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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02777554
• Collaborator: (none)
• Enrollment: 144
• Locations: 2
• Arms: 6
• Actual Duration (Months): 3.2
• Patients Per Site: 72
• Patients Per Site Per Month: 22.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Apremilast IR; Drug: Apremilast XL	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: Aug 17, 2016
• Actual Primary Completion Date: Nov 22, 2016
• Actual Study Completion Date: Nov 22, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.]

2. 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.]

3. 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.]

4. 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.]

5. 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

1. Number of Participants With Treatment-emergent Adverse Events [Part 1: Up to 7 days after last dose in each treatment period (14 days); Part 2: Up to 7 days after each dose.]

   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.

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 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

9. Must have a negative pregnancy test

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

11. 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.

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 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).

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

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

3. 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.

4. 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).

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

6. 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.

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

8. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance-Daytona Beach	Daytona Beach	Florida	United States	32117
2	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: NCT02777554
• Other Study ID Numbers: CC-10004-CP-035
• First Posted: May 19, 2016
• Last Update Posted: Jul 22, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Amgen: Healthy Subjects; Apremilast; Pharmacokinetic
• Additional relevant MeSH terms: Thalidomide; Apremilast

Study Results

Participant Flow

Recruitment Details	This study was conducted at 2 clinical sites in the United States. The study consisted of 2 parts. Part 1 was a multiple-dose two-period, two-sequence, crossover study. Part 2 was a four-period, four-sequence crossover study. Both parts enrolled healthy volunteers.
Pre-assignment Detail	In Part 1 participants were randomly assigned to 1 of 2 treatment sequences. In Part 2 participants were randomly assigned to 1 of 4 treatment sequences.

Arm/Group Title	Part 1: Apremilast 30 mg IR BID / Apremilast 75 mg XL QD	Part 1: Apremilast 75 mg XL QD / Apremilast 30 mg IR BID	Part 2: Sequence 1	Part 2: Sequence 2	Part 2: Sequence 3	Part 2: Sequence 4
Arm/Group Description	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. There was a 5.5 to 9.5-day washout period between each treatment period.	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. There was a 6 to 10-day washout period between each treatment period.	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 in the morning and evening 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. There was a washout period of approximately 6 to 10 days between each treatment period.	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 in the morning and evening 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. There was a washout period of approximately 6 to 10 days between each treatment period.	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 in the morning and evening under fasted conditions. There was a washout period of approximately 6 to 10 days between each treatment period.	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 in the morning and evening under fasted conditions; Treatment period 4: Apremilast 75 mg XL formulation under fasted conditions. There was a washout period of approximately 6 to 10 days between each treatment period.
Period Title: Overall Study
STARTED	62	62	5	5	5	5
COMPLETED	32	37	4	4	5	5
NOT COMPLETED	30	25	1	1	0	0

Baseline Characteristics

Arm/Group Title	Part 1	Part 2	Total
Arm/Group Description	Participants in Part 1 received apremilast 30 mg IR tablet BID for 7 days and apremilast 75 mg XL formulation QD for 7 days in each treatment period depending on sequence assignment.	Participants in Part 2 received a single dose of the following treatments in 4 treatment periods according to sequence assignment: Apremilast 30 mg IR tablet in the morning and evening under fasted conditions; Apremilast 75 mg XL formulation after a high-fat meal; Apremilast 75 mg XL formulation under fasted conditions; Apremilast 75 mg XL formulation after a standard meal.	Total of all reporting groups
Overall Participants	124	20	144
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	37.8	34.7	37.4
Sex: Female, Male (Count of Participants)
Female	46 37.1%	7 35%	53 36.8%
Male	78 62.9%	13 65%	91 63.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	52 41.9%	8 40%	60 41.7%
Not Hispanic or Latino	72 58.1%	12 60%	84 58.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	1 0.8%	0 0%	1 0.7%
Black or African American	47 37.9%	10 50%	57 39.6%
White	70 56.5%	10 50%	80 55.6%
Asian	4 3.2%	0 0%	4 2.8%
Other	2 1.6%	0 0%	2 1.4%

Outcome Measures

1. Primary Outcome

Title	Part 1: Peak Maximum Plasma Concentration (Cmax) of Apremilast
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population (all participants who received at least one dose of apremilast and had at least one measurable concentration datum) with available data.

Arm/Group Title	Part 1: Apremilast 30 mg IR BID	Part 1: Apremilast 75 mg XL QD
Arm/Group Description	Participants received apremilast 30 mg IR tablet BID for 7 days.	Participants received apremilast 75 mg XL formulation QD for 7 days.
Measure Participants	91	89
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	451 (49.0)	459 (35.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 30 mg IR BID, Part 1: Apremilast 75 mg XL QD
	Comments	To assess the exposure between the extended release apremilast formulation, and Reference IR (30 mg reference IR BID) tablet following multiple oral doses, an analysis of variance (ANOVA) model, with sequence, period, and treatment as fixed effects, and subject nested within sequence as a random effect, was performed on the natural log-transformed Day 7 Cmax.
	Type of Statistical Test	Equivalence
	Comments	Equivalent exposure of the QD formulation to the BID tablet was established if the 90% confidence intervals (CIs) of the geometric mean ratio for Day 7 AUC0-24 and Cmax were completely contained within the range of 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	101.6
	Confidence Interval	(2-Sided) 90%; 95.1 to 108.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL QD / Apremilast 30 mg IR BID) from an ANOVA model, expressed as a percentage.

2. Primary Outcome

Title	Part 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Apremilast
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The PK population with available data

Arm/Group Title	Part 1: Apremilast 30 mg IR BID	Part 1: Apremilast 75 mg XL QD
Arm/Group Description	Participants received apremilast 30 mg IR tablet BID for 7 days.	Participants received apremilast 75 mg XL formulation QD for 7 days.
Measure Participants	91	89
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	6370 (51.2)	6090 (46.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 30 mg IR BID, Part 1: Apremilast 75 mg XL QD
	Comments	To assess the exposure between the extended release apremilast formulation, and Reference IR (30 mg reference IR BID) tablet following multiple oral doses, an ANOVA model, with sequence, period, and treatment as fixed effects, and subject nested within sequence as a random effect, was performed on the natural log-transformed Day 7 AUC0-24.
	Type of Statistical Test	Equivalence
	Comments	Equivalent exposure of the QD formulation to the BID tablet was established if the 90% CIs of the geometric mean ratio for Day 7 AUC0-24 and Cmax were completely contained within the range of 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	95.3
	Confidence Interval	(2-Sided) 90%; 88.9 to 102.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL QD / Apremilast 30 mg IR BID) from an ANOVA model, expressed as a percentage.

3. Primary Outcome

Title	Part 2: Peak Maximum Plasma Concentration (Cmax) of Apremilast
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PK population; two participants were excluded from PK analyses due to predose concentrations > 5% than their Cmax values.

Arm/Group Title	Part 2: Apremilast 30 mg IR BID (Fasted)	Part 2: Apremilast 75 mg XL (Fasted)	Part 2: Apremilast 75 mg XL (Standard Meal)	Part 2: Apremilast 75 mg XL (High Fat Meal)
Arm/Group Description	Participants received one apremilast 30 mg IR tablet in the morning and one in the evening under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation after a standard meal.	Participants received a single dose of apremilast 75 mg XL formulation after a high-fat meal.
Measure Participants	18	17	16	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	379 (29.9)	402 (32.5)	436 (33.2)	496 (25.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 30 mg IR BID, Part 1: Apremilast 75 mg XL QD
	Comments	To estimate the exposure of apremilast following single dose administration of extended release (QD) relative to the Reference IR (BID) tablet under fasted conditions, 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	103.9
	Confidence Interval	(2-Sided) 90%; 93.6 to 115.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL / Apremilast 30 mg IR BID) from an ANOVA model, expressed as a percentage.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (Standard Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	90.9
	Confidence Interval	(2-Sided) 90%; 81.6 to 101.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (Fasted) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Apremilast 75 mg XL (Standard Meal), Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	115.0
	Confidence Interval	(2-Sided) 90%; 103.3 to 128.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	126.5
	Confidence Interval	(2-Sided) 90%; 113.7 to 140.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Fasted)) from an ANOVA model, expressed as a percentage.

4. Primary Outcome

Title	Part 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Observable Concentration (AUC0-t) of Apremilast
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PK population; two participants were excluded from PK analyses due to predose concentrations > 5% than their Cmax values.

Arm/Group Title	Part 2: Apremilast 30 mg IR BID (Fasted)	Part 2: Apremilast 75 mg XL (Fasted)	Part 2: Apremilast 75 mg XL (Standard Meal)	Part 2: Apremilast 75 mg XL (High Fat Meal)
Arm/Group Description	Participants received one apremilast 30 mg IR tablet in the morning and one in the evening under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation after a standard meal.	Participants received a single dose of apremilast 75 mg XL formulation after a high-fat meal.
Measure Participants	18	17	16	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	7030 (31.5)	6650 (42.5)	7580 (31.1)	7400 (31.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 30 mg IR BID, Part 1: Apremilast 75 mg XL QD
	Comments	To estimate the exposure of apremilast following single dose administration of extended release (QD) relative to the Reference IR (BID) tablet under fasted conditions, 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	92.9
	Confidence Interval	(2-Sided) 90%; 81.3 to 106.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL / Apremilast 30 mg IR BID) from an ANOVA model, expressed as a percentage.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (Standard Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	86.0
	Confidence Interval	(2-Sided) 90%; 74.9 to 98.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (Fasted) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Apremilast 75 mg XL (Standard Meal), Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	97.3
	Confidence Interval	(2-Sided) 90%; 84.9 to 111.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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 of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	113.2
	Confidence Interval	(2-Sided) 90%; 98.8 to 129.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Fasted)) from an ANOVA model, expressed as a percentage.

5. Primary Outcome

Title	Part 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PK population; two participants were excluded from PK analyses due to predose concentrations > 5% than their Cmax values.

Arm/Group Title	Part 2: Apremilast 30 mg IR BID (Fasted)	Part 2: Apremilast 75 mg XL (Fasted)	Part 2: Apremilast 75 mg XL (Standard Meal)	Part 2: Apremilast 75 mg XL (High Fat Meal)
Arm/Group Description	Participants received one apremilast 30 mg IR tablet in the morning and one in the evening under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation after a standard meal.	Participants received a single dose of apremilast 75 mg XL formulation after a high-fat meal.
Measure Participants	18	17	16	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	7100 (31.4)	6680 (42.4)	7600 (31.1)	7450 (31.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 30 mg IR BID, Part 1: Apremilast 75 mg XL QD
	Comments	To estimate the exposure of apremilast following single dose administration of extended release (QD) relative to the Reference IR (BID) tablet under fasted conditions, 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-∞ of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	92.6
	Confidence Interval	(2-Sided) 90%; 81.1 to 105.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL / Apremilast 30 mg IR BID) from an ANOVA model, expressed as a percentage.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (Standard Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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-∞ of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	86.1
	Confidence Interval	(2-Sided) 90%; 75.0 to 98.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (Fasted) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Apremilast 75 mg XL (Standard Meal), Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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-∞ of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	97.5
	Confidence Interval	(2-Sided) 90%; 85.0 to 111.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Standard Meal)) from an ANOVA model, expressed as a percentage.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part 1: Apremilast 75 mg XL QD, Part 2: Apremilast 75 mg XL (High Fat Meal)
	Comments	To estimate the effect of food on the PK of a single oral dose of extended release apremilast (QD), 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-∞ of apremilast.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Means
	Estimated Value	113.2
	Confidence Interval	(2-Sided) 90%; 98.8 to 129.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric mean ratio (Apremilast 75 mg XL (High Fat) / Apremilast 75 mg XL (Fasted)) from an ANOVA model, expressed as a percentage.

6. 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 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.
Time Frame	Part 1: Up to 7 days after last dose in each treatment period (14 days); Part 2: Up to 7 days after each dose.

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of apremilast

Arm/Group Title	Part 1: Apremilast 30 mg IR BID	Part 1: Apremilast 75 mg XL QD	Part 2: Apremilast 30 mg IR BID (Fasted)	Part 2: Apremilast 75 mg XL (Fasted)	Part 2: Apremilast 75 mg XL (Standard Meal)	Part 2: Apremilast 75 mg XL (High Fat Meal)
Arm/Group Description	Participants received apremilast 30 mg IR tablet BID for 7 days.	Participants received apremilast 75 mg XL formulation QD for 7 days.	Participants received one apremilast 30 mg IR tablet in the morning and one in the evening under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation under fasted conditions.	Participants received a single dose of apremilast 75 mg XL formulation after a standard meal.	Participants received a single dose of apremilast 75 mg XL formulation after a high-fat meal.
Measure Participants	108	107	20	19	18	19
Any treatment-emergent adverse event (TEAE)	50 40.3%	47 235%	2 1.4%	4 NaN	3 NaN	2 NaN
TEAE related to study drug	45 36.3%	41 205%	2 1.4%	3 NaN	2 NaN	2 NaN
Serious adverse events	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
Serious adverse events related to study drug	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
TEAE leading to discontinuation	3 2.4%	5 25%	1 0.7%	0 NaN	0 NaN	0 NaN
TEAE related to study drug leading to discontinuation	3 2.4%	5 25%	1 0.7%	0 NaN	0 NaN	0 NaN
Deaths	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN

Adverse Events

Time Frame	Part 1: Up to 7 days after last dose in each treatment period (14 days); Part 2: Up to 7 days after each dose.
Arm/Group Title	Part 1: Apremilast 30 mg IR BID		Part 1: Apremilast 75 mg XL QD		Part 1 Total		Part 2: Apremilast 30 mg IR (Fasted)		Part 2: Apremilast 75 mg XL (Fasted)		Part 2: Apremilast 75 mg XL (Standard Meal)		Part 2: Apremilast 75 mg XL (High Fat Meal)		Part 2 Total
Arm/Group Description	Participants received apremilast 30 mg IR tablet BID for 7 days.		Participants received apremilast 75 mg XL formulation QD for 7 days.		Participants in Part 1 received apremilast 30 mg IR tablet BID for 7 days and apremilast 75 mg XL formulation QD for 7 days in each treatment period depending on sequence assignment.		Participants received one apremilast 30 mg IR tablet in the morning and one in the evening under fasted conditions		Participants received a single dose of apremilast 75 mg XL formulation under fasted conditions.		Participants received a single dose of apremilast 75 mg XL formulation after a standard meal.		Participants received a single dose of apremilast 75 mg XL formulation after a high-fat meal.		Participants in Part 2 received a single dose of the following treatments in 4 treatment periods according to sequence assignment: Apremilast 30 mg IR tablet in the morning and evening under fasted conditions; Apremilast 75 mg XL formulation under fasted conditions; Apremilast 75 mg XL formulation after a standard meal; Apremilast 75 mg XL formulation after a high-fat meal.
All Cause Mortality
	Part 1: Apremilast 30 mg IR BID		Part 1: Apremilast 75 mg XL QD		Part 1 Total		Part 2: Apremilast 30 mg IR (Fasted)		Part 2: Apremilast 75 mg XL (Fasted)		Part 2: Apremilast 75 mg XL (Standard Meal)		Part 2: Apremilast 75 mg XL (High Fat Meal)		Part 2 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Apremilast 30 mg IR BID		Part 1: Apremilast 75 mg XL QD		Part 1 Total		Part 2: Apremilast 30 mg IR (Fasted)		Part 2: Apremilast 75 mg XL (Fasted)		Part 2: Apremilast 75 mg XL (Standard Meal)		Part 2: Apremilast 75 mg XL (High Fat Meal)		Part 2 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/108 (0%)		0/107 (0%)		0/124 (0%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Apremilast 30 mg IR BID		Part 1: Apremilast 75 mg XL QD		Part 1 Total		Part 2: Apremilast 30 mg IR (Fasted)		Part 2: Apremilast 75 mg XL (Fasted)		Part 2: Apremilast 75 mg XL (Standard Meal)		Part 2: Apremilast 75 mg XL (High Fat Meal)		Part 2 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/108 (38%)		35/107 (32.7%)		59/124 (47.6%)		2/20 (10%)		4/19 (21.1%)		3/18 (16.7%)		2/19 (10.5%)		8/20 (40%)
Gastrointestinal disorders
Abdominal pain	4/108 (3.7%)		3/107 (2.8%)		6/124 (4.8%)		1/20 (5%)		1/19 (5.3%)		0/18 (0%)		0/19 (0%)		1/20 (5%)
Diarrhoea	15/108 (13.9%)		13/107 (12.1%)		21/124 (16.9%)		1/20 (5%)		2/19 (10.5%)		0/18 (0%)		0/19 (0%)		2/20 (10%)
Dyspepsia	3/108 (2.8%)		0/107 (0%)		3/124 (2.4%)		1/20 (5%)		0/19 (0%)		1/18 (5.6%)		0/19 (0%)		1/20 (5%)
Nausea	11/108 (10.2%)		7/107 (6.5%)		16/124 (12.9%)		1/20 (5%)		1/19 (5.3%)		0/18 (0%)		2/19 (10.5%)		3/20 (15%)
Vomiting	2/108 (1.9%)		3/107 (2.8%)		5/124 (4%)		1/20 (5%)		0/19 (0%)		0/18 (0%)		1/19 (5.3%)		2/20 (10%)
General disorders
Fatigue	5/108 (4.6%)		5/107 (4.7%)		7/124 (5.6%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Malaise	0/108 (0%)		0/107 (0%)		0/124 (0%)		1/20 (5%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		1/20 (5%)
Pain	6/108 (5.6%)		0/107 (0%)		6/124 (4.8%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Metabolism and nutrition disorders
Hypovolaemia	1/108 (0.9%)		0/107 (0%)		1/124 (0.8%)		1/20 (5%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/108 (1.9%)		7/107 (6.5%)		8/124 (6.5%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Costochondritis	0/108 (0%)		0/107 (0%)		0/124 (0%)		0/20 (0%)		1/19 (5.3%)		0/18 (0%)		0/19 (0%)		1/20 (5%)
Muscle spasms	6/108 (5.6%)		3/107 (2.8%)		8/124 (6.5%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Myalgia	8/108 (7.4%)		8/107 (7.5%)		15/124 (12.1%)		0/20 (0%)		0/19 (0%)		0/18 (0%)		0/19 (0%)		0/20 (0%)
Nervous system disorders
Dizziness	2/108 (1.9%)		2/107 (1.9%)		4/124 (3.2%)		1/20 (5%)		1/19 (5.3%)		0/18 (0%)		0/19 (0%)		2/20 (10%)
Headache	27/108 (25%)		25/107 (23.4%)		43/124 (34.7%)		0/20 (0%)		1/19 (5.3%)		2/18 (11.1%)		2/19 (10.5%)		5/20 (25%)
Lethargy	1/108 (0.9%)		0/107 (0%)		1/124 (0.8%)		0/20 (0%)		1/19 (5.3%)		0/18 (0%)		0/19 (0%)		1/20 (5%)

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.