Natalizumab in the Treatment of Rheumatoid Arthritis in Subjects Receiving Methotrexate

• Sponsor: Biogen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00083759
• Collaborator: Elan Pharmaceuticals (Industry)
• Enrollment: 299
• Locations: 12
• Arms: 2
• Patients Per Site: 24.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety, tolerability and efficacy of natalizumab in subjects diagnosed with moderate to severe rheumatoid arthritis (RA) receiving concomitant treatment with methotrexate (MTX). It is thought that natalizumab may stop the movement of certain white blood cells, known as lymphocytes, into joint tissue. These cells are thought to cause damage in the joints leading to the symptoms of RA.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: natalizumab; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 299 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Double-blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Intravenous Natalizumab (300 mg) in Subjects With Moderate to Severe Rheumatoid Arthritis (RA) Receiving Concomitant Treatment With Methotrexate (MTX)
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: Feb 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: natalizumab	Drug: natalizumab; Other Names: TYSABRI
Placebo Comparator: placebo	Drug: placebo

Outcome Measures

Primary Outcome Measures

1. American College of Rheumatology (ACR)20. [Month 6]

   ≥20% reduction from baseline in painful/tender joint count and swollen joint count and ≥20% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)

Secondary Outcome Measures

1. American College of Rheumatology (ACR)50 [Month 6]

   ≥50% reduction from baseline in painful/tender joint count and swollen joint count and ≥50% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)

2. American College of Rheumatology (ACR)70 [Month 6]

   ≥70% reduction from baseline in painful/tender joint count and swollen joint count and ≥70% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects will be eligible to begin study participation if they meet all of the following inclusion criteria:

• Subject is able to read, understand, and voluntarily sign the approved Informed Consent form prior to the performance of any study-specific procedures;

• Male or female subjects, ≥18 to ≤75 years of age, who has a diagnosis of rheumatoid arthritis Functional Class 1 to 3 by the 1987 Revised American Rheumatism Association Criteria for the Classification of Rheumatoid Arthritis for at least 6 months prior to screening;

• Subject is on a stable dose of MTX of at least 10 mg/week for ≥3 months prior to randomization (Month 0) without an adequate response;

• Female subjects of childbearing potential agree to use adequate, contraceptive methods (either intrauterine device [IUD], oral or depot contraceptive, or barrier plus spermicide). Female subjects of childbearing potential use adequate contraception for at least 2 months prior to study entry and continue contraception for at least 3 months after their last infusion of study drug;

• Subject is willing and able to complete all planned study procedures;

• Subject has at least 10 painful/tender and 6 swollen joints at the Month 0 (Baseline) visit;

• Subject has an elevated CRP level (defined as >2.87 mg/L) at Screening.

Exclusion Criteria:

Subjects will be excluded from the study if they meet any of the following exclusion criteria:

• Subject is pregnant or lactating;

• Subject who has experienced an inadequate therapeutic response after at least 3 months of treatment with at least one TNF-alpha inhibitor;

• Subject who has received treatment with anakinra;

• Subject who has received prior treatment with natalizumab;

• Subject does not meet the following criteria regarding concomitant medications for RA:

• Use of any oral steroid exceeding 10 mg/day of prednisone (or equivalent dose) and not administered at a stable dose for at least 1 month prior to randomization (Month 0);

• Use of any NSAIDs unless stable for at least 1 month prior to randomization (Month 0);

• Use of other anti-arthritic treatments, including approved or experimental oral, topical, or injectable biologics or drugs, or devices within 1 month prior to randomization (Month 0);

• Intra-articular corticosteroid injections within 1 month prior to randomization (Month 0);

• Treatment with any TNF-alpha inhibitor within 2 months prior to randomization (Month 0);

• Subject who is expected to be unavailable for the duration of the trial, likely to be noncompliant with the Protocol, or felt to be unsuitable by the Investigator for any other reason;

• Subject who has a history of a malignancy (other than basal cell carcinoma of the skin);

• Subject who has a history of clinically significant and/or persistent gastrointestinal, pulmonary, chronic infection, cardiovascular, renal, hepatic, neurological, dermatological, immunological, major psychiatric (including drug or alcohol abusers) or hematological illness, which, in the opinion of the Investigator placed the subject at unacceptable risk for participation in the study;

• Subject who has any laboratory test at Screening considered significantly abnormal. An alanine transaminase (ALT) or aspartate transaminase (AST) ≥1.5 x upper limits of normal (ULN) and cytopenia (included any of the following: WBC <3.5 x 1000/uL; hemoglobin [Hb] <8 g/dL; platelets <100 x 1000/uL; and/or neutrophils absolute <1.0 x 1000/uL) were considered significantly abnormal;

• Subject who intends to donate blood or blood products during the period of the study or within 1 month following completion of the study;

• Subject who has a positive tuberculosis (TB) skin test at Screening or within the 30 days prior to Screening (defined as ≥10 mm induration);

• Subject who plans or requires any surgical procedure during the study treatment period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Clinical Research Unit / University of Arizona	Tucson	Arizona	United States	85719
3	Arthritis Medical Clinic of North County, Inc.	Escondido	California	United States	92025-4402
4	Jacksonville Center for Clinical Research	Jacksonville	Florida	United States	32216
5	Massachusetts General Hospital	Boston	Maine	United States	02114
6	Clinical Pharmacology Study Group	Worcester	Massachusetts	United States	01610
7	Justus Fiechtner, MD, PC	Lansing	Michigan	United States	48910
8	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
9	Rheumatic Disease Associates	Willow Grove	Pennsylvania	United States	19090
10	Radiant Research	Dallas	Texas	United States	75235
11	St. Clare's Mercy Hospital	St. John's	Newfoundland and Labrador	Canada	A1C 5B8
12	The Arthritis Program Research Group Inc.	Newmarket	Ontario	Canada	L3Y 3R7

Sponsors and Collaborators

• Biogen
• Elan Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT00083759
• Other Study ID Numbers: ELN100226-RA201
• First Posted: Jun 3, 2004
• Last Update Posted: Jul 18, 2016
• Last Verified: Apr 1, 2009

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Natalizumab

Study Results

Participant Flow

Recruitment Details	First patient entered 24 May 2004, study terminated 28 February 2005. A total of 299 patients were evaluable for safety and 273 patients for efficacy. Study conducted in Argentina, Australia, Canada, Czech Republic, Poland, Slovakia, and the United States.
Pre-assignment Detail	Patients who met these criteria were randomized to natalizumab or placebo: aged 18-75 with a diagnosis of rheumatoid arthritis (RA) Functional Class 1-3 for ≥ 6 months, on a stable dose of methotrexate (MTX), having ≥ 10 painful/tender joints, and with elevated C-reactive protein. Stratification based on baseline number of painful/tender joints.

Arm/Group Title	Natalizumab	Placebo
Arm/Group Description	Natalizumab 300 mg as monthly IV infusions + methotrexate (MTX)	Placebo IV infusions + methotrexate (MTX)
Period Title: Overall Study
STARTED	150	149
COMPLETED	66	66
NOT COMPLETED	84	83

Baseline Characteristics

Arm/Group Title	Natalizumab	Placebo	Total
Arm/Group Description	Natalizumab 300 mg as monthly IV infusions + methotrexate (MTX)	Placebo IV infusions + methotrexate (MTX)	Total of all reporting groups
Overall Participants	137	136	273
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.9 (10.5)	53.6 (10.4)	52.3 (10.5)
Sex: Female, Male (Count of Participants)
Female	111 81%	107 78.7%	218 79.9%
Male	26 19%	29 21.3%	55 20.1%
Baseline Count of Painful/Tender Joints (participants) [Number]
<20	44 32.1%	43 31.6%	87 31.9%
>20	93 67.9%	93 68.4%	186 68.1%

Outcome Measures

1. Primary Outcome

Title	American College of Rheumatology (ACR)20.
Description	≥20% reduction from baseline in painful/tender joint count and swollen joint count and ≥20% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Placebo
Arm/Group Description	Natalizumab 300 mg as monthly IV infusions + methotrexate (MTX)	Placebo IV infusions + methotrexate (MTX)
Measure Participants	137	136
Number [participants]	59 43.1%	45 33.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

2. Secondary Outcome

Title	American College of Rheumatology (ACR)50
Description	≥50% reduction from baseline in painful/tender joint count and swollen joint count and ≥50% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Placebo
Arm/Group Description	Natalizumab 300 mg as monthly IV infusions + methotrexate (MTX)	Placebo IV infusions + methotrexate (MTX)
Measure Participants	137	136
Number [participants]	23 16.8%	15 11%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	American College of Rheumatology (ACR)70
Description	≥70% reduction from baseline in painful/tender joint count and swollen joint count and ≥70% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant)
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Placebo
Arm/Group Description	Natalizumab 300 mg as monthly IV infusions + methotrexate (MTX)	Placebo IV infusions + methotrexate (MTX)
Measure Participants	137	136
Number [participants]	13 9.5%	10 7.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.526
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Limitations/Caveats

The study was terminated prematurely on 28 February 2005. The biological effect seen with natalizumab was not sufficient to warrant further development in RA.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor will have at least 30 days to request revisions to a proposed Publication. Institution will delete any Confidential Information provided by Sponsor, will delay Publication submission for a further 90 days for the filing of patent applications, and will not issue a press release about the Study without the Sponsor's prior written consent.