Study to Evaluate the Pressor Effect of Oral Tyramine During Ozanimod Treatment in Healthy Adult Participants

A Phase 1, Randomized, Double-blind, Placebo- and Positive-controlled Study to Evaluate the Effect of Ozanimod on Pressor Response to Oral Tyramine in Healthy Adult Subjects

This is a Phase 1, randomized, double-blind, placebo-controlled, active-controlled, comparator controlled, multi-dose, parallel-group study divided into three treatment periods and a follow-up period with five treatment groups. This study will be conducted at 1 clinical research unit (CRU) in the United States (US).

Period 1 will consist of daily escalating doses of tyramine administered until tyramine pressor response (defined as the tyramine dose required to increase systolic blood pressure by at least 30 mm Hg from the daily defined baseline in 3 consecutive measurements within 4 hours after tyramine dosing) is achieved or Day 7.

Participants who achieve tyramine pressor response at tyramine doses >/= 200mg and </= 700mg are eligible for continuation into Period 2 and will be randomized accordingly.

Depending on the group to which a participant is randomized, participants will receive rasagiline, phenelzine, ozanimod (therapeutic dose), ozanimod (supra-therapeutic dose), or placebo in Period 2. The duration of dosing depends on the group to which a participant is randomized.

In Period 3, all participants will undergo a sham tyramine challenge and receive a single dose of tyramine placebo. Participants who do not achieve tyramine pressor response following the sham challenge will continue with the tyramine challenge (ie, tyramine pressor tests) for up to 12 additional days.

Participants who receive at least one dose of study drug in Period 2 will participate in a follow-up phase during which 2 follow-up telephone calls will be performed, the last of which will occur approximately 80 to 100 days after the last dose of study drug.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Other: Placebo; Drug: Phenelzine; Drug: Rasigiline; Drug: Ozanimod

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Local Institution - 001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Participants must satisfy the following criteria to be enrolled in the study:

1. Be a male or non-pregnant, non-lactating female, 25 to 55 years of age, inclusive, at the time of signing the informed consent form.
2. Must understand and voluntarily sign an informed consent form prior to any study-related assessments/procedures being conducted.
3. Is willing and able to adhere to the study visit schedule and other protocol requirements.

4. Female participant must meet at least 1 of the following criteria:

   • Have a negative serum pregnancy test at Screening and Day -1 (females of child-bearing potential only).
   • Be postmenopausal (defined as 2 years after the last period and follicle-stimulating hormone > 40 IU/L).
   • Have received surgical sterilization (eg, bilateral tubal ligation, bilateral oophorectomy, hysterectomy) at least 6 months before Screening.

5. Female of child-bearing potential:

   Must agree to practice a highly effective method of contraception at least 28 days prior to first dose of investigational product until completion of the 90-day safety follow-up period. Highly effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly.

   Examples of acceptable methods of birth control in this study are the following:

   • Combined hormonal (estrogen and progestogen containing) contraception, which may be oral, intravaginal, or transdermal
   • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable
   • Placement of an intrauterine device or intrauterine hormone-releasing system
   • Bilateral tubal occlusion
   • Vasectomised partner
   • Complete sexual abstinence Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
6. Has a body weight of at least 110 pounds (50 kg); body mass index within the range of 18.0 to 30.0 kg/m2, inclusive.
7. Is in good health, as determined by no clinically significant findings from medical or surgical history, 12-lead ECG, PE, clinical laboratory safety tests, and vital signs.
8. Has a mean systolic blood pressure (SBP) of 90 to 139 mm Hg, a diastolic blood pressure (DBP) of 50 to 89 mm Hg from three consecutive measurements at Screening and Day -1.

Exclusion Criteria:

The presence of any of the following will exclude a participant from enrollment:

1. an unstable SBP (ie, SBP exceeds a maximum range of 15 mm Hg between the lowest and highest values in three consecutive measurements within 15 minutes during Screening).
2. the presence or history of any clinically relevant abnormality, condition, or disease (such as glaucoma, liver disease or abnormal liver function tests, cardiovascular or pulmonary diseases) that, in the opinion of the Investigator, may affect absorption, distribution, metabolism, or elimination of the IPs, that would prevent the participant from participating in the study, or which places the participant at unacceptable risk if he/she were to participate in the study.
3. any condition that confounds the ability to interpret data from the study.
4. history of bipolar, depression or suicidal ideation or behavior, or a history of psychiatric illnesses.
5. history of clinically significant or unstable vascular disease, a history of syncope associated with hypotension within the last 2 years, a history of orthostatic hypotension (ie, SBP decrease of > 20 mm Hg between 2 and 5 minutes after standing compared with supine SBP), or a history of tachycardia or hypertension.
6. an estimated glomerular filtration rate (eGFR) < 80 mL/min/1.73 m2 according to the 2009 chronic kidney disease (CKD) epidemiology collaboration (CKD EPI) equation: eGFR = 141 × min(Scr/κ, 1) × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if African American] where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.
7. a seated heart rate outside 55 to 95 beats per minute at Screening or Day -1.
8. a resting QTcF > 450 msec (males) or > 470 msec (females) or PR interval > 210 msec at Screening or Day -1 or at additional risk for QT interval prolongation.
9. a history of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c (HbA1c) > 8%.
10. a history of uveitis (within the last year prior to Screening) or clinically confirmed diagnosis of macular edema.
11. a history of alcoholism, drug abuse, or addiction within 24 months prior to Screening.

12. a known active bacterial, viral, fungal (excluding fungal infection of nail beds, minor upper respiratory tract infections, and minor skin infections), mycobacterial infection (including tuberculosis or atypical mycobacterial disease) or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 30 days of Screening or oral antibiotics within 14 days of Screening.

    • In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
13. a positive serum test for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus .
14. used any tobacco- or nicotine-containing products (including but not limited to cigarettes, pipes, cigars, electronic cigarettes, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 3 months prior to the first dose of IP.
15. consumed marijuana products within 3 months prior to the first dose of IP.
16. a positive urine drug test including cotinine at Screening or Day -1.
17. a positive alcohol breath or urine test at Screening or Day -1.
18. received any investigational drug within 30 days or 5 times the elimination half-life (if known), whichever is longer, prior to the first dose of IP.
19. received a live or live attenuated vaccine within 4 weeks prior to the first dose of IP.
20. used any over-the-counter medication (excluding acetaminophen up to 1 g/day), dietary or herbal supplement (excluding vitamins/multi-vitamins), octopamine within 14 days prior to the first dose of IP. St. John's wort must be discontinued at least 28 days prior to the first dose of IP.
21. used any systemic prescription medication (excluding hormonal contraceptives) within 28 days or 5 times the elimination half-life, whichever is longer, prior to the first dose of IP.
22. used any MAO inhibitors within 90 days prior to the first dose of IP.
23. a history of allergic reaction to tyramine, phenelzine, rasagiline, or S1P agonist.
24. a history of adverse reactions to tyramine-containing foods.
25. ingested alcohol within 7 days prior to the first dose of IP.
26. fails or is unwilling to abstain from strenuous physical activities for at least 24 hours prior to the first dose of IP.
27. poor peripheral venous access.
28. donated greater than 400 mL of blood within 60 days prior to Day 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rasagiline group; Participants will receive rasagiline once daily (QD) for 14 days from Days 59 to 72.	Other: Placebo; Placebo; Drug: Rasigiline; Rasigiline
Experimental: Phenelzine group; Participants will receive phenelzine twice daily (BID) for 14 days from Days 59 to 72.	Other: Placebo; Placebo; Drug: Phenelzine; Phenelzine
Experimental: Ozanimod Therapeutic group; Participants will receive ozanimod QD for 65 days (including the initial 7-day dose escalation) from Days 8 to 72.	Other: Placebo; Placebo; Drug: Ozanimod; Ozanimod
Experimental: Ozanimod Supra-therapeutic group; Participants will receive ozanimod QD for 65 days (including the initial 10-day dose escalation) from Days 8 to 72.	Other: Placebo; Placebo; Drug: Ozanimod; Ozanimod
Placebo Comparator: Placebo; Participants will receive matched appropriate placebos from Days 8 to 72.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tyramine Sensitivity Factor (TSF)	The ratio of Tyramine pressor response (Tyr30) in Period 1 over Tyr30 in Period 3.	Up to Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Rate (HR)	Will be summarized descriptively by period, treatment group, day, and nominal time (where appropriate) using the per protocol (PP) population.	Up to Day 85
Systolic Blood Pressure (SBP)	Will be summarized descriptively by period, treatment group, day, and nominal time (where appropriate) using the per protocol (PP) population.	Up to Day 85
Diastolic Blood Pressure (DBP)	Will be summarized descriptively by period, treatment group, day, and nominal time (where appropriate) using the per protocol (PP) population.	Up to Day 85
CC112273 Pharmacokinetics: Cmax	Maximum observed plasma concentration within the dosing interval.	Up to Day 85
CC112273 Pharmacokinetics: Cmin	Minimum observed plasma concentration within the dosing interval.	Up to Day 85
CC112273 Pharmacokinetics: Tmax	Time to Cmax.	Up to Day 85
CC112273 Pharmacokinetics: AUC0-24	Area under the concentration-time curve from time 0 to 24 hours.	Up to Day 85
CC112273 Pharmacokinetics: Ctrough	Predose or trough concentration.	Up to Day 85
CC1084037 Pharmacokinetics: Cmax	Maximum observed plasma concentration within the dosing interval.	Up to Day 85
CC1084037 Pharmacokinetics: Cmin	Minimum observed plasma concentration within the dosing interval.	Up to Day 85
CC1084037 Pharmacokinetics: Tmax	Time to Cmax.	Up to Day 85
CC1084037 Pharmacokinetics: AUC0-24	Area under the concentration-time curve from time 0 to 24 hours.	Up to Day 85
CC1084037 Pharmacokinetics: Ctrough	Predose or trough concentration.	Up to Day 85
Ozanimod Pharmacokinetics: Cmax	Maximum observed plasma concentration within the dosing interval.	Up to Day 85
Ozanimod Pharmacokinetics: Cmin	Minimum observed plasma concentration within the dosing interval.	Up to Day 85
Ozanimod Pharmacokinetics: Tmax	Time to Cmax.	Up to Day 85
Ozanimod Pharmacokinetics: AUC0-24	Area under the concentration-time curve from time 0 to 24 hours.	Up to Day 85
Ozanimod Pharmacokinetics: Ctrough	Predose or trough concentration.	Up to Day 85
Pharmacokinetics for tyramine: Cave	Average observed plasma concentration within the dosing interval.	Up to Day 85
Incidence of Adverse Events (AEs)	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.	From screening until at least 90 days after last dose of study treatment (except for participants who discontinue from the study during Period 1 in which case AEs will be recorded from screening until 24 hours after the last dose of tyramine)

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Massimo Attanasio, MD, Celgene

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2021
• Primary Completion (Actual): February 26, 2023
• Study Completion (Actual): February 26, 2023

Study Registration Dates

• First Submitted: July 16, 2021
• First Submitted That Met QC Criteria: July 16, 2021
• First Posted (Actual): July 27, 2021

Study Record Updates

• Last Update Posted (Actual): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Healthy Volunteers; Phase 1
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Psychotropic Drugs; Antidepressive Agents; Monoamine Oxidase Inhibitors; Sphingosine 1 Phosphate Receptor Modulators; Ozanimod; Phenelzine
• Other Study ID Numbers: RPC-1063-CP-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

• IPD Sharing Time Frame: See Plan Description
• IPD Sharing Access Criteria: See Plan Description
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No