Item 6b: Explanation for choice of comparators.
“Choice of comparator
In spite of the increasing numbers of resistant strains, chloroquine monotherapy is still recommended as standard blood-stage therapy for patients with P. [Plasmodium] vivax malaria in the countries in which this trial will be conducted. Its selection as comparator is therefore justified. The adult dose of chloroquine will be 620 mg for 2 days followed by 310 mg on the third day and for children 10 mg/kg for the first two days and 5 mg/kg for the third day. Total dose is in accordance with the current practice in the countries where the study is conducted. The safety profile of chloroquine is well established and known. Although generally well tolerated, the following side-effects of chloroquine treatment have been described:
Gastro-intestinal disturbances, headache, hypotension, convulsions, visual disturbances, depigmentation or loss of hair, skin reactions (rashes, pruritus) and, rarely, bone-marrow suppression and hypersensitivity reactions such as urticaria and angioedema. Their occurrence during the present trial may however be unlikely given the short (3-day) duration of treatment.” 85
The choice of control interventions has important implications for trial ethics, recruitment, results, and interpretation. In trials comparing an intervention to an active control or usual care, a clear description of the rationale for the comparator intervention will facilitate understanding of its appropriateness.86;87 For example, a trial in which the control group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice; conversely, an inappropriately high dose in the control group will lead to an underestimate of the relative harms of the study intervention.87;88
The appropriateness of using placebo-only control groups has been the subject of extensive debate and merits careful consideration of the existence of other effective treatments, the potential risks to trial participants, and the need for assay sensitivity–that is, ability to distinguish an effective intervention from less effective or ineffective interventions.89;90 In addition, surveys have demonstrated that a potential barrier to trial participation is the possibility of being allocated a placebo-only or active control intervention that is perceived to be less desirable than the study intervention.68;69;91;92 Evidence also suggests that enrolled participants perceive the effect of a given intervention differently depending on whether the control group consists of an active comparator or only placebo.93-96
Finally, studies suggest that some ‘active’ comparators in head-to-head randomised trials are presumed by trial investigators to be effective despite having never previously been shown to be superior to placebo.74;97 In a systematic review of over 100 head-to-head antibiotic trials for mild to moderate chronic obstructive pulmonary disease74 cumulative meta-analysis of preceding placebo-controlled trials did not show a significant effect of antibiotics over placebo. Such studies again highlight the importance of providing a thorough background and rationale for a trial and the choice of comparators – including data from an up-to-date systematic review – to enable potential participants, physicians, REC/IRBs, and funders to discern the merit of the trial.
|6a: Background and rationale||7: Objectives|