Many questions in healthcare are currently not sufficiently studied in clinical trials, despite their high societal importance (e.g. comparison between medication and surgery, between different surgical techniques, between lifestyle changes and a medical intervention, or questions addressing the needs of older people). 'Comparative effectiveness' studies compare two treatment options (with ‘no treatment’ being one of the possible treatment options) that are already in use in clinical practice in a given indication, but are not yet sufficiently directly compared (i.e. which of the two treatment options work best in daily practice). Since 2015, KCE is managing a national funding programme of such pragmatic practice-oriented clinical trials, the KCE Trials Programme. The annual budget is 9.5 € Million. To date, 34 clinical trials have been selected within this programme (see funded trials for more information on these trials or our dynamic dashboards for progress in recruitment).
KCE Trials has been commissioned by RIZIV/INAMI to fund a trial on fixed-duration daratumumab versus daratumumab until disease progression combined with lenalidomide and dexamethasone (DRd) in newly diagnosed multiple myeloma patients with at least a very good partial response. KCE Trials invites research teams who are willing to set up a clinical trial to answer this specific research question to submit their research proposals to this call.
Decision problem to be addressed by this research:
The recent publication of the MAIA trial results concluded on the benefit of adding daratumumab (D) to the lenalidomide and dexamethasone (Rd) combination in the improvement of the progression free survival (PFS) in newly diagnose multiple myeloma (NDMM) patients who are not eligible for autologous stem cell transplantation. However, no difference in overall survival benefit has yet been shown (follow-up still ongoing). In terms of response, in the DRd arm of the MAIA trial about 50% of the patients achieved at least a complete response (CR) and about 80% at least a very good partial response (VGPR). (Facon et al. N Engl J Med 2019;380:2104 and Kumar, ASH 2020, abstract 2276)
The majority of the MM patients will achieve their best response in the first 12 months of treatment with DRd and the current rational to treat until progression is to maintain the level of response by sustained control of the residual disease. Based on the current available data, it is not known if, after 24 cycles of daratumumab, continuation of daratumumab for the control of the residual disease is required or if maintenance with Rd alone would be sufficient. In elderly NDMM patients, the superiority of continuous versus fixed duration of Rd (for 18 months) on progression-free survival (but not on overall survival) has been already proven (Facon et al. Blood 2018;131:301). The optimal duration of treatment with DRd still needs to be explored.
Demonstrating non-inferiority of Rd maintenance alone versus DRd would provide:
1) Benefit to patients who will be treated by an oral therapy instead of continuous administrations of daratumumab (avoid extension with a SC medicine / less drugs/ less side effects). This trial could be a proof of concept/first attempt to compare the maintenance of full treatment till progression vs a less intensive approach and could potentially apply to other situations
2) Less expenditures for the health insurance (less expensive for same/similar efficacy results and better tolerability), at least on a short-term
3) Note that the costs for lenalidomide will be lower from mid-2021 due to patent cliff.
4) Patients can be re-administered daratumumab in case of disease progression
Who can submit to the 2021 Commissioned call?
Investigators who submit a research proposal outline should have the support of a non-commercial sponsor to perform the trial. Preferably, trials are conducted with the assistance of a clinical trial unit or equivalent.
Only multi-centre studies will be accepted. Participating centres should include at least one centre from each region (Flanders, Brussels, Wallonia), unless there is a good justification not to do so.
Participation of Belgian centres to an international non-commercial trial within the scope of this call, is also eligible for funding. In that case, the sponsor of the international trial should sign a commitment letter, confirming acceptance of the KCE Trials terms and conditions regarding a) the non-commercial nature of the trial and b) data sharing policy.
For international trials with a Belgian sponsor and with more than 10% of patients recruited abroad, participation of other funders in the sponsor and site costs will be required.
Is fixed duration of 24 injections of daratumumab equally effective as continuous administration when combined with lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients who achieve at least a very good partial response with this regimen?
Patient group: Patients with newly diagnosed multiple myeloma (CRAB criteria and measurable disease) not considered for stem cell transplantation (age ≥ 65 years, OR important comorbidity in patients under 65) who will be treated in first line for a minimum of 12 months with the lenalidomide, dexamethasone and daratumumab combination and who achieve at least a very good partial response (IMWG criteria). Patients need to have an estimated life expectancy of at least 6 months and an ECOG performance status of 2 or lower.
Intervention: Interruption of daratumumab after 24 administrations and continuation of treatment with lenalidomide and dexamethasone.
Control: Continuation of treatment with lenalidomide, dexamethasone, daratumumab until progression
Important outcomes: overall survival, Quality of life (including EQ5D-5L), time to progression
Study design: multicenter, randomized controlled trial
Inclusion criteria for the commissioned 2021 call on multiple myeloma
The primary aim of the study should be non-commercial (see Belgian law of May 7, 2004 related to experiments on human person).
The candidate sponsor should qualify as a non-commercial sponsor under the applicable laws, including the law of May 7, 2004 related to experiments on human person or equivalent e.g. if the sponsor is not located in Belgium.
The holder of the intellectual property rights on the studied intervention or comparator to which the experiment relates is neither directly nor indirectly the sponsor of the experiment.
The sponsor exercises the intellectual property rights to the concept of the experiment, its implementation and the scientific data resulting from it.
The agreement must comply with the European state aid regulations.
The specified research question is to be addressed.
A more detailed definition of inclusion and exclusion criteria, interventions and outcomes needs to be included in the submissions.
Studies for which recruitment has already started, or which have already been submitted to an ethics committee or to the FAMHP (Federal Agency for Medicines and Health products) are out of scope. International studies that have already started abroad are eligible if all other criteria are met.
Proposals without this implementation plan will be considered out of scope.
The goal of this call is to accept one of the submitted projects if the conditions are met. The following criteria will be taken into account during the prioritisation process: (see also annex I in Call text)
The quality of the study design and methodological rigour.
The feasibility of the submitted project.
The geographical spread of the participating centres is well balanced over the different regions.
The study budget is acceptable within the overall budget of KCE Trials.
You can find the complete call text here
How to submit
The call will be open to submissions from 1st June 2021 until 13h on 9th September 2021.
As a first step, candidates are asked to submit a research outline. Shortlisted candidates will be invited to submit a full research proposal (FRP) (with the study protocol) at a later stage.
We suggest to contact KCE Trials (trials”at”kce.fgov.be) in advance if you want to resubmit a proposal that was not selected in a previous call.
All submissions must be done using the KCE Trials online submission platform. To be able to submit, you have to create an account, if not yet done so. Please create an account as soon as possible and at least 1 week before the submission deadline to enable us to correct possible problems with the online submission platform. Once you have created the account, you can find information to start your submission under the “funding opportunities” tab.
You may prefer to prepare your application using the application form in Word format, which is available on the KCE Trials website for your convenience (no application submitted in the word template will be accepted). This document also contains guidance on how to complete your application.
Only the chief investigator can start an application and complete the submission. However, other members of the research team can help completing the application form if added to the contacts list. You are encouraged to contact your legal advisor, clinical trial unit or equivalent early in the process and give them also access to your application.
A detailed budget should be submitted using the dedicated budget tool, for which separate guidance notes are also available. It is advisable to complete the budget tool in collaboration with the clinical trial unit.
All documents for the submission are detailed below in the “ Links & downloads” section below.
To be deemed valid and to enter the selection process, a submission should:
Be written in English.
Be submitted through the online submission platform before the deadline.
Include details of chief investigator and candidate sponsor.
Include a sponsor support letter using the KCE Trials template or, for international trials with a non-Belgian sponsor, a support letter from the Belgian coordinating centre and a commitment letter signed by the international sponsor, using the applicable KCE Trials templates.
If there is any collaboration with a commercial partner (e.g. delivery of free/discounted medication, apps, medical devices etc.), a signed commitment letter from the commercial partner accepting the KCE Trials terms and conditions using the applicable KCE template or the contract should be included in the initial submission in order to assess the non-commercial nature of the trial. Simple purchasing on normal market condition does not require this signed commitment letter.
Include a clearly defined research question in the PICO format (Patients, Intervention, Comparator, Outcome).
Documents for trials with sponsor in Belgium
- 2021 Commissioned Call text (pdf) version 1.1, 04 June 2021 and Overview important dates (pdf) version 1.0, 21 May 2021
- Research application form including guidance (Word) version 1.0, 21 May 2021
- Budget tool (Excel) version 6.0, 15 May 2021 + guidance (pdf) version 6.0, 18 May 2021
- Template support letter candidate sponsor (Word) version 1.2, 10 May 2021
- Template commitment letter co-funder (Word) version 1.0, dated 11 May 2021
- Research agreement template (Word) version 5.1, 03 June 2021
- Protocol template for Full Research Proposal (Word) V2.2 13 Aug 2020
- Top ten tips and tricks for a successful research outline (pdf) version 3.1, 11 May 2021
- Patient involvement document (pdf) version 1.0, 12 May 2021
Documents for trials with international sponsor
Presentations from Strengthening Workshop (Call 2021) – 7th & 10th June 2021 can be found by following this link and scrolling to the bottom of the page
Contact and further information
For any questions, contact us at trials[@]kce.fgov.be