A Study in Healthy People to Compare 3 Different Formulations of Apremilast Tablets Taken With or Without Food

Study Overview
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Brief Summary
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The aim of this trial is to establish bioequivalence between EU-, US- and Japan-sourced Otezla® tablet formulations to assure comparability of results from Phase III trials of BI 730357 (new oral agent for treatment of psoriasis as well as other T helper 17 cells (Th17)-mediated diseases) regardless of whether only the EU-sourced Otezla® or EU and US-sourced Otezla®/Japan-sourced Otezla® have been used as an active comparator.

Official Title
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Bioequivalence of Three Different Tablet Formulations of 30 mg of Apremilast (EU-sourced Otezla® vs. US-sourced Otezla® vs. Japan-sourced Otezla®) Administered in Healthy Male and Female Subjects in the Fasted State as Well as (for EU-sourced Otezla® vs. US-sourced Otezla®) in the Fed State (an Open-label, Randomised, Single-dose, Five-period, Ten-sequence Crossover Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: EU-sourced Otezla®
* Drug: US-sourced Otezla®
* Drug: Japan-sourced Otezla®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood pressure (BP), Pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests Age of 18 to 55 years (inclusive) Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation Male subjects, or female subjects who meet any of the following criteria for a highly effective contraception from at least 30 days before the first administration of trial medication until 30 days after trial completion: Use of combined (estrogen and progestogen containing) hormonal contraception that prevents ovulation (oral, intravaginal or transdermal), plus condom Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants), plus condom Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) Surgically sterilised (including hysterectomy or bilateral occlusion) Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory) Exclusion Criteria: Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm Any laboratory value outside the reference range that the investigator considers to be of clinical relevance Any evidence of a concomitant disease assessed as clinically relevant by the investigator Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders History of relevant orthostatic hypotension, fainting spells, or blackouts Further exclusion criteria apply.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Five-period, ten-sequence crossover trial. Periods: (A): EU-sourced Otezla - fasted condition (B): US-sourced Otezla - fasted condition (C): EU-sourced Otezla - fed condition (C): US-sourced Otezla - fed condition (E): Japan-sourced Otezla - fasted condition Sequences: see Arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EU-Otezla fasted(A)/ Japan-Otezla fasted(E)/ US-Otezla fasted(B)/ US-Otezla fed(D)/ EU-Otezla fed(C)<br>Treatment sequence AEBDC is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: US-Otezla fasted(B)/ EU-Otezla fasted(A)/ EU-Otezla fed(C)/ Japan-Otezla fasted(E)/ US-Otezla fed(D)<br>Treatment sequence BACED is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: EU-Otezla fed(C)/US-Otezla fasted(B)/US-Otezla fasted(D)/EU-Otezla fasted(A)/ Japan-Otezla fasted(E)<br>Treatment sequence CBDAE is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: US-Otezla fed(D)/ EU-Otezla fed(C)/ Japan-Otezla fasted(E)/ US-Otezla fasted(B)/ EU-Otezla fasted(A)<br>Treatment sequence DCEAB is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: Japan-Otezla fasted(E)/ US-Otezla fed(D)/ EU-Otezla fasted(A)/EU-Otezla fed(C)/ US-Otezla fasted(B)<br>Treatment sequence EDACB is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: EU-Otezla fasted(A)/ US-Otezla fasted(B)/ Japan-Otezla fasted(E)/ EU-Otezla fed(C)/ US-Otezla fed(D)<br>Treatment sequence ABECD is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: US-Otezla fasted(B)/ EU-Otezla fed(C)/ EU-Otezla fasted(A)/ US-Otezla fed(D)/ Japan-Otezla fasted(E)<br>Treatment sequence BCADE is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: EU-Otezla fed(C)/ US-Otezla fed(D)/ US-Otezla fasted(B)/ Japan-Otezla fasted(E)/ EU-Otezla fasted(A)<br>Treatment sequence CDBEA is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: US-Otezla fed(D)/ Japan-Otezla fasted(E)/ EU-Otezla fed(C)/ EU-Otezla fasted(A)/ US-Otezla fasted(B)<br>Treatment sequence DECAB is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|
| Experimental: Japan-Otezla fasted(E)/ EU-Otezla fasted(A)/ US-Otezla fed(D)/ US-Otezla fasted(B)/ EU-Otezla fed(C)<br>Treatment sequence EADBC is applied. The 5 treatments were separated by a washout period of at least 5 days. | Drug: EU-sourced Otezla®<br>* Test product<br>* Other names: Apremilast;Drug: US-sourced Otezla®<br>* Reference product 1<br>* Other names: Apremilast;Drug: Japan-sourced Otezla®<br>* Reference product 2<br>* Other names: Apremilast;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of Apremilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | The area under the concentration-time curve of apremilast in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. | 1 hour (h) before and 30 minutes (min), 1h, 1h30min, 2h, 2h30min, 3h, 3h30min, 4h, 5h, 6h, 8h, 11h, 15h, 24h, 36h, 48h after study drug administration. | 
| Area Under the Concentration-time Curve of Apremilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | The area under the concentration-time curve of apremilast in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. | 1 hour (h) before and 30 minutes (min), 1h, 1h30min, 2h, 2h30min, 3h, 3h30min, 4h, 5h, 6h, 8h, 11h, 15h, 24h, 36h, 48h after study drug administration. | 
| Maximum Measured Concentration of Apremilast in Plasma (Cmax) | The maximum measured concentration of apremilast in plasma (Cmax) is reported. | 1 hour (h) before and 30 minutes (min), 1h, 1h30min, 2h, 2h30min, 3h, 3h30min, 4h, 5h, 6h, 8h, 11h, 15h, 24h, 36h, 48h after study drug administration. |