Open-label, Normal Healthy Volunteer Clinical Trial of a Novel Ondansetron Formulation

Phase Ia/Ib Study of Normal Healthy Volunteer Clinical Trial of a Novel Ondansetron Formulation

The goals of this open-label Phase Ia study are to evaluate the Pharmacokinetics (PK) profiles of new novel single-dose Ondansetron Pulsatile Release (Ond-PR) formulations in normal healthy volunteers. After this initial phase, the investigators will follow with the Phase Ib study to determine Pharmacokinetic/Pharmacodynamic (PK/PD), safety, and tolerability interactions following simultaneous administration of these ondansetron formulations with a 10 mg Methylphenidate Immediate Release (MPh-IR) tablet in normal healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Ond-PR1; Drug: Ond-PR1 + MPh-IR; Drug: Ond-PR2; Drug: Ond-PR2 +_ MPh-IR

Detailed Description

We will compare 2 different pulsatile-release formulations of ondansetron, PR1 and PR2. Ond-PR1 is a pH-sensitive formulation while Ond-PR2 is osmotic-sensitive.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must give written informed consent to participate in the study prior to screening. Consent will be documented by the subject's dated signature that will be counter-signed and dated by a witness.
• Healthy non-smoking, by history, adult male and/or female volunteers between the ages of 18 and 45 years old and with a Body Mass Index (BMI) of ≥18-≤32 kg/m2.
• Subjects must be in good health as determined by screening medical history, physical examination, vital signs, electrocardiogram, blood chemistry, hematology, and urinalysis (U/A) performed at screening.
• Normal Hematology Clinical Laboratory, Results, including: Normal White Blood Cell (WBC) and differential, Hematocrit, Hemoglobin, Platelet Counts
• Normal Electrocardiogram (ECG) and a measure between Q wave and T wave in the heart's electrical cycle at baseline (QTcB) ≤ 430 msec (males) or ≤ 430 msec (females)

Exclusion Criteria:

• Male and/or female subjects who consume more than 28 units of alcohol per week (one unit of alcohol equals ½ pint of beer, 4 ounces of wine, or 1 ounce of spirits) or those subjects who have a significant history of alcoholism or drug/chemical abuse within the last 2 years. Subjects must agree to abstain from alcohol, cola, tea, coffee, chocolate and other caffeinated drink and food from 2 days before Period 1, Day 1 and throughout confinement.
• Subjects who have used tobacco products or nicotine-containing products (including smoking cessation aids, such as gums or patches) within 3 months prior to Day -1.
• Subjects with positive results on tests for drugs of abuse, or alcohol at screening and check-in.
• Concomitant Medications: Any drugs, vitamins, over the counter (OTC) medicines and nutraceuticals if used within the previous 7 days of check-in as deemed clinically significant by the Principal Investigator (PI).
• Subjects who have used any drugs or substances known to be strong inhibitors or strong inducers of CYP 3A4/5 enzymes (also known as cytochrome P-450 enzymes) or P-Glycoprotein (Pgp) within 30 days prior to Period 1, Day -1. Subjects must agree to abstain from grapefruit/grapefruit juice and seville oranges for 2 days before period Ia, Day -1 and throughout the study.
• Use of other investigational drugs at the time of enrollment (consenting), or 5 half-lives of enrollment whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.
• History of unstable psychiatric illness requiring medications or hospitalization within the previous 12 months.
• History of concurrent illness that required hospitalization within 14 days prior to Day 1 of the study.
• Any condition that in the clinical judgment of the Investigator would make the subject unsuitable for participation.
• Allergies or allergic reactions to any of the products used in this study.
• Subjects who have had a clinically significant illness within 4 weeks prior to Day -1.
• Subjects with QTcB interval duration >430 msec (males) or >450 (females) obtained from the ECG recorder's measurements on the screening ECG taken after at least 5 minutes of quiet rest in supine position.
• History or current evidence of clinically significant hepatic, renal, cardiovascular (i.e., deep venous thrombosis, pulmonary embolism), psychological, pulmonary, metabolic, endocrine, neurologic (i.e., transient ischemic attack or stroke within the past 6 months) infectious, gastrointestinal (i.e., any condition which may affect drug absorption) hematologic, oncologic disease, retinopathy, or other medical disorders, as determined by screening history, physical examination, laboratory test results, or 12-lead ECG.
• History of unexplained syncope.
• Subjects with creatinine clearance < 80 mL/min (based on Cockcroft-Gault equation).
• Subjects who, in the opinion of the Investigator, should not participate in the study.
• Any employee of the Duke Clinical Research Unit (DCRU).
• Subjects who have blood relatives of another study participant.
• Subjects must be compliant and meet all inclusion and exclusion criteria unless, following discussions between the Principal Investigator or his designate, it is determined that a minor exception is not indicative of clinically significant safety risk and unlikely to confound the results of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ond-PR1 followed by (Ond-PR1 + MPh-IR); Oral dose of 8 mg of ondansetron pulsatile-release formulation 1 followed by Oral dose of 8 mg of ondansetron pulsatile-release formulation 1 (Ond-PR1) plus 10 mg methylphenidate immediate release (Mph-IR)	Drug: Ond-PR1; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 1 (Ond-PR1); Other Names: Zofran (ondansetron hydrochloride); Drug: Ond-PR1 + MPh-IR; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 1 (Ond-PR1) plus 10 mg methylphenidate immediate release (Mph-IR); Other Names: Zofran (ondansetron hydrochloride); Ritalin (methylphenidate hydrochloride); Drug: Ond-PR2; Single oral dose of 8 mg ondansetron pulsatile-release formulation 2 (Ond-PR2); Other Names: Zofran (ondansetron hydrochloride); Drug: Ond-PR2 +_ MPh-IR; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 2 (Ond-PR2) plus 10 mg methylphenidate immediate release (Mph-IR); Other Names: Zofran (ondansetron hydrochloride); Ritalin (methylphenidate hydrochloride)
Experimental: Ond-PR2 followed by (Ond-PR2 + MPh-IR); Oral dose of 8 mg of ondansetron pulsatile-release formulation 2 followed by Oral dose of 8 mg of ondansetron pulsatile-release formulation 2 (Ond-PR2) plus 10 mg methylphenidate immediate release (Mph-IR)	Drug: Ond-PR1; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 1 (Ond-PR1); Other Names: Zofran (ondansetron hydrochloride); Drug: Ond-PR1 + MPh-IR; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 1 (Ond-PR1) plus 10 mg methylphenidate immediate release (Mph-IR); Other Names: Zofran (ondansetron hydrochloride); Ritalin (methylphenidate hydrochloride); Drug: Ond-PR2; Single oral dose of 8 mg ondansetron pulsatile-release formulation 2 (Ond-PR2); Other Names: Zofran (ondansetron hydrochloride); Drug: Ond-PR2 +_ MPh-IR; Single oral dose of 8 mg of ondansetron pulsatile-release formulation 2 (Ond-PR2) plus 10 mg methylphenidate immediate release (Mph-IR); Other Names: Zofran (ondansetron hydrochloride); Ritalin (methylphenidate hydrochloride)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The release profile of Ondansetron Pulsatile Release (Ond-PR) in the human gastrointestinal (GI) tract matches the one predicted from test tube dissolution experiments.	Serum levels of ondansetron after oral administration of Ond-PR in healthy human volunteers. Standard PK parameters will be calculated based on the serum levels to verify that the drug levels reach the peak blood concentration 5 - 6 hours after oral administration. Time Frame: Blood samples will be taken immediately before oral Ond-PR administration, followed by sampling at 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6 and 10 hours after drug administration.	The time to reach peak blood concentration (tmax) for oral Ondansetron Standard (Ond-St) is ~2 hours (h). Therefore, tmax for Ond-PR with in vitro dissolution time of 3 - 4 h is expected to be 5 - 6 h (i.e., 3 - 4 h delay + normal absorption time).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine drug-drug interactions of Ond-PR with a simultaneously-administered MPh-IR.	For our secondary objective we plan to determine drug-drug interactions between Ond-PR and MPh-IR when they are simultaneously administered orally. Specific parameters to be assessed include changes in the PK, properties (see above for the specific parameter list), safety/tolerability profiles of Ond-PR.	5 - 6 h

Collaborators and Investigators

• Sponsor: Tong Lee
• Investigators: Principal Investigator: Robert Noveck, MD, PhD, Duke University; Principal Investigator: Ashwin Patkar, MD, Duke University

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: January 9, 2011
• First Submitted That Met QC Criteria: February 3, 2011
• First Posted (Estimate): February 4, 2011

Study Record Updates

• Last Update Posted (Estimate): August 1, 2014
• Last Update Submitted That Met QC Criteria: July 31, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Ondansetron; Methylphenidate
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Anti-Anxiety Agents; Dopamine Uptake Inhibitors; Antipruritics; Central Nervous System Stimulants; Methylphenidate; Ondansetron
• Other Study ID Numbers: Pro00024378; 110034 (Pro00024378) (Other Identifier: FDA IND); 110195 (Pro00026674) (Other Identifier: FDA IND); Pro00026674