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

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT02641353
Collaborator
(none)
34
1
3
1.7
19.5

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Apremilast Tablet
  • Drug: Apremilast Oral Suspension
Phase 1

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 Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
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
Actual Study Start Date :
Jan 5, 2016
Actual Primary Completion Date :
Feb 27, 2016
Actual Study Completion Date :
Feb 27, 2016

Arms and Interventions

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:
  • Otzela
  • CC-10004
  • 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:
  • Otzela
  • CC-10004
  • 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:
  • Otzela
  • CC-10004
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum Observed Plasma Concentration (Cmax) 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.]

      Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.

    2. Area Under the Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) for 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.]

      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.

    3. Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) for 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.]

      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.

    4. Time to Maximum Observed Plasma Concentration (Tmax) 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.]

      Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.

    5. 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.]

    6. 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.]

    7. 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.]

    8. Lag Time (Tlag) 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.]

      Lag time is the delay between the time of administration and start of absorption.

    9. Relative Bioavailability (F) of Apremilast Oral Suspension Formulation [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 of the oral suspension formulation compared to the tablet formulation, calculated as (AUC0-∞/Dose[oral suspension]) / (AUC0-∞/Dose[tablet]) * 100%.

    Secondary Outcome Measures

    1. Number of Participants With Treatment-emergent Adverse Events [From first dose of study drug in treatment period 1 to 8 days after the last dose; up to 18 days.]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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.

    1. 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.

    2. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Covance Clinical Research Unit Inc Madison Wisconsin United States 53704

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02641353
    Other Study ID Numbers:
    • CC-10004-CP-032
    • 20200157
    First Posted:
    Dec 29, 2015
    Last Update Posted:
    Aug 5, 2021
    Last Verified:
    Jul 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Amgen
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at a single site in the United States. The study consisted of three treatment periods separated by a 5-day washout period.
    Pre-assignment Detail Participants were randomly assigned to one of six treatment sequences. On day 1 of each treatment sequence participants received one of the following according to their assigned treatment sequence: Treatment A: Single oral dose of 30 mg apremilast tablet under fasted conditions Treatment B: Single oral dose of 30 mg apremilast oral suspension formulation under fasted conditions Treatment C: Single oral dose of 30 mg apremilast oral suspension formulation under fed conditions
    Arm/Group Title Sequence 1: Treatments ACB Sequence 2: Treatments CBA Sequence 3: Treatments BAC Sequence 4: Treatments ABC Sequence 5: Treatments CAB Sequence 6: Treatments BCA
    Arm/Group Description Participants received 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 1, 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 2, and 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 3. Participants received 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 1, 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 2, and 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 3. Participants received 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 1, 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 2, and 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 3. Participants received 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 1, 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 2, and 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 3. Participants received 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 1, 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 2, and 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 3. Participants received 30 mg apremilast oral suspension after an overnight fast on day 1 of treatment period 1, 30 mg apremilast oral suspension after a high-fat meal on day 1 of treatment period 2, and 30 mg apremilast oral tablet after an overnight fast on day 1 of treatment period 3.
    Period Title: Overall Study
    STARTED 5 5 6 6 6 6
    COMPLETED 5 5 6 6 6 6
    NOT COMPLETED 0 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Total
    Arm/Group Description Participants received a single dose of the following three treatments in one of six treatment sequences: Treatment A: Single oral dose of 30 mg apremilast tablet under fasted conditions Treatment B: Single oral dose of 30 mg apremilast oral suspension formulation under fasted conditions Treatment C: Single oral dose of 30 mg apremilast oral suspension formulation under fed conditions
    Overall Participants 34
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    33.3
    Sex: Female, Male (Count of Participants)
    Female
    9
    26.5%
    Male
    25
    73.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    2.9%
    Not Hispanic or Latino
    33
    97.1%
    Unknown or Not Reported
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    1
    2.9%
    Asian
    1
    2.9%
    Black or African American
    14
    41.2%
    White
    17
    50%
    Other
    1
    2.9%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Observed Plasma Concentration (Cmax) of Apremilast
    Description Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic (PK) population included all participants who received at least one dose of apremilast and had at least one measurable concentration datum.
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    323
    (34.5)
    274
    (32.2)
    215
    (33.7)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Treatment A: Apremilast 30 mg Tablet - Fasted, Treatment B: Apremilast 30 mg Oral Suspension - Fasted
    Comments To assess the bioavailability between the apremilast oral suspension and tablet formulation an analysis of variance (ANOVA) model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed Cmax.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 84.9
    Confidence Interval (2-Sided) 90%
    77.3 to 93.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment B / Treatment A) expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Treatment B: Apremilast 30 mg Oral Suspension - Fasted, Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Comments To assess the effect of food on the PK of apremilast oral suspension formulation, an ANOVA model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed Cmax.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 78.2
    Confidence Interval (2-Sided) 90%
    71.2 to 86.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment C / Treatment B) expressed as a percentage.
    2. Primary Outcome
    Title Area Under the Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) for Apremilast
    Description 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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    3130
    (38.9)
    2740
    (43.1)
    3160
    (41.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Treatment A: Apremilast 30 mg Tablet - Fasted, Treatment B: Apremilast 30 mg Oral Suspension - Fasted
    Comments To assess the bioavailability between the apremilast oral suspension and tablet formulation an ANOVA model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-t.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 87.6
    Confidence Interval (2-Sided) 90%
    83.0 to 92.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment B / Treatment A) expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Treatment B: Apremilast 30 mg Oral Suspension - Fasted, Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Comments To assess the effect of food on the PK of apremilast oral suspension formulation, an ANOVA model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-t.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 115.3
    Confidence Interval (2-Sided) 90%
    109.2 to 121.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment C / Treatment B) expressed as a percentage.
    3. Primary Outcome
    Title Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) for Apremilast
    Description 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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    3160
    (38.7)
    2760
    (43.2)
    3190
    (41.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Treatment A: Apremilast 30 mg Tablet - Fasted, Treatment B: Apremilast 30 mg Oral Suspension - Fasted
    Comments To assess the bioavailability between the apremilast oral suspension and tablet formulation an ANOVA model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-∞.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 87.8
    Confidence Interval (2-Sided) 90%
    83.2 to 92.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment B / Treatment A) expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Treatment B: Apremilast 30 mg Oral Suspension - Fasted, Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Comments To assess the effect of food on the PK of apremilast oral suspension formulation, an ANOVA model, with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-∞.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 115.0
    Confidence Interval (2-Sided) 90%
    109.0 to 121.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of adjusted geometric means (Treatment C / Treatment B) expressed as a percentage.
    4. Primary Outcome
    Title Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast
    Description Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The PK population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Median (Full Range) [hours]
    2.00
    2.00
    5.00
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Treatment A: Apremilast 30 mg Tablet - Fasted, Treatment B: Apremilast 30 mg Oral Suspension - Fasted
    Comments Tmax was analyzed by nonparametric methods. The median difference and 90% confidence interval (CI) of the median difference were calculated from the Hodges-Lehrmann estimate.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1508
    Comments
    Method Wilcoxon signed-rank test
    Comments
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 0.25
    Confidence Interval (2-Sided) 90%
    0.00 to 0.50
    Parameter Dispersion Type:
    Value:
    Estimation Comments Median difference (Treatment B - Treatment A) calculated from the Hodges-Lehmann estimate
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Treatment B: Apremilast 30 mg Oral Suspension - Fasted, Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Comments Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon signed-rank test
    Comments
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 2.25
    Confidence Interval (2-Sided) 90%
    1.27 to 3.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments Median difference (Treatment C - Treatment B) calculated from the Hodges-Lehmann estimate
    5. Primary Outcome
    Title Terminal Elimination Half-life (T1/2) of Apremilast
    Description
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    PK population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    7.89
    (34.5)
    8.51
    (31.8)
    7.54
    (30.8)
    6. Primary Outcome
    Title Apparent Clearance of Apremilast From Plasma After Extravascular Administration (CL/F)
    Description
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    PK population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [L/h]
    9.51
    (38.7)
    10.9
    (43.2)
    9.42
    (41.3)
    7. Primary Outcome
    Title Apparent Volume of Distribution of Apremilast During the Terminal Phase (Vz/F)
    Description
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    PK population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Geometric Mean (Geometric Coefficient of Variation) [L]
    108
    (45.2)
    133
    (43.7)
    102
    (38.9)
    8. Primary Outcome
    Title Lag Time (Tlag) of Apremilast
    Description Lag time is the delay between the time of administration and start of absorption.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    PK population
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Median (Full Range) [hours]
    0.00
    0.00
    0.00
    9. Primary Outcome
    Title Relative Bioavailability (F) of Apremilast Oral Suspension Formulation
    Description Relative bioavailability of the oral suspension formulation compared to the tablet formulation, calculated as (AUC0-∞/Dose[oral suspension]) / (AUC0-∞/Dose[tablet]) * 100%.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    PK population. Relative bioavailability calculated for each of the oral suspension treatments as pre-specified in the Protocol.
    Arm/Group Title Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34
    Geometric Mean (Geometric Coefficient of Variation) [percent availability]
    87.6
    (16.1)
    101
    (14.3)
    10. Secondary Outcome
    Title Number of Participants With Treatment-emergent Adverse Events
    Description 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.
    Time Frame From first dose of study drug in treatment period 1 to 8 days after the last dose; up to 18 days.

    Outcome Measure Data

    Analysis Population Description
    The safety population included all participants who received at least one dose of apremilast.
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal.
    Measure Participants 34 34 34
    Any treatment-emergent adverse event (TEAE)
    8
    23.5%
    10
    NaN
    6
    NaN
    TEAEs related to study drug
    4
    11.8%
    7
    NaN
    4
    NaN
    Serious adverse events
    0
    0%
    0
    NaN
    0
    NaN
    TEAEs leading to discontinuation
    0
    0%
    0
    NaN
    0
    NaN
    TEAEs leading to death
    0
    0%
    0
    NaN
    0
    NaN

    Adverse Events

    Time Frame From first dose of study drug in treatment period 1 to 8 days after the last dose; up to 18 days.
    Adverse Event Reporting Description
    Arm/Group Title Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed Total
    Arm/Group Description A single oral dose of 30 mg apremilast tablet after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after an overnight fast. A single oral dose of 30 mg apremilast oral suspension formulation (6 mL) after a high-fat meal. Participants received a single dose of the following three treatments in one of six treatment sequences: Treatment A: Single oral dose of 30 mg apremilast tablet under fasted conditions Treatment B: Single oral dose of 30 mg apremilast oral suspension formulation under fasted conditions Treatment C: Single oral dose of 30 mg apremilast oral suspension formulation under fed conditions
    All Cause Mortality
    Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/34 (0%) 0/34 (0%) 0/34 (0%) 0/34 (0%)
    Other (Not Including Serious) Adverse Events
    Treatment A: Apremilast 30 mg Tablet - Fasted Treatment B: Apremilast 30 mg Oral Suspension - Fasted Treatment C: Apremilast 30 mg Oral Suspension - Fed Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/34 (14.7%) 10/34 (29.4%) 3/34 (8.8%) 15/34 (44.1%)
    Gastrointestinal disorders
    Constipation 0/34 (0%) 2/34 (5.9%) 1/34 (2.9%) 3/34 (8.8%)
    Diarrhoea 0/34 (0%) 5/34 (14.7%) 1/34 (2.9%) 5/34 (14.7%)
    Dyspepsia 1/34 (2.9%) 1/34 (2.9%) 0/34 (0%) 2/34 (5.9%)
    Flatulence 0/34 (0%) 1/34 (2.9%) 1/34 (2.9%) 2/34 (5.9%)
    Nausea 2/34 (5.9%) 2/34 (5.9%) 0/34 (0%) 4/34 (11.8%)
    General disorders
    Feeling hot 0/34 (0%) 2/34 (5.9%) 0/34 (0%) 2/34 (5.9%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain 1/34 (2.9%) 1/34 (2.9%) 0/34 (0%) 2/34 (5.9%)
    Nervous system disorders
    Headache 2/34 (5.9%) 2/34 (5.9%) 2/34 (5.9%) 4/34 (11.8%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02641353
    Other Study ID Numbers:
    • CC-10004-CP-032
    • 20200157
    First Posted:
    Dec 29, 2015
    Last Update Posted:
    Aug 5, 2021
    Last Verified:
    Jul 1, 2021