|- candidate number||4813|
|- NTR Number||NTR1605|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||24-dec-2008|
|- Secondary IDs||(2008/234)/NL24611.091.08/80-82310-98-09026 MEC/ABR/ZonMw|
|- Public Title||(English) Cost-effectiveness of new medicines (Mabthera and Orencia) compared to a second TNF blocking medicine, for patients with inadequate effect of a first TNF blocking medicine. |
(Dutch)Onderzoek naar de kosteneffectiviteit van nieuwe medicijnen (Mabthera en Orencia) vergeleken met een tweede TNF blokerend middel, voor patienten met onvoldoende effect van een eerste behandeling met TNF blokkerende middelen.
|- Scientific Title||The cost-effectiveness of abatacept, rituximab or anti-TNF alpha for patients with rheumatoid arthritis.
|- ACRONYM||Dutch Rheumatoid Arthritis Monitoring (DREAM) / Targeted Immune Modulator Evaluation (TIME) Trial|
|- hypothesis||It is hypothesized that rituximab and abatacept are non-inferior alternatives to a second TNF alpha inhibiting therapy, for patients who have been adequately treated with a first TNF inhibiting therapy with insufficient effect.|
|- Healt Condition(s) or Problem(s) studied||Rheumatoid arthritis|
|- Inclusion criteria||1. RA diagnosis according to ACR criteria;|
2. Having been treated adequately with one of the anti-TNF alpha agents with insufficient effects;
3. A moderate to high disease activity (DAS28 > 3.2).
|- Exclusion criteria||1. Former treatment with abatacept or rituximab;|
2. Patient's or physician's preference for one of the agents;
3. Contraindications for the use of one of the agents.
|- mec approval received||yes|
|- multicenter trial||yes|
|- control||Not applicable|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-jan-2009|
|- planned closingdate||31-mrt-2013|
|- Target number of participants||132|
|- Interventions||After having signed an informed consent form, patients will be randomly assigned to either rituximab, abatacept or second TNF alpha blocking therapy. Further treatment decisions are at the rheumatologists descretion, following daily clinical practice.|
|- Primary outcome||The primary clinical outcome is the mean of the DAS28 score measured at 6, 9 and 12 months follow-up. Furthermore costs (measured from a societal perspective), and quality adjusted life years (measured using utilities generated by the Euroqol 5D), over the first 12 months are additional primary outcomes.|
|- Secondary outcome||Secondary outcomes are the health assessment questionnaire, the short-form 36, time to failure and the percentage of patients crossing over to another treatment.|
|- Timepoints||Before the start of treatment patients will undergo a baseline assessment. According to daily clinical practice patients will be assessed each 3 months. Patients will be followed for a minimum of one year.|
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||dr. W. Kievit|
|- CONTACT for SCIENTIFIC QUERIES||Prof. dr. P.L.C.M. Riel, van|
|- Sponsor/Initiator ||University Medical Centre Sint Radboud, Department of Rheumatology |
(Source(s) of Monetary or Material Support)
|ZON-MW, The Netherlands Organization for Health Research and Development|
|- Brief summary||Objective(s): |
To compare the cost-effectiveness from a societal perspective of three treatment options, abatacept, rituximab or a anti-TNF alpha agent, for patients with rheumatoid arthritis who failed at least one anti-TNF alpha agent. Simultaneously, this study will provide data on the use of these medications in detail with regard to doses, frequencies and patient population in daily clinical practice.
We propose, following upcoming guidelines about expensive inpatient pharmaceuticals, a pragmatic randomized trial. To prevent confounding by indication, all patients are being randomized to start treatment either with abatacept, rituximab or an anti TNF alpha agent. Thereafter, the treatment strategy will be at the discretion of the attending rheumatologist meaning that the rheumatologist is free to change treatment.
patients are included in the study when the rheumatologist has the intention to change treatment because of failure on an anti-TNF alpha agent.
a treatment with abatacept, rituximab or an anti-TNF alpha agent.
Primary outcomes are the mean of the DAS28 score measured at 6, 9 and 12 months follow-up, quality adjusted life years and societal costs over 12 months.
Secondary outcomes are the health assessment questionnaire, the short-form 36, time to failure and the percentage of patients crossing over to another treatment.
Sample size calculation/data analysis:
Assuming a equivalence margin of 0.3 DAS28, 80% power and 10% drop-out, 87 patients are needed in each group to prove statistical equivalence between all treatment strategies. Analysis of covariance will be performed on all continuous outcome measures adjusting for baseline levels.
Two types of incremental cost-effectiveness ratios will be calculated, namely the additional costs per point DAS28 reduction and the additional costs per QALY gained.
This proposed study granted by ZonMw will then take place from January 2009 till December 2011. The one and a half year will be spend on an patients inclusion and data collection. Data collection will be proceeded for one other year. The last half year will be spend on data analysis and reporting of the results. At that time of analyses the minimum follow-up time will be 12 months and the maximum follow-up time will be two and a half years.
|- Main changes (audit trail)||Amendment to original DREAM Time study protocol concerning power calculation.
To date, 101 patients have been included into the study. One patient has stopped due to metastasized cancer. Thirty-five patients have been randomized to rituximab, 33 to abatacept and 32 to a TNF alpha blocking agent. Due to an unexpected low inclusion rate, we are forced to adjust the sample size calculation. If an equivalence margin of 0.4 (instead of 0.3) on the DAS28 is accepted with a power of 80% and a drop-out rate of 10%, we would need 44 patients per group (instead of 79) to proof that the three treatment arms are statistically equivalent.
The Figure shows the relation between several possible equivalence margins and the required sample size with a power of 80%. To decrease the equivalence margin from 0.4 to 0.3 we need a disproportionate number of extra patients. We havenít realized this enough while writing the protocol. An equivalence margin of 0.4 is still below the threshold of what is thought to be a clinically relevant difference of the DAS28 (equals 0.6) and is smaller that halve of the standard error in the population (equals 1.2).
We expect to finish inclusion in March 2012. We can finalize the analyses from March 2013 on because 1 year FU is required for analyses.
This amendment is approved by the funding agency at September 22, 2011 and by the local ethics committee at February 2, 2012.
|- RECORD||24-dec-2008 - 14-feb-2012|