Drug-drug Interaction Study of Ozanimod With Tyramine to Evaluate the Effect on Pressor Response
| Status: | Recruiting |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 25 - 55 |
| Updated: | 10/24/2018 |
| Start Date: | July 24, 2018 |
| End Date: | January 8, 2019 |
| Contact: | Associate Director Clinical Trial Disclosure |
| Email: | clinicaltrialdisclosure@celgene.com |
| Phone: | 1-888-260-1599 |
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
The purpose of this study is to evaluate the potential effect of ozanimod on pressor response
when co-administered with oral tyramine in healthy adult subjects.
Study Design This is a Phase 1, randomized, double-blind (subjects and study site personnel
[except pharmacist or designee] are blinded to the treatments until 7 ± 2 days postdose
follow-up), placebo- and positive-controlled study.
Study design is described below:
Subjects will be screened for participation in this study within 28 days prior to dosing in
Period 1.
Period 1: To exclude subjects with very low or very high sensitivity to tyramine, oral
tyramine pressor tests will be performed prior to randomization on all subjects after
eligibility has been confirmed at Screening (in the absence of any other investigational
product [IP] treatment) to determine the pressor response to tyramine. The pressor response,
referred to hereafter as Tyr30, is defined as the tyramine dose required to increase systolic
blood pressure (SBP) by at least 30 mm Hg from daily defined baseline in three consecutive
measurements within 4 hours after tyramine dosing. The test consists of daily administration
of escalating doses of tyramine (up to 10 days) until a sustained SBP increase of ≥ 30 mm Hg
is observed relative to the daily‐defined baseline values. Sustained increase is determined
by 3 consecutive SBP measurements within 4 hours after tyramine administration. The
daily‐defined baseline SBP value is defined as the average of five SBP measurements with
approximately 5-minute interval after an initial 10‐ minute rest in the supine position and
within 30 minutes prior to tyramine administration. Only subjects who present Tyr30 ≥ 200 mg
and ≤ 800 mg will then be randomized.
Subjects will be randomized into one of three treatment groups (phenelzine, ozanimod, or
placebo) in a 1:1:1 fashion while stratifying for sex in such a manner that each treatment
will have a minimum of 30% of either sex.
Period 2: Subjects will receive IPs (active and/or placebo) twice daily (BID) depending on
the randomization. Subjects randomized to the phenelzine group will receive phenelzine 15 mg
BID for 7 days from Days 32 to 38. Subjects randomized to the ozanimod group will receive
ozanimod 1.84 mg once daily (QD) for 28 days (including the initial 10-day dose escalation).
Subjects randomized to the placebo group will receive placebos for 28 days. Placebos will be
matched to phenelzine or ozanimod in appearance to blind the study.
Period 3: Upon completion of Period 2, subjects in all three treatment groups will undergo a
second Tyr30 test for up to 11 days. Tyramine challenge in Period 3 will remain blinded since
phenelzine group has different tyramine dose schedules.
Study Population The study will enroll approximately 92 healthy men and non-pregnant,
non-lactating women, ages 25 to 55 years, inclusive, with a body weight of at least 110
pounds (50 kg) and body mass index within the range of 18.0 to 30.0 kg/m2, inclusive. This is
to ensure a total of 69 subjects with Tyr30 ≥ 200 mg and ≤ 800 mg at the end of Period 1 to
be randomized and to allow approximately 54 subjects (18 subjects per group) to complete all
three periods. A minimum of 30% of each sex will be randomized into each treatment group.
Length of Study The study duration is up to 84 ± 2 days (including a 28-day Screening period,
Period 1 of up to 10 days, Period 2 of 28 days, Period 3 of up to 11 days, and a follow-up
period up through 7 ± 2 days after the last dose of IP).
when co-administered with oral tyramine in healthy adult subjects.
Study Design This is a Phase 1, randomized, double-blind (subjects and study site personnel
[except pharmacist or designee] are blinded to the treatments until 7 ± 2 days postdose
follow-up), placebo- and positive-controlled study.
Study design is described below:
Subjects will be screened for participation in this study within 28 days prior to dosing in
Period 1.
Period 1: To exclude subjects with very low or very high sensitivity to tyramine, oral
tyramine pressor tests will be performed prior to randomization on all subjects after
eligibility has been confirmed at Screening (in the absence of any other investigational
product [IP] treatment) to determine the pressor response to tyramine. The pressor response,
referred to hereafter as Tyr30, is defined as the tyramine dose required to increase systolic
blood pressure (SBP) by at least 30 mm Hg from daily defined baseline in three consecutive
measurements within 4 hours after tyramine dosing. The test consists of daily administration
of escalating doses of tyramine (up to 10 days) until a sustained SBP increase of ≥ 30 mm Hg
is observed relative to the daily‐defined baseline values. Sustained increase is determined
by 3 consecutive SBP measurements within 4 hours after tyramine administration. The
daily‐defined baseline SBP value is defined as the average of five SBP measurements with
approximately 5-minute interval after an initial 10‐ minute rest in the supine position and
within 30 minutes prior to tyramine administration. Only subjects who present Tyr30 ≥ 200 mg
and ≤ 800 mg will then be randomized.
Subjects will be randomized into one of three treatment groups (phenelzine, ozanimod, or
placebo) in a 1:1:1 fashion while stratifying for sex in such a manner that each treatment
will have a minimum of 30% of either sex.
Period 2: Subjects will receive IPs (active and/or placebo) twice daily (BID) depending on
the randomization. Subjects randomized to the phenelzine group will receive phenelzine 15 mg
BID for 7 days from Days 32 to 38. Subjects randomized to the ozanimod group will receive
ozanimod 1.84 mg once daily (QD) for 28 days (including the initial 10-day dose escalation).
Subjects randomized to the placebo group will receive placebos for 28 days. Placebos will be
matched to phenelzine or ozanimod in appearance to blind the study.
Period 3: Upon completion of Period 2, subjects in all three treatment groups will undergo a
second Tyr30 test for up to 11 days. Tyramine challenge in Period 3 will remain blinded since
phenelzine group has different tyramine dose schedules.
Study Population The study will enroll approximately 92 healthy men and non-pregnant,
non-lactating women, ages 25 to 55 years, inclusive, with a body weight of at least 110
pounds (50 kg) and body mass index within the range of 18.0 to 30.0 kg/m2, inclusive. This is
to ensure a total of 69 subjects with Tyr30 ≥ 200 mg and ≤ 800 mg at the end of Period 1 to
be randomized and to allow approximately 54 subjects (18 subjects per group) to complete all
three periods. A minimum of 30% of each sex will be randomized into each treatment group.
Length of Study The study duration is up to 84 ± 2 days (including a 28-day Screening period,
Period 1 of up to 10 days, Period 2 of 28 days, Period 3 of up to 11 days, and a follow-up
period up through 7 ± 2 days after the last dose of IP).
Inclusion Criteria:
1. Subject is a man or non-pregnant, non-lactating woman, ages 25 to 55 years, inclusive.
2. Female subjects must meet at least 1 of the following criteria:
- Negative serum pregnancy test at Screening and Day -1 (WOCBP only).
- Postmenopausal (defined as 2 years after the last period and follicle-stimulating
hormone (FSH) > 40 IU/L).
- Received surgical sterilization (eg, bilateral tubal ligation, bilateral
oophorectomy, hysterectomy) at least 6 months before Screening.
3. Females of child-bearing potential: Must agree to practice a highly effective method of
contraception throughout the study until completion of the 75-day Safety Follow-up. 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.
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
- Vasectomized partner
- Sexual abstinence
Male subjects:
Must agree to use a latex condom with spermicide during sexual contact with WOCBP while
participating in the study until completion of the 75-day Safety Follow-up.
All subjects:
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.
4. Male subjects must agree to refrain from donating sperm during the study until 75 days
after the last dose of IP.
5. Subject has a body weight of at least 110 pounds (50 kg); body mass index (BMI) within
the range of 18.0 to 30.0 kg/m2, inclusive (Screening and Day -1 only).
6. Subject is in good health, as determined by no clinically significant findings from
medical or surgical history, 12-lead ECG, physical examination, clinical laboratory tests,
and vital signs.
7. Subject has a mean SBP of 90 to 140 mm Hg, a DBP of 50 to 90 mm Hg from three
consecutive measurements at Screening and Day -1.
8. Subject must be able to comprehend and provide written informed consent, and must be
able to comply with the requirements of the study, including the study visit schedule and
other protocol requirements.
Exclusion Criteria:
1. Subject has an unstable SBP (ie, SBP exceeds a maximum range of 10 mmHg between the
lowest and highest values in three consecutive measurements within 15 minutes during
Screening).
2. Subject has a presence or history of any abnormality or illness (such as glaucoma,
liver disease or abnormal liver function tests) that, in the opinion of the
investigator, may affect absorption, distribution, metabolism, or elimination of the
IP(s) or would limit the subject's ability to participate in and complete this
clinical study.
3. Subject has a history of bipolar, depression or suicidal ideation or behavior, or a
history of psychiatric illnesses.
4. Subject has a 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 (or SBP decrease of ≥ 20 mm Hg 2 minutes after standing
compared with supine SBP), or a history of tachycardia or hypertension.
5. Subject with a seated pulse rate outside 55 to 90 bpm at Screening or Day -1.
6. Subject with a resting QTcF > 450 msec (males) or > 470 msec (females) or PR > 200
msec at Screening or Day -1.
7. Subject has a history of alcoholism, drug abuse, or addiction within 24 months prior
to Screening.
8. Subject has a positive serum test for human immunodeficiency virus (HIV), hepatitis B
virus (HBV), or hepatitis C virus (HCV).
9. Subject has 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.
10. Subject has consumed any marijuana products within 3 months prior to the first dose of
IP.
11. Subject has a positive urine drug test including cotinine at Screening or Day -1.
12. Subject has a positive alcohol breath test at Screening or Day -1.
13. Subject has 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.
14. Subject has used any systemic over-the-counter medication (excluding acetaminophen up
to 1 g/day), dietary or herbal supplement (including vitamins/multi-vitamins) within
14 days prior to the first dose of IP(s). St. John's wort must be discontinued at
least 28 days prior to the first dose of IP.
15. Subject has 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.
16. Subject has used any MAO inhibitors within 90 days prior to the first dose of IP and
the use of fluoxetine within 5 weeks prior to the first dose of IP.
17. Subject has a history of adverse reactions to tyramine-containing foods
18. Subject has a history of allergic reaction to tyramine, phenelzine or S1P agonist.
19. Subject has ingested alcohol within 7 days prior to the first dose of IP.
20. Subject fails or is unwilling to abstain from strenuous physical activities for at
least 24 hours prior to the first dose of IP.
21. Subject has poor peripheral venous access.
22. Subject has donated greater than 400 mL of blood within 60 days prior to Day 1.
23. Subject has a history of any medical condition or medical history that, in the opinion
of the investigator, might confound the results of the study or jeopardize the safety
or welfare of the subject.
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