A Study Of Tocilizumab in Patients With Moderate to Severe Active Rheumatoid Arthritis Who Have an Inadequate Response to or Are Unable to Tolerate Biologic and Non-Biologic Disease-modifying Antirheumatic Drugs (DMARDs) - Full Text View

Sponsor:	Hoffmann-La Roche
Information provided by (Responsible Party):	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00891020

Purpose

This 3 arm randomized open label study will evaluate the safety, tolerability and efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis, who have had inadequate response to or are unable to tolerate DMARDs. The protocol incorporates risk mitigation strategies developed in partnership with the FDA to manage known and potential risks associated with the treatment of tocilizumab. Patients will be randomized to receive tocilizumab either 4 mg/kg intravenous (iv) or 8 mg/kg iv with concomitant non-biologic DMARDs, or 8 mg/kg iv without concomitant non-biologic DMARDs, every 4 weeks, for a total of 6 infusions. The anticipated time on study treatment is 3-12 months, and the target sample size is 500-1000 individuals.

Condition	Intervention	Phase
Rheumatoid Arthritis	Drug: tocilizumab [RoActemra/Actemra] Drug: Nonbiologic DMARDs of investigator's choice	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis on Background Non-biologic DMARDs and Monotherapy Who Have an Inadequate Response to Current Non-Biologic or Biologic DMARDs

Resource links provided by NLM:

MedlinePlus related topics: Rheumatoid Arthritis

Drug Information available for: Tocilizumab

U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:

Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
An SAE was any adverse event that at any dose fulfilled at least one of the following criteria:
- Was fatal (results in death)
- Was life-threatening
- Required in-patient hospitalization or prolongation of existing hospitalization
- Resulted in persistent or significant disability/incapacity
- Was a congenital anomaly/birth defect
- Was medically significant or required intervention to prevent one or other of the outcomes listed above.

Secondary Outcome Measures:

Percentage of Participants Experiencing Serious Adverse Events of Special Interest [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
Serious Adverse Events of Special interest include:
- Serious infections including opportunistic infections
- Complications of diverticulitis (including lower gastrointestinal [GI] perforations)
- Myocardial infarction/acute coronary syndrome
- Stroke
- Spontaneous or serious bleeding
- Malignant neoplasms
Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
Non-serious adverse Events of Special interest include:
- Serious/Medically Significant Hepatic Events
- Spontaneous /Serious Bleeding
- Malignant Neoplasms
Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 [ Time Frame: Weeks 8,16,24 ] [ Designated as safety issue: No ]
Clinical Remission is defined as a Disease Activity Score 28 [DAS28] < 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 [ Time Frame: Baseline, Weeks 8,16,24 ] [ Designated as safety issue: No ]
The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of < 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of > 5.1 represents high disease activity.

The Change from Baseline to Weeks 8, 16 and 24 is reported.
Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 [ Time Frame: Baseline, Weeks 8,16,24 ] [ Designated as safety issue: No ]
The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in:
1. Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and
2. At least 3 of the following 5 assessments:
  - Patient's global assessment of pain-Visual Analog Scale (VAS)
  - Patient global assessment of disease activity-(VAS)
  - Physician global assessment of disease activity-(VAS)
  - Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire)
  - Acute phase response C-Reactive Protein (CRP)
Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8 [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts.
Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 [ Time Frame: Weeks 12,16, 20 ] [ Designated as safety issue: No ]
Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12.
Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 [ Time Frame: Baseline, Weeks 8,16,24 ] [ Designated as safety issue: No ]
The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement.
Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 [ Time Frame: Baseline, Weeks 8,16,24 ] [ Designated as safety issue: No ]
The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement.

Enrollment:	886
Study Start Date:	May 2009
Study Completion Date:	March 2011
Primary Completion Date:	July 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Tocilizumab 8 mg/kg Monotherapy Participants received Tocilizumab 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.	Drug: tocilizumab [RoActemra/Actemra] 8 mg/kg intravenous every 4 weeks for 24 weeks
Experimental: Tocilizumab 4 mg/kg + DMARD Participants received Tocilizumab (TCZ) 4 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants not achieving a 20% improvement from baseline in tender and swollen joint counts at Week 8 were to have their dosage increased to 8 mg/kg, per protocol. Beginning at Week 12 dosage increase to 8 mg/kg was at the discretion of the investigator. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.	Drug: tocilizumab [RoActemra/Actemra] 8 mg/kg intravenous every 4 weeks for 24 weeks Drug: tocilizumab [RoActemra/Actemra] 4 mg/kg every 4 weeks for 24 weeks Drug: Nonbiologic DMARDs of investigator's choice Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed
Experimental: Tocilizumab 8 mg/kg + DMARD Participants received Tocilizumab (TCZ) 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.	Drug: tocilizumab [RoActemra/Actemra] 8 mg/kg intravenous every 4 weeks for 24 weeks Drug: Nonbiologic DMARDs of investigator's choice Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

adult patients, >=18 years of age;
moderate to severe active rheumatoid arthritis for >6 months;
inadequate clinical response or unable to tolerate current or prior biologic or non-biologic Disease-modifying antirheumatic drug (DMARD) therapy;
Swollen joint count (SJC) >/=4 and Tender joint count (TJC) >/=4
body weight </=150kg
current permitted non-biologic DMARDs must be on stable dose for >/= 7 weeks prior to baseline;

Exclusion Criteria:

history of autoimmune disease or inflammatory joint disease other than rheumatoid arthritis;
functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in rheumatoid arthritis;
treatment with rituximab within 6 months before screening;
intraarticular corticosteroids within 8 weeks or intramuscular (im)/ intravenous (iv) corticosteroids within 12 weeks prior to screening;
known active current or history of recurrent infections, or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00891020

Show 227 Study Locations

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director:

Clinical Trials

Hoffmann-La Roche

More Information

No publications provided

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00891020 History of Changes
Other Study ID Numbers:	ML22533
Study First Received:	April 29, 2009
Results First Received:	February 28, 2012
Last Updated:	March 23, 2012
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases

Autoimmune Diseases
Immune System Diseases
Antirheumatic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2012