Trial Outcomes & Findings for A Phase IIIb Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate (NCT NCT00420199)
NCT ID: NCT00420199
Last Updated: 2012-01-18
Results Overview
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3\*3 wrist regions), indicating most severe damage. Change in synovitis = Follow-up synovitis score - baseline score.
COMPLETED
PHASE3
50 participants
At baseline
2012-01-18
Participant Flow
Participant milestones
| Measure |
Abatacept (ABA) + Methotrexate (MTX)
Abatacept was administered intravenously (IV) on Day 1, 15, 29 and every 28 days up to and including Day 113.Abatacept was given as a dose based on body weight: 500 mg for participants weighing \< 60 kg, 750 mg for participants weighing 60 to 100 kg and 1 gram for participants weighing \> 100 kg.
|
Placebo (PLA) + MTX
PLA was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
|---|---|---|
|
Overall Study
STARTED
|
27
|
23
|
|
Overall Study
COMPLETED
|
26
|
23
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
Abatacept (ABA) + Methotrexate (MTX)
Abatacept was administered intravenously (IV) on Day 1, 15, 29 and every 28 days up to and including Day 113.Abatacept was given as a dose based on body weight: 500 mg for participants weighing \< 60 kg, 750 mg for participants weighing 60 to 100 kg and 1 gram for participants weighing \> 100 kg.
|
Placebo (PLA) + MTX
PLA was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
|---|---|---|
|
Overall Study
Participant no longer met study criteria
|
1
|
0
|
Baseline Characteristics
A Phase IIIb Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate
Baseline characteristics by cohort
| Measure |
Abatacept (ABA) + Methotrexate (MTX)
n=27 Participants
Abatacept was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113.Abatacept was given as a dose based on body weight: 500 mg for participants weighing \< 60 kg, 750 mg for participants weighing 60 to 100 kg and 1 gram for participants weighing \> 100 kg.
|
Placebo (PLA) + MTX
n=23 Participants
PLA was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
Total
n=50 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age Continuous
|
51.7 years
STANDARD_DEVIATION 11.2 • n=5 Participants
|
52.5 years
STANDARD_DEVIATION 11.5 • n=7 Participants
|
52.1 years
STANDARD_DEVIATION 11.2 • n=5 Participants
|
|
Sex: Female, Male
Female
|
16 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
32 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
11 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
18 Participants
n=5 Participants
|
|
Region of Enrollment
Belgium
|
9 participants
n=5 Participants
|
7 participants
n=7 Participants
|
16 participants
n=5 Participants
|
|
Region of Enrollment
Germany
|
10 participants
n=5 Participants
|
6 participants
n=7 Participants
|
16 participants
n=5 Participants
|
|
Region of Enrollment
Netherlands
|
3 participants
n=5 Participants
|
4 participants
n=7 Participants
|
7 participants
n=5 Participants
|
|
Region of Enrollment
Spain
|
2 participants
n=5 Participants
|
2 participants
n=7 Participants
|
4 participants
n=5 Participants
|
|
Region of Enrollment
Sweden
|
2 participants
n=5 Participants
|
3 participants
n=7 Participants
|
5 participants
n=5 Participants
|
|
Region of Enrollment
United Kingdom
|
1 participants
n=5 Participants
|
1 participants
n=7 Participants
|
2 participants
n=5 Participants
|
|
Rheumatoid Factor (RF) Status
Negative
|
12 participants
n=5 Participants
|
4 participants
n=7 Participants
|
16 participants
n=5 Participants
|
|
Rheumatoid Factor (RF) Status
Positive
|
15 participants
n=5 Participants
|
19 participants
n=7 Participants
|
34 participants
n=5 Participants
|
|
Anti-CCP2 Status
Negative
|
14 participants
n=5 Participants
|
6 participants
n=7 Participants
|
20 participants
n=5 Participants
|
|
Anti-CCP2 Status
Positive
|
13 participants
n=5 Participants
|
17 participants
n=7 Participants
|
30 participants
n=5 Participants
|
|
Duration of Rheumatoid Arthritis
|
25.7 months
STANDARD_DEVIATION 18.0 • n=5 Participants
|
28.2 months
STANDARD_DEVIATION 17.0 • n=7 Participants
|
26.8 months
STANDARD_DEVIATION 17.4 • n=5 Participants
|
|
Disease Activity Score (DAS) 28 (C-Reactive Protein [CRP])
|
5.3 units on a scale
STANDARD_DEVIATION 1.1 • n=5 Participants
|
5.3 units on a scale
STANDARD_DEVIATION 0.9 • n=7 Participants
|
5.3 units on a scale
STANDARD_DEVIATION 1.0 • n=5 Participants
|
|
Number of Tender Joints
|
12.9 joints
STANDARD_DEVIATION 7.1 • n=5 Participants
|
13.3 joints
STANDARD_DEVIATION 7.2 • n=7 Participants
|
13.1 joints
STANDARD_DEVIATION 7.2 • n=5 Participants
|
|
Number of Swollen Joints
|
11.3 joints
STANDARD_DEVIATION 6.6 • n=5 Participants
|
8.5 joints
STANDARD_DEVIATION 4.1 • n=7 Participants
|
10.0 joints
STANDARD_DEVIATION 5.7 • n=5 Participants
|
|
Cross Classification of RF Status and CCP2 Status at Baseline
RF negative, anti-CCP2 negative
|
12 participants
n=5 Participants
|
3 participants
n=7 Participants
|
15 participants
n=5 Participants
|
|
Cross Classification of RF Status and CCP2 Status at Baseline
RF negative, anti-CCP2 positive
|
0 participants
n=5 Participants
|
1 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Cross Classification of RF Status and CCP2 Status at Baseline
RF positive, anti-CCP2 negative
|
2 participants
n=5 Participants
|
3 participants
n=7 Participants
|
5 participants
n=5 Participants
|
|
Cross Classification of RF Status and CCP2 Status at Baseline
RF positive, anti-CCP2 positive
|
13 participants
n=5 Participants
|
16 participants
n=7 Participants
|
29 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: At baselinePopulation: All randomized participants who received at least 1 dose of study medication and had synovitis assessments available at baseline.
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3\*3 wrist regions), indicating most severe damage. Change in synovitis = Follow-up synovitis score - baseline score.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Mean Synovitis Scores at Baseline As Measured by the Rheumatoid Arthritis Clinical Trials 6 (OMERACT 6) Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS)
|
4.48 units on a scale
Standard Deviation 2.10
|
3.52 units on a scale
Standard Deviation 2.43
|
PRIMARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and had wrist synovitis assessments available at baseline and Day 113.
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3\*3 wrist regions), indicating most severe damage. Change in synovitis=Follow-up synovitis score-baseline score.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Planned Analysis Using Non-Parametric ANCOVA
|
-0.44 units on a scale
Standard Deviation 1.47
|
0.52 units on a scale
Standard Deviation 1.38
|
PRIMARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and who had wrist synovitis assessments available at baseline and Day 113.
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3\*3 wrist regions), indicating most severe damage. Change in synovitis score=Follow-up synovitis score-baseline synovitis score.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Post Hoc Sensitivity Analysis Using Parametric ANCOVA Analysis
|
-0.31 units on a scale
Standard Deviation 0.26
|
0.38 units on a scale
Standard Deviation 0.27
|
SECONDARY outcome
Timeframe: At baselinePopulation: All randomized participants who received at least 1 dose of study medication and had erosion OMERACT 6 assessments available at baseline.
Bone erosion assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage) according to erosion of the original articular bone (each unit=10% loss of articular bone). The total erosion score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 230. Increasing score=greater severity.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Baseline Mean Erosion OMERACT 6 Scores
|
12.60 units on a scale
Standard Deviation 9.41
|
9.65 units on a scale
Standard Deviation 10.11
|
SECONDARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and had erosion OMERACT 6 assessments available at baseline and Day 113.
Bone erosion assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached hand. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage), indicating erosion (each unit=10% bone loss) of original articular bone. Total erosion score for hands/wrists is sum of the individual scores for each location. Thus the maximum score per hand/wrist is 230. Increasing score=greater severity. Adjusted change from baseline in erosion score=mean score at Day 113-mean erosion score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Adjusted Mean Change From Baseline in Erosion OMERACT 6 Scores
|
0.45 units on a scale
Standard Deviation 0.43
|
0.95 units on a scale
Standard Deviation 0.45
|
SECONDARY outcome
Timeframe: At baselinePopulation: All randomized participants who received at least 1 dose of study medication and had osteitis OMERACT 6 assessments available at baseline.
Osteitis assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 to 3, indicating involvement of original articular bone. The total score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 23 (total number of anatomic locations) \* 3 (maximum per joint)=69. Minimum score=0, indicating normal. Increasing score=greater severity.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Baseline Mean Osteitis OMERACT 6 Scores
|
7.72 units on a scale
Standard Deviation 7.04
|
8.00 units on a scale
Standard Deviation 9.72
|
SECONDARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and had osteitis OMERACT 6 assessments available at baseline and Day 113.
Osteitis assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached. Each site scored in 1.0 increments, indicating involvement of original articular bone (0=none to 3=severe). Total score for hands/wrists is sum of scores for each location. Maximum score per hand/wrist is 23 (total anatomic locations)\*3 (maximum score per joint)=69. Minimum score=0(normal). Increasing score=greater severity. Adjusted mean change from baseline in osteitis score=mean score at Day 113-mean score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Adjusted Mean Change From Baseline in Osteitis OMERACT 6 Scores
|
-1.94 units on a scale
Standard Deviation 0.86
|
1.54 units on a scale
Standard Deviation 0.90
|
SECONDARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and had erosion, edema, and synovitis assessments available at baseline and Day 113.
Bone erosion and osteitis were assessed at a total of 23 anatomic locations according to erosion (for bone erosion) or involvement (for osteitis) of the original articular bone. Synovitis assessed as above-normal post-gadolinium enhancement in 3 wrist regions: distal radioulnar joint, radiocarpal joint, and intercarpal and carpometacarpal joints.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
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Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
≥1 newly involved joints (Bone Erosion)
|
5 participants
|
7 participants
|
|
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
0 newly involved joints (Edema/Osteitis)
|
18 participants
|
16 participants
|
|
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
≥1 newly involved joints (Edema/Osteitis)
|
7 participants
|
7 participants
|
|
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
0 newly involved joints (Synovitis)
|
23 participants
|
20 participants
|
|
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
≥1 newly involved joints (Synovitis)
|
2 participants
|
3 participants
|
|
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
0 newly involved joints (Bone Erosion)
|
20 participants
|
16 participants
|
SECONDARY outcome
Timeframe: BaselinePopulation: All randomized participants who received at least 1 dose of study medication and had RAMRIS assessments available at baseline.
RAMRIS score is the sum of its core components: Synovitis Score, Osteitis Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Osteitis scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score + Osteitis Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Osteitis Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Baseline Mean RAMRIS Scores
|
24.80 units on a scale
Standard Deviation 16.36
|
21.17 units on a scale
Standard Deviation 20.45
|
SECONDARY outcome
Timeframe: Baseline to Day 113Population: All randomized participants who received at least 1 dose of study medication and had RAMRIS assessments available at baseline and Day 113.
RAMRIS Score=sum of core components: Synovitis (S), Osteitis (O), and Erosion (E) Scores. S scored 0 (none) to 9 (maximum distension of synovial cavity); O scored 0 (none) to 69 (maximum articular bone involvement); E scored 0 (none) to 230 (maximum erosion of articular bone). RAMRIS=S+O+E Scores. RAMRIS minimum score=0 (normal), maximum=308 (severe structural damage). Adjusted change from baseline in RAMRIS=mean RAMRIS at Day 113-mean RAMRIS at baseline. Adjustment based on ANCOVA model: treatment=factor, baseline value=covariate.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=25 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Adjusted Mean Change From Baseline in RAMRIS Scores
|
-1.82 units on a scale
Standard Deviation 1.13
|
2.89 units on a scale
Standard Deviation 1.18
|
SECONDARY outcome
Timeframe: Baseline to Days 15, 29, 57, 85, and 113Population: All randomized participants who received at least 1 dose of study medication.
PINP and osteocalcin are markers of bone formation. Osteocalcin is synthesized by osteoblasts and is associated with osteoblast synthetic activity. Osteoblasts secrete type 1 procollagen, and cleavage of large fragments from the carboxy and amino terminal ends result in formation of mature type 1 collagen and production of PINP fragments.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 15 osteocalcin (n=25, n=21)
|
1.82 percent change
Interval -10.2 to 12.1
|
4.41 percent change
Interval -12.7 to 15.6
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 15 serum intact PINP (n=25, n=21)
|
6.83 percent change
Interval -3.9 to 15.7
|
3.94 percent change
Interval -8.4 to 13.9
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 29 osteocalcin (n=26, n=21)
|
2.43 percent change
Interval -8.8 to 18.2
|
12.14 percent change
Interval -10.1 to 19.2
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 29 serum intact PINP (n=26, n=21)
|
11.62 percent change
Interval 1.1 to 30.8
|
-0.18 percent change
Interval -9.3 to 23.5
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 57 osteocalcin (n=25, n=21)
|
4.02 percent change
Interval -7.7 to 25.4
|
10.53 percent change
Interval -3.7 to 22.8
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 57 serum intact PINP (n=25, n=21)
|
3.68 percent change
Interval -8.1 to 43.1
|
12.18 percent change
Interval -6.7 to 20.2
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 85 osteocalcin (n=24, n=21)
|
4.76 percent change
Interval -11.5 to 34.1
|
10.62 percent change
Interval -14.8 to 25.8
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 85 serum intact PINP (n=24, n=21)
|
5.97 percent change
Interval -10.6 to 36.3
|
-7.23 percent change
Interval -18.1 to 14.8
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 113 osteocalcin (n=24, n=21)
|
3.18 percent change
Interval -8.2 to 11.8
|
7.87 percent change
Interval -8.3 to 19.0
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Day 113 serum intact PINP (n=24, n=21)
|
2.98 percent change
Interval -19.8 to 28.8
|
4.75 percent change
Interval -16.1 to 24.7
|
SECONDARY outcome
Timeframe: Baseline to Days 15, 29, 57, 85, and 113Population: All randomized participants who received at least 1 dose of study medication.
CTX-I and ICTP are biochemical markers of bone resorption or bone degradation
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 15 CTX-1 (n=25, n=21)
|
1.65 percent change
Interval -23.0 to 13.0
|
-6.37 percent change
Interval -24.6 to 23.2
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 15 ICTP (n=25, n=21)
|
-5.56 percent change
Interval -17.1 to 10.9
|
6.25 percent change
Interval -6.2 to 18.6
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 29 CTX-1 (n=26, n=21)
|
0.48 percent change
Interval -28.2 to 32.2
|
-0.72 percent change
Interval -21.2 to 18.6
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 29 ICTP (n=26, n=21)
|
-3.47 percent change
Interval -10.1 to 10.0
|
4.34 percent change
Interval -3.7 to 20.4
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 57 CTX-1 (n=25, n=21)
|
15.13 percent change
Interval -17.9 to 26.5
|
7.02 percent change
Interval -11.4 to 16.7
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 57 ICTP (n=25, n=21)
|
-5.08 percent change
Interval -15.9 to 14.5
|
8.73 percent change
Interval -3.7 to 21.6
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 85 CTX-1 (n=24, n=21)
|
-6.94 percent change
Interval -35.9 to 21.5
|
15.65 percent change
Interval -18.9 to 40.8
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 85 ICTP (n=24, n=21)
|
-6.36 percent change
Interval -24.7 to 4.7
|
2.25 percent change
Interval -7.1 to 9.7
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 113 CTX-1 (n=24, n=21)
|
-7.23 percent change
Interval -36.4 to 21.3
|
0.00 percent change
Interval -27.5 to 35.3
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Day 113 ICTP (n=24, n=21)
|
-11.29 percent change
Interval -27.7 to 1.5
|
11.64 percent change
Interval -2.2 to 29.9
|
SECONDARY outcome
Timeframe: Baseline to Days 15, 29, 57, 85, and 113Population: All randomized participants who received at least 1 dose of study medication.
Urinary CTX-II is a biochemical marker of type II collagen breakdown. In participants with early rheumatoid arthritis, increased levels of CTX-II can be predictive of rapid radiographic progression over periods of 1 to 5 years. These markers of cartilage destruction can predict progression of joint damage, independent of clinical and biologic indices of disease activity and baseline joint damage.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Day 15 UCTX2C (n=24, n=21)
|
-8.51 percent change
Interval -35.9 to 13.7
|
5.14 percent change
Interval -11.7 to 8.4
|
|
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Day 29 UCTX2C (n=21, n=19)
|
-3.40 percent change
Interval -16.5 to 5.8
|
6.81 percent change
Interval -25.1 to 13.5
|
|
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Day 57 UCTX2C (n=23, n=19)
|
0.24 percent change
Interval -50.0 to 25.0
|
5.43 percent change
Interval -12.3 to 24.8
|
|
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Day 85 UCTX2C (n=22, n=20)
|
-10.83 percent change
Interval -38.4 to 14.7
|
9.67 percent change
Interval -13.8 to 29.2
|
|
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Day 113 UCTX2C (n=22, n=20)
|
-18.49 percent change
Interval -46.9 to 54.2
|
9.86 percent change
Interval -22.4 to 46.3
|
SECONDARY outcome
Timeframe: Baseline to Days 15, 29, 57, 85, and 113Population: All randomized participants who received at least 1 dose of study medication.
Glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) is a specific biochemical marker reflecting the degradation of the synovial tissue membrane. It is a glycosylated derivative of the collagen crosslink pyridinoline, and it is present in significant amounts only in the synovial membrane; it is absent from bone and present in minutes amounts in cartilage and other soft tissues. Increased urinary levels of Glc-Gal-PYD have been found in early and long-standing rheumatoid arthritis, high levels being associated with rapid destruction.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Day 15 UGGPC (n=24, n=20)
|
4.44 percent change
Interval -20.5 to 65.0
|
-3.84 percent change
Interval -13.7 to 12.4
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Day 29 UGGPC (n=22, n=18)
|
-1.83 percent change
Interval -19.3 to 76.9
|
-3.19 percent change
Interval -25.6 to 26.8
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Day 57 UGGPC (n=23, n=16)
|
1.58 percent change
Interval -24.8 to 23.4
|
5.73 percent change
Interval -12.6 to 28.2
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Day 85 UGGPC (n=22, n=18)
|
0.32 percent change
Interval -31.0 to 54.5
|
16.29 percent change
Interval -14.4 to 39.7
|
|
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Day 113 UGGPC (n=22, n=18)
|
-12.16 percent change
Interval -27.9 to 53.3
|
-3.10 percent change
Interval -31.5 to 32.3
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
Deaths
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
SAEs
|
0 participants
|
2 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
Treatment-related SAEs
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
SAEs Leading to Discontinuation
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
AEs
|
20 participants
|
14 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
Treatment-related AEs
|
8 participants
|
6 participants
|
|
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
AEs Leading to Discontinuation
|
0 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including serious, opportunistic, and all other infections; autoimmune disorders; neoplasms; acute infusional AEs (prespecified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (prespecified AEs occurring within 24 hours of start of infusion).
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With AEs of Special Interest
Infections
|
1 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With AEs of Special Interest
Malignancies
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With AEs of Special Interest
Autoimmune disorders
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With AEs of Special Interest
Acute infusional AEs
|
0 participants
|
4 participants
|
|
Double-blind Period: Number of Participants With AEs of Special Interest
Peri-infusional AEs
|
4 participants
|
5 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
Infections/Infestations of Special Interest are AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). AE=any new untoward medical occurrence or worsening of a preexisting medical condition which does not necessarily have a causal relationship with this treatment.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Infections/Infestations of Special Interest
|
1 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
Acute infusional AEs are AEs with onset during the first hour after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events ,Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Grade 1 diarrhea
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Grade 1 overdose
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Grade 1 headache
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Grade 1 flushing
|
0 participants
|
1 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
Peri-infusional AEs are AEs occurring during the first 24 hours after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events, Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 1 nausea
|
3 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 1 headache
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 2 headache
|
1 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 1 flushing
|
0 participants
|
2 participants
|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 2 arthralgia
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Grade 1 cough
|
0 participants
|
1 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
BL=baseline; LLN=lower limit of normal; ULN=upper limit of normal. Marked abnormality criteria: Hemoglobin: \>3 g/dL decrease from BL. Hematocrit: \<0.75\*BL. Erythrocytes: \<0.75\*BL. Platelets: \<0.67\*LLN/\>1.5\*ULN, or if BL \<LLN, use 0.5\*BL/\<100,000 mm\^3. Leukocytes: \<0.75\*LLN/\>1.25\*ULN, or if BL\<LLN, use \<0.8\*BL/\>ULN, or if BL\>ULN, use \>1.2\*BL/\<LLN. Neutrophils+bands: \<1.0\*10\^3 c/uL. Eosinophils: \>0.750\*10\^3 c/uL. Basophils: \> 400 mm\^3. Monocytes: \>2000 mm\^3. Lymphocytes: \<0.750\*10\^3 c/uL/\>7.50\*10\^3 c/uL.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low hemoglobin
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low hematocrit
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low erythrocytes
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low platelets
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High platelets
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low leukocytes
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High leukocytes
|
1 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low neutrophils+bands
|
0 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Low lymphocytes
|
2 participants
|
2 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High lymphocytes
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High monocytes
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High basophils
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
High eosinophils
|
0 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and including up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
ULN=upper limit of normal; BL=baseline. Marked abnormality criteria: Alkaline phosphatase: \>2\*ULN, or if BL\>ULN, use \>3\*BL; aspartate aminotransferase: \>3\*ULN, or if BL\>ULN,use \>4\*BL; alanine aminotransferase: \>3\*ULN, or if BL\>ULN, use \>4\*BL; G-Glutamyl transferase: \>2\*ULN, or if BL\>ULN, use \>3\*BL; Bilirubin: \>2\*ULN, or if BL\>ULN, use \>4\*BL; blood urea nitrogen: \>2\*BL; creatinine: \>1.5\*BL.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High alkaline phosphatase
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High aspartate aminotransferase
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High alanine aminotransferase
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High G-Glutamyl transferase
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High bilirubin
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High blood urea nitrogen
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
High creatinine
|
1 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Marked abnormality: Sodium: \<0.95\*LLN/\>1.05\*ULN,or if BL\<LLN, use 0.95\*BL or \>ULN,or if BL\>ULN, use\>1.05\*BL or \<LLN. Potassium: \<0.9\*LLN/\>1.1\* ULN,or if BL\<LLN, use 0.9\*BL or \>ULN, or if BL\>ULN, use\>1.1\*BL or \<LLN. Chloride: \<0.9\*LLN/\>1.1\*ULN, or if BL\<LLN, use 0.9\*BL or \>ULN, or if BL\>ULN, use\>1.1\*BL or \<LLN. Calcium: \<0.8\*LLN/\>1.2\*ULN, or if BL\<LLN, use 0.75\*BL or \>ULN, or if BL\>ULN, use\>1.25\*BL or \<LLN. Phosphorous: \<0.75\*LLN/\>1.25\*ULN, or if BL\<LLN, use 0.67\*BL or \>ULN, or if BL\>ULN, use\>1.33\*BL or \<LLN.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Low sodium
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
High sodium
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Low potassium
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
High potassium
|
1 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Low chloride
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
High chloride
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Low calcium
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
High calcium
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Low phosphorous
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
High phosphorous
|
0 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label periodPopulation: All randomized participants who received at least 1 dose of study medication.
LLN=lower limit of normal; ULN=upper limit of normal; BL-baseline. Marked abnormality c: serum glucose:\<65 mg/dL/\>220 mg/dL; fasting serum glucose: \<0.8\* LLN/\>1.5\* ULN, or if BL\<LLN, use 0.8\*BL or \>ULN, or if BL\>ULN, use \>2.0\*BL or \<LLN; total protein: \<0.9\*LLN/\>1.1\* ULN; albumin: \<0.9\*LLN,or if BL\<LLN, use \<0.75 BL; uric acid: \>1.5\* ULN, or if BL\>ULN, use \>2\*BL. Urinalysis (Urine protein, urine Glu, urine blood, leukocyte esterase, red blood cells, white blood cells):Use ≥2 when BL value missing or value ≥4,or when predose=0 or 0.5. Use ≥3 when predose=1. Use ≥4 when predose=2 or 3
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
Low serum glucose (n=27, n=23)
|
1 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High serum glucose (n=27, n=23)
|
1 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
Low fasting glucose (n=20, n=17)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High fasting glucose (n=20, n=17)
|
1 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
Low total protein (n=27, n=23)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High total protein (n=27, n=23)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
Low albumin (n=27, n=23)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High uric acid (n=27, n=23)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High urine protein (n=27, n=23)
|
1 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High urine glucose (n=27, n=23)
|
0 participants
|
0 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High urine blood (n=27, n=23)
|
2 participants
|
1 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High leukocyte esterase (n=27, n=23)
|
4 participants
|
4 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High urine white blood cells (n=10, n=9)
|
2 participants
|
3 participants
|
|
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
High urine red blood cells (n=10, n=8)
|
3 participants
|
3 participants
|
SECONDARY outcome
Timeframe: Days 1, 15, 29, 57, 85, and 113Population: All randomized participants who received at least 1 dose of study medication.
Vital signs, which included blood pressure, heart rate, respiration, and temperature, were monitored predose and 1 hour after start of infusion. Changes in vital signs were determined to be significantly abnormal at the discretion of the investigator but were generally those that either exceeded, or failed to reach, normal parameters. Normal vital sign parameter ranges varied by site.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
n=23 Participants
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period:Number of Participants With Significantly Abnormal Changes in Vital Signs
|
0 participants
|
0 participants
|
SECONDARY outcome
Timeframe: Day 1 to Day 113Population: All randomized participants who received at least 1 dose of study medication.
On-Rx=on treatment; post-Rx=post treatment. ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction Category=reactivity against constant regions and/or hinge region of human IgG1.
Outcome measures
| Measure |
Abatacept + Methotrexate
n=27 Participants
Abatacept was administered intravenously on Days 1, 15, and 29 and every 28 days up to and including Day 113. Abatacept dose was based on body weight: 500 mg for participants weighing \<60 kg, 750 mg for participants weighing 60 to 100 kg, and 1 gram for participants weighing \>100 kg.
|
Placebo + Methotrexate
Placebo was administered IV on Days 1, 15, and 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of at least 15 mg (or a maximum tolerated dose, such as 10 mg weekly) of methotrexate).
|
|---|---|---|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall on-Rx visits, CTLA4 + possibly Ig (n=27)
|
0 participants
|
—
|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall on-Rx visits, Ig and/or junction (n=27)
|
0 participants
|
—
|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall post-Rx visits, CTLA4 + possibly Ig (n=1)
|
0 participants
|
—
|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall post-Rx visits, Ig and/or junction (n=1)
|
0 participants
|
—
|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall visits, CTLA4 + possibly Ig (n=27)
|
0 participants
|
—
|
|
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Overall visits, Ig and/or junction (n=27)
|
0 participants
|
—
|
Adverse Events
ABA + MTX
PLA + MTX
Serious adverse events
| Measure |
ABA + MTX
n=27 participants at risk
Abatacept was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113.Abatacept was given as a dose based on body weight: 500 mg for participants weighing \< 60 kg, 750 mg for participants weighing 60 to 100 kg and 1 gram for participants weighing \> 100 kg. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
PLA + MTX
n=23 participants at risk
PLA was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
|---|---|---|
|
Cardiac disorders
ATRIAL FIBRILLATION
|
0.00%
0/27
|
4.3%
1/23
|
|
Injury, poisoning and procedural complications
OVERDOSE
|
0.00%
0/27
|
4.3%
1/23
|
Other adverse events
| Measure |
ABA + MTX
n=27 participants at risk
Abatacept was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113.Abatacept was given as a dose based on body weight: 500 mg for participants weighing \< 60 kg, 750 mg for participants weighing 60 to 100 kg and 1 gram for participants weighing \> 100 kg. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
PLA + MTX
n=23 participants at risk
PLA was administered IV on Day 1, 15, 29 and every 28 days up to and including Day 113. In addition, participants received a weekly dose of MTX of at least 15 mg or a maximum tolerated dose (ie, 10 mg weekly)
|
|---|---|---|
|
Vascular disorders
FLUSHING
|
0.00%
0/27
|
8.7%
2/23
|
|
Nervous system disorders
HEADACHE
|
3.7%
1/27
|
8.7%
2/23
|
|
Nervous system disorders
DIZZINESS
|
7.4%
2/27
|
0.00%
0/23
|
|
Gastrointestinal disorders
NAUSEA
|
14.8%
4/27
|
0.00%
0/23
|
|
Gastrointestinal disorders
DIARRHOEA
|
7.4%
2/27
|
4.3%
1/23
|
|
Infections and infestations
SINUSITIS
|
7.4%
2/27
|
0.00%
0/23
|
|
Infections and infestations
NASOPHARYNGITIS
|
3.7%
1/27
|
8.7%
2/23
|
|
Musculoskeletal and connective tissue disorders
BACK PAIN
|
11.1%
3/27
|
0.00%
0/23
|
|
Respiratory, thoracic and mediastinal disorders
COUGH
|
7.4%
2/27
|
4.3%
1/23
|
|
Respiratory, thoracic and mediastinal disorders
EPISTAXIS
|
0.00%
0/27
|
8.7%
2/23
|
|
General disorders
FATIGUE
|
7.4%
2/27
|
0.00%
0/23
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
- Publication restrictions are in place
Restriction type: OTHER