WSO - February 2024 - 170

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International Journal of Stroke 19(2)
Introduction
Appropriate control comparator design is critical for rigorously
testing a trial hypothesis. The benefit of an experimental
intervention is established relative to a pre-specified
comparator. The ability to demonstrate a difference between
an experimental and comparator intervention can be
reduced by poor comparator choice. For example, the control
comparator may include active ingredient(s) resulting
in near identical interventions that will bias to the null
hypothesis, or the control comparator may be unacceptable
to participants resulting in a higher proportion of dropouts.1,2
Poor comparator design can negatively impact
internal (i.e. can the outcome be causally attributed to the
intervention?) and external (i.e. are the findings generalizable?)
validity and the clinical utility of trial findings. Past
reviews have demonstrated that little to no rationale is provided
for comparator choice, and fewer words and references
are used to describe a comparator as compared to the
experimental intervention,2,3 which was reflected in scores
obtained using the Template for Intervention Description
and Replication (TIDieR).4 Consequently, the rationale for
and details of the comparator control intervention in trials
are often unknown. This reduces our ability to advance
upon and replicate results.
Stroke recovery and rehabilitation interventions can be
complex and involve multiple interacting components or
ingredients.5,6 Careful consideration of active and inactive
ingredients within a trial is required.7,8 How to relate
controls between preclinical and/or clinical trials is also
a major barrier to translation.9 Even a usual care comparator
can pose considerable challenges, with vast variation at
the micro (i.e. within and between trial sites) and macro
(i.e. between countries) level.10 While the challenge of
Box 1. Definitions.
Trial: any research (preclinical or clinical) that prospectively assigns participants or groups of participants to one or more
health-related interventions to evaluate the effects on health outcomes. This extends the National Institutes of Health (NIH)
definition16 to include preclinical research.
Participant: animal or human taking part in a trial.
Experimental intervention: an intervention that manipulates the participants' biology, behavior, and/or environment
(cause) for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints
(effect). This extends the NIH definition16 to encompass manipulation of not only the environment but also biology or
behavior.
Control comparator (intervention): comparator of interest for the experimental intervention.16 Numerous types of
control exist (Table 1). May take the form of a group, condition, or objective-criterion.
Template for Intervention Description and Replication (TIDieR): checklist that contains the minimum
recommended items for describing an intervention4 which extends Item 5 of the Consolidated Standards of Reporting Trials
(CONSORT) statement.17
Threat: potential alternative explanation (other than experimental intervention) for the anticipated effect or outcome that
may threaten the internal validity of a trial.18,19
Active ingredient: one or more component(s) of the intervention that is(are) hypothesized to have a causal effect.
This extends the Rehabilitation Treatment Specification System view5,20 to differentiate and describe active and inactive
ingredients.
Inactive ingredient: any additional medium or component(s) that is delivered alongside the hypothesized active ingredient
component(s) that may or may not causally affect the health outcome(s).
International Journal of Stroke, 19(2)
appropriate control comparator design has been discussed
in neurorehabilitation literature,11,12 there is no tool available
to guide decision-making. This may explain why, for
example, most upper limb rehabilitation trials almost
always adopt a comparator that is usual care or dosematched
usual care2,13 rather than a control that seeks to
have all but the active ingredients of the experimental intervention
present. Such a one-size-fits-all approach overlooks
other comparator options that may suit the research
question, trial phase,14 stage of stroke recovery,15 experimental
intervention (considering active/inactive ingredients),
geography (e.g. health care system and its funding),
and feasibility (e.g. funding, regulatory) considerations, as
well as the perspectives of people with lived experience.
Establishing guidance to support appropriate selection,
description, and reporting of control comparator interventions
is needed.
The control taskforce of the third Stroke Recovery and
Rehabilitation Roundtable (SRRRIII) aimed to understand
the challenges for control comparator design; produce a
tool to guide control comparator selection, description, and
reporting; and provide recommendations, which if adopted,
would advance the science of preclinical and clinical trials
in stroke recovery and rehabilitation. Definitions used
throughout are provided in Box 1. We present four hypothetical
exemplars (Supplemental 1) that apply the developed
CONtrol comparator deSIGN (CONSIGN) decision
support tool to diverse stroke domains, intervention
approaches, trial phases, recovery stages, settings, and populations.
Our broad and multidisciplinary focus highlights
how control comparator considerations affect all domains
of stroke recovery and rehabilitation, and the broader
research community involved in the conduct of preclinical
and clinical trials.

WSO - February 2024

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