Clinical Trial Results:
CareRA2020: Effectiveness of a combination of Methotrexate and a step down glucocorticoid regimen (COBRA-Slim) for remission induction in patients with early Rheumatoid Arthritis (RA), with or without fast access to 24 weeks of Tumor Necrosis Factor (TNF) blockade in insufficient responders, a randomised, multicenter, pragmatic trial.
Summary
|
|
EudraCT number |
2017-004054-41 |
Trial protocol |
BE |
Global end of trial date |
01 Jul 2022
|
Results information
|
|
Results version number |
v2(current) |
This version publication date |
29 May 2024
|
First version publication date |
19 Aug 2023
|
Other versions |
v1 |
Version creation reason |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
KCE-16002
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03649061 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
University Hospitals Leuven
|
||
Sponsor organisation address |
herestraat 49, Leuven, Belgium, 3000
|
||
Public contact |
Patrick Verschueren, University Hospitals Leuven, +32 1634 25 41, patrick.verschueren@uzleuven.be
|
||
Scientific contact |
Patrick Verschueren, University Hospitals Leuven, +32 1634 25 41, patrick.verschueren@uzleuven.be
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
06 Jun 2023
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
01 Jul 2022
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
01 Jul 2022
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
The primary objective is to compare in an early RA population with insufficient response (not achieving DAS28CRP≤3.2 within 32 weeks or DAS28CRP<2.6 at week 32) to COBRA-Slim remission induction, the long term effectiveness of accelerated access to a six-month course of anti-TNF therapy (etanercept) within a time window from week 8 up to week 32, versus further treatment adaptation according to the standard COBRA-Slim strategy.
|
||
Protection of trial subjects |
This is a pragmatic trial rooted in daily practice. Patients were started on therapy based on the remission induction principle and were followed by the treat to target principle which means treatment adapatations were done whenever patients fail to comply with low disease activity as defined in the protocol.
Patients in need for an adaptation, despite methotrexate (MTX) dose increase, during the remission induction phase of the treatment were eligible for randomisation according to the protocol.
Patients rights were protected according to GCP-ICH, Belgian legislation and GDPR.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Mar 2018
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
3 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Belgium: 276
|
||
Worldwide total number of subjects |
276
|
||
EEA total number of subjects |
276
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
215
|
||
From 65 to 84 years |
60
|
||
85 years and over |
1
|
|
||||||||||||||||||||||||||||
Recruitment
|
||||||||||||||||||||||||||||
Recruitment details |
284 participants were recruited between June 2018 and June 2020. Patients were recruited in 19 rheumatology centers in Belgium. Patients were recruited in different type of centers: university hospitals, general hospitals and private practices. | |||||||||||||||||||||||||||
Pre-assignment
|
||||||||||||||||||||||||||||
Screening details |
Of the 284 patients screened 276 were eligible for the trial. 122 met the criteria of early insufficient reponders to the initial proposed remission-induction regimen (Cobra-Slim). Of this last group 112 were randomised, however 2 were considered randomisation errors. 10 patients were eligible for randomisation, but were not randomised. | |||||||||||||||||||||||||||
Period 1
|
||||||||||||||||||||||||||||
Period 1 title |
Remission-induction phase
|
|||||||||||||||||||||||||||
Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Not applicable
|
|||||||||||||||||||||||||||
Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
|
||||||||||||||||||||||||||||
Arm title
|
Remission-induction | |||||||||||||||||||||||||||
Arm description |
All 276 patients started with a COBRA-Slim remission-induction regimen. Patients who fail to reach low disease activity between week 8 and 32, or remission at week 32, were early insufficient responders and considered eligible for randomisation. Of the 276 patients who entered the trial, 264 reached the end of the remission-induction phase (week 32). Of these patients, 112 were considered early insufficient responders and randomised, however 2 of them were considered randomisation-error and excluded from analysis. Subsequently 110 patients started the proposed randomised treatment regimen and were considered for analysis. | |||||||||||||||||||||||||||
Arm type |
No intervention | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Period 2
|
||||||||||||||||||||||||||||
Period 2 title |
Insufficient responders
|
|||||||||||||||||||||||||||
Is this the baseline period? |
Yes [1] | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||
Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
|
||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||
Arm title
|
Standard COBRA-Slim | |||||||||||||||||||||||||||
Arm description |
Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
leflunomide
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
10 mg PO daily
|
|||||||||||||||||||||||||||
Arm title
|
COBRA-Slim Bio-induction | |||||||||||||||||||||||||||
Arm description |
Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
etanercept
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
|||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||||||||
Dosage and administration details |
50mg SC weekly for a period of 6 months
|
|||||||||||||||||||||||||||
Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial. [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard COBRA-Slim
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
COBRA-Slim Bio-induction
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Remission-induction
|
||
Reporting group description |
All 276 patients started with a COBRA-Slim remission-induction regimen. Patients who fail to reach low disease activity between week 8 and 32, or remission at week 32, were early insufficient responders and considered eligible for randomisation. Of the 276 patients who entered the trial, 264 reached the end of the remission-induction phase (week 32). Of these patients, 112 were considered early insufficient responders and randomised, however 2 of them were considered randomisation-error and excluded from analysis. Subsequently 110 patients started the proposed randomised treatment regimen and were considered for analysis. | ||
Reporting group title |
Standard COBRA-Slim
|
||
Reporting group description |
Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen. | ||
Reporting group title |
COBRA-Slim Bio-induction
|
||
Reporting group description |
Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen. |
|
|||||||||||||
End point title |
Area under the curve (AUC) of DAS28CRP over 104 weeks. | ||||||||||||
End point description |
Long-term effectiveness.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
104 weeks (Baseline (BL) until week 104)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Area under the Curve (AUC) over 104 weeks | ||||||||||||
Statistical analysis description |
To compare the two randomisation groups, a linear mixed model with DAS28-CRP as outcome (Bell et al. 2014), including random intercepts per patient, adjusted for baseline DAS28-CRP, randomisation timepoint, and RF and/or ACPA seropositivity was used. Superiority of COBRA-Slim Bio-induction compared to Standard COBRA-Slim in terms of disease control over 2 years could not be demonstrated (ß = -0.204, 95% CI [-0.486 to 0.078], p = 0.157).
|
||||||||||||
Comparison groups |
Standard COBRA-Slim v COBRA-Slim Bio-induction
|
||||||||||||
Number of subjects included in analysis |
110
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
|
||||||||||
End point title |
Proportion of insufficient responders achieving DAS28CRP remission 28 weeks after randomisation | |||||||||
End point description |
Short-time efficacy.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Randomisation until 28 weeks after randomisation.
|
|||||||||
|
||||||||||
Statistical analysis title |
short time efficacy | |||||||||
Statistical analysis description |
To obtain this outcome, a binomial generalized linear mixed effect model for repeated measures of remission from randomisation up until 28 weeks after was carried out, adjusted for baseline DAS28-CRP, moment of randomisation, and RF and/or ACPA seropositivity. Patients in the COBRA-Slim Bio-induction group had a significantly higher odds of reaching DAS28-CRP remission during 28 weeks after randomisation compared to the Standard COBRA-Slim group (Odds ratio 2.06 (95% CI 1.20-3.56), p=0.009).
|
|||||||||
Comparison groups |
Standard COBRA-Slim v COBRA-Slim Bio-induction
|
|||||||||
Number of subjects included in analysis |
110
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Confidence interval |
|
|||||||||||||
End point title |
Proportion of patients in remission (DAS28CRP<2.6) at week 104 | ||||||||||||
End point description |
Proportion of patients achieving DAS28CRP<2.6 at the end of the trial (week 104).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
week 104
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events were collected over a two year period per patient (BL-week 104).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
In the CareRA2020 trial, adverse events were collected if they were related to RA, the RA treatment, or in case of an event of special interest.
All adverse events were registered by health care professionals questioning the patients at each visit.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard COBRA-Slim
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
addition of leflunomide to the standard COBRA-Slim remission induction regimen | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
COBRA-Slim Bio-induction
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
addition of etanercept for 6 months to the standard COBRA-Slim remission induction regimen | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
11 Feb 2019 |
addition of 5 extra sites to the protocol |
||
13 May 2019 |
change in investigator at site 014 |
||
09 Jul 2019 |
addition of 1 extra site to the protocol |
||
17 Apr 2020 |
to add measurements to cover COVID19 pandemic |
||
19 Aug 2020 |
change in investigator at site005 |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |