Azithromycin distribution and childhood mortality in compliance-related subgroups in Niger: complier average causal effect and spillovers in a cluster-randomized, placebo-controlled trial

Background Biannual azithromycin distribution to children 1–59 months old reduced all-cause mortality by 18% [incidence rate ratio (IRR) 0.82, 95% confidence interval (CI): 0.74, 0.90] in an intention-to-treat analysis of a randomized controlled trial in Niger. Estimation of the effect in compliance-related subgroups can support decision making around implementation of this intervention in programmatic settings. Methods The cluster-randomized, placebo-controlled design of the original trial enabled unbiased estimation of the effect of azithromycin on mortality rates in two subgroups: (i) treated children (complier average causal effect analysis); and (ii) untreated children (spillover effect analysis), using negative binomial regression. Results In Niger, 594 eligible communities were randomized to biannual azithromycin or placebo distribution and were followed from December 2014 to August 2017, with a mean treatment coverage of 90% [standard deviation (SD) 10%] in both arms. Subgroup analyses included 2581 deaths among treated children and 245 deaths among untreated children. Among treated children, the incidence rate ratio comparing mortality in azithromycin communities to placebo communities was 0.80 (95% CI: 0.72, 0.88), with mortality rates (deaths per 1000 person-years at risk) of 16.6 in azithromycin communities and 20.9 in placebo communities. Among untreated children, the incidence rate ratio was 0.91 (95% CI: 0.69, 1.21), with rates of 33.6 in azithromycin communities and 34.4 in placebo communities. Conclusions As expected, this analysis suggested similar efficacy among treated children compared with the intention-to-treat analysis. Though the results were consistent with a small spillover benefit to untreated children, this trial was underpowered to detect spillovers.

The Complier Average Causal Effect Parameter for Multiarmed RCTs

In randomized controlled trials, the complier average causal effect (CACE) parameter is often of policy interest because it pertains to intervention effects for study units that comply with their research assignments and receive a meaningful dose of treatment services. Causal inference methods for identifying and estimating the CACE parameter using an instrumental variables (IV) framework are well established for designs with a single treatment and control group. This article uses a parallel IV framework to discuss and build on the much smaller literature on estimation of CACE parameters for designs with multiple treatment groups. The key finding is that the conditions to identify and estimate CACE parameters are much more complex for multiarmed designs and may not be tractable in some cases. Practical steps are provided on how to proceed, and a case study demonstrates key issues. The results suggest that ensuring compliance is particularly important in multiarmed trials so that intention-to-treat estimates on the offer of intervention services (which can be identified) can provide meaningful information on the CACE parameters.

Paracetamol bei Rückenschmerzen nicht empfohlen

Schreijenberg M, Lin CC, McLachlan AJ et al. Paracetamol is Ineffective for Acute Low Back Pain even for Patients Who Comply with Treatment: Complier Average Causal Effect Analysis of a Randomized Controlled Trial. Pain 2019; 160: 2848–2854. doi: 10.1097/j.pain.0000000000001685

Role of good oral hygiene on clinical evolution of rheumatoid arthritis: a randomized study nested in the ESPOIR cohort

Objective There is a relationship between RA and periodontal disease. We aimed to investigate if a good oral hygiene could improve activity of RA. Methods The patients with RA according to ACR/EULAR 2010 criteria and included in the French early arthritis ESPOIR cohort were included in a randomized nested study into: (i) intervention group: general recommendations of good oral hygiene including teeth brushing, daily antiseptic mouthwash and twice a year scaling; and (ii) control group: no intervention. The primary end point was the delta DAS28-ESR. Results Four hundred and seventy-two patients were randomized (238 in intervention and 234 in control). 92/238 from the intervention group accepted the procedure and 81 had a first visit to the dentist. 56% of patients had periodontal disease at baseline. Duration of RA was 9.0±0.7 years. Baseline DAS28-ESR was 2.7±1.3. After a median duration of 24 months, delta DAS28-ESR was −0.17±1.29 and −0.09±1.28 in intervention and control groups, respectively (mean difference (complier average causal effect): −0.37 (95% CI −1.12, 0.37), P = 0.33). In the intervention group, there was a significant decrease of the bacteria involved in the red complex: Porphyromonas gingivalis (P = 0.002), Tannerella forsythia (P = 0.002) and Treponema denticola (P = 0.019). The patients with baseline periodontal disease and those who became negative for one red complex bacterium had a slightly more important decrease of DAS28-ESR. Conclusion Oral hygiene instruction together with regular scaling and polishing of the teeth significantly decreased the load of periodontal pathogens but did not decrease RA activity. This intervention should be tested in patients with earlier RA and more active disease. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01831648.