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

Study Overview
=================
Brief Summary
-----------------
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.

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).

Official Title
-----------------
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

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Apremilast Tablet
* Drug: Apremilast Oral Suspension


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must satisfy ALL of the following criteria to be eligible for enrollment into the study: Must understand and voluntarily sign a written Informed Consent (ICF) prior to any study-related procedures being performed. 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. 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. Have a Body Mass Index (BMI) between 18 and 33 kg/m^2 (inclusive). No clinically significant laboratory test results as determined by the investigator. 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. Must have a normal or clinically acceptable 12-lead electrocardiogram (ECG). Subjects must have a QTcF value ≤ 450 msec. 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. 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. 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: 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. 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. Use of any prescribed systemic or topical medication within 30 days of the first dose administration. 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. 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). Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center. 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. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or a positive alcohol screen. 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. -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Apremilast, Healthy volunteers, Bioavailability, Food effect, Pharmacokinetic