Date: November 18, 2021
Prof. dr. H. Knoop, responsible for the ReCOVer research, Clinical psychologist, Professor, Department of Medical Psychology AMC – Academic Medical Center
Drs. Y. Jansen, Support Group ME and Disability
Mr. A. de Groot, lawyer, Group ME The Hague
Drs. L. Corsius, ME/CFS Association
This meeting takes place in response to the WOB (“FOI”) procedure in which the three patient organizations have requested information about the assessment and award by ZonMw of the subsidy application for the ReCOVer study. This conversation was planned as a spin off from that procedure.
The patient organizations warn against the possible consequences of the treatment for patients who suffer from a post-viral syndrome after COVID-19 which may lead to a worsening of complaints to such an extent that a very serious healthsituation can develop. The question is whether this has been taken into account in the research design and, if so, how will this be followed up.
Professor. Knoop indicates that there is a clear difference compared to CFS patients; the longcovid patients undergo treatment at a very early stage in contrast to CFS patients who are only treated after 5-6 years. The ReCOVer study is based on the hypothesis that early treatment by means of cognitive behavioral therapy (CBT) according to a specific protocol can prevent chronicity of the complaints.
Questions to Professor Knoop
Professor. Knoop’s answers are in italics and begin with (K).
1. The underlying idea for this particular CBT treatment is that thoughts and behavior perpetuate the disease. Part of the treatment protocol is that patients should not focus on their complaints, but should continue with a time-contingent increase of activities regardless of the complaints. This could mean that patients may not report worsening.
(K) That is not worded correctly. We ask patients to shift their focus. The risk of this treatment is small. Studies into the use of this treatment in other diseases largely demonstrate the efficacy of the treatment and show that there is no increased risk. The Medical Ethics Review Committee (METC) has also established this.
2. Is the treatment protocol available?
(K) The treatment protocol is not available. This has to do with two reasons: 1. The university has Intellectual Property (IP) on the protocol and only the university can and may determine what happens to it and 2. The treatment must first be tested in research. Otherwise, there is a risk that others will adopt the treatment that has not yet been studied because there are so few treatment options available for this patient group. (Mr Knoop does share the view that the results of the protocol and the protocol should be made available through eventual publications, even if research shows that the protocol has shortcomings or turns out to be unusable).
3. What is seen as deterioration in the study? In what terms are these adverse events described? Are dropouts followed up? Are the results of the actometer also taken into account?
(K) As adverse events, we register hospitalization and visits to a doctor and we have a questionnaire to inventory Postexertional malaise (PEM). The actometer plays no role in this.
4. The study design shows that actometry is not considered a primary or secondary outcome measure. Actometry does take place. What is done with the results of the actometer?
(K) The actometer is only used to divide the patients into an active group and a less active group prior to treatment.
We are seriously concerned about the possibility that you will not recognize deterioration, partly as a result of the fact that you do not use an objective outcome measure such as the actometer or objective data on labor participation.
5. It is known that measuring only subjective outcome parameters in such an open trial has a high risk for bias. Therefore, objective outcome parameters must be used also. How do you handle that?
(K) Why are patient organizations so obsessed with objective measures? Objective measures are subjective too. They depend on how you interpret them.
It is well known that the outcomes on subjective measures such as fatigue are directly influenced by the treatment (we have used the term ‘manipulated’ in the conversation).
(K) So you’re basically saying you don’t trust the outcomes reported by the patients themselves? How does that relate to the fact that you as a patient organization represent these patients while you do not take their answers seriously?
We take patients very seriously. But with regard to your research, we indicate that the treatment is aimed directly at influencing the patient’s thoughts about fatigue, the main outcome measure. That leads to bias.
(K) We have only subjective primary and secondary outcome parameters. In medical research, more and more researchers are moving away from objective outcomes and they are looking at what is relevant for the patient and how he feels. The outcome measurements we perform are in accordance with ZonMw’s decision.
In previous research, we have shown that there is no correlation between the objective and subjective outcome parameters.
Isn’t that a strong indication that there is bias in the subjective measurements?
6. What is the cut-off point for the primary outcome measure, the CIS-F, which represents fatigue? in other words when is the treatment considered effective?
(K) Treatment is considered effective if the post-treatment CIS-F score is less than 35 (correction april 2022) combined with at least 6 points change from the first measurement. A score equal to 35 or higher prior to treatment is the inclusion criterion. This is considered severely fatigued.
7. What are the results in the interim report to ZonMw? (i.e. the way of monitoring of deterioration and the results of that monitoring)
This is not mentioned in the interim report on the ZonMw website.
(K) We did include that in our report to ZonMw. They determine what is published on the website.
The patient representatives will contact the relevant ZonMw program manager about this.
We thank Mr Knoop for the conversation. We find that there is a big difference between his view and ours about the possible risks associated with the treatment and about the need to measure objective outcome measures too. We note that we are unable to reach an agreement and that we remain deeply concerned about the possibility that the ReCOVer study may fail to recognize a possible deterioration in patients as a result of treatment.
(End of report)
There is a big difference between Professor Knoop’s and our opinion about the possible beneficial effects and especially about the possible risks associated with treatment with this particular version of CBT and about the need to also measure objective outcomes. We note that we are unable to reach an agreement and that we continue to have serious concerns about the possibility that the ReCOVer study will fail to recognize possible deterioration of patients as a result of treatment. We expect that false positive results will be claimed.
We asked ZonMw about the interim report on ReCOVer and whether Professor Knoop has described the way in which any damage as a result of the treatment is measured and whether there has been any damage. This led to the following response by ZonMw: “The ReCOVer research project group has indeed answered and justified the relevant questions sufficiently. There are no indications for a decline in functioning in the intervention group.”