(Cognitive behavioral therapy in longCovid)
January 17, 2022
Introduction
In July 2020, ZonMw awarded a grant of €308,000 to Professor Knoop of the Dutch Knowledge Center for Chronic Fatigue (NKCV) for research into the efficacy of iCBT (cognitive behavioral therapy via the Internet) in patients with longCOVID (ReCOVer). This research proposal has been qualified as “very relevant” and “of very good quality”. As representatives of the Group ME Den Haag, the Steungroep ME en Arbeidsongeschiktheid and the ME/cvs Vereniging participating in the ZonMW ME/CFS biomedical research agenda steering committee, we had serious questions about this decision.
After discussions with ME/CFS program managers and the program managers of ZonMw’s Covid-19 program, we submitted a request based on the Dutch legislation (Wet Openbaarheid Bestuur), similar to an FOI request, to obtain more clarity about the process that led to awarding a €308.000 grant to the ReCOVer study). At the same time, our goal was to prevent that in the future grants will be awarded to a treatment that is not based on scientific knowledge about the nature and cause of the disease, but on the assumption that the patient maintains his own fatigue through unhelpful thoughts and wrong behaviour. The treatment in the ReCover study has the same principles as ‘CBT for CFS’. The British NICE has determined that the quality of the scientific evidence for this treatment is low to very low. It is also clear from Dutch and foreign patient surveys that this form of CBT does not help the majority of patients and leads to deterioration in a considerable number of patients. We aim to prevent this for longCOVID patients too.
In retrospect we provide an overview of the steps taken. A number of questions have remained unclear, such as:
Who were the 3 reviewers,
What is their background and
How did the program committee ultimately come to the judgement “very good quality” and “very relevant”.
Looking back
The ReCOVer study started in October 2020, led by professor J.A. Knoop of the Knowledge Center for Chronic Fatigue in The Netherlands (NKCV). The research protocol can be found here . This study investigates whether early treatment of longCOVID patients using cognitive behavioral therapy via the Internet (or possibly live) can lead to a significantly lower fatigue score. As the registration of the study describes: “This intervention is based on the cognitive-behavioural model of fatigue, stating that disease and/or its treatment initially triggers fatigue while cognitive-behavioural variables perpetuate fatigue”.
The research is subsidized by ZonMw. The processing of the subsidy application took place in the period May-July of the year 2020
We were surprised that ZonMw is subsidizing this research. After all, we know that cognitive behavioral therapy (CBT), based on the assumption that the complaints are maintained by thoughts and behaviour, usually does not help in ME patients and can even lead to damage. This has recently been reaffirmed in the new UK NICE guideline for ME/CFS. The recommendation to offer cognitive behavioral therapy as a curative treatment was abandoned because the evidence for the effectiveness of that treatment is low to mostly very low. Part of this specific type of CBT that is based on the cognitive-behavioral model of fatigue is a time-contingent build-up of activities. Time contingent means building up activity without taking into account any increase in complaints. This is called Graded Activity or Graded Exercise Therapy (GET). The NICE guidelines state that GET should not be used in ME/CFS and warn against any form of treatment that includes this time-contingent activity build-up. In addition to a lack of evidence, the experience that this treatment can lead to health damage is also an important consideration.
On behalf of the Groep ME Den Haag, de Steungroep ME en Arbeidsongeschiktheid en de ME/cvs Vereniging, we warn against the possible consequences of such treatment in patients with a post-viral syndrome after a COVID-19 infection. We are referring to the CBT/GET treatment that can potentially lead to serious worsening of complaints. Some of those patients have to deal with a disease that resembles ME.
Our questions to the program managers
We asked the program managers for biomedical research ME/CFS and Covid-19 at ZonMw how it could have been possible that the study proposal has been judged to be highly relevant and of very good quality, while it is known that an open trial like this, in which the researchers and those studied know which treatment is used, with only subjective outcome measures is known for a very high riskof bias and that therefore objective outcomes must also be measured. Knowing what treatment is being given to a patient can influence their response to treatment. A patient who knows that he is receiving a new drug that will be evaluated may have an a priori positive attitude towards this treatment and thus will report a better therapeutic response, especially when it comes to more subjective outcome measures. Patients tend to be nice to their therapist and therefore describe the results of the treatment more positively (‘pleasing the doctor’). And if patients are taught during treatment that they should not focus on their fatigue and should not think and talk about it, they will probably give their fatigue a lower score in a questionnaire, without anything actually having improved. Patients entering the control group may feel disadvantaged, which can affect their scores.
We also asked whether the study design took into account the risk of damage as a result of the treatment and, if so, how this will be investigated. We have been in contact with ZonMw about this subject by telephone and e-mail. Our letter of 3 September 2020 to the ZonMw program manager below reflects the core of the discussion.
Letter to ZonMw programm manager
Dear Mrs (…)
Thank you for the explanation in response to our questions about the grant awarded to Professor Knoop for ReCOVer, Can cognitive behavioral therapy via the internet prevent fatigue symptoms of COVID-19 patients from becoming chronic? A controlled and randomized study
project number: 10430012010025.
First of all, a response to what you wrote:
“We know and respect your views on Cognitive Behavioral Therapy (CBT) as an intervention in the treatment of chronic fatigue in ME/CFS. ZonMw has consistently shown this.”
It is not about ‘opinions about CBT’, it is about scientifically proven facts and systematically inventoried experiences of many patients at home and abroad. It is to ZonMw’s credit that it shows respect for the factual scientific findings; it’s not about accommodating us or doing us a favor. The ZonMw project of the ME/CFS research agenda arises from the recommendations from the GR (Dutch Health Council) report of March 2018 and the order of parliament and the minister, not from what we would like to see.
‘But that does not mean that ZonMw must reject all research questions relating to CBT from now on’.
That is a rather short-sighted view of what we stand for. It is a widespread misconception that ME patients are basically dismissive of CBT (and GET) as an intervention. ME patients are opposed to any intervention that has been shown to worsen symptoms and complaints, and ZonMw should do the same. It seems to us that would be a moral obligation. ME patients also reject the specific CBT treatment for CFS according to the protocol of Prof. Knoop and the NKCV. This is based on an incorrect, refuted hypothesis about the nature of the disease. The treament contains a structured build-up of activities in which the increase in complaints must be ignored. In addition, ‘CBT for CFS’ is recommended as a curative treatment, while the majority of patients do not improve or even worsen (we have included an appendix reviewing the methodological quality of the studies on CBT for CFS and its bias).
ME patients are aware of the fact that CBT in general (i.e. not according to the procotol ‘CBT for CFS’) can be supportive to some in coping with a chronic illness. At the same time, your sentence implies that ZonMw does indeed have the authority to reject an application on medical-scientific grounds. Without being sufficiently aware of the scientific controversy surrounding the research into ‘CBT in CFS’ and the patient experiences with this treatment, Prof. Knoop’s proposal cannot be properly assessed. As far as we know, it is ZonMW’s responsibility and authority to engage the appropriate reviewers.
More and more publications show the analogy between a post-viral syndrome after COVID-19 and ME. No research has yet been conducted into PEM/PENE in a post-viral syndrome after COVID-19. We would like to warn against the consequences of experiments in patients who suffer from a post-viral syndrome after COVID-19 and who may suffer from aggravation of complaints to such an extent that a very serious disease can develop. Thus, experiments are underway with possible harmful consequences known in advance. The question is whether this has been taken into account in the research design and, if so, how this will be followed up.
We would like to receive the text of the relevant grant application and the research protocol, how was it handled procedurally.
Which committee handled the application?
How was the committee formed?
How is it determined that the committee members do not have a COI?
Who performed the peer review?
What is the committee’s positive opinion based on?
What is the subsidy amount?
We assume that all this has been done in an open and transparent manner.
Thanks in advance,
On behalf of Groep ME Den Haag, Rob Wijbenga
On behalf of the Steungroep ME en Arbeidsongeschiktheid, Ynske Jansen
On behalf of the ME/cvs Vereniging, Lou Corsius
End of letter
WOB request
According to the Dutch legislation (WOB), we then requested data regarding the processing of the subsidy application. Our aim was to draw attention to the problems with this kind of treatment in the future and to prevent patients from undergoing an ineffective and potentially harmful treatment.
We have received data in response to the WOB request. These data are public and have been added as Appendix 1. However, a number of questions we asked were not clarified, not on paper and not during the discussion we had with 3 program managers of the MEC/CFS research program and the COVID-19 program, the department head and a lawyer, all from ZonMw. This concerns in particular the question how it has been possible that the program committee has given this positive assessment, who were the reviewers and what is their background? Were they aware of the developments regarding CBT/GET in ME/CFS and QFS?
ZonMw does not disclose a part of the information, and that includes the names of the reviewers. Because we consider this information to be of great importance, we have submitted an objection (see appendix 2.). The hearing of the objections committee took place in June 2021, in which Professor Knoop also participated.
We wanted to avoid turning our request and our objection into a legal matter because we are concerned about the scientific content. That is why we agreed during that session that we would have another meeting with the program managers at ZonMw ànd that we would have a meeting with Professor Knoop. The conversation with Professor Knoop was to aim at the possible damage to some of the patients as a result of the treatment and the way in which he monitors the possible deterioration in his research.
Follow-up to the hearing
On 20 September 2021, as a follow-up to the hearing, we had a meeting with three program managers at ZonMw. As a result of that meeting, we received the following email sent by them on September 24:
“Dear Arthur, Lou and Ynske
First of all, thank you very much for the meeting we had last week (Monday 20 September). Your concern about the possible consequences of applying CBT and especially GET is clear to us. Although we cannot and will not exclude applications with this subject from handling within ZonMw, we have promised that we will inform colleagues from adjacent programs such as COVID-19, Lyme and Q fever and infectious disease control about your concerns and the underlying reasons. You have indicated that you will let us know within two weeks whether you will withdraw the objection.
Thanks again for the pleasant conversation.
Yours faithfully
(name and position)
ZonMw”
We withdrew our objection by letter dated 12 October 2021. In the letter we once again emphasized the substantive arguments.
Withdrawal and explanation
Dear members of the Objections Committee,
Following the digital hearing on 3 June 2021, a meeting has taken place between ZonMw, represented by the ladies … and mr … and on behalf of the objectors A. de Groot and L. Corsius.
We also recently informed Mr Knoop that we accepted his invitation to talk about the ReCOVer study.
Based on the hearing and the meeting with ZonMw, we have decided to withdraw the objection.
The reason for withdrawal lies in the fact that the substantive aspects of the subject matter to us are paramount. We consider it important that ZonMw pays attention to this subject, especially during the handling and weighing of research proposals and during the evaluation of research that has been carried out.
We want to emphasize the following points:
- The “CBT for CFS treatment” is based on the assumption that the disease is perpetuated by the perception of the disease. An earlier response from ZonMw that biomedical research into ME/CFS does not mean that ZonMw will never again subsidize a CBT study shows a lack of understanding of the difference between CBT and ‘CBT for CFS’. Employees of ZonMw and assessors of research proposals should be aware of the fact that Cognitive Behavioral Therapy (CBT) for CFS (and for Q fever and longCOVID) is not ordinary CBT. It focuses on a time-contingent building up of activities and pretends to be curative, while that is explicitly not the case for other forms of CBT. ZonMw’s representatives have pledged that they will “inform and notify those involved in the assessments about this subject”.
- In our view, the public interest is served by openness. Not only being able to find committee members and assessors (the argument for not disclosing data) is important, but also the quality and objectivity of the assessment is important. It is in the public interest that assessors take responsibility for their judgment. We regret the fact that ZonMw does not provide this openness in this case, and as we understand, it does not in any case.
- In addition to the fact that we will also talk to Mr. Knoop, ZonMw will, in accordance to their promises, check during the interim evaluation of the study whether and how the harmful effects of the treatment are reported. We are curious how this will be implemented. We have reported that the way in which adverse effects have been examined in previous studies in ME/CFS provides insufficient insight. This concerns, among other things, the definition of adverse effects, the lack of follow-up of dropouts and the omission of the results of the objective measurements. The measurement in the ReCOVer study using the actometer at T3, the main objective measurement, is not guaranteed. We talked about the importance of objective outcome parameters. This is an essential point given the increased chance of bias in purely subjective measurements in such an open trial. It is important to be able to measure the negative effects. We have agreed with Mr (ZonMw program manager name removed) that we may approach him if we have any questions about the (interim) evaluation of the ReCOVer study.
- Finally, we expressed our concern that on the one hand, biomedical research in ME/CFS is being worked on and, on the other hand, a group is being subsidized for a treatment that is again based on the premise that patients no are longer ill as a result of biomedical factors, but because of perpetuating thoughts and behavior.
- During the meeting with ZonMw, we once again explained our substantive objections and we appreciate ZonMw’s commitment that the relevant assessors will be informed.
As stated above, this promise has led us to withdraw our objection.
Yours faithfully,
drs. Y. Jansen (drs. Is the title equal to Msc)
mr. A. de Groot (mr. is the title for a lawyer)
drs. L. Corsius
Copy to: ZonMw
Meeting with Professor Knoop
On November 18, 2021 we had a meeting with Professor Knoop. Afterwards we sent him the report below on November 26, in order to correct any factual inaccuracies. We received the following response:
“I don’t have the time for this, would you like to explicitly state that it is your reproduction of the conversation.
gr,
Hans knoop”
On December 2, we presented the draft to Professor Knoop again with a response period of more than six weeks. He rejected this request too.
“I’m sorry, I can’t manage that.
Greeting,
Hans knoop”
Note: We have carefully prepared the report below and we are convinced it is an accurate representation of the discussion.
Report of the conversation with professor Dr. H. Knoop about the risk of deterioration as a result of CBT treatment for longcovid patients.
Date: November 18, 2021
Participants: 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
Introduction
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 with 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 a 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.
Closing
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)
Postscript
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 measure objective outcomes too. 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.”
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