Clinical trial NCT01925768: Safety and Efficacy Study of Apremilast to Treat Psoriatic Arthritis
Official title: A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) Monotherapy in Subjects With Active Psoriatic Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Psoriatic Arthritis
Keywords: Apremilast, Psoriatic Arthritis, PDE4 inhibitor
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2013-08-20
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether apremilast is safe and effective for treating patients with psoriatic arthritis.

Detailed description: This is a Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of apremilast monotherapy in subjects with active psoriatic arthritis.

Approximately 214 subjects will be randomized in a 1:1 ratio to either apremilast 30 mg BID (twice a day) or identically-appearing placebo, with approximately 107 subjects per treatment group.

This is a 113-week study. The subjects will spend 24 weeks in the double-blind, placebo-controlled treatment phase, followed by 28 weeks of active treatment phase (ie, up to Week 52 visit). The original treatment assignments (apremilast 30 mg BID (twice a day) or placebo) will remain blinded until all subjects have completed their Week 52 visit (or have discontinued). After the Week 52 visit, all subjects in the extension phase will continue to receive treatment with apremilast 30 mg BID (twice a day) until the end of the study (ie, up to Week 104 visit) or until early discontinuation from the trial.

The study will consist of 5 phases:

1. Screening Phase - up to 5 weeks
2. Randomized, Placebo-controlled, Double Blind Treatment Phase - Weeks 0 to 24
3. Active Treatment Phase - Week 24 to Week 52
4. Open-label Extension Phase - Week 52 to Week 104
5. Post-treatment Observational Follow-up Phase

Eligibility criteria: Inclusion Criteria:

1. Males or females, 18 years and older at time of consent.
2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Have a documented diagnosis of psoriatic arthritis (by any criteria) of at least 3 months' duration
5. Meet the classification criteria for psoriatic arthritis (CASPAR) at the time of screening.
6. Have at least 3 swollen AND at least 3 tender joints.
7. Must have high sensitivity C-Reactive Protein (hs-CRP) of at least 0.5 mg/dL at screening and at baseline.
8. Must be receiving treatment on an outpatient basis.
9. Must be tumor necrosis factor (TNF) blocker naive and other Biologic naïve for dermatologic and rheumatic conditions
10. Subjects taking disease modifying anti-rheumatoid drugs (DMARDs), with the exception of cyclosporine and leflunomide (see 7.3. Exclusion Criteria 20, 21), do not require a washout, however, they must discontinue the DMARD treatment at least one day prior to their baseline visit (ie, Visit 2, Day 0)
11. Subjects who have been previously treated with leflunomide will require a 12-week washout or treatment with the cholestyramine, per leflunomide prescribing label (ie. 8 g cholestyramine 3 times daily for 11 days.
12. Subjects who have been previously treated with cyclosporine will require a 4-week washout prior to randomization to participate in the study
13. If taking oral corticosteroids, must be on a stable dose of prednisone less than or equal to 10 mg/day or equivalent for at least 30 days prior to baseline visit (ie, Day 0)
14. If taking nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotic analgesics, must be on stable dose for at least 30 days prior to baseline visit (ie, Day 0) and until they have completed the Week 24 study visit.
15. Must meet the following laboratory criteria:

    * White blood cell count greater than 3000/mm\^3 (greater than 3.0 X 10\^9/L) and less than 14,000/mm\^3 (less than 14 X 10\^9/L)
    * Platelet count at least 100,000/mm\^3 (at least 100 X 10\^9/L)
    * Serum creatinine less than or equal to 1.5 mg/dL (less than or equal to 132.6 μmol/L)
    * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to twice upper limit of normal (ULN). If initial test shows ALT or AST greater than 2 times the ULN, one repeat test is allowed during the screening period.
    * Total bilirubin less than or equal to 2 mg/dL (less than or equal to 34 μmol/L) or Albumin greater than LLN. If initial test result is greater than 2 mg/dL, one repeat test is allowed during the screening period.
    * Hemoglobin at least 9 g/dL (at least 5.6 mmol/L)
    * Hemoglobin A1c less than or equal to 9.0%
16. All females of childbearing potential (FCBP) must use one of the approved contraceptive options as described below while on investigational product and for at least 28 days after administration of the last dose of the investigational product.

    At the time of study entry, and at any time during the study when a female subject of childbearing potential'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.

    Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. 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 method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.
17. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural \[animal\] membrane \[for example, polyurethane\]) while on investigational product and for at least 28 days after the last dose of investigational product.

Exclusion Criteria:

1. History of clinically significant (as determined by the investigator) cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.
2. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
3. Clinically significant abnormality on a 12-lead electrocardiogram (ECG) at Screening.
4. Pregnant or breast feeding.
5. History of allergy to any component of the investigational product.
6. Hepatitis B surface antigen positive at screening.
7. Hepatitis C antibody positive at screening.
8. History of positive human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease).
9. Active tuberculosis or a history of incompletely treated tuberculosis.
10. Clinically significant abnormality based upon chest radiograph with at least posterior-anterior (PA) view (the radiograph must be taken within 12 weeks prior to Screening or during the Screening visit). An additional lateral view is strongly recommended but not required.
11. Active substance abuse or a history of substance abuse within 6 months prior to Screening.
12. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections must have been completed and the infection cured, at least 4 weeks prior to Screening.
13. Malignancy or history of malignancy, except for:

    1. treated \[ie, cured\] basal cell or squamous cell in situ skin carcinomas;
    2. treated \[ie, cured\] cervical intraepithelial neoplasia \[CIN\] or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years.
14. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
15. Erythrodermic, guttate, or generalized pustular psoriasis at randomization.
16. Rheumatic autoimmune disease other than PsA, including, but not limited to: systemic lupus erythematosis (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or fibromyalgia.
17. Functional Class IV, as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis.
18. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive arthritis, rheumatoid arthritis (RA), ankylosing spondylitis, Lyme disease).
19. Prior treatment with more than one non-biologic DMARD
20. Use of the following systemic therapy(ies) within 4 weeks of randomization: cyclosporine or other calcineurin inhibitors, corticosteroids exceeding 10 mg daily prednisone equivalent, as well as other oral agents such as retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, tacrolimus.
21. Use of leflunomide within 12 weeks of randomization, unless subject has taken cholestyramine, 8g TID (three times a day) x 11 days after stopping leflunomide.
22. Previous treatment with biologic agents for rheumatic diseases such as, but not limited to: adalimumab, abatacept, canakinumab, etanercept, golimumab, infliximab, rilonacept, certolizumab pegol, or tocilizumab.
23. Previous treatment with biologic agents for dermatologic diseases such as alefacept, anti-TNFs (eg etanercept, adalinumab) or ustekinumab.
24. Previous treatment with tofacitinib, Anti IL-17 agents or secukinumab
25. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, alemtuzumab, ocrelizumab, alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20).
26. Treatment with intravenous gamma globulin, plasmapheresis, or Prosorba® column
27. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
28. Prior treatment with any non-biologic DMARDS other than methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, fumeric acid esters, cyclosporine, or leflunomide
29. Prior treatment with apremilast, or participation in a clinical study, involving apremilast
30. Use of any investigational drug within 4 weeks of randomization, or 5 pharmacokinetic/ pharmacodynamic half lives, if known (whichever is longer).

Primary outcomes:
measure: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Week 16
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the 28-Joint Disease Activity Score Using C-reactive Protein as the Acute-Phase Reactant (DAS28 [CRP]) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Medical Outcomes Short Form Health Survey (SF-36) V2 Physical Function Domain Score at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the 36-item SF-36 Physical Component Summary Score at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Duration of Morning Stiffness at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants With Improved Change in Severity of Morning Stiffness at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16
timeFrame: Baseline and Week 16
measure: Change From Baseline in the Disease Activity Score DAS28 (CRP) at Week 16
timeFrame: Baseline and Week 16
measure: Change From Baseline in 36-item Short Form Health Survey (SF-36) V 2 Physical Functioning Domain at Week 16
timeFrame: Baseline and Week 16
measure: Mean Change From Baseline in the Duration of Morning Stiffness at Week 16
timeFrame: Baseline and Week 16
measure: Percentage of Participants Whose Severity of Morning Stiffness at Week 16 Improved From Baseline
timeFrame: Baseline and Week 16
measure: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 2, 4, 6, 8, 12 and 20
timeFrame: Baseline and at Weeks 2, 4, 6, 8, 12 and 20
measure: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Change From Baseline in the Disease Activity Score (DAS28) at Week 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Change From Baseline in 36-item SF-36 (V2.0) Physical Functioning Domain Score at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Change From Baseline in the Duration of Morning Stiffness at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Percentage of Participants Whose Severity of Morning Stiffness at Week 52 and 104 Improved From Baseline
timeFrame: Baseline and Weeks 52 and 104
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the 24 Week Placebo Controlled Phase
timeFrame: Date of first dose of study drug to Week 24; median duration of exposure during placebo controlled phase was 24.14 weeks
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Apremilast-Exposure Period
timeFrame: Start of lst dose of IP up to week 104: Weeks 0 to104 for those initially randomized to APR 30 mg BID, Weeks 16 -104 for PBO-treated patients who EE to APR at Week 16 and from Weeks 24-104 for PBO-treated patients who transitioned to APR at Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Achieve Clinical Research LLC
state: Alabama
city: Palm Desert
country: United States
facility: Desert Medical Advances
state: California
city: Brandon
country: United States
facility: Bay Area Arthritis and Osteoporosis
state: Florida
city: Brandon
country: United States
facility: Health Point Medical Group
state: Florida
city: Hialeah
country: United States
facility: Palmetto Medical Research
state: Florida
city: Naples
country: United States
facility: Jeffrey Alper MD Research
state: Florida
city: New Port Richey
country: United States
facility: Suncoast Clinical Research
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Coeur d'Alene
country: United States
facility: Coeur D'Alene Arthritis Clinic
state: Idaho
city: Rockford
country: United States
facility: Rockford Orthopedic Associates, LLC
state: Illinois
city: Lansing
country: United States
facility: Advanced Rheumatology
state: Michigan
city: Kalispell
country: United States
facility: Research West Incorporated
state: Montana
city: Omaha
country: United States
facility: Heartland Clinical Research, Inc.
state: Nebraska
city: Greenville
country: United States
facility: Physicians East
state: North Carolina
city: Winston-Salem
country: United States
facility: Piedmont Medical Research Associates Inc
state: North Carolina
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Jackson
country: United States
facility: West Tennessee Research Institute
state: Tennessee
city: Memphis
country: United States
facility: Ramesh C Gupta MD
state: Tennessee
city: Austin
country: United States
facility: Austin Regional Clinic
state: Texas
city: Dallas
country: United States
facility: Baylor Research Institute
state: Texas
city: Houston
country: United States
facility: Houston Medical Research
state: Texas
city: Lubbock
country: United States
facility: Arthritis and Osteoporosis Associates LLP
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Clarksburg
country: United States
facility: Mountain State Clinical Research
state: West Virginia
city: Victoria Park
country: Australia
facility: Colin Bayliss Research and Teaching Unit
state: Western Australia
city: Box Hill
country: Australia
facility: Eastern Health Clinical School
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Hobart,
country: Australia
facility: Menzies Centre for Population Health Research
city: Kogarah
country: Australia
facility: Optimus Clinical Research Pty. Ltd
city: Maroochydore
country: Australia
facility: Coastal Joint Care
city: Westmead, NSW
country: Australia
facility: Westmead Cancer Care Center
city: Vancouver
country: Canada
facility: Manna Research
state: British Columbia
city: Winnipeg
country: Canada
facility: Manitoba Clinic
state: Manitoba
city: Saint John's
country: Canada
facility: Karma Clinical Trials
state: Newfoundland and Labrador
city: St John's
country: Canada
facility: Nexus Clinical Research
state: Newfoundland and Labrador
city: Hamilton
country: Canada
facility: MAC Research Incorporated
state: Ontario
city: Toronto
country: Canada
facility: Arthur Karasik Private Practice
state: Ontario
city: Toronto
country: Canada
facility: Manna Research
state: Ontario
city: Windsor
country: Canada
facility: Jude Rodrigues Private Practice
state: Ontario
city: Quebec
country: Canada
facility: CHUL du CHU de Quebec
city: Praha 2
country: Czechia
facility: Revmatologicky ustav
city: Praha 4
country: Czechia
facility: Revmatologicka Ambulance
city: Sokolov
country: Czechia
facility: Revmatologicka Ambulance
city: Zlin
country: Czechia
facility: PV - MEDICAL, s.r.o.
city: Tallinn
country: Estonia
facility: Innomedica Medical and Research Centre
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital
city: Tartu
country: Estonia
facility: Clinical Research Centre Ltd
city: Budapest
country: Hungary
facility: Qualiclinic kft
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum
city: Szolnok
country: Hungary
facility: MAV Korhaz es Rendelointezet Szolnok
city: Veszprém
country: Hungary
facility: Veszprém Megyei Önkormányzat Csolnoky Ferenc Kórház-Rendelöintézet
city: Hamilton
country: New Zealand
facility: Waikato hospital
city: Manukau
country: New Zealand
facility: Middlemore Clinical Trials
city: Timaru
country: New Zealand
facility: Timaru Hospital
city: Bucharest
country: Romania
facility: Sf. Maria Clinical Hospital
city: Cluj-Napoca
country: Romania
facility: Emergency County Clinical Hospital
city: Galati
country: Romania
facility: Sf Apostol Andrei Emergency Clinical County Hospital
city: Sfantu Gheorghe, Covasna
country: Romania
facility: SC Covamed SRL
city: Kazan
country: Russian Federation
facility: Research Medical Complex Vashe Zdorovie
city: Penza
country: Russian Federation
facility: Penza Regional Clinical Hospital n.a. N.N. Burdenko
city: Smolensk
country: Russian Federation
facility: Departmental Hospital at Smolensk Station RZhD JSC
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl Regional Clinical Hospital
city: A Coruña
country: Spain
facility: Hospital Universitario a Coruna
city: Barcelona, Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Bilbao
country: Spain
facility: Hospital de Basurto-Osakidetza
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital General Carlos Haya
city: Sabadell
country: Spain
facility: Corporacion Sanitaria Parc Tauli
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Nash P, Ohson K, Walsh J, Delev N, Nguyen D, Teng L, Gomez-Reino JJ, Aelion JA; ACTIVE investigators. Early and sustained efficacy with apremilast monotherapy in biological-naive patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE). Ann Rheum Dis. 2018 May;77(5):690-698. doi: 10.1136/annrheumdis-2017-211568. Epub 2018 Jan 17.