Phase 3b Safety and Efficacy Study of Apremilast to Treat Moderate to Severe Plaque-plaque Psoriasis

Phase 3

Completed

Conditions: Psoriasis
Psoriatic Arthritis

Interventions: Drug: Apremilast
Drug: Etanercept
Drug: Placebo injection
Drug: Placebo tablet

Registration Number: NCT01690299

Lead Sponsor: Amgen

Brief Summary: This study will test the clinical effectiveness and safety of apremilast compared with placebo as well as etanercept compared with placebo in the same group of patients with moderate to severe plaque psoriasis.

Detailed Description: This is a phase 3b, multicenter, randomized, placebo-controlled, double-blind, double-dummy, study of the efficacy and safety of apremilast, etanercept, and placebo, in adults with moderate to severe plaque psoriasis.

250 participants will be randomized 1:1:1 to the three treatment groups. All subjects will receive both tablets and injections through Week 16.

The study will consist of four phases:

* Screening Phase - up to 35 days

* Double-blind Placebo-controlled Phase - Weeks 0-16

* Apremilast Extension Phase - Weeks 16-104

* Post-treatment Observational Follow-up Phase

During the double-blind, placebo-controlled phase, subjects will receive treatment with one of the following:

* apremilast (APR) 30 mg tablets orally twice a day (BID) plus once weekly (QW) evaluator/subject-blinded subcutaneous (SC) saline (placebo) injections (1 mL x 2 injections SC), or

* etanercept (ETN) 50 mg evaluator/subject-blinded subcutaneous (SC) once weekly (QW) injections (2 x 25 mg) plus placebo tablets orally twice a day (BID), or

* placebo tablets and evaluator/subject-blinded subcutaneous (SC) saline (placebo) injections.

All subjects will be asked to participate in a 4-week Post-treatment Observational Follow-up Phase either upon completion of the study or upon discontinuation of investigational product for those subjects who terminate the study early.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 250

Inclusion Criteria

Males or females, ≥ 18 years of age
Diagnosis of chronic, moderate to severe plaque psoriasis for at least 12 months prior to Screening, and a candidate for phototherapy and/or systemic (including etanercept) therapy
Had an inadequate response, intolerance, or contraindication to at least 1 conventional systemic agent for the treatment of psoriasis.
No prior exposure to biologics for treatment of psoriatic arthritis or psoriasis

Exclusion Criteria

Other than psoriasis, history of any clinically significant and uncontrolled systemic diseases; any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she were to participate in the study.
Pregnant or breast feeding.
Have failed more than 3 systemic agents for treatment of psoriasis.
History of allergy to any component of the investigational product (IP), including human immunoglobulin (Ig) proteins or allergy to etanercept.
Hepatitis B surface antigen or anti-hepatitis C antibody positive at Screening.
Latent, active tuberculosis (TB) or inadequately treated TB; nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis, Clostridium difficile).
Have a history of, or ongoing, chronic or recurrent infectious disease
Have received, or are expected to receive, any live virus or bacterial vaccination within 3 months before first administration of IP, or through Week 20 during the study.
Had a Bacillus Calmette-Guérin (BCG) vaccination within 1 year prior to screening.
History of positive human immunodeficiency virus (HIV), or have congenital or acquired immunodeficiency (eg, common variable immunodeficiency disease).
Active substance abuse or a history of substance abuse within 6 months prior to Screening.
Malignancy or history of malignancy, except for treated [ie, cured] basal cell or squamous cell in situ skin carcinomas and cervical intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years.
Psoriasis flare or rebound within 4 weeks prior to Screening.
Topical therapy within 2 weeks of randomization or systemic therapy for psoriasis within 4 weeks prior to randomization
Use of phototherapy within 4 weeks prior to randomization or prolonged sun exposure or use of tanning booths or other ultraviolet (UV) light sources.
Any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half lives, if known (whichever is longer).
Prior treatment with apremilast or etanercept.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Oral placebo tablets plus SC placebo injections	Placebo injection	Identically matching placebo tablets and evaluator/subject-blinded SC injections
Etanercept 50 mg plus placebo tablet	Placebo tablet	Etanercept 50 mg evaluator/subject-blinded SC QW injections plus placebo tablets orally BID
Apremilast 30 mg plus placebo injection	Placebo injection	Apremilast 30 mg tablets orally twice a day (BID) plus once weekly (QW) evaluator/subject-blinded subcutaneous (SC) saline (placebo) injections
Oral placebo tablets plus SC placebo injections	Placebo tablet	Identically matching placebo tablets and evaluator/subject-blinded SC injections
Apremilast 30 mg plus placebo injection	Apremilast	Apremilast 30 mg tablets orally twice a day (BID) plus once weekly (QW) evaluator/subject-blinded subcutaneous (SC) saline (placebo) injections
Etanercept 50 mg plus placebo tablet	Etanercept	Etanercept 50 mg evaluator/subject-blinded SC QW injections plus placebo tablets orally BID

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Achieved a 75% Improvement (Response) in the Psoriasis Area Severity Index (PASI-75) for the Comparison Between Apremilast and Placebo at Week 16 From Baseline	Baseline to Week 16	PASI-75 response is the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 16. The improvement in PASI score was used as a measure of efficacy. The PASI was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Achieved a 75% Improvement (Response) in the Psoriasis Area and Severity Index (PASI) for the Comparison Between Etanercept 50mg SC QW and Placebo at Week 16	Baseline and Week 16	PASI-75 response is the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 16. The improvement in PASI score was used as a measure of efficacy. The PASI was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing.
Percentage of Participants Who Achieved a Static Physician Global Assessment (sPGA) Score of Clear (0) or Almost Clear (1) With at Least 2 Points Reduction for Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline and Week 16	The sPGA is an assessment by the Investigator of the overall disease severity at the time of evaluation. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. When making the assessment of overall severity, the Investigator should factor in areas that have already been cleared (ie, have scores of 0) and not just evaluate remaining lesions for severity, ie, the severity of each sign is averaged across all areas of involvement, including cleared lesions. In the event of different severities across disease signs, the sign that is the predominant feature of the disease should be used to help determine the sPGA score.
Percent Change From Baseline in the Affected Body Surface Area (BSA) for Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline to Week 16	BSA is a measurement of involved skin. The overall BSA affected by psoriasis was estimated based on the palm area of the participant's hand (entire palmar surface or "handprint" including the fingers), which equates to approximately 1% of total body surface area. BSA percent change from baseline was determined at each visit of the study, and is calculated as 100\*(post-baseline BSA - baseline BSA) / baseline BSA.
Percentage of Participants Who Achieved a 50% Improvement (Response) in the Psoriasis Area Severity Index (PASI-50) for Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline to Week 16	PASI-50 response is the percentage of participants who achieved at least a 50% reduction (improvement) from baseline in PASI score at Week 16. The PASI score was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing.
Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score In Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline to Week 16	DLQI is a simple, compact, and practical questionnaire for use in a dermatology clinical setting to assess limitations related to the impact of skin disease. The instrument contains ten items dealing with the participant's skin. With the exception of Item Number 7, the participant responds on a four-point scale, ranging from "Very Much" (score 3) to "Not at All" or "Not relevant" (score 0). Item Number 7 is a multi-part item, the first part of which ascertains whether the participant's skin prevented them from working or studying (Yes or No, scores 3 or 0 respectively), and if "No," then the participant is asked how much of a problem the skin has been at work or study over the past week, with response alternatives being "A lot," "A little," or "Not at all" (scores 2, 1, or 0 respectively). The DLQI total score is derived by summing all item scores, which has a possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 corresponding to the best.
Change From Baseline in the Mental Component Summary (MCS) Score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline to Week 16	The SF-36 is a 36-item general health status instrument and consists of 8 scales: physical function (PF), role limitations-physical (RP), vitality (VT), general health perceptions (GH), bodily pain (BP), social function (SF), role limitations-emotional (RE), and mental health (MH). Scale scores range from 0 to 100, with higher scores indicating better health. Scores from the 8 scales were transformed to the norm-based scores using weights from U.S. general population to have a mean of 50 and variance = 10, with higher scores indicating better health. From these 8 scale, two overall summary scores were obtained - a Physical Component Summary score (PCS) and a Mental Component Summary score (MCS), both having the same mean of 50 and variance = 10 as noted for the individual scales for the U.S. general population, and with higher scores indicating better health. For MCS, change from baseline was calculated, where change = visit value - baseline value.
Percentage of Participants Who Achieved a Lattice System Physician's Global Assessment (LS-PGA) Score of Clear (0) or Almost Clear at Week 16 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16	Baseline to Week 16	The Lattice System Physician's Global Assessment is a global assessment performed by the investigator of psoriasis severity. Integrating ranges of BSA involvement with assessments of overall plaque severity (using a 4 point scale from none to marked for the signs of plaque elevation, erythema and scale), the LS-PGA produces an overall assessment of psoriasis severity on an 8-point scale, ranging from clear to very severe. To determine the final score, the lattice portion is governed by the BSA and among the plaque qualities, weights plaque elevation as most important, erythema next, and scale least.
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Phase	Week 0 to Week 16; mean duration of exposure was 14.90 weeks for placebo group, 15.13 weeks for apremilast group and 15.87 weeks for Etanercept group	A TEAE is an AE with a start date on or after the date of the first dose of study drug and no later than 28 days after the last dose of study drug for participants who discontinued early. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the patient's health, including laboratory test values, regardless of etiology. Any worsening (ie, clinically significant adverse change in frequency or intensity of a preexisting condition) should be considered an AE. A serious AE (SAE) is any untoward AE that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly/birth defect, or is a condition that may jeopardize or may require intervention to prevent one of the outcomes above.
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Apremilast-exposure Period	From the first dose of apremilast (either Week 0 for participants originally randomized to apremilast or Week 16 for those originally randomized to placebo or etanercept who were switched to apremilast at week 16) until 28 days after last apremilast dose	A TEAE in the apremilast-exposure phase is an AE with a start date on or after the date of the first dose of study drug and no later than 28 days after the last dose of study drug. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the 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. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. A serious AE (SAE) is any untoward AE that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly/birth defect, or is a condition that may jeopardize or may require intervention to prevent one of the outcomes listed above.
Psoriasis Flare/Rebound	From the first dose of apremilast (either Week 0 or Week 16 for participants originally randomized to placebo or etanercept who were switched at Week 16) until 28 days after the last dose of apremilast.	Psoriasis flare is an AE and represents an atypical or unusual worsening of disease during treatment. It is defined as a sudden intensification of psoriasis requiring medical intervention or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is an AE and is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. This exacerbation is characterized by a PASI ≥125% of baseline or a new generalized pustular, erythrodermic, or more inflammatory psoriasis after stopping therapy. PASI ≥125% of baseline score at any visit after the last dose date for those who discontinued within the phase.

Trial Locations

Locations (82): University of California Irvine-Department of Dermatology
🇺🇸
Irvine, California, United States
Florida Academic Dermatology Center
🇺🇸
Miami, Florida, United States
International Dermatology Research
🇺🇸
Miami, Florida, United States
NorthShore University HealthSystem
🇺🇸
Skokie, Illinois, United States
Dawes Fretzin Clinical Research Group, LLC
🇺🇸
Indianapolis, Indiana, United States
University Hospitals Case Medical Center
🇺🇸
Cleveland, Ohio, United States
Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Dermatology Associates of Seattle
🇺🇸
Seattle, Washington, United States
Q & T Research Sherbrooke Inc.
🇨🇦
Sherbrooke, Quebec, Canada
Whipps Cross University Hospital
🇬🇧
London, United Kingdom
Adoria Ltd
🇱🇻
Riga, Latvia
University Hospital of Liege CHU Liege
🇧🇪
Liege, Belgium
Gemeinschaftspraxis Mahlow
🇩🇪
Mahlow, Germany
University Hospital of Wales
🇬🇧
Cardiff, United Kingdom
Cliniques Universitaires St-Luc
🇧🇪
Brussels, Belgium
Leeds Teaching Hospitals Trust
🇬🇧
Leeds, United Kingdom
Comprehensive Center of Inflammatory Medicine (CCIM) University Medical Center Schleswig-Holstein
🇩🇪
Lübeck, Germany
Forest Hills Dermatology Group
🇺🇸
Forest Hills, New York, United States
Bakersfield Dermatology and Skin Cancer Medical Group
🇺🇸
Bakersfield, California, United States
Lawrence Green, MD, LLC
🇺🇸
Rockville, Maryland, United States
Renstar Medical Research
🇺🇸
Ocala, Florida, United States
Gairdner Hospital
🇦🇺
Victoria Park, Australia
UniversitatsKlinikum Leipzig A.o.R.
🇩🇪
Leipzig, Germany
University Hospital Munster
🇩🇪
Münster, Germany
SCIderm GmbH
🇩🇪
Hamburg, Germany
Sinclair Dermatology
🇦🇺
East Melbourne, Victoria, Australia
Radboud University Medical Centre
🇳🇱
Nijmegen, Netherlands
Arija's Ancane's Family Doctor Private Practice
🇱🇻
Baldone, Latvia
Východoceské dermatologické centrum Homea s.r.o.
🇨🇿
Pardubice, Czechia
St Helier Hospital
🇬🇧
London, United Kingdom
George Eliot Hospital
🇬🇧
Nuneaton, United Kingdom
Fremantle Dermatology
🇦🇺
Fremantle, Western Australia, Australia
Allergo-Derm Bakos Kft.
🇭🇺
Szolnok, Hungary
LTD M & M centrs
🇱🇻
Adazi, Latvia
Riga 1st Hospital Skin and Sexually Transmitted Diseases Clinical Centre
🇱🇻
Riga, Latvia
Family Doctor's Indra's Kenina's Practice
🇱🇻
Riga, Latvia
Health Center of Talsi Ltd
🇱🇻
Talsi, Latvia
Tolna Megyei Balassa Janos Korhaz
🇭🇺
Szekszárd, Hungary
Praxis fr Dermatologie und Venerologie
🇩🇪
Wuppertal, Germany
Arizona Research Center
🇺🇸
Phoenix, Arizona, United States
Horizons Clinical Research
🇺🇸
Denver, Colorado, United States
Florida Center for Dermatology, PA
🇺🇸
Jacksonville, Florida, United States
Atlanta Dermatology, Vein and Research Center, PC
🇺🇸
Alpharetta, Georgia, United States
Dermatology and Advanced Aesthetics
🇺🇸
Lake Charles, Louisiana, United States
NYU Department of Dermatology
🇺🇸
New York, New York, United States
Virginia Clinical Research Inc
🇺🇸
Norfolk, Virginia, United States
The Skin Centre
🇦🇺
Benowa, Queensland, Australia
The Education and Research Foundation
🇺🇸
Lynchburg, Virginia, United States
Rheumatology unit Ward 5C Queen Elizabeth Hospital
🇦🇺
Woodville, Australia
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
George Washington University
🇺🇸
Washington, District of Columbia, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Robert Wood Johnson Medical School
🇺🇸
Somerset, New Jersey, United States
Veracity Clinical Research
🇦🇺
Woolloongabba, Australia
Skin Center for Dermatology
🇨🇦
Peterborough, Ontario, Canada
University Hospital Ghent
🇧🇪
Ghent, Belgium
Eastern Canada Cutaneous Research Associates Ltd
🇨🇦
Halifax, Nova Scotia, Canada
K. Papp Clinical Research Inc.
🇨🇦
Waterloo, Ontario, Canada
Siena Medical Research
🇨🇦
Montreal, Quebec, Canada
Dorothea, Kožní a korektivne dermatologické pracovište
🇨🇿
Chomutov, Czechia
Dermamedica
🇨🇿
Nachod, Czechia
Krajská nemocnice Pardubice, Kožní oddelení
🇨🇿
Pardubice, Czechia
Dermatovenerologicka ambulance
🇨🇿
Svitavy, Czechia
Dermatologische Praxis
🇩🇪
Berlin, Germany
South Estonian Hospital Ltd
🇪🇪
Meegomäe Village, Võru County, Estonia
Koznia zilni ambulance
🇨🇿
Ústí nad Labem, Czechia
Psoriasis Study Center
🇩🇪
Berlin, Germany
Dermatology Clinic of Tartu University Hospital
🇪🇪
Tartu, Estonia
University Hospital Carl Gustav Carus
🇩🇪
Dresden, Germany
Klinische Forschung Berlin - Buch GmbH
🇩🇪
Berlin, Germany
Hautklinik Universitatsklinikum Erlangen
🇩🇪
Erlangen, Germany
University Hospital Frankfurt
🇩🇪
Frankfurt, Germany
Universitatsklinikum Heidelberg
🇩🇪
Heidelberg, Germany
Institute for Health Services Research in Dermatology and Nursing - IVDP, University Medical Center
🇩🇪
Hamburg, Germany
Academic Medical Center
🇳🇱
Amsterdam, Netherlands
University of California San Diego Medical Center
🇺🇸
San Diego, California, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Tennesse Clinical Research Center
🇺🇸
Nashville, Tennessee, United States
Teckton Research
🇺🇸
Austin, Texas, United States