Clinical trial NCT01209702: A Study of RoActemra/Actemra (Tocilizumab) in Patients With Ankylosing Spondylitis Who Have Failed Treatment With NSAIDs
Official title: A Ph II/III Seamless, Multi-center, Randomized, Double-blind, Placebo-controlled Study of the Reduction in Signs and Symptoms and Inhibition of Structural Damage During Treatment With Tocilizumab Versus Placebo in Patients With Ankylosing Spondylitis Who Have Failed Non-steroidal Anti-inflammatory Drugs and Are naïve to TNF Antagonist Therapy NSAIDs
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Spondylitis, Ankylosing
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2010-09-27
Enrollment: 306
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: This randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of RoActemra/Actemra (tocilizumab) in patients with ankylosing spondylitis (AS) who have failed treatment with non-steroidal anti-inflammatory drugs and are naïve to tumor necrsos factor (TNF) antagonist therapy. In Part 1 of the study, patients will be randomized to receive either RoActemra/Actemra 8 mg/kg intravenously (IV) or placebo every 4 weeks for 12 weeks. In Part 2, patients will be randomized to receive RoActemra at either 8 mg/kg or 4 mg/kg IV or placebo every 4 weeks for 24 weeks. The double-blind treatment period will be followed by open-label treatment with RoActemra/Actemra 8 mg/kg iv every 4 weeks until Week 208 for all patients. Anticipated time on study treatment is 208 weeks.

Detailed description: This study was planned as a Phase II/III seamless, multicenter, randomized, double-blind, placebo-controlled study in patients with AS who were naïve to TNF antagonist therapy. The study consisted of 2 parts, each preceded by a screening visit and followed by a common open-label extension phase. Recruitment into Part 2 commenced after completion of enrollment for Part 1.

Part 1 was designed as a Phase II study exploring the efficacy and safety of tocilizumab therapy versus placebo. Part 1 was intended to determine whether Part 2 of the study would continue, based on a Week 12 analysis.

Part 2 was designed to provide pivotal Phase III efficacy and safety data for tocilizumab in patients with AS. Approximately 400 patients were to be enrolled. Once randomization into Part 1 was complete, randomization into Part 2 of the study was to be initiated.

Based on the results of the Week 12 Part 1 analyses of the primary endpoint (ASAS20) and secondary endpoints, and in consideration of all available safety data, a benefit/risk assessment was made and it was decided to halt the study because of lack of overall efficacy. Most patients did not complete the 24-week double-blind treatment period in Part 2.

Eligibility criteria: Inclusion Criteria

* Adult patients, ≥ 18 years of age
* Ankylosing Spondylitis as defined by the modified New York criteria for ≥ 3 months prior to baseline
* Active disease at screening and baseline (Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] ≥4.0, spinal pain visual analog scale \[VAS\] ≥40)
* Inadequate response or intolerant to 1 or more previous non-steroidal anti-inflammatory drugs (NSAIDs)
* Traditional disease-modifying anti-rheumatic drugs (DMARDs) must be withdrawn for at least 4 weeks prior to baseline (methotrexate, sulfasalazine and hydroxychloroquine or chloroquine may be allowed if at stable dose for at least 4 weeks prior to baseline)
* Oral corticosteroids (≥ 10 mg/day prednisone or equivalent) and NSAIDs/COX-2 inhibitors must be at stable dose for at least 4 weeks prior to baseline

Exclusion Criteria:

* Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after randomization
* Total ankylosis of spine (as determined by investigator)
* Inflammatory rheumatic disease other than ankylosing spondylitis
* Active, acute uveitis at baseline
* Treatment with tumor necrosis factor (TNF) antagonist therapy at any time prior to baseline
* Intra-articular or tendon injections or parenteral corticosteroids within 4 weeks prior to screening
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
* Active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infection
* History of or currently active primary or secondary immunodeficiency
* Body weight \> 150 kg

Primary outcomes:
measure: Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
timeFrame: Baseline and Week 12
measure: Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12
timeFrame: Baseline and Week 12
measure: Part 2: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
timeFrame: Baseline and Week 12
measure: Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI)
timeFrame: Baseline and Week 12
measure: Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI)
timeFrame: Baseline and Week 12
measure: Change From Baseline in C-Reactive Protein
timeFrame: Baseline and Week 12
measure: Part 2: Area Under the Plasma Concentration Versus Time Curve of Tocilizumab
timeFrame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
measure: Part 2: Peak Plasma Concentration of Tocilizumab
timeFrame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
measure: Part 2: Elimination Half-life of Tocilizumab
timeFrame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
measure: Part 2: Clearance of Tocilizumab
timeFrame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
measure: Part 2: Volume of Distribution of Tocilizumab
timeFrame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
measure: Change From Baseline in the Level of Interleukin-6
timeFrame: Baseline and Week 12
measure: Change From Baseline in Level of Soluble Interleukin-6 Receptor
timeFrame: Baseline and Week 12
measure: Number of Participants With Anti-tocilizumab Antibodies
timeFrame: From Baseline until end of study (a maximum treatment duration of 40 weeks).
measure: Part 2: Radiographic Change According to the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)
timeFrame: Baseline and Week 104
measure: Part 2: Percentage of Participants With a Reduction of Magnetic Resonance Imaging (MRI) Proven Spinal Inflammation
timeFrame: Baseline and Week 24
measure: Part 1: The Number of Participants With Adverse Events
timeFrame: Up to 40 weeks
Other outcomes:
Locations:
city: Huntington Beach
country: United States
state: California
city: Aventura
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Decatur
country: United States
state: Georgia
city: Marietta
country: United States
state: Georgia
city: Idaho Falls
country: United States
state: Idaho
city: Wichita
country: United States
state: Kansas
city: Cumberland
country: United States
state: Maryland
city: St. Claire Shores
country: United States
state: Michigan
city: Charlotte
country: United States
state: North Carolina
city: Greensboro
country: United States
state: North Carolina
city: Duncansville
country: United States
state: Pennsylvania
city: Hickory
country: United States
state: South Carolina
city: Houston
country: United States
state: Texas
city: Adelaide
country: Australia
city: Heidelberg
country: Australia
city: Hobart
country: Australia
city: Malvern East
country: Australia
city: Maroochydore
country: Australia
city: Sydney
country: Australia
city: Woodville
country: Australia
city: Bruxelles
country: Belgium
city: Kortrijk
country: Belgium
city: Liege
country: Belgium
city: Yvoir
country: Belgium
city: Cuiabá
country: Brazil
city: Goiania
country: Brazil
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: São Paulo
country: Brazil
city: Plovdiv
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Ruse
country: Bulgaria
city: Sevlievo
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Calgary
country: Canada
state: Alberta
city: Winnipeg
country: Canada
state: Manitoba
city: St John's
country: Canada
state: Newfoundland and Labrador
city: Kitchener
country: Canada
state: Ontario
city: Mississauga
country: Canada
state: Ontario
city: St. Catharines
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Quebec City
country: Canada
state: Quebec
city: Sainte-foy
country: Canada
state: Quebec
city: Trois-rivieres
country: Canada
state: Quebec
city: Bruntal
country: Czech Republic
city: Hlucin
country: Czech Republic
city: Olomouc
country: Czech Republic
city: Prague
country: Czech Republic
city: Praha 11
country: Czech Republic
city: Praha 4 Nusle
country: Czech Republic
city: Praha 4
country: Czech Republic
city: Sokolov
country: Czech Republic
city: Uherske Hradiste
country: Czech Republic
city: Zlin
country: Czech Republic
city: Besancon
country: France
city: Boulogne-billancourt
country: France
city: Creteil
country: France
city: Grenoble
country: France
city: Montpellier
country: France
city: Paris
country: France
city: Strasbourg
country: France
city: Toulouse
country: France
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Gommern
country: Germany
city: Hannover
country: Germany
city: Köln
country: Germany
city: Würzburg
country: Germany
city: Ahmedabad
country: India
city: Bangalore
country: India
city: Bangalore
country: India
city: Bangalore
country: India
city: Bangalore
country: India
city: Hyderabad
country: India
city: Jaipur
country: India
city: New Delhi
country: India
city: New Delhi
country: India
city: Secunderabad
country: India
city: Ferrara
country: Italy
city: Firenze
country: Italy
city: Monserrato
country: Italy
city: Prato
country: Italy
city: Reggio Emilia
country: Italy
city: Roma
country: Italy
city: Siena
country: Italy
city: Kaunas
country: Lithuania
city: Klaipeda
country: Lithuania
city: Vilnius
country: Lithuania
city: Bydgoszcz
country: Poland
city: Krakow
country: Poland
city: Krakow
country: Poland
city: Lublin
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Torun
country: Poland
city: Warszawa
country: Poland
city: Warszawa
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Voronezh
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Kosice
country: Slovakia
city: Piestany
country: Slovakia
city: Cape Town
country: South Africa
city: Cape Town
country: South Africa
city: Cape Town
country: South Africa
city: Durban
country: South Africa
city: Pretoria
country: South Africa
city: Pretoria
country: South Africa
city: Pretoria
country: South Africa
city: Stellenbosch
country: South Africa
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: La Coruna
country: Spain
city: Lugo
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Oviedo
country: Spain
city: Oviedo
country: Spain
city: Sabadell
country: Spain
city: Basingstoke
country: United Kingdom
city: Bath
country: United Kingdom
city: Cannock
country: United Kingdom
city: Greenock
country: United Kingdom
city: Leeds
country: United Kingdom
city: London
country: United Kingdom
city: Salford
country: United Kingdom
city: Stoke-on-trent
country: United Kingdom
city: Wigan
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014 Jan;73(1):95-100. doi: 10.1136/annrheumdis-2013-203559. Epub 2013 Jun 13.