Study Comparing Etanercept and Methotrexate vs. Methotrexate Alone in Rheumatoid Arthritis

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Wyeth is now a wholly owned subsidiary of Pfizer

ClinicalTrials.gov Identifier:

NCT00195494

First received: September 13, 2005

Last updated: August 1, 2012

Last verified: August 2012

History of Changes

Results First Received: March 31, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Drug: Etanercept Drug: Methotrexate Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were recruited worldwide from November 2004 to February 2006.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were randomly assigned equally to 1 of 4 blinded treatment groups: Group (G) 1a received the combination of etanercept (E) and methotrexate (M) in year Y1 and Y2. G1b received the combination of E and M in Y1 and E alone in Y2. G2a received M alone in Y1 and the combination of E and M in Y2. G2b received M alone in Y1 and Y2.

Reporting Groups

	Description
Year 1 E+M / Year 2 E+M	Following a blinded transition from year one- Etanercept injection- two injections 25 mg weekly (given at the same time at different sites)+ oral Methotrexate capsules weekly (same day as injection). Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 M / Year 2 E+M	Following a blinded transition from year one- Etanercept two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection). Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 E+M / Year 2 E	Following a blinded transition from year one-Etanercept two injections 25 mg weekly (given at the same time at different sites).
Year 1 M / Year 2 M	Following a blinded transition from year one- Methotrexate dose consistent with the ending dose of year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 M+Placebo	Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites. MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.
Year 1 E+M	Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection). MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Participant Flow for 2 periods

Period 1: Year 1

	Year 1 M+Placebo	Year 1 E+M
STARTED	268	274
COMPLETED	189	221
NOT COMPLETED	79	53
Adverse Event	34	27
System Toxicity	0	1
Lack of Efficacy	24	9
Compliance	5	1
Lost to Follow-up	1	0
Missed >4 consecutive doses	3	2
Protocol deviation	2	3
Physician Decision	1	0
Withdrawal by Subject	8	9
Protocol Violation	1	1

Period 2: Year 2

	Year 1 E+M / Year 2 E+M	Year 1 M / Year 2 E+M	Year 1 E+M / Year 2 E	Year 1 M / Year 2 M
STARTED	111 ^[1]	90	111 ^[1]	99
COMPLETED	104	74	93	76
NOT COMPLETED	7	16	18	23
Adverse Event	3	7	5	9
Lack of Efficacy	0	1	7	7
Compliance	1	0	0	2
Lost to Follow-up	0	0	1	1
Missed >4 consecutive doses	1	1	1	0
Protocol deviation	0	1	0	0
Physician Decision	1	1	0	0
Withdrawal by Subject	1	5	4	3
System toxicity	0	0	0	1

[1]	A patient with Year 1 termination had taken drug briefly during Year 2 and thus counted in the data.

Baseline Characteristics

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Reporting Groups

	Description
Year 1 M+Placebo	Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites. MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.
Year 1 E+M	Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection). MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.
Total	Total of all reporting groups

Description

Year 1 M+Placebo

Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites.

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Year 1 E+M

Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Total

Total of all reporting groups

Baseline Measures

	Year 1 M+Placebo	Year 1 E+M	Total
Number of Participants [units: participants]	268	274	542
Age ^[1] [units: years] Median ( Full Range )	51.50 ( 20.00 to 84.00 )	52.50 ( 18.00 to 82.00 )	52.00 ( 18.00 to 84.00 )
Gender ^[2] [units: Year 1 participants]
Female	194	204	398
Male	74	70	144

[1]	Year 1 Overall Number of Baseline Participants is 542
[2]	Year 1 participants collected from Arms M and E+M equal the stated overall participant population of 542. 411 of those participants were then entered into Year 2 Arms E+M/E+M, M/M+E, E+M/E, M/M. This measure provides the gender population for Year 1 only in order to accurately reflect the overall baseline population of 542.

Outcome Measures

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1. Primary:

The Number of Participants Achieving Remission As Measured by a Disease Activity Score for 28 Joints (DAS 28) < 2.6. [ Time Frame: 12 months ]

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2. Primary:

Year 1 Participants Having an Annualized Modified Total Sharp Score (mTSS) < 0.5. [ Time Frame: 12 months ]

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3. Secondary:

Safety Measured by Number of Participants Reporting a Serious Adverse Event That Led to Death [ Time Frame: 12 and 24 months ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Year 1 E+M / Year 2 E+M	Following a blinded transition from year one- Etanercept injection- two injections 25 mg weekly (given at the same time at different sites)+ oral Methotrexate capsules weekly (same day as injection). Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 M / Year 2 E+M	Following a blinded transition from year one- Etanercept two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection). Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 E+M / Year 2 E	Following a blinded transition from year one-Etanercept two injections 25 mg weekly (given at the same time at different sites).
Year 1 M / Year 2 M	Following a blinded transition from year one- Methotrexate dose consistent with the ending dose of year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.
Year 1 M+Placebo	Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites. MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.
Year 1 E+M	Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection). MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Other Adverse Events

	Year 1 E+M / Year 2 E+M	Year 1 M / Year 2 E+M	Year 1 E+M / Year 2 E	Year 1 M / Year 2 M	Year 1 M+Placebo	Year 1 E+M
Total, other (not including serious) adverse events
# participants affected	91	71	89	79	241	246
Blood and lymphatic system disorders
Blood and lymphatic ^*
# participants affected / at risk	6/111 (5.41%)	2/90 (2.22%)	2/111 (1.80%)	4/99 (4.04%)	4/268 (1.49%)	20/274 (7.30%)
Cardiac disorders
Cardiac disorders ^*
# participants affected / at risk	0/111 (0.00%)	5/90 (5.56%)	3/111 (2.70%)	1/99 (1.01%)	14/268 (5.22%)	14/274 (5.11%)
Ear and labyrinth disorders
Ear and labyrinth ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	16/268 (5.97%)	11/274 (4.01%)
Eye disorders
Eye ^*
# participants affected / at risk	5/111 (4.50%)	4/90 (4.44%)	5/111 (4.50%)	7/99 (7.07%)	20/268 (7.46%)	28/274 (10.22%)
Gastrointestinal disorders
Abdominal pain upper ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	27/268 (10.07%)	23/274 (8.39%)
Diarhhea ^*
# participants affected / at risk	4/111 (3.60%)	2/90 (2.22%)	6/111 (5.41%)	7/99 (7.07%)	20/268 (7.46%)	24/274 (8.76%)
Nausea ^*
# participants affected / at risk	8/111 (7.21%)	8/90 (8.89%)	4/111 (3.60%)	8/99 (8.08%)	48/268 (17.91%)	53/274 (19.34%)
Vomiting ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	18/268 (6.72%)	11/274 (4.01%)
Dyspepsia ^*
# participants affected / at risk	1/111 (0.90%)	0/90 (0.00%)	3/111 (2.70%)	5/99 (5.05%)	0/268 (0.00%)	0/274 (0.00%)
General disorders
Administration site conditions ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	50/268 (18.66%)	67/274 (24.45%)
Infections and Infestations ^*
# participants affected / at risk	47/111 (42.34%)	33/90 (36.67%)	49/111 (44.14%)	42/99 (42.42%)	0/268 (0.00%)	0/274 (0.00%)
Gastroenteritis ^*
# participants affected / at risk	7/111 (6.31%)	1/90 (1.11%)	1/111 (0.90%)	1/99 (1.01%)	0/268 (0.00%)	0/274 (0.00%)
Lower respiratory tract infection ^*
# participants affected / at risk	2/111 (1.80%)	1/90 (1.11%)	4/111 (3.60%)	5/99 (5.05%)	0/268 (0.00%)	0/274 (0.00%)
Rhinitis ^*
# participants affected / at risk	2/111 (1.80%)	2/90 (2.22%)	6/111 (5.41%)	1/99 (1.01%)	0/268 (0.00%)	0/274 (0.00%)
Infections and infestations
Nasopharyngitis ^*
# participants affected / at risk	10/111 (9.01%)	10/90 (11.11%)	10/111 (9.01%)	13/99 (13.13%)	42/268 (15.67%)	44/274 (16.06%)
Upper respiratory tract infections ^*
# participants affected / at risk	6/111 (5.41%)	8/90 (8.89%)	5/111 (4.50%)	9/99 (9.09%)	19/268 (7.09%)	18/274 (6.57%)
Urinary tract infections ^*
# participants affected / at risk	0/111 (0.00%)	2/90 (2.22%)	6/111 (5.41%)	4/99 (4.04%)	10/268 (3.73%)	17/274 (6.20%)
Injury, poisoning and procedural complications
Post procedural nausea ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	23/268 (8.58%)	18/274 (6.57%)
Injury, poisoning and procedural complications ^*
# participants affected / at risk	13/111 (11.71%)	11/90 (12.22%)	15/111 (13.51%)	9/99 (9.09%)	0/268 (0.00%)	0/274 (0.00%)
Investigations
Investigations ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	50/268 (18.66%)	49/274 (17.88%)
Alanine aminotransferase increased ^*
# participants affected / at risk	5/111 (4.50%)	7/90 (7.78%)	2/111 (1.80%)	1/99 (1.01%)	0/268 (0.00%)	0/274 (0.00%)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis ^*
# participants affected / at risk	6/111 (5.41%)	6/90 (6.67%)	4/111 (3.60%)	15/99 (15.15%)	36/268 (13.43%)	13/274 (4.74%)
Back pain ^*
# participants affected / at risk	2/111 (1.80%)	3/90 (3.33%)	4/111 (3.60%)	6/99 (6.06%)	0/268 (0.00%)	0/274 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign ^*
# participants affected / at risk	0/111 (0.00%)	7/90 (7.78%)	2/111 (1.80%)	3/99 (3.03%)	0/268 (0.00%)	0/274 (0.00%)
Nervous system disorders
Headache ^*
# participants affected / at risk	8/111 (7.21%)	4/90 (4.44%)	6/111 (5.41%)	4/99 (4.04%)	20/268 (7.46%)	29/274 (10.58%)
Psychiatric disorders
Psychiatric ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	23/268 (8.58%)	28/274 (10.22%)
Depression ^*
# participants affected / at risk	1/111 (0.90%)	5/90 (5.56%)	0/111 (0.00%)	0/99 (0.00%)	0/268 (0.00%)	0/274 (0.00%)
Renal and urinary disorders
Renal and urinary ^*
# participants affected / at risk	8/111 (7.21%)	5/90 (5.56%)	2/111 (1.80%)	5/99 (5.05%)	19/268 (7.09%)	21/274 (7.66%)
Respiratory, thoracic and mediastinal disorders
Cough ^*
# participants affected / at risk	7/111 (6.31%)	2/90 (2.22%)	8/111 (7.21%)	6/99 (6.06%)	26/268 (9.70%)	23/274 (8.39%)
Skin and subcutaneous tissue disorders
Alopecia ^*
# participants affected / at risk	0/111 (0.00%)	0/90 (0.00%)	0/111 (0.00%)	0/99 (0.00%)	8/268 (2.99%)	15/274 (5.47%)
Rash ^*
# participants affected / at risk	4/111 (3.60%)	5/90 (5.56%)	3/111 (2.70%)	4/99 (4.04%)	14/268 (5.22%)	16/274 (5.84%)
Vascular disorders
Hypertension ^*
# participants affected / at risk	5/111 (4.50%)	0/90 (0.00%)	3/111 (2.70%)	6/99 (6.06%)	22/268 (8.21%)	17/274 (6.20%)

*	Events were collected by non-systematic assessment

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: U. S. Contact Center
Organization: Wyeth
e-mail: clintrialresults@wyeth.com

No publications provided by Wyeth is now a wholly owned subsidiary of Pfizer

Publications automatically indexed to this study:

Zhang W, Sun H, Emery P, Sato R, Singh A, Freundlich B, Anis AH. Does achieving clinical response prevent work stoppage or work absence among employed patients with early rheumatoid arthritis? Rheumatology (Oxford). 2012 Feb;51(2):270-4. Epub 2011 Jun 29.

Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008 Aug 2;372(9636):375-82. Epub 2008 Jul 16.

Responsible Party:	Wyeth is now a wholly owned subsidiary of Pfizer
ClinicalTrials.gov Identifier:	NCT00195494 History of Changes
Other Study ID Numbers:	0881A-101548
Study First Received:	September 13, 2005
Results First Received:	March 31, 2009
Last Updated:	August 1, 2012
Health Authority:	European Union: European Medicines Agency

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