedures (including staying overnight in the research facility for required period for PK sampling).
4. Regular menstrual period.
5. All subjects should be non-lactating, have a negative urine pregnancy test result, and do not plan on become pregnant during the study, must practice or be willing to continue to practice appropriate birth control (such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner) during the entire study duration.

6. Has been on a stable treatment regimen with any of the following medications for a minimum of 90 days prior to screening:

   • Hormone replacement therapy;
   • Oral contraceptives.

Exclusion Criteria:

1. Has abnormal body composition, either overweight or obesity (BMI > 27 Kg/m2) or undernourishment (BMI < 18.5 Kg/m2).
2. Has had a significant body weight loss of >4 kg in the 90 days prior to screening.
3. Pregnancy or lactation.
4. Has recently started a smoking cessation program.
5. Has known sensitivity to betahistine or olanzapine.
6. Having first degree relatives with diabetes.
7. Personal history of gestational diabetes.
8. Subjects diagnosed with polycystic ovary disease.

9. Has a clinically significant history or presence of any of the following conditions:

   • Active or past history of cardiovascular or cerebrovascular disease including unstable angina, myocardial infarction, transient ischemic attacks/stroke, clinically significant arrhythmia, congestive heart failure, or cardiac valve abnormalities
   • Diabetes mellitus (type 1 or 2)
   • Fasting blood glucose level > 100 mg/dL or HBA1c > 6.0% at screening.
   • Renal insufficiency defined as a serum creatinine >1.5 mg/dL (133 µmol/L) at screening
   • Malignant disease within 5 years of screening
   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 ULN
   • Thyroid-stimulating hormone (TSH) outside of the normal range
   • Plans on having any surgery (elective or otherwise) during the course of the study
   • Has hypertension (sitting blood pressure >140/90 mmHg at screening or randomization),
   • Has hyperlipidemia (triglycerides [TG] >200 mg/dL or low-density lipoprotein cholesterol [LDL-C] >190 mg/dL),
   • History of asthma
   • History of peptic ulcers
   • History of HIV, Hepatitis B, Hepatitis C
   • Has clinical laboratory test values (chemistry, hematology, metabolic or urinalysis) judged to be clinically significant by the investigator
   • Has a physical examination or electrocardiogram (ECG) with significant abnormalities, as judged by the investigator
   • Currently abuses drugs or alcohol or has a history of abuse that in the investigator's opinion could cause the subject to be noncompliant with study procedures
   • Has psychiatric or neurological disorders requiring chronic medications (e.g., antidepressants, anti-psychotic or anti anxiety agents).
   • Chronic or as needed use of antihistamines
10. Has been treated over the past 60 days, is currently treated, or is expected to require or undergo treatment with any medications for a period of more than 3 days (with the exception of antibiotic treatment for a period of less than 7 days).
11. Has received any investigational drug within 90 days prior to screening.
12. Is an immediate family member of personnel directly affiliated with the study at the investigative site, or is personally directly affiliated with the study at the investigative site; or is employed by OBEcure Ltd.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Betahistine 48 mg TID; 08:00, 13:00 and 18:00 (144 mg/day total)and Olanzapine (10 mg/day)	Drug: Betahistine; The study will be comprised of three treatment periods for a total of 4 weeks treatment duration: Period I 1 week (Days 1-7) administration of betahistine 48 mg three times daily (144 mg/day total) or matching placebo Period II 1 week (Days 8-14) titration of olanzapine once daily (from 2.5 mg up to 10 mg) and continuation of betahistine or matching placebo administration (three times daily as in Period I) Period III 2 weeks (Days 15-28) of co-administration of betahistine or matching placebo (three times daily; as in Periods II and III) and olanzapine once daily (7.5 or 10 mg, as tolerated) On Day 1, after a 7-day screening period, eligible subjects will be randomized to one of the two treatment groups in a 1:1 ratio: Betahistine 48 mg TID; 08:00, 13:00 and 18:00 (144 mg/day total) Matching placebo TID; 08:00, 13:00 and 18:00
Active Comparator: Control; Matching placebo TID; 08:00, 13:00 and 18:00 and Olanzapine (10 mg/day).	Drug: Betahistine; The study will be comprised of three treatment periods for a total of 4 weeks treatment duration: Period I 1 week (Days 1-7) administration of betahistine 48 mg three times daily (144 mg/day total) or matching placebo Period II 1 week (Days 8-14) titration of olanzapine once daily (from 2.5 mg up to 10 mg) and continuation of betahistine or matching placebo administration (three times daily as in Period I) Period III 2 weeks (Days 15-28) of co-administration of betahistine or matching placebo (three times daily; as in Periods II and III) and olanzapine once daily (7.5 or 10 mg, as tolerated) On Day 1, after a 7-day screening period, eligible subjects will be randomized to one of the two treatment groups in a 1:1 ratio: Betahistine 48 mg TID; 08:00, 13:00 and 18:00 (144 mg/day total) Matching placebo TID; 08:00, 13:00 and 18:00

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary objectives are to evaluate the safety, tolerability, pharmacokinetic profiles and drug-drug interactions of betahistine and olanzapine at steady-state in healthy female subjects.	3 weeks

Collaborators and Investigators

• Sponsor: OBEcure Ltd.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: February 23, 2009
• First Submitted That Met QC Criteria: February 26, 2009
• First Posted (Estimate): February 27, 2009

Study Record Updates

• Last Update Posted (Estimate): May 5, 2009
• Last Update Submitted That Met QC Criteria: May 3, 2009
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: Betahistine; Olanzapine; Safety of co-administration of Betahistien and Olanzapine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Histamine Agents; Histamine Agonists; Betahistine
• Other Study ID Numbers: OBE 209