Trial By Error: More on the Canadian Long COVID Trial with Plans to Lie to Participants Receiving an Exercise Intervention

By David Tuller, DrPH

I recently posted a blog about the protocol for a Canadian Long COVID exercise trial in which the investigators proposed lying to the participants about the nature of both the study and the intervention being assessed. 

While acknowledging that a significant number of people with Long COVID report experiencing post-exertional malaise (PEM), the investigators appear to believe they have the right to deceive participants into believing they are receiving “standard post-COVID-19 treatment” when in fact they are receiving an experimental exercise intervention. The intervention, called COVIDEx, includes two 50-minute physical therapy sessions each week for eight weeks, delivered virtually by trained instructors to groups of six patients. 

(This protocol has been published even as a recent article in The Sick Times revealed that fewer than 20% of dozens of Long COVID exercise studies even mentioned PEM. I recently interviewed Simon Spichak, the Canadian journalist who wrote the article.)

I thought this new trial, led by investigators from Western University in London, Ontario, warranted further comment. If the description in the protocol is accurate, it appears to represent a serious breach of ethical standards. It is perplexing that it was approved in the current form by the Western University Health Sciences Research Ethics Board.

The protocol reports that the investigators have adopted what they call a “modified Zelen design.” In 1979, Harvard biostatistics professor Marvin Zelen proposed a trial design in which investigators randomize unsuspecting potential participants to intervention and control arms. After randomization, they inform those in the intervention arm about the intervention and obtain their consent. This strategy seeks to eliminate the bias arising from disappointment and related responses among participants assigned to usual care instead of an intervention.

Per the protocol, the new Long COVID exercise trial seriously ramps up the deception. In this case, even those receiving the intervention are not told that they’re receiving an intervention. Here’s how the protocol describes its consent procedures:

“All patient participants will be informed that they are part of an observational study designed to follow the natural progression of Long COVID and to evaluate the costs associated with standard post-COVID-19 treatments. This includes both the COVIDEx and usual care groups…Blinding patients to the presence of the experimental group will mitigate the effects of feeling disappointed, frustrated or discouraged about being assigned usual care. This is important given that the study is also assessing fatigue, a subjective, patient-reported outcome measure. This approach can also reduce the likelihood that participants in the usual care group begin self-motivated programmes trying to mimic the intervention.” 

In other words, those assigned to the intervention arm are not told anything different than those getting usual care. Note that while all the participants are being deceived, the explanations for the deception relate solely to the responses in the usual care group. The investigators do not explain why they also need to lie to those in the intervention arm by pretending these participants are receiving “standard post-COVID-19 treatment” rather than an experimental exercise program.

The reference for the statement about a “modified Zelen design” is to a 2005 trial called “Adapting the randomized consent (Zelen) design for trials of behavioural interventions for chronic disease: feasibility study.” But that trial did not involve, or seek to justify, the level of deceit revealed in the protocol for the Canadian study. In the 2005 study, all the patients were consented before randomization to be in what they were told was an observational study. Here’s what happened after that: 

“Those patients randomized to the treatment group were given an additional written patient information leaflet which explained the further study to test the effectiveness of physiotherapy and exercise treatment for OA, and were invited to take part. These patients were contacted at home by telephone a few days later to check if they were still willing to participate. If they agreed, they were then asked to provide a second consent relating to the intervention.”

In other words, those receiving the intervention would have presumably also been given appropriate information about possible risks. As a 2021 review article, called “Zelen design clinical trials: why, when, and how,” noted: “Zelen’s proposal presumed a traditional informed consent process at the time any study treatment is offered. That process would typically include all essential elements of informed consent: explicit notification that the offer is a research activity, a description of expected procedures, a description of potential benefits and risks, notification that participation or acceptance is voluntary, and a description of alternatives to the treatment offered.”

While there might be unusual circumstances in which this requirement could conceivably be waived, the protocol doesn’t make a case, or mount any effort to make a case, for such a rare and drastic exemption. And they do not explain why they have chosen to deviate from the “modified Zelen design” described in the reference they cite. 

Their hypothesis is that “a structured, individualised rehabilitation approach will improve fatigue and quality of life in Long COVID patients while minimising the risk of symptom exacerbation such as PEM.” Does that mean the investigators managed to persuade the ethics board that this study posed minimal risks to patients, even though they are trialing an exercise intervention in a population prone to PEM and mininizing those risks is part of the hypothesis they are assessing? Or did they argue that the intervention includes safeguards to prevent negative outcomes, so it wasn’t necessary to notify participants about the potential risks being assessed? 

Whatever the case, it is hard to understand how a plan to lie to vulnerable patients in this context could have been approved. The Western University Health Sciences Research Ethics Board should revisit this problematic decision—unless the institution wants to be known for experimenting on human subjects without their consent.

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Beyond that very core issue, the study has other problems as well. For one, the investigators write that “the intervention was informed by existing rehabilitation frameworks, which have shown promise in managing chronic fatigue syndromes.” 

The reference for this statement is an article titled “Development and preliminary evaluation of a cognitive behavioural approach to fatigue management in people with multiple sclerosis.” Hm. The reliance on “a cognitive behavioral approach” as the inspiration for COVIDEx is obviously a red flag. More importantly, the investigators do not explain why they think a program designed to alleaviate MS-associated fatigue is appropriate for those with Long COVID.

I guess they think all fatigue is the same?