A Study to Evaluate the Pharmacokinetic Exposure of 2 Formulations of Apremilast in Healthy Adults

A Phase 1, Open Label, Randomized, Two Part Study to Evaluate the Pharmacokinetic Exposure of a Once-Daily (QD) Apremilast Formulation Relative to the Twice-Daily (BID) Reference Immediate Release (IR) Tablet and the Effect of Food on the QD Apremilast Formulation in Healthy Subjects.

The purpose of this study is to evaluate the relative bioavailability of apremilast once-daily formulation relative to a twice daily formulation when administered as multiple doses (Part 1), and when administered as a single dose under fasting and fed conditions (Part 2). Information on safety and tolerability will also be obtained.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Apremilast IR; Drug: Apremilast XL

Detailed Description

Part 1: This is an open-label, randomized, two-period, two-sequence, crossover study in healthy subjects. The study will consist of a screening phase, a baseline phase, two treatment periods, and a follow-up phone call. Each period will be ten days in duration including 7 days of dosing and sample collection for up to 72 hours post Day 7 morning dose. There will be a washout between period 1 and period 2.

Part 2: This is an open-label, randomized, four-period, four-sequence crossover study to evaluate the PK and exposure of apremilast following single dose administration of different formulations of apremilast. Part 2 will consist of a screening phase, baseline, four treatment periods, and a follow-up phone call. Each period will be four days in duration for dosing (Day 1) and sample collection for up to 72 hours post Day 1.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Covance-Daytona Beach
  • Wisconsin
    • Madison, Wisconsin, United States, 53704
      • Covance Clinical Research Unit Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study (Part 1 and Part 2):

1. Must understand and voluntarily sign a written Informed consent form (ICF) prior to any study-related procedures being performed.
2. Must be able to communicate with the investigator, understand and comply with the requirements of the study, and agree to adhere to restrictions and examination schedules.
3. Male and female subjects of any race between 18 to 55 years of age (inclusive), and in good health as determined by the Investigator at the time of signing the informed consent document.
4. Have a body mass index (BMI) between 18 and 33 kg/m^2 (inclusive).
5. No clinically significant laboratory test results as determined by the investigator.
6. At the screening visit, must be afebrile, with supine systolic blood pressure (BP): 90 to 140 mmHg, supine diastolic BP: 50 to 90 mmHg, and pulse rate: 40 to 110 bpm. Eligibility criteria for vital signs performed during check-in and/or predose on Day 1 will be at the discretion of the Investigator.
7. Must have a normal or clinically acceptable 12-lead electrocardiogram (ECG). Subjects must have a QT interval corrected using the Fridericia formula (QTcF) value ≤ 450 msec.

8. Female subjects

   1. Must have a negative pregnancy test
   2. If postmenopausal: must have follicular stimulating hormone (FSH) test result > 40 IU/L and a negative pregnancy test

9. Contraception Requirements:

   Must comply with the following acceptable forms of contraception. All Female of child bearing potential (FCBP)1 must use one of the approved contraceptive options as described below while taking apremilast and for at least 28 days after administration of the last dose of the apremilast. At the time of study entry, and at any time during the study when a FCBP's contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy.

   All FCBP must have a negative pregnancy test at Screening and Day -1 of each Treatment Period. All FCBP subjects who engage in activity in which conception is possible must use one of the approved contraceptive options described below:

   Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or non-latex condom NOT made out of natural [animal] membrane [for example, polyurethane]); Plus one additional barrier(c) contraceptive sponge with spermicide.

   Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex or non-latex condoms NOT made out of natural [animal] membrane [for example, polyurethane]) while on Investigational Product (IP) and for at least 28 days after the last dose of IP.

10. Must agree to refrain from donating sperm, blood or plasma (other than for this study) while participating in this study and for at least 28 days after the last dose of investigational product.
11. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

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

1. History of any clinically significant and relevant neurological, psychiatric, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, or other major disorders.
2. Any condition which places the subject at unacceptable risk if he were to participate in the study, or confounds the ability to interpret data from the study.

1 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 consecutive months).

3. Use of any prescribed systemic or topical medication within 30 days of the first dose administration (exception, FCBP may use hormonal contraception).

4. Use of any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days of the first dose administration.

5. Any surgical or medical condition possibly affecting drug absorption, distribution, metabolism and excretion, eg, bariatric procedure, colon resection, irritable bowel syndrome, Crohn's disease, etc. Subjects with cholecystectomy and appendectomy may be included.

6. Exposure to an investigational drug (new chemical entity) within 30 days prior to the first dose administration or 5 half-lives of that investigational drug, if known (whichever is longer).

7. Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center.

8. History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual [DSM]) within 2 years before dosing, or a positive drug screen reflecting consumption of illicit drugs.

9. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or a positive alcohol screen.

10. Known to have hepatitis, or known to be a carrier of the hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV Ab), or have a positive result to the test for human immunodeficiency virus (HIV) antibodies at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Apremilast 30 mg IR BID / Apremilast 75 mg XL QD; Participants received apremilast 30 mg immediate release (IR) tablet twice a day (BID) for 7 days in treatment period 1 then apremilast 75 mg extended release (XL) formulation once a day (QD) for 7 days in treatment period 2.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet
Experimental: Part 1: Apremilast 75 mg XL QD / Apremilast 30 mg IR BID; Participants received apremilast 75 mg XL formulation once a day for 7 days in treatment period 1 then apremilast 30 mg IR tablet twice a day for 7 days in treatment period 2.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet
Experimental: Part 2: Sequence 1; Participants received a single dose of apremilast in each of 4 treatment periods according to the following: Treatment period 1: Apremilast 30 mg IR tablet under fasted conditions; Treatment period 2: Apremilast 75 mg XL formulation after a high-fat meal; Treatment period 3: Apremilast 75 mg XL formulation under fasted conditions; Treatment period 4: Apremilast 75 mg XL formulation after a standard meal.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet
Experimental: Part 2: Sequence 2; Participants received a single dose of apremilast in each of 4 treatment periods according to the following: Treatment period 1: Apremilast 75 mg XL formulation under fasted conditions; Treatment period 2: Apremilast 30 mg IR tablet under fasted conditions; Treatment period 3: Apremilast 75 mg XL formulation after a standard meal; Treatment period 4: Apremilast 75 mg XL formulation after a high-fat meal.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet
Experimental: Part 2: Sequence 3; Participants received a single dose of apremilast in each of 4 treatment periods according to the following: Treatment period 1: Apremilast 75 mg XL formulation after a standard meal; Treatment period 2: Apremilast 75 mg XL formulation under fasted conditions; Treatment period 3: Apremilast 75 mg XL formulation after a high-fat meal; Treatment period 4: Apremilast 30 mg IR tablet under fasted conditions.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet
Experimental: Part 2: Sequence 4; Participants received a single dose of apremilast in each of 4 treatment periods according to the following: Treatment period 1: Apremilast 75 mg XL formulation after a high-fat meal; Treatment period 2: Apremilast 75 mg XL formulation after a standard meal; Treatment period 3: Apremilast 30 mg IR tablet under fasted conditions; Treatment period 4: Apremilast 75 mg XL formulation under fasted conditions.	Drug: Apremilast IR; Apremilast immediate release tablet; Other Names: Otezla®; Drug: Apremilast XL; Apremilast extended release formulation tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part 1: Peak Maximum Plasma Concentration (Cmax) of Apremilast	Apremilast IR: Day 7 predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, and 24 hours after the morning dose. Apremilast XL: Day 7 predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours after the morning dose.
Part 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Apremilast	Apremilast IR: Day 7 predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, and 24 hours after the morning dose. Apremilast XL: Day 7 predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours after the morning dose.
Part 2: Peak Maximum Plasma Concentration (Cmax) of Apremilast	Apremilast IR: Predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the morning dose. Apremilast XL: Predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, 60, and 72 hours postdose.
Part 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Observable Concentration (AUC0-t) of Apremilast	Apremilast IR: Predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the morning dose. Apremilast XL: Predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, 60, and 72 hours postdose.
Part 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast	Apremilast IR: Predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the morning dose. Apremilast XL: Predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, 60, and 72 hours postdose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events	An adverse event (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 subject's health, including laboratory test values, regardless of etiology. A serious AE is any AE occurring at any dose that: Resulted in death;; Was life-threatening;; Required inpatient hospitalization or prolongation of existing hospitalization;; Resulted in persistent or significant disability/incapacity;; Was a congenital anomaly/birth defect;; Constituted an important medical event. The Investigator determined the relationship between the administration of study drug and the occurrence of each AE as Not Suspected or Suspected as defined in the Protocol.	Part 1: Up to 7 days after last dose in each treatment period (14 days); Part 2: Up to 7 days after each dose.

Collaborators and Investigators

• Sponsor: Amgen

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2016
• Primary Completion (Actual): November 22, 2016
• Study Completion (Actual): November 22, 2016

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 17, 2016
• First Posted (Estimate): May 19, 2016

Study Record Updates

• Last Update Posted (Actual): July 22, 2021
• Last Update Submitted That Met QC Criteria: July 2, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Apremilast; Healthy Subjects; Pharmacokinetic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 4 Inhibitors; Thalidomide; Apremilast
• Other Study ID Numbers: CC-10004-CP-035

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)