Study to Evaluate Bioavailability of Apremilast Oral Suspension Relative to Tablet and to Assess Effect of Food on the Pharmacokinetics (PK) of the Oral Suspension

A Phase 1, Open-Label, Randomized Three-Period, Six-Sequence Crossover Study In Healthy Adult Subjects To Evaluate The Bioavailablity Of An Oral Suspension Formulation Relative To The Tablet Formulation Of Apremilast And To Assess The Effect Of Food On The Pharmacokinetics Of The Oral Suspension Formulation

The purpose of this study is to assess how much of apremilast is found in the blood unchanged when administered as an oral suspension compared to when it is administered as a tablet formulation. The effect of food on apremilast oral suspension will also be evaluated. In addition, information on the safety and tolerability of apremilast will be obtained.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Apremilast Tablet; Drug: Apremilast Oral Suspension

Detailed Description

This is a phase 1, open-label, randomized, three-period, six-sequence crossover study in healthy subjects. The study will consist of a screening phase, baseline (Day -1), three study periods, and a follow-up phone call. Each study period will be four days in duration (Day 1 through Day 4) followed by a five-day washout between doses.

Eligible participants will be admitted into the study center on Day -1 of study Period 1 for baseline measurements. During each study period, participants will receive a single 30 mg oral dose of apremilast on Day 1 according to the assigned treatment sequence. Participants will be confined at the study center from Day 1 of study Period 1 through Day 4 of study Period 3, including the 5 day washout between doses. All participants will be discharged from the study center on Day 4 of study Period 3 following completion of required study procedures. A follow-up phone call will occur approximately four days after the discharge from the study center.

The study will be conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practices (GCPs).

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Expanded Access

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

Contacts and Locations

Study Locations

• United States
  • 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: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects must satisfy ALL of the following criteria to be eligible for enrollment into the study:

1. Must understand and voluntarily sign a written Informed Consent (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 QTcF value ≤ 450 msec.

8. Contraception Requirements:

   • Must comply with the following acceptable forms of contraception. All female of childbearing potential (FCBP) 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 Visits 1 and 2. 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 of the following additional barrier methods: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (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.

9. 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.
10. 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 any healthy subject from enrollment into the study:

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.
3. Use of any prescribed systemic or topical medication within 30 days of the first dose administration.
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, 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.
5. 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).
6. Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center.
7. 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.
8. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or a positive alcohol screen.

9. 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 HBsAg, HCV Ab, or human immunodeficiency virus (HIV) antibodies at Screening.

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Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment A: Apremilast 30 mg Tablet - Fasted; A single oral dose of 30 mg apremilast tablet after an overnight fast.	Drug: Apremilast Tablet; 30 mg tablet; Other Names: CC-10004; Otzela
Experimental: Treatment B: Apremilast 30 mg Oral Suspension - Fasted; A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast.	Drug: Apremilast Oral Suspension; 30 mg oral suspension; Other Names: CC-10004; Otzela
Experimental: Treatment C - Apremilast 30 mg Oral Suspension - Fed; A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.	Drug: Apremilast Oral Suspension; 30 mg oral suspension; Other Names: CC-10004; Otzela

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Apremilast	Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Area Under the Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) for Apremilast	Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. AUC from time zero to the last measured time point was calculated by the linear trapezoidal method.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) for Apremilast	Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. AUC from time zero to infinity was calculated as (AUC0-t + Ct/λz), where Ct is the last quantifiable concentration, and λz is the apparent terminal rate constant.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast	Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Terminal Elimination Half-life (T1/2) of Apremilast		Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Apparent Clearance of Apremilast From Plasma After Extravascular Administration (CL/F)		Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Apparent Volume of Distribution of Apremilast During the Terminal Phase (Vz/F)		Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Lag Time (Tlag) of Apremilast	Lag time is the delay between the time of administration and start of absorption.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.
Relative Bioavailability (F) of Apremilast Oral Suspension Formulation	Relative bioavailability of the oral suspension formulation compared to the tablet formulation, calculated as (AUC0-∞/Dose[oral suspension]) / (AUC0-∞/Dose[tablet]) * 100%.	Predose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60 and 72 hours after dosing on day 1 of each treatment period.

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 participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) 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.	From first dose of study drug in treatment period 1 to 8 days after the last dose; up to 18 days.

Collaborators and Investigators

• Sponsor: Amgen

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2016
• Primary Completion (Actual): February 27, 2016
• Study Completion (Actual): February 27, 2016

Study Registration Dates

• First Submitted: December 23, 2015
• First Submitted That Met QC Criteria: December 23, 2015
• First Posted (Estimate): December 29, 2015

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 14, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Healthy volunteers; Food effect; Bioavailability; Apremilast; 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-032; 20200157 (Other Identifier: Amgen Study ID)

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; SAP; ICF; CSR