The pragmatic randomised trial : a simple research design for real-world evaluation of innovation in tuberculosis care

Tuberculosis was the first disease in history whose treatment regimens were systematically established using randomised controlled trials (RCTs). As a result TB drug treatment regimens are standardised globally, and have been entirely evidence-based for decades. And yet attempts to establish the same level of evidence for the mode of delivery for these treatment regimens have proved contentious. As a result, WHO and IUATLD disseminate global strategies for promoting adherence by patients, and defining the role of nurses and lay health workers in TB care that are not evidence-based.

This thesis includes four RCTs, each of which helped to establish the effectiveness of an aspect of primary care in South Africa. The randomised trials in this thesis evaluate the impact on successful TB treatment completion of compulsory daily nurse observation of treatment at a primary care clinic- no effect overall, and harm to retreatment patients (Paper I), and of lay health workers as TB treatment supporters- highly effective (Paper II); of multifaceted educational outreach on syndromic management for improving the sensitivity of nurse diagnosis of TB, and respiratory disease care in primary care clinics- effective (Paper III), and of the effects of a more intensive version of this strategy on a wider range of illnesses, still including TB but adding HIV/AIDS and anti-retroviral treatment (ART)- effective (Paper IV). In the course of conducting these studies I learned how to design randomised trials to evaluate the effects, under real world conditions, of complex interventions. Some of these lessons are captured in a methodological guideline for the conduct of such trials (Paper V).

The results of these four RCTs suggest that direct support for improvement of TB treatment outcomes is a task best carried out by lay health workers, not by nurses; and that our outreach approach improves the clinical care offered by nurses to people with TB, HIV/AIDS or other complex conditions, previously treated by doctors only. Paradoxically, our exploratory analysis showed that this clinically focussed multifaceted educational strategy aimed at nurses in clinic teams also has a positive impact on successful treatment completion rates among TB retreatment patients. This hints at the possibility that when nurses are confident clinicians, they have better patient relationships.

This series of randomised trials helped to provide a firm evidence base for the organisation of TB diagnosis and treatment supervision, care of other respiratory diseases and HIV/AIDS/ART delivery in primary care in South Africa, with applicability elsewhere.

Low and middle income countries cannot afford the costs of assuming that interventions based on theory, no matter how plausible, will be effective. We recommend wider use of pragmatic RCTs to provide rigorous evidence in support of decision makers choosing the best among alternative feasible options for health and healthcare.

List of scientific papers

I. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M (1998). Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet. 352(9137): 1340-3.
https://pubmed.ncbi.nlm.nih.gov/9802271

II. Clarke M, Dick J, Zwarenstein M, Lombard CJ, Diwan VK (2005). Lay health worker intervention with choice of DOT superior to standard TB care for farm dwellers in South Africa: a cluster randomised control trial. Int J Tuberc Lung Dis. 9(6): 673-9.
https://pubmed.ncbi.nlm.nih.gov/15971396

III. Fairall LR, Zwarenstein M, Bateman ED, Bachmann M, Lombard C, Majara BP, Joubert G, English RG, Bheekie A, van Rensburg D, Mayers P, Peters AC, Chapman RD (2005). Effect of educational outreach to nurses on tuberculosis case detection and primary care of respiratory illness: pragmatic cluster randomised controlled trial. BMJ. 331(7519): 750-4.
https://pubmed.ncbi.nlm.nih.gov/16195293

IV. Zwarenstein M, Fairall LR, Lombard C, for the PALSA PLUS study group: Mayers P, Bheekie A, English RG, Lewin S, Shai-Mhatu P, Bachmann M , Bateman ED (2009). Integration through outreach education and mentoring improves adult HIV/AIDS and tuberculosis primary care: the PALSA PLUS pragmatic cluster randomized trial. [Submitted]

V. Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D; CONSORT group; Pragmatic Trials in Healthcare (Practihc) group (2008). Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ. 337: a2390.
https://pubmed.ncbi.nlm.nih.gov/19001484