Clinical Trial Results:
SWITCH: Randomised-controlled trial of switching to alternative tumour-necrosis factor (TNF)-blocking drugs or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-blocking drug.
Summary
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EudraCT number |
2010-023880-17 |
Trial protocol |
GB |
Global end of trial date |
23 Nov 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Jul 2018
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First version publication date |
07 Jul 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RR10/9589
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Additional study identifiers
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ISRCTN number |
ISRCTN89222125 | ||
US NCT number |
NCT01295151 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Leeds
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Sponsor organisation address |
Hyde Terrace, Leeds, United Kingdom, LS2 9LN
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Public contact |
Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk
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Scientific contact |
Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Dec 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Nov 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Nov 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To compare alternative-mechanism-TNF-inhibitor and abatacept to rituximab in terms of disease response, quality of life, cost-effectiveness, and toxicity and safety over a 12 month period.
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Protection of trial subjects |
The randomised treatments in the study are all licensed having demonstrated health benefits with well characterised safety profiles. In addition, in order to be eligible for the trial patients must have already have been established on a biological therapy. Patients were monitored closely throughout the trial and were asked to attend regular outpatient appointments.
CTRU prepared annual safety reports containing anonymised data to the MHRA, main REC and sponsor. The Data Monitoring and Ethics Committee reviewed un-blinded periodic safety data to determine patterns and trends of events or to identify safety issues which would not be apparent on an individual case basis.
Trial data was collected on paper CRFs and was sent to CTRU where it was entered into a trial database application - MACRO. The database is stored on a private network protected by a firewall. Access is restricted to staff working on the trial by login and password. The trial data was then filed in locked filing cabinets.
CTRU comply with all aspects of the Data Protection Act 1998. All information collected during the trial has been kept strictly confidential. Patient names were collected on the Consent Form and sent to CTRU and patients were informed in the Patient Information Sheet that their names were processed this way. For all other data collection forms that were transferred to or from CTRU, the data was coded with a trial number, the patients initials and date of birth.
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Background therapy |
All participants were required to be on a stable dose of methotrexate for 4 weeks prior to the screening visit and were expected to continue on this therapy for the duration of the study. Interruption of dose was permitted however. The protocol indicated participants would receive standard folic acid as per local policy. In addition, methylprednisolone was administered intravenously at a dose of 100mg prior to each rituximab infusion. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Jul 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 122
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Worldwide total number of subjects |
122
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EEA total number of subjects |
122
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
90
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From 65 to 84 years |
32
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85 years and over |
0
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Recruitment
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Recruitment details |
Between July 2012 and December 2014, 678 patients were pre-screened for the trial across 35 centres. Of these, 149/678 patients appeared suitable for and consented to pre-randomisation tests to confirm eligibility. Of these, 122/149 patients were confirmed eligible, maintained their consent, and proceeded to randomisation. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Of the 678 patients screened 529 patients were excluded pre-registration. 417 failed to meet the eligibility criteria. The main reasons were: had not failed an initial TNFi agent (95 patients), were not on a stable dose of methotrexate over the over the previous 28 days (92) and had received more than one TNFi drug or other biological agent (72) | ||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
678 [1] | ||||||||||||||||||||||||||||||||||||
Number of subjects completed |
122 | ||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Declined to consent (pre-consent): 90 | ||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Other reason for non-registration (pre-consent): 22 | ||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Ineligible to be randomised (pre-consent): 417 | ||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Ineligible to be randomised (post-consent): 19 | ||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Other reason for non-randomisation (post consent): 6 | ||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Withdrew consent (post-consent): 2 | ||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: "Numbers started pre-assignment period" is the total number considered for enrolment, including those that were not approached due to being clearly ineligible, those that did not consent to trial specific tests, those that consented to tests, but were not randomised, and those that were randomised. "Worldwide number enrolled" is the number of patients randomised and took part in the SWITCH trial. |
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
N/A
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Alternative mechanism TNFi | ||||||||||||||||||||||||||||||||||||
Arm description |
a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion) | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Etanercept
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Etanercept was administered at either a dose of 50mg by subcutaneous injection per week or as two 25mg injections per week for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24, treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.
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Investigational medicinal product name |
Adalimumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled pen, Solution for injection/infusion, Solution for injection/infusion in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Adalimumab was given at a dose of 40mg by subcutaneous injection every 2 weeks for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.
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Investigational medicinal product name |
Certolizumab Pegol
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Certolizumab pegol was given at a dose of 400mg by subcutaneous injection at weeks 0, 2, 4 and then at a dose of 200mg every 2 weeks thereafter for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 200mg every 2 weeks regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.
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Investigational medicinal product name |
Golimumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection, Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Golimumab will be given at a dose of 50mg by subcutaneous injection every 4 weeks for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.
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Investigational medicinal product name |
Infliximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Infliximab was given at a dose of 3mg/kg per intravenous infusion. The intravenous infusions were administered at week 0, 2 (+/- 2 days), 6 (+/- 2 days) and then 8-weekly thereafter (+/- 7 days) for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 8-weekly regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.
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Arm title
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Abatacept | ||||||||||||||||||||||||||||||||||||
Arm description |
Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
abatacept
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Abatacept was given at a dose of 125 mg by subcutaneous injection at week 0 and once weekly thereafter for a minimum of 24 weeks. For participants who are responding to treatment at week 24 treatment will continue following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.
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Arm title
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Rituximab | ||||||||||||||||||||||||||||||||||||
Arm description |
Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary. | ||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at days 0 (week 0) and 15 (week 2; +5 days).
In line with standard practice, a participant who loses an initial 6 month (week 24) response as per NICE guidance may receive a further cycle of rituximab after a minimum of 6 months following the first dose. The second cycle of rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at a 2 week interval (+5 days) e.g. week 24 and 26 (+5 days).
Subsequent treatment following week 48 will be at the discretion of the treating clinician. Prior to receiving rituximab, intravenous methylprednisolone 100mg will also be given.
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Baseline characteristics reporting groups
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Reporting group title |
Alternative mechanism TNFi
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Reporting group description |
a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Abatacept
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Reporting group description |
Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituximab
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Reporting group description |
Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention-to-treat
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Subject analysis set type |
Intention-to-treat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients randomised
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Subject analysis set title |
Per-protocol population
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Subject analysis set type |
Per protocol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received
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End points reporting groups
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Reporting group title |
Alternative mechanism TNFi
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Reporting group description |
a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion) | ||
Reporting group title |
Abatacept
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Reporting group description |
Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb. | ||
Reporting group title |
Rituximab
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Reporting group description |
Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary. | ||
Subject analysis set title |
Intention-to-treat
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients randomised
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Subject analysis set title |
Per-protocol population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received
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End point title |
Absolute reduction in DAS28 at 24 weeks post randomisation | ||||||||||||||||
End point description |
Endpoint description:
DAS28 is a measure of disease activity in RA. The composite score is calculated as a function of the number of tender and swollen joints (total 28 joints), the erythrocyte sedimentation rate (ESR) and the patient’s global assessment of their arthritis measured
- Tender Joint Count (TJC: Range 0-28)
- Swollen Joint Count (SJC: Range 0-28)
- Erythrocyte Sedimentation Rate (ESR: Range 0-99)
- Patient-completed Visual Analogue Scale of Global Assessment of Arthritis
With these four items, the DAS28 score is calculated in the following manner:
DAS28=(0.56×√TJC)+(0.28×√SJC)+(0.7×log[e] ESR)+(0.014×VAS(mm))
Where log[e] is the natural logarithm function.
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End point type |
Primary
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End point timeframe |
Baseline to 24 weeks post randomisation
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Notes [1] - Prior to multiple imputation of missing values, 36/41 patients had complete data at weeks 0 and 24. [2] - Prior to multiple imputation of missing values, 34/41 patients had complete data at weeks 0 and 24. [3] - Prior to multiple imputation of missing values, 32/40 patients had complete data at weeks 0 and 24. |
|||||||||||||||||
Statistical analysis title |
Primary endpoint analysis (ITT - TNFi vs RTX) | ||||||||||||||||
Statistical analysis description |
Mixed-effects linear regression model. Outcome: Reduction in DAS28 between Weeks 0 and 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects) and randomising centre (random effect). Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. Non-Inferiority concluded if 95% CI lies wholly above NI margin of -0.6.
|
||||||||||||||||
Comparison groups |
Alternative mechanism TNFi v Rituximab
|
||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
non-inferiority [4] | ||||||||||||||||
P-value |
= 0.0094 [5] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.3
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.45 | ||||||||||||||||
upper limit |
1.05 | ||||||||||||||||
Notes [4] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval judged in relation to margin. If 2-sided interval lies wholly above -0.6, NI conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population. [5] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol population P-value=0.489; non-inferiority to rituximab not demonstrated |
|||||||||||||||||
Statistical analysis title |
Primary endpoint analysis (ITT - ABT vs RTX) | ||||||||||||||||
Statistical analysis description |
Mixed-effects linear regression model. Outcome: Reduction in DAS28 between Weeks 0 and 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects) and randomising centre (random effect). Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. Non-Inferiority concluded if 95% CI lies wholly above NI margin of -0.6.
|
||||||||||||||||
Comparison groups |
Abatacept v Rituximab
|
||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
non-inferiority [6] | ||||||||||||||||
P-value |
= 0.0493 [7] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.04
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.72 | ||||||||||||||||
upper limit |
0.79 | ||||||||||||||||
Notes [6] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval for (abatacept - rituximab) judged in relation to margin. If 2-sided interval lies wholly above -0.6, Non-inferiority conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population. [7] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol Population P-value=0.216; non-inferiority to rituximab not demonstrated. |
|
|||||||||||||||||||||
End point title |
ACR20 Response at 24 weeks | ||||||||||||||||||||
End point description |
The ACR20 (American College of Rheumatology) response criterion is a composite endpoint. To achieve response, a patient must achieve between baseline and 24 weeks:
20% reduction in Tender Joint Counts and 20% reduction in Swollen Joint Counts and 20% reduction in 3 of the following 5 criteria:
Patient-completed Pain VAS (Range 0-100mm)
Patient-completed general health VAS (Range 0-100mm)
Patient-completed assessment of disability (HAQ-DI, Range 0-3)
Physician-completed assessment of disease activity (Range 0-100mm)
Either C-reactive Protein or Erythrocyte Sedimentation Rate measure.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
From baseline to 24 weeks.
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [8] - Prior to multiple imputation of missing values, 36/41 patients had complete data for ACR Response. [9] - Prior to multiple imputation of missing data, 35/41 patients had complete data for ACR20 Response. [10] - Prior to multiple imputation of missing data, 37/40 patients had complete data for ACR20 Response. |
|||||||||||||||||||||
Statistical analysis title |
ACR20 Response at 24 weeks (ITT - TNFi v RTX) | ||||||||||||||||||||
Statistical analysis description |
Fixed-effects logistic regression model. Outcome: ACR20 Response at week 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects). Randomising centre not fitted due to non-convergence. Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. ITT analysis population.
|
||||||||||||||||||||
Comparison groups |
Alternative mechanism TNFi v Rituximab
|
||||||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.15 [11] | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
2.06
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.77 | ||||||||||||||||||||
upper limit |
5.53 | ||||||||||||||||||||
Notes [11] - 2-sided P-Value for null hypothesis that ACR20 response rates at 24 weeks are equal. |
|||||||||||||||||||||
Statistical analysis title |
ACR20 Response at 24 weeks (ITT - ABT v RTX) | ||||||||||||||||||||
Statistical analysis description |
Fixed-effects logistic regression model. Outcome: ACR20 Response at week 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects). Randomising centre not fitted due to non-convergence. Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. ITT analysis population.
|
||||||||||||||||||||
Comparison groups |
Abatacept v Rituximab
|
||||||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.736 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
1.19
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.44 | ||||||||||||||||||||
upper limit |
3.21 |
|
|||||||||||||||||
End point title |
DAS28 Score | ||||||||||||||||
End point description |
For a description of the derivation of the DAS28 score, please refer to description given under Primary Endpoint.
NB: Values of mean and Std dev given here are at Week 48.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to 48 weeks. Measured at baseline, weeks 12, 24, 36 and 48.
|
||||||||||||||||
|
|||||||||||||||||
Notes [12] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints. [13] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints. [14] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints. |
|||||||||||||||||
Statistical analysis title |
DAS28 Score (ITT TNFi vs RTX) | ||||||||||||||||
Statistical analysis description |
Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.338 (24weeks), P=0.071 (36 weeks), P=0.552 (48 weeks).
|
||||||||||||||||
Comparison groups |
Alternative mechanism TNFi v Rituximab
|
||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.249 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-0.39
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-1.04 | ||||||||||||||||
upper limit |
0.27 | ||||||||||||||||
Statistical analysis title |
DAS28 Score (ITT - ABT vs RTX) | ||||||||||||||||
Statistical analysis description |
Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.976 (24weeks), P=0.871 (36 weeks), P=0.755 (48 weeks).
|
||||||||||||||||
Comparison groups |
Abatacept v Rituximab
|
||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.859 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.06
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.59 | ||||||||||||||||
upper limit |
0.71 |
|
|||||||||||||||||||||
End point title |
DAS28 Response | ||||||||||||||||||||
End point description |
Response defined as the achievement of a reduction in DAS28 of 1.2 or more (ie a change of -1.2 or less) since baseline.
NB: The reported number of patients responding given here are for Week 48.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to 48 weeks. DAS28 measured at baseline, 12, 24, 36 and 48 weeks.
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [15] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints. [16] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints. [17] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints. |
|||||||||||||||||||||
Statistical analysis title |
DAS28 Response over 48 weeks (ITT - TNFi vs RTX) | ||||||||||||||||||||
Statistical analysis description |
Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for
interaction between trt-time are P=0.116 (24weeks), P=0.327 (36weeks), P=0.699 (48weeks).
|
||||||||||||||||||||
Comparison groups |
Alternative mechanism TNFi v Rituximab
|
||||||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.543 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
1.4
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.47 | ||||||||||||||||||||
upper limit |
4.19 | ||||||||||||||||||||
Statistical analysis title |
DAS28 Response over 48 weeks (ITT - ABT vs RTX) | ||||||||||||||||||||
Statistical analysis description |
Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for
interaction between trt-time are P=0.930 (24weeks), P=0.888 (36weeks), P=0.675 (48weeks).
|
||||||||||||||||||||
Comparison groups |
Abatacept v Rituximab
|
||||||||||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.869 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
0.91
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.3 | ||||||||||||||||||||
upper limit |
2.73 |
|
|||||||||||||||||
End point title |
HAQ-DI | ||||||||||||||||
End point description |
HAQ-DI questionnaire (See: Pincus T, Summey JA, Soraci SA, et al. Assessment of patient satisfaction in activities of daily living using a modified stanford health assessment questionnaire. Arthritis & Rheumatism. 1983;26(11):1346-53.). Patients respond to 20 questions across 8 domains relating to physical function, and the need for any help or aids to undertake daily activities. The extent of disability is scored from 0 (no disability) to 3 (severe disability) for each item relating to rising, dressing, walking and other activities. The use of help or aids increases the category score from 0 or 1 to a 2. If the category score is already a 2 or 3, no adjustment is made. The total score is derived by taking the maximum score across all domains and dividing by 8 to provide an average score in the range 0-3.
NB: the median and IQR given here corresponds to Week 48
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
HAQ-DI questionnaire completed by the patient at baseline and weeks 12, 24, 36, 48.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
RAQOL | ||||||||||||||||
End point description |
See de Jong Z, van der Heijde D, McKenna SP, Whalley D. The reliability and construct validity of the RAQoL: a rheumatoid arthritis-specific quality of life instrument. Rheumatology. 1997 August 1, 1997;36(8):878-83.
Thirty item questionnaire, each item having a Yes (score as 1) / No (score as 0) response to ascertain the extent of rheumatoid arthritis symptoms experienced, maximum score 30.
NB: the median and IQR given here corresponds to Week 48
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and weeks 12, 24, 36, 48.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information [1]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All AEs/ARs and SAEs were monitored from randomisation until a minimum of 30 days* post last dose of randomised treatment during the interventional phase (week 48 max). Monitoring for SARs and SUSARs continued during the observational phase (week 96 max).
|
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Adverse event reporting additional description |
At each clinical assessment visit (weeks 12, 24, 36, 48) patients were asked to reported adverse events. Serious Adverse Events, Serious Adverse Reactions and Suspected Unexpected Serious Adverse Reactions were subject to expedited reporting.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alternative TNFi
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All participants randomised to receive alternative TNFi. One participant was withdrawn prior to receiving any IMP due to eligibility randomisation, this patient reported no Adverse Events. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Abatacept
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All participants randomised to abatacept. All participants received at least one injection of abatacept. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituximab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All patients randomised to receive rituximab. All participants received at least one infusion of rituximab. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed. |
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||
Substantial protocol amendments (globally) |
|||||||
Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
01 Mar 2012 |
Inclusion of the option for subcutaneous IMPs to be sourced and delivered to participants homes by a third party home healthcare providers as per local hospital practice. |
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01 Mar 2012 |
Amendment from intravenous formulation of abatacept to subcutaneous formulation following agreement from manufacturers of abatacept to provide trial supplies. This also required changes to other documentation to i) include a further vendor responsible for packaging and labelling of the abatacept trial supplies and ii) amend wording on the labels for sub-cutaneous abatacept. |
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06 Mar 2012 |
Wording added to the label for subcutaneous abatacept as requested by Bristol Myers Squibb (the manufacturers of abatacept). |
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29 May 2012 |
Addition of Almac Limited as the responsible party for the packaging, labelling and batch release of abatacept. Also, addition of trial identifier (the word 'SWITCH') to the already approved label for abatacept. |
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15 May 2013 |
Clarification included in the proptocol that where local practice indicates the use of a home healthcare provider for the delivery of subcutaneous IMPs, the trial procedures will map onto the established, standard care practices in place at each individual site in terms of services and record keeping and retention requirements. |
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09 Oct 2013 |
Approval was obtained for a letter to provide to participants that explained a discrepancy between the expiry date given on the internal and external packaging of abatacept. Amendment was submitted to ethics committee only as competent authority |
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09 Oct 2013 |
Addition of a Patient Advert designed to advertise the trial directly to patients, with the intention that sites display the patient advert in patient waiting rooms etc. In addition, information contained within the advert was intended to be used via various means e.g. patient websites, e-bulletins, social media for the purpose of advertising the trial to the wider rheumatoid arthritis community. Submitted to Main Research Ethics Committee only as related only to information to be provided to the participant. |
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10 Dec 2013 |
Addition of golimumab to alternative mechanism TNFi arm following feedback from sites that use of golimumab was becoming more commonplace and therefore the ability to use this may expand the field of potential patients/increase pragmatism of study/would reflect standard practice more closely. |
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10 Dec 2013 |
Modification of the primary endpoint from a dichotomous endpoint (whether or not the patient achieved a reduction of greater than 1.2 units in DAS28 with no toxicity) to a continuous endpoint (change in DAS28 score). |
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02 May 2014 |
R&D form amended to enable the use of Participant Identification Centres in order to identify further participants. Submitted to Main Research Ethics Committee only. |
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16 May 2014 |
Corrections of errors noted in the Research Ethics Committee form and the Patient Information Sheet relating to the amount of radiation patients would be exposed to as part of the imaging aspects of the study. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet. |
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08 Aug 2014 |
A Participant Information Summary Sheet was created to summarise and complement the main Participant Information Sheet & Informed Consent Document before the patient reads the main Participant Information Sheet and Informed Consent Form following feedback from patient and public involvement representatives that the current Participant Information Sheet and Informed Consent Form was lengthy and a supplementary summary sheet would be beneficial. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |