Clinical Trial Results:
The BRIDGE-PMR study: B-cell depletion with Rituximab for Dose reduction of Glucocorticoids: Efficacy in PolyMyalgia Rheumatica
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Summary
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EudraCT number |
2018-002641-11 |
Trial protocol |
NL |
Global end of trial date |
19 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Dec 2021
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First version publication date |
02 Dec 2021
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Other versions |
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Summary report(s) |
BRIDGE-PMR article |
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 |
BRIDGE-PMR
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Sint Maartenskliniek
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Sponsor organisation address |
Hengstdal 3, Nijmegen, Netherlands, 6500 GM
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Public contact |
Principal investigator, Sint Maartenskliniek, +31 0243659985, a.vandermaas@maartenskliniek.nl
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Scientific contact |
Principal investigator, Sint Maartenskliniek, +31 0243659985, a.vandermaas@maartenskliniek.nl
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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 |
14 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Aug 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Aug 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of rituximab, and explore whether it has a glucocorticoid-sparing effect, in recently diagnosed and relapsing patients with polymyalgia rheumatic
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Protection of trial subjects |
Monitoring and quality assurance was established following the advice of the NFU. Research conduct was according to WMO, WBP, WGBO, ‘richtlijn kwaliteitsborging mensgebonden onderzoek’, ‘code goed gedrag’, and ‘code goed gebruik’. The classification for risk was estimated negligible risk since there is a small chance of frequent and or serious adverse events. Therefore the monitoring consisted of the following:
- Frequency of one visit per year
- Check of rate of inclusion and dropout
- Investigator file: presence and completeness
- Check for written informed consent in 10% of participants
- Check for in- and exclusion criteria of the first 3 participants and 10% of the following
participants
- Verification of source data of 10% of the participants
- Check for missed SAE’s in 10% of the participants and verify reported SAE’s
- Check if the laboratory and the department of radiology are certified
- Monitoring was executed by a qualified monitor of the department of Research of the Sint Maartenskliniek Nijmegen, who has successfully attended the BROK-course or equivalent GCPII training.
- Monitoring frequency: at initiation and afterwards yearly of 5 patients per time
Although not formally obligated, a data safety monitoring board (DSMB) of independent professionals was installed to monitor study conduct, recruitment, AE reporting. The DSMB met every 3 months.
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Background therapy |
All patients received the same prednisolone treatment. A regular glucocorticoid tapering scheme was started with 15mg per day and than slowly tapered accorinding to local usual care protocol, which was accelerated after 11 weeks to stop at week 18. When a patient experienced a relapse after initial response (secondary non-responder), prednisolone was increased up to the last effective dose for 2 weeks and the accelerated tapering scheme was resumed when remission was reported again. If a second relapse occurred, the prednisolone dose was again increased to the last effective dose and after 2 weeks was subsequently tapered according to the slower, local usual care tapering scheme. In case of recurrence of disease after glucocorticoid cessation, prednisolone was reinitiated and subsequently tapered (accelerated approach or usual care depending on if it was the first or second relapse during the study). All patients received osteoporosis prophylaxis (alendronic acid 70 mg per week and calcium carbonate 500 mg plus colecalciferol 800 units). Use of non-steroidal anti-inflammatory drugs (NSAIDs) was permitted when necessary. | ||
Evidence for comparator |
Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoidsparing agents with a strong evidence base in polymyalgia rheumatica are absent. As polymyalgia rheumatica is not clearly associated with autoantibodies, it does not appear to be a typical B-celldriven disease. However, B cells are part of the inflammatory cascade and produce interleukin (IL)-6, which is involved in the pathogenesis of polymyalgia rheumatica. In addition, disturbed B-cell homeostasis was reported in patients with newly diagnosed, untreated polymyalgia rheumatica and giant cell arteritis (a large-vessel vasculitis associated with polymyalgia rheumatica), and there has been one case report of a patient with giant cell arteritis with polymyalgia rheumatica who was successfully treated with rituximab. Therefore, although not yet supported by strong evidence, B cells might have a pathophysiological role in polymyalgia rheumatica. Rituximab is a chimeric monoclonal antibody against CD20. There is sufficient clinical experience in other inflammatory rheumatic diseases to show that rituximab is well tolerated. Advantages of this drug include that it is safe, although rituximab can cause infusion-related side-effects and there is a dose-dependent risk of infection. | ||
Actual start date of recruitment |
03 Dec 2018
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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 |
Netherlands: 49
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Worldwide total number of subjects |
49
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EEA total number of subjects |
49
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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) |
26
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From 65 to 84 years |
23
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85 years and over |
0
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Recruitment
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Recruitment details |
Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled and randomly assigned. Patients from throughout the Netherlands were included. | |||||||||
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Pre-assignment
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Screening details |
Inclusion: 2012 EULAR/ ACR polymyalgia rheumatica classification, recently diagnosed and relapsers on prednisolone>7.5 mg. Glucocorticoid use over 30mg/ day, use of immunesuppressant drugs in the last 4 months, other rheumatic inflammatory diseases were important exclusion criteria. | |||||||||
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Period 1
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Period 1 title |
Baseline period (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
An independent pharmacist generated the randomisation scheme by computerised
procedure with varying block size (2 blocks of 20 participants, 1 block of 10). Treatment allocation was not revealed to patients until at least 1 year after infusion. Researchers were unmasked only after analyses of the primary efficacy outcome were completed. Rituximab and placebo were prepared by the local hospital pharmacy. It was impossible to discern between the two
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Rituximab | |||||||||
Arm description |
A single infusion of 1000 mg rituximab with premedication (single dose intravenous methylprednisolone 50 mg, oral paracetamol 1000 mg, and oral cetirizine 10 mg) | |||||||||
Arm type |
Experimental | |||||||||
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 concentrate for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
A single infusion of Rituximab (Rixathon, Sandoz, Holzkirchen, Germany; ATC code L01X C02) 500 mg concentrate for solution for infusion was given. Each 50 mL vial contains 500 mg of rituximab and was diluted in 500 mL in sodium chloride 0.9%. Premedication was given: single dose intravenous methylprednisolone 50 mg, oral paracetamol 1000 mg, and oral cetirizine 10 mg
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Arm title
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Placebo | |||||||||
Arm description |
A single intravenous infusion of placebo consisting of sodium chloride 0,9%, indiscernable from the rituximab infusion | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for concentrate for solution for infusion
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Routes of administration |
Concentrate for solution for infusion
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Dosage and administration details |
Placebo
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Baseline characteristics reporting groups
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Reporting group title |
Rituximab
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Reporting group description |
A single infusion of 1000 mg rituximab with premedication (single dose intravenous methylprednisolone 50 mg, oral paracetamol 1000 mg, and oral cetirizine 10 mg) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
A single intravenous infusion of placebo consisting of sodium chloride 0,9%, indiscernable from the rituximab infusion | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rituximab
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Reporting group description |
A single infusion of 1000 mg rituximab with premedication (single dose intravenous methylprednisolone 50 mg, oral paracetamol 1000 mg, and oral cetirizine 10 mg) | ||
Reporting group title |
Placebo
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Reporting group description |
A single intravenous infusion of placebo consisting of sodium chloride 0,9%, indiscernable from the rituximab infusion | ||
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End point title |
Glucocorticoid free remission | ||||||||||||
End point description |
Percentage of patients with glucocorticoid free remission at week 21 after RTX/PBO infusion , where remission was defined as PMR-activity score<10.
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End point type |
Primary
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End point timeframe |
21 weeks
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Statistical analysis title |
low dose glucocorticoid (5mg or less per day) | ||||||||||||
Statistical analysis description |
patients that achieved low dose glucocorticoid at week 21
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Comparison groups |
Placebo v Rituximab
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Number of subjects included in analysis |
47
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
46
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Confidence interval |
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95% | ||||||||||||
sides |
1-sided
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lower limit |
20 | ||||||||||||
upper limit |
- | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - one sided n=23 (100% in the rituximab group versus n=13 (54%) in the placebo group |
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Adverse events information [1]
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Timeframe for reporting adverse events |
During 21 weeks
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Adverse event reporting additional description |
Safety endpoints were any glucocorticoid-related and rituximab-related adverse events, graded according to Common Terminology Criteria for Adverse Events version 5.0. An elaborate assessment of glucocorticoidrelated toxicity was assessed at baseline, 11 and 21 weeks using the glucocorticoid toxicity index
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
common terminology | ||
Dictionary version |
5
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| Frequency threshold for reporting non-serious adverse events: 1% | |||
| 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: Please see the reference to the article for full publication of all adverse events |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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18 Apr 2019 |
the cutoff point of remission by the polymyalgia
rheumatica activity score, the classification criteria used
for study inclusion, the inclusion of not only glucocorticoidnaive
patients but also patients on short-term
glucocorticoid treatment, and the inclusion of relapsing
patient |
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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 | |||||||
