Augustine Choko, Charles Weijer, Elizabeth Corbett, Katherine Fielding Lessons from an adaptive multi-arm multi-stage cluster randomized trial of strategies for improving linkage into HIV care or prevention in Malawi Augustine Choko, Charles Weijer, Elizabeth Corbett, Katherine Fielding

Research Question What are the most promising candidate interventions for increasing HIV testing, care and prevention in partners of pregnant women?

Multi-arm multi-stage (MAMS) cluster randomised trial design (Phase 2) Unit of randomisation: ANC day (cluster) One interim analysis (end of first stage) drop for Futility or Safety Primary outcome: % male partners of antenatal clinic attendees Test for HIV and link to care or prevention within 28 days Choko et al Trials 2017

Recruitment, participation & follow-up interview by trial stage Stage 1 (n = 36 clusters) 6 arms Stage 2 (n = 35 clusters) 5 arms; lottery dropped Enrolment Women present in ANC (1404) Ineligible (n = 320, 23%) Discontinued (n = 77, 7%) Women present in ANC (1733) Ineligible (n = 468, 27%) Discontinued (n = 39, 3%) Allocation Randomisation (n = 36 clusters) Randomisation (n = 35 clusters) Reasons for ineligibility <18y old Absent partner Partner on ART Not 1st ANC visit Already recruited Lost to follow-up (n = 0 clusters) Interviewed @ 4 weeks (n = 745; 69%) Lost to follow-up (n = 0 clusters) Interviewed @ 4 weeks (n = 1120; 89%) Follow-up # eligible (n=1084) Mean cluster size: 26 Range: 11 to 60 # eligible (n=1265) Mean cluster size: 29 Range: 9 to 67 Analysis

Primary outcome results (adjusted analysis) Proportion of male partners tested + linked to care or prevention within 28d Intention-to-treat analysis Stage 1 & 2 combined data: Linked: 676/2349 (28.8%) 630 (93%) confirmed HIV-ve: 408 already circumcised; 222 uncircumcised men referred for VMMC 46 (7%) confirmed HIV +ve; 42 (91.3%) started ART 44.0% first time testing 3 adverse events no serious adverse events Lottery arm dropped at interim 100 % - RR 2.57 (2.04, 3.10) RR 1.13 (0.90, 1.35) RR 1.97 (1.53, 2.41) 80 % - RR 1.21 (0.96, 1.45) RR 1.17 (0.86, 1.60) 60 % - 40 % - 20 % - 0 % - P=0.075 P<0.001 P<0.001 P=0.240 P=0.159 SOC ST only ST+$3 ST+$10 Lottery Reminder

4 Ethical issues Was the use of an adaptive cluster randomized design justified? Nature of intervention (s) Group level effects Efficiency (smaller sample size, short recruitment time, ?cost) 8 months recruit + FU 2350 participants Choice of unit of randomization vs risk of contamination Day of the week vs clinic Zingwangwa health center, Blantyre-Malawi

Randomise an antenatal clinic (ANC) day to any one of the six arms 4 Ethical issues Randomise an antenatal clinic (ANC) day to any one of the six arms Trial arms Standard of care Self-test kits (ST) only Self-test kits + Low amount incentive ($3) Self-test kits + High amount incentive ($10) Self-test kits + Low amount through lottery ST + phone call reminder Informed consent Hard to achieve Cluster size ? contamination / discouragement Waiver for men Undermines principle of autonomy Source of conflict in the relationship Group session with women in ANC waiting area Trial introduction and overview, no arm information Seek verbal consent to participate by show of hands Exclusions Refuses to participate before trial screening One-on-one session with women who show interest Eligibility screen Exclusions Couple testing in this pregnancy <18 years old Man is already on HIV treatment 2nd or later ANC visit Already recruited Lives outside urban Blantyre One-on-one session with women who show interest All six arms Go through arm-specific information sheet Obtain written or thumb print consent Give male partner invitation letter Intervention arms only Self-test instructions + demonstrate how to self-test Give two self-test kits Exclusions Refuses to participate after information All six arms Study information sheet Personalised invitation letter Intervention arms only Self-test instructions OraQuick oral self-test kits Woman to deliver to her male partner at “home”

4 Ethical issues Equipoise after interim analysis 100% RR 4.01 P<0.001 Equipoise after interim analysis Assumed efficacy: 25% Observed at interim: 13% Dilemma ? Can’t drop SOC 80% RR 4.08 P<0.001 RR 2.34 P=0.027 RR 1.53 P=0.297 60% 40% RR 1.09 P=0.341 20% 0% SOC ST only ST+$3 ST+$10 Lottery Reminder SOC: standard of care; ST: self-test kits; + means ST and

Choko et al J Int AIDS Soc 2017 On transport equivalent financial incentive 4 Ethical issues “Because when he self-tests, if you tell him to go to the clinic to receive counselling he would say he has no transport to go there but if transport money is there he won’t have any excuse” Female, FGD, Ndirande Post trial access Financial incentive interventions: ? Only ones significantly improved primary outcome Smallest cost per man tested + linked Not liked by policy makers Ethical dilemma Effective interventions that are unlikely to be implemented On high amount ($10) financial incentive “When you come to the clinic you spend the whole day with no food for today. Providing a high financial incentive would encourage other male partners upon hearing that their friend has food for today by going to the clinic” Male, FGD, Zingwangwa Choko et al J Int AIDS Soc 2017

Conclusions A novel adaptive cluster randomized trial design was successfully implemented More efficiency: smaller sample size and shorter recruitment period Choice of cluster type to be considered carefully in future Potential problems with obtaining informed consent Nature of the cluster Accessing men via women: autonomy (Lack) equipoise after interim analysis Some interventions clearly better than SOC but 2-stage design Post trial access to (?controversial) interventions Financial incentives improved the primary outcome in a hard to reach group Policy makers unwilling to pilot or implement interventions

Acknowledgements PASTAL team Trial main team Gladys Namacha Tione Salema Zao Mateyu Kondwani Zuze MLW data team Clemens Masesa Moses Kamzati Lumbani Makhanza Clinic in-charges Maureen: Zingwangwa Mgungwe: Bangwe Modester: Ndirande Collaborators LSHTM Aurelia Lepine LSTM / MLW Nicola Desmond University of Warwick Nigel Stallard Hendy Maheswaran MLW Moses Kumwenda Doreen Sakala Katherine Fielding Liz Corbett PASTAL team Charles Weijer