1. 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

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

3. 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

4. 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)
4 weeks (n = 745; 69%)
Lost to follow-up (n = 0 clusters)
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

5. 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

6. 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

7. 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”

8. 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

9. 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

10. 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

11. 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