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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ond-PR1
* Drug: Ond-PR1 + MPh-IR
* Drug: Ond-PR2
* Drug: Ond-PR2 +_ MPh-IR


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ondansetron, Methylphenidate