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Introduction The ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies. Methods Using a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study. Results Consistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the ‘twofold’ multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study’s reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority. Conclusions Using carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.

INTRODUCTION The TB-PRACTECAL study trialed a shorter, more tolerable regimen of oral drugs than standard of care (SoC) – which can last for up to 20 months and involve both injectables and up to 20 tablets a day. In this sub-study, PRACTECAL-PRO, we measured and explored trial participant quality of life, experiences, and perspectives on treatment, to understand outcomes more fully. Both studies were conducted in Uzbekistan, South Africa, and Belarus. METHODS We conducted a mixed-methods evaluation using quality of life (QoL) surveys and in-depth interviews. Participants in investigational and SoC arms completed the Short Form 12 (SF-12) and St George’s Respiratory Questionnaire (SGRQ) at four timepoints (baseline, 12, 24, and 48 weeks). Healthy age- and sex-matched volunteers were surveyed at a single timepoint to establish locally relevant controls. Participants from investigational arms were purposively sampled for in-depth interviews to describe qualitatively patient satisfaction and experience with the investigational arm trial, including factors enabling toleration or rejection of a novel treatment by patients. ETHICS This study was approved by the MSF Ethics Review Board and by the ethics review committees of the Ministry of Health of the Republic of Uzbekistan; the Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Belarus; the regulatory authority of the Ministry of Health of the Republic of Belarus and Pharma Ethics Independent Ethics Committee, South Africa. RESULTS Overall, of 137 trial participants 28.5% (39) and 71.5% (98) were randomised to the SoC arm and one of three investigational arms, respectively. Statistically significant univariate scores by arm were observed at week 48 for SGRQ Impact domain (median -3.8, 95% confidence interval (CI), -5.7 to 0.0) and at week 24 for SF-12 physical component score (median 3.1, 95%CI 0.2 to 6.7). Longitudinal analysis showed that the proportional reduction in SGRQ scores per month was higher in the investigational group compared to the SoC for all domains and the total score. For both the SGRQ and SF-12, baseline scores indicated worse quality of life for the trial participant group (that is, investigational arms and SoC together) than for the healthy control group. Qualitative analysis showed early treatment satisfaction was a useful predictor of better adherence. Treatment acceptability was linked to participants’ support networks and their experience of counselling and clinical advice. Tolerability of the regimen helped reassure patients and household members on efficacy and value of the treatment. Participants reported that early improvement helped them return to productive lives sooner, with the potential to address social determinants with financial protection schemes for a shorter investment period. Patient perspectives around residual burden of disease can help inform clinicians about ongoing care. CONCLUSION All PRACTECAL-PRO participants reported worse generic and disease-specific QoL at baseline, compared to an age and sex-matched healthy control group. Participants taking a novel shortened oral regimens demonstrated both a quicker improvement in their respiratory disease-specific QoL over 48 weeks than those receiving SoC, and an improvement that exceeded the SGRQ’s minimum clinically important difference. In-depth interviews give insights suggesting investment toward patient-sensitive and socially responsive treatment and care. For interviewees, the supportive care experienced was as important as their satisfaction and tolerability of the novel drug regimen. Patient perspectives are an essential component of assessing clinical trial outcomes. CONFLCITS OF INTEREST None declared.

INTRODUCTION Rifamipcin-resistant tuberculosis (RR-TB) affects around 465,000 people each year globally. Current treatment is of 9-20 months’ duration; is toxic and poorly efficacious. TB-PRACTECAL is a multi-arm, 2-stage, randomised controlled, multi-country, non-inferiority trial comparing 24-week regimens to the locally approved standard of care (control). We report TB-PRACTECAL stage 1 and 2 outcomes as well as additional analyses from dropped arms. METHODS Participants 15 years and above with pulmonary RR-TB from Uzbekistan, South Africa, and Belarus were included regardless of HIV status or CD4 count. Patients were randomized in a 1:1:1:1 ratio in stage 1 and 1:1 in stage 2. Randomization lists were stratified according to trial site. The BPaL regimen was comprised of bedaquiline 400mg daily for 2 weeks then 200mg three times weekly for 22 weeks, pretomanid 200mg daily for 24 weeks, and linezolid 600mg daily for 16 weeks followed by 300mg daily for 8 weeks. BPaLM additionally contained moxifloxacin 400mg daily and BPaLC contained clofazimine 100mg daily. Treatment was administered daily under observation. Transition to stage 2 occurred after enrolment of 240 participants and BPaLM was found to be the most promising arm. Randomisation continued during transition and all participants continued their allocated regimen and were followed up to 108 weeks. A post-hoc analysis was conducted comparing the three investigational arms to control using the primary efficacy outcome: proportion of patients with unfavourable outcome (death, treatment discontinuation, treatment failure, recurrence, lost to follow-up) at 72 weeks. We also assessed the proportion of patients with grade ≥3 or serious adverse events (SAE) by 72 weeks and mean change in QT corrected using Fridericia’s formula (QTcF) at week 24. ETHICS This study was approved by the Ethics Review Board (ERB) of the London School of Hygiene and Tropical Medicine and the local ERBs in Uzbekistan, Belarus and South Africa; and by the MSF ERB. RESULTS In March 2021, TB-PRACTECAL was terminated for efficacy at which point, 552 patients were enrolled. In the modified intention-to-treat population (comprising all randomised patients dispensed study medication at least once, excluding patients who did not have microbiologically-proven RR-TB), 252 patients had reached 72 weeks of follow-up, 44.0% of whom were female and 22.6% were HIV positive. In the modified intention- to-treat population, the percentage of unfavourable outcomes was 48.5% (32/66) for control, 23.3% (14/60) for BPaL, 18.8% (12/64) for BPaLC, and 11.3% (7/62) for BPaLM. There were three recurrences in BPaL, one in BPaLC, and none in BPaLM. Percentage of Grade ≥3 or SAE were 19.4% (14/72; 16 events), 31.9% (23/72; 32 events) and 21.7% (15/69; 24 events) in BPaLM, BPaLC and BPaL respectively, compared with 58.9% (43/73; 69 events) in the control. Mean change in QTcF at week 24 was 27.0 milliseconds (ms), 40.2 ms, and 23.3 ms in BPaLM, BPaLC, and BPaL respectively; compared with 44.89 ms in the control. CONCLUSION 24-week all-oral regimens of bedaquiline, pretomanid and tapered-dose linezolid, with and without clofazamine or moxifloxacin are safe and efficacious in the treatment of RR-TB. Trial results show that treatment with BPaLM was more effective and had a better safety profile than the Control. BPaLC and BPaL were also highly effective. CONFLICTS OF INTEREST None declared.

As climate change continues to be politically divisive, developing communications that align with right-leaning beliefs may increase bipartisan support for climate policy. In two experimental studies (Study 1, Australia, N = 558; Study 2, United States, N = 859), we tested whether an economic loss or national identity loss message would elicit greater support for mitigation and adaptation policies when compared to one another and to a control message. We also tested whether the direct effects of these message types were conditional on political orientation (specifically, identifying as politically right-leaning). In both studies, preliminary analyses indicated that the message manipulations were effective and that there was a high level of support for both types of climate policy. When compared to left-wing adherents, those who were politically right-leaning were less likely to support mitigation and adaptation policies in either sample. Australian (Study 1) identification – although not American identity (Study 2) – also uniquely predicted adaptation support (but not mitigation support). Yet, there were no significant message frame or interaction effects in the Australian (Study 1) or U.S. sample (Study 2). This suggests that neither an economic loss nor national identity loss message frame may be effective in overcoming the political polarization of climate change in Australia or the United States. Nevertheless, national identity could still play a useful role in Australian climate communications given its positive relationship to adaptation policy support, and therefore warrants further investigation.

SETTING: \ud Ten primary health clinics in rural Thyolo District, Malawi.\ud \ud OBJECTIVE: \ud Tuberculosis (TB) is a common initial presentation of human immunodeficiency virus (HIV) infection. We investigated the time from TB symptom onset to HIV diagnosis to describe TB health-seeking behaviour in adults newly diagnosed with HIV.\ud \ud DESIGN: \ud We asked adults (18 years) about the presence and duration of TB symptoms at the time of receiving a new HIV diagnosis. Associations with delayed health seeking (defined as >30 and >90 days from the onset of TB symptoms) were evaluated using multivariable logistic regression.\ud \ud RESULTS: \ud TB symptoms were reported by 416 of 1265 participants (33%), of whom 36% (150/416) had been symptomatic for >30 days before HIV testing. Most participants (260/416, 63%) were below the poverty line (US$0.41 per household member per day). Patients who first sought care from informal providers had an increased odds of delay of >30 days (adjusted odds ratio [aOR] 1.6, 95%CI 0.9-2.8) or 90 days (aOR 2.0, 95%CI 1.1-3.8).\ud \ud CONCLUSIONS: \ud Delayed health seeking for TB-related symptoms was common. Poverty was ubiquitous, but had no clear relationship to diagnostic delay. HIV-positive individuals who first sought care from informal providers were more likely to experience diagnostic delays for TB symptoms.

Trial protocol for the STAMP trial- a multi-country (Malawi and South Africa) individually randomised clinical trial to determine the impact on early mortality of the addition of rapid, urine-based TB screening to the standard of care TB screening in HIV-infected patients requiring admission to medical wards in hospitals in southern Africa.