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A Study to Evaluate the Effectiveness of Infliximab and Changes in Hand and Wrist Magnetic Resonance Imaging (MRI) in Participants With Active Rheumatoid Arthritis (RA) (P08136)

Primary Purpose

Arthritis, Rheumatoid

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Infliximab

Placebo

About this trial

This is an interventional treatment trial for Arthritis, Rheumatoid

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Must have a clinical diagnosis of rheumatoid arthritis for at least 6 months
Must have at least 6 tender joints AND 6 swollen joints
Has a C-reactive protein ≥ 1.0 mg/L OR Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/hr
Baseline MRI must show evidence of synovitis in the wrist
Must have screening laboratory tests within acceptable levels
Women of childbearing potential and all men must agree to use a medically accepted method of contraception prior to entering the study and continue throughout study up to 6 weeks after study completion
Must meet tuberculosis (TB) screening criteria
Have received methotrexate therapy for ≥ 3 months; dose must be stable for at least 8 weeks
If taking the a disease modifying anti-rheumatic drug (DMARD) in combination with methotrexate must be on a stable dose
Must have a clinically acceptable 12 lead electrocardiogram (ECG)
If taking oral corticosteroids must be on a stable dose equivalent to ≤10 mg of prednisone (or prednisolone) per day for ≥2 weeks
If taking daily non-steroidal anti-inflammatory drug (NSAID) must be on a stable dose for ≥2 weeks; if taking NSAID on an as-needed basis must agree to discontinue use for at least 3 days and use only acetaminophen for breakthrough pain for 3 days before each MRI and clinic visit
If received biological therapies, the last dose of these drugs was to be received ≥ 3 months prior to the baseline visit AND the reason for discontinuations was not for safety considerations OR lack of efficacy

Exclusion Criteria:

Are pregnant, intend to become pregnant, or are breastfeeding
Has inflammatory arthritis other than RA
Has uncontrolled hypertension
Has moderate or severe congestive heart failure
Has a history of or current signs and/or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease
Has a history of demyelinating disease or symptoms suggestive of multiple sclerosis or optic neuritis
Is currently participating in another clinical study or have participated in a clinical study (e.g., laboratory or clinical evaluation) within 4 weeks
Has history of any tumor with the exception of adequately treated basal cell carcinoma or carcinoma in situ of the cervix
Has a history of any latent or active granulomatous infection including histoplasmosis, or coccidiomycosis
Had a non-tuberculous mycobacterial infection or opportunistic infection (e.g. cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months
Has a history of an infected joint prosthesis which has not been removed or replaced
Has a known hypersensitivity to human immunoglobulin proteins or other components of infliximab
Has received rituximab or natalizumab
Has known claustrophobia or other contraindication to MRI
Does not meet washout period guidelines for previous treatments/injections/vaccinations

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Infliximab

Placebo

Arm Description

3 mg/kg of Infliximab intravenous infusion

saline via intravenous infusion

Outcomes

Primary Outcome Measures

Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans)

Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) was performed on one hand at baseline, and then at treatment week 14 to measure the rate constant of transfer of contrast (Ktrans).

Secondary Outcome Measures

Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20).

ACR20 requires that both tender and swollen joint counts improve by at least 20% from baseline, as well as a 20% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and C-reactive protein (CRP).

Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50).

ACR50 requires that both tender and swollen joint counts improve by at least 50% from baseline, as well as a 50% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and CRP.

Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans.

Clinical disease activity score (DAS28 CRP) is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), Patient Global Assessment of Disease Status (GADP) on a 100 mm visual analog scale (VAS) and concentration of CRP. Ktrans is the volume transfer rate from the blood plasma to the enhancing synovium. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic.

Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis.

DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of CRP. RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations, ranging from 0 to 24 total. RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations, ranging from 0 to 75 total. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic.

Full Information

NCT ID

NCT01313520

First Posted

February 25, 2011

Last Updated

April 4, 2017

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT01313520

Brief Title

A Study to Evaluate the Effectiveness of Infliximab and Changes in Hand and Wrist Magnetic Resonance Imaging (MRI) in Participants With Active Rheumatoid Arthritis (RA) (P08136)

Official Title

A Randomized Clinical Trial to Study the Effects of Infliximab on Clinical Efficacy and Hand and Wrist Magnetic Resonance Imaging (MRI) in Patients With Active Rheumatoid Arthritis (RA)(Protocol No. P08136)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Completed

Study Start Date

March 1, 2011 (Actual)

Primary Completion Date

March 1, 2012 (Actual)

Study Completion Date

March 1, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This is a study to compare the effect of infliximab versus placebo on synovial inflammation as measured by dynamic contrast enhanced (DCE)-MRI of one wrist. The primary hypothesis is that over 14 weeks of therapy, the change from baseline in the volume transfer rate in enhancing synovium is larger due to treatment with infliximab than with placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Arthritis, Rheumatoid

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

61 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Infliximab

Arm Type

Experimental

Arm Description

3 mg/kg of Infliximab intravenous infusion

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

saline via intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Infliximab

Other Intervention Name(s)

SCH 215596, Remicade

Intervention Description

3 mg/kg of Infliximab at Weeks 0, 2, 6, 14 via intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

250 mL of 0.9% sodium chloride at Weeks 0, 2, 6, 14 via intravenous infusion

Primary Outcome Measure Information:

Title

Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans)

Description

Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) was performed on one hand at baseline, and then at treatment week 14 to measure the rate constant of transfer of contrast (Ktrans).

Time Frame

Baseline and week 14

Secondary Outcome Measure Information:

Title

Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20).

Description

Time Frame

Baseline and week 14

Title

Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50).

Description

Time Frame

Baseline and week 14

Title

Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans.

Description

Time Frame

Baseline and Week 14

Title

Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis.

Description

Time Frame

Baseline and Week 14

Other Pre-specified Outcome Measures:

Title

Change From Baseline in DAS28 CRP.

Description

DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of serum CRP. Scores can range from 2-10; with higher values corresponding to higher disease activity, and lower values to better outcomes.

Time Frame

Baseline and Week 14

Title

Change From Baseline in RAMRIS Synovitis.

Description

RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations. The scores can range from 0 to 24, with higher values corresponding to higher disease activity, and lower values to better outcomes.

Time Frame

Baseline and Week 14

Title

Change From Baseline in RAMRIS Osteitis.

Description

RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations. The scores can range from 0 to 75, with higher values corresponding to higher disease activity, and lower values to better outcomes.

Time Frame

Baseline and Week 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Must have a clinical diagnosis of rheumatoid arthritis for at least 6 months Must have at least 6 tender joints AND 6 swollen joints Has a C-reactive protein ≥ 1.0 mg/L OR Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/hr Baseline MRI must show evidence of synovitis in the wrist Must have screening laboratory tests within acceptable levels Women of childbearing potential and all men must agree to use a medically accepted method of contraception prior to entering the study and continue throughout study up to 6 weeks after study completion Must meet tuberculosis (TB) screening criteria Have received methotrexate therapy for ≥ 3 months; dose must be stable for at least 8 weeks If taking the a disease modifying anti-rheumatic drug (DMARD) in combination with methotrexate must be on a stable dose Must have a clinically acceptable 12 lead electrocardiogram (ECG) If taking oral corticosteroids must be on a stable dose equivalent to ≤10 mg of prednisone (or prednisolone) per day for ≥2 weeks If taking daily non-steroidal anti-inflammatory drug (NSAID) must be on a stable dose for ≥2 weeks; if taking NSAID on an as-needed basis must agree to discontinue use for at least 3 days and use only acetaminophen for breakthrough pain for 3 days before each MRI and clinic visit If received biological therapies, the last dose of these drugs was to be received ≥ 3 months prior to the baseline visit AND the reason for discontinuations was not for safety considerations OR lack of efficacy Exclusion Criteria: Are pregnant, intend to become pregnant, or are breastfeeding Has inflammatory arthritis other than RA Has uncontrolled hypertension Has moderate or severe congestive heart failure Has a history of or current signs and/or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease Has a history of demyelinating disease or symptoms suggestive of multiple sclerosis or optic neuritis Is currently participating in another clinical study or have participated in a clinical study (e.g., laboratory or clinical evaluation) within 4 weeks Has history of any tumor with the exception of adequately treated basal cell carcinoma or carcinoma in situ of the cervix Has a history of any latent or active granulomatous infection including histoplasmosis, or coccidiomycosis Had a non-tuberculous mycobacterial infection or opportunistic infection (e.g. cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months Has a history of an infected joint prosthesis which has not been removed or replaced Has a known hypersensitivity to human immunoglobulin proteins or other components of infliximab Has received rituximab or natalizumab Has known claustrophobia or other contraindication to MRI Does not meet washout period guidelines for previous treatments/injections/vaccinations

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf http://engagezone.msd.com/ds_documentation.php

Citations:

PubMed Identifier

29236711

Citation

Beals C, Baumgartner R, Peterfy C, Balanescu A, Mirea G, Harabagiu A, Popa S, Cheng A, Feng D, Ashton E, DiCarlo J, Vallee MH, Dardzinski BJ. Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring. PLoS One. 2017 Dec 13;12(12):e0187397. doi: 10.1371/journal.pone.0187397. eCollection 2017.

Results Reference

derived

PubMed Identifier

25504080

Citation

MacIsaac KD, Baumgartner R, Kang J, Loboda A, Peterfy C, DiCarlo J, Riek J, Beals C. Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients. PLoS One. 2014 Dec 12;9(12):e113937. doi: 10.1371/journal.pone.0113937. eCollection 2014.

Results Reference

derived

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A Study to Evaluate the Effectiveness of Infliximab and Changes in Hand and Wrist Magnetic Resonance Imaging (MRI) in Participants With Active Rheumatoid Arthritis (RA) (P08136)

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