Study of Apremilast to Treat Subjects With Active Ankylosing Spondylitis

Ankylosing Spondyloarthritis Clinical Trial

— POSTURE  

Official title:

A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN THE TREATMENT OF ACTIVE ANKYLOSING SPONDYLITIS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01583374
• Other study ID #: CC-10004-AS-001
• Secondary ID: 2011-001555-37
• Status: Completed
• Phase: Phase 3
• Start date: May 2, 2012
• Est. completion date: October 25, 2018

Study information

• Verified date: October 2019
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Apremilast is a new, orally available, small molecule drug that specifically inhibits phosphodiesterase 4 (PDE4), an enzyme that modulates inflammatory cytokines. This clinical study tests whether apremilast can improve the signs and symptoms of ankylosing spondylitis.

Description:

Patients were randomized in a 1:1:1 ratio to placebo, apremilast 20 mg BID and apremilast 30 mg BID. The duration of the study was approximately 5 years. The double blind period (when patients nor the physician knew whether placebo or apremilast was taken) was 24 weeks. At Week 16, participants who did not have either a ≥ 20% improvement or a ≥ 1 unit improvement from baseline in at least two of the four SpondyloArthritis international Society (ASAS) domains were entered in "early escape" from their current treatment in a double-blinded manner. However, such participants were permitted to continue in the study. At Week 24, participants may have entered a long-term extension phase for up to an additional 4.5 years (236 weeks). At "second escape" (at Week 24), apremilast 20 mg BID treated participants transitioned to receive double-blinded apremilast 30 mg BID and remained on double-blinded apremilast 30 mg BID because they continued to improve with a longer duration of treatment. After Week 24 and during the early portion of the long-term extension through Week 52, all participants continued on either double-blinded apremilast 20 mg BID or 30 mg BID treatment. After all participants had completed Week 52 or had terminated early from the study and the 52-week data base was locked, apremilast 20 mg BID or 30 mg BID treatment was provided.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 490
• Est. completion date: October 25, 2018
• Est. primary completion date: February 24, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Must have a documented diagnosis of ankylosing spondylitis as defined by low back pain and stiffness, which improves with exercise, but is not relieved by rest for more than 3 months prior to screening. At the completion of screening procedures, a documented diagnosis of definite active AS, as defined by the modified New York criteria (1984) whereby both criteria, at least 1 radiographic criterion and at least 1 clinical criterion, must be met

• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is = 4

• Total back pain is = 4

• On stable dose of AS medication (or lack of medication) prior to randomization and through week 24

Exclusion Criteria:

• Prior treatment with a Tumor Necrosis Factor (TNF) blocker and any biologic treatment for AS

Related Conditions & MeSH terms

• Ankylosing Spondyloarthritis
• Spondylarthritis
• Spondylitis
• Spondylitis, Ankylosing

Intervention

Drug:
• Apremilast tablet 20 mg
Apremilast 20 mg was taken orally twice a day (BID)
• Apremilast tablet 30 mg BID
Apremilast 30 mg was taken orally twice a day
• Placebo
Identically matched placebo tablets were taken orally twice a day during the placebo controlled phase.

Locations

Country	Name	City	State
Australia	Emeritus Research	Camberwell	Victoria
Australia	Southern Clinical Research	Hobart	Tasmania
Australia	Coastal Joint Care	Maroochydore
Australia	Royal Perth Hospital	Perth
Australia	The Queen Elizabeth Hospital	Woodville South
Austria	Krankenhaus Wien-Hietzing	Wien
Bulgaria	Diagnostic and Consulting Center Sv. Pantaleymon	Pleven
Bulgaria	17 Diagnostic and Consulting Centre	Sofia
Bulgaria	Military Medical Academy - MHAT	Sofia
Bulgaria	National Multiprofile Transport Hospital Tzar Boris III	Sofia
Bulgaria	Diagnostic Consulting Center N4	Varna
Canada	Clinic: University of Calgary Heritage Medical Research Clinic (HMRC),Teaching Research and Wellness (TRW)	Calgary	Alberta
Canada	Cividino Medicine Professional Corporation	Hamilton	Ontario
Canada	Dr. William G. Bensen Medicine Professional Corporation	Hamilton	Ontario
Canada	Credit Valley Professional Building	Mississauga	Ontario
Canada	The Arthritis Program Research Group Inc.	Newmarket	Ontario
Canada	Rheumatology Research Associates	Ottawa	Ontario
Canada	Centre de Recherche Saint-Louis	Saint-Louis	Quebec
Canada	Nexus Clinical Research	St John's	Newfoundland and Labrador
Canada	Toronto Western Hospital	Toronto	Ontario
Czechia	Revmatologie s.r.o.	Brno
Czechia	ARTMEDI UPD s.r.o.	Hostivice
Czechia	ARTHROMED s.r.o.	Pardubice
Czechia	Fakultni Thomayerova nemocnice s poliklinikou - Klinicko-farmakologicka jednotka	Praha
Czechia	Medifin a.s, Šustova	Praha 11
Czechia	Revmatologicka Ambulance	Praha 4
Czechia	Revmatologicka Ambulance	Sokolov
Czechia	PV-Medical s.r.o.	Zlin
Estonia	East Tallinn Central Hospital	Tallinn
Estonia	Innomedica Medical and Research Centre	Tallinn
Estonia	Clinical Research Centre Ltd	Tartu
Estonia	Tartu University Hospital	Tartu
France	Hopital Ambroise-Pare	Boulogne
France	Hopital Henri Mondor	Créteil
France	IPROS - CHR ORLEANS - Hôpital de la Source	Orléans Cedex 2
France	Groupe Hospitalier Pitié- Salpétrière	Paris
France	Hopital Cochin	Paris
Germany	Charite - Universitätsmedizin Berlin	Berlin
Germany	Universitatsklinikum Erlangen	Erlangen
Germany	Centrum fur innovative Diagnostik und Therapie Rheumatologie Immunologie GmbH	Frankfurt
Germany	Schön Klink Hamburg-Eilbek	Hamburg
Germany	Universitatsklinikum Heidelberg	Heidelberg
Germany	Rheumazentrum Ruhrgebiet	Herne
Hungary	Qualiclinic kft	Budapest
Hungary	Synexus Magyarország Kft.	Budapest
Hungary	Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum	Debrecen
Hungary	Pest Megyei Flor Ferenc Korhaz	Kistarcsa
Hungary	Veszprem Megyei Csolnoky Ferenc Korhaz-Rendelointezet	Veszprém
Netherlands	Leiden Universitair Medisch Centrum	Leiden
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
Poland	Gabinet Internistyczno-Reumatologiczny Piotr Adrian Klimiuk	Bialystok
Poland	NZOZ Osteo-Medic sc A. Racewicz J. Supronik	Bialystok
Poland	Szpital Uniwersytecki nr 2 im. Dr Jana Biziela w Bydgoszczy	Bydgoszcz
Poland	Synexus SCM Sp. z o.o.	Gdynia
Poland	Zespol Poradni Specjalistycznych	Lublin
Poland	Prywatna Praktyka Lekarska Pawel Hrycaj	Poznan
Poland	NZOZ NASZ LEKARZ Praktyka Grupowa Lekarzy Rodzinnych z Przychodnia Specjalistyczna	Torun
Poland	Synexus SCM Sp. z o.o.	Wroclaw
Romania	Cristei R. Rodica - Private Medical Practice	Braila
Romania	Sf. Maria Clinical Hospital	Bucharest
Romania	Emergency County Clinical Hospital	Cluj-Napoca
Romania	Sf Apostol Andrei Emergency Clinical County Hospital	Galati
Romania	RK Medcenter SRL	Iasi
Russian Federation	Sverdlovsk Regional Clinical Hospital 1	Ekaterinburg
Russian Federation	Research Medical Complex Vashe Zdorovie	Kazan
Russian Federation	Kemerovo Regional Clinical Hospital	Kemerovo
Russian Federation	Federal State Budget Institution "Rheumatology Research Institute RAMS"	Moscow
Russian Federation	Nizhniy Novgorod State Medical Academy of Roszdrav	Nizhniy Novgorod
Russian Federation	Departmental Hospital at Smolensk Station RZhD JSC	Smolensk
Russian Federation	Regional Clinical Hospital	Vladimir
Slovakia	Narodny ustav reumatickych chorob	Piestany
Slovakia	MUDr. Zuzana Cizmarikova, s.r.o., Reumatologick ambulancia	Poprad
Spain	Hospital Universitario a Coruna	A Coruña
Spain	Hospital de Bellvitge	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Corporacio Sanitaria Parc Tauli de Sabadell	Sabadell
Spain	Complejo Hospitalario Universitario de Santiago de Compostela Travesía de la Choupana s/n	Santiago de Compostela
Sweden	Skånes Universitetssjukhus- Malmö	Malmö
United Kingdom	Barnsley Hospital	Barnsley
United Kingdom	Royal National Hospital for Rheumatic Diseases	Bath
United Kingdom	Chapel Allerton Hospital	Leeds
United Kingdom	Nuffield Orthopaedic Centre	Oxford
United States	Austin Regional Clinic	Austin	Texas
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	MetroHealth Medical Systems	Cleveland	Ohio
United States	Klein and Associates MD, PA	Cumberland	Maryland
United States	STAT Research, Inc.	Dayton	Ohio
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Saint Paul Rheumatology, PA	Eagan	Minnesota
United States	Rheumatology and Immunotherapy Center	Franklin	Wisconsin
United States	Klein and Associates MD, PA	Hagerstown	Maryland
United States	The Arthritis Clinic	Jackson	Tennessee
United States	University of California, San Diego	La Jolla	California
United States	Ramesh C Gupta MD	Memphis	Tennessee
United States	Desert Medical Advances	Palm Desert	California
United States	Sun Valley Arthritis Center	Peoria	Arizona
United States	Advent Clinical Research Centers, Inc	Pinellas Park	Florida
United States	University of Utah Hospitals and Clinics	Salt Lake City	Utah
United States	UCSF Arthritis Center	San Francisco	California
United States	Burnette & Silverfield, MDS PLC	Tampa	Florida
United States	Alastair Kennedy, MD Research	Vero Beach	Florida
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  Canada,  Czechia,  Estonia,  France,  Germany,  Hungary,  Netherlands,  Poland,  Romania,  Russian Federation,  Slovakia,  Spain,  Sweden,  United Kingdom, 

References & Publications (2)

Gladman DD, Kavanaugh A, Gómez-Reino JJ, Wollenhaupt J, Cutolo M, Schett G, Lespessailles E, Guerette B, Delev N, Teng L, Edwards CJ, Birbara CA, Mease PJ. Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies. RMD Open. 2018 Jun 27;4(1):e000669. doi: 10.1136/rmdopen-2018-000669. eCollection 2018. — View Citation

Kavanaugh A, Gladman DD, Edwards CJ, Schett G, Guerette B, Delev N, Teng L, Paris M, Mease PJ. Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis. Arthritis Res Ther. 2019 May 10;21(1):118. doi: 10.1186/s13075-019-1901-3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS 20) Response at Week 16	ASAS 20 was defined as achieving an improvement from baseline of = 20% and = 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from baseline of = 20% and = 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains are: Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active and the right-hand box = very active; Total Back Pain (0 to 10 unit NRS); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = "no pain" and the right-hand box = "most severe pain"; Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); participant provides a self-administered survey of 10 questions assessing for degree of mobility and functional ability; Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit)	Baseline and Week 16
Secondary	Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24	The BASFI is a composite score based on a self-administered survey of 10 questions using a 0 to 10 unit numerical rating scale (NRS) that assesses the degree of mobility and functional ability. The survey consists of 8 questions regarding function in AS and the last 2 reflect the ability to manage everyday life. The patient marks a box with an X on a 0 to 10 unit NRS for 10 questions; the left-hand box of 0 = easy; the right-hand box = impossible. The resulting 0 to 100 score is divided by 10 to give a final 0 to 10 BASFI score. The overall score is the mean of the 10 items and ranges from 0 to 10. A higher score correlates to reduced functional ability.	Baseline and Week 24
Secondary	Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24	The BASDAI is a composite score based on a participant self-administered survey of six questions measured using a 0 to 10 unit numerical rating scale (NRS) that assessed the participants' five major symptoms of AS: 1) fatigue; 2) spinal pain; 3) peripheral joint pain/swelling; 4) areas of localized tenderness; 5a) morning stiffness severity upon wakening; 5b) morning stiffness duration upon wakening. The participant was asked to mark the box with an X on a 0 to 10 unit NRS for each of the 6 questions. To give each of the five symptoms equal weighting, the mean of the two scores relating to morning stiffness was taken. The resulting 0 to 50 score was divided by 5 to give a final 0 to 10 BASDAI score. A BASDAI score of 4 or greater was considered to be indicative of active AS disease.	Baseline and Week 24
Secondary	Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS) Response at Week 24	ASAS 20 was defined as achieving an improvement from baseline of = 20% and = 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from baseline of = 20% and = 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains are: Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active and the right-hand box = very active; Total Back Pain (0 to 10 unit NRS); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = "no pain" and the right-hand box = "most severe pain"; Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); participant provides a self-administered survey of 10 questions assessing for degree of mobility and functional ability; Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit)	Baseline and Week 24
Secondary	Change From Baseline in the Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score at Week 24	The ASQoL is a validated disease specific patient reported outcomes instrument to assess the impact of ankylosing spondylitis on the quality of life of individuals with emphasis on the ability of the person to fulfill his or her needs. It consisted of 18 items requesting a yes (score=1) or no (score=0) response to questions related to the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. The summary score ranges 0-18 with higher scores indicating worse quality of life.	Baseline and Week 24
Secondary	Change From Baseline in the Physical Component Summary Score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) at Week 24	The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) was a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores (based on US general population with mean of 50 and standard deviation of 10) were used in analyses. Higher scores indicate a higher level of functioning. The PCS encompasses physical functioning, role-physical, and bodily pain, as well as general health and vitality. A positive change from baseline score indicates an improvement	Baseline and Week 24
Secondary	Change From Baseline in Bath Ankylosing Spondylitis Metrology Index-Linear (BASMI-Linear) at Week 24	The BASMI-Linear was designed to assess axial status (ie, cervical, dorsal and lumbar spine, hips, and pelvic soft tissue) and to define clinically significant changes in spinal movement. Five dimensions of movement (lateral lumbar flexion, tragus to wall, forward lumbar flexion, maximal intermalleolar distance, and cervical rotation) were measured and normalized on 0 to 10 unit NRS. The average of these scores was the total BASMI score, ranging from 0-10 with higher values indicating more severe limitation in spinal mobility.	Baseline and Week 24
Secondary	Change From Baseline in the Radiographic Score Using the Modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 and Week 260	The Modified Stoke Ankylosing Spondylitis Spine Score is a scoring method used to determine the amount or degree of ankylosing spondylitis disease that is in the spine based on x-ray radiographs of the spine. The m-SASSS scores 0-3.; 0 = No abnormality, 1 = Erosion, Sclerosis or Squaring, 2 = Syndesmophyte, 3 = Total bony Bridging at each Site. An increase in the m-SASSS indicated a worsening of AS disease.	Baseline to Week 104 and 260
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Phase	A TEAE was an adverse event (AE) with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. A serious AE = results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; or constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort.	From Week 0 to Week 24; the median duration of exposure was 23.57 weeks for the placebo arm, 23.71 weeks for the apremilast 20 mg arm and 24.00 weeks for the apremilast 30 mg arm.
Secondary	Number of Participants With Treatment Emergent Adverse Events During the Apremilast Exposure Period	A TEAE was an adverse event (AE) with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. A serious AE = results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; or constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort.	Week 0 to week 260; overall mean duration of exposure to apremilast 20 mg and 30 mg BID was 160.96 weeks