1. High Cohort Retention in a Phase III Trial of the Diaphragm and Lubricant Gel in Southern Africa
Presented by Constancia Watadzaushe
University of Zimbabwe – University of California, San Francisco
Collaborative Research Programme
IAS 2007 Conference
GOODMORNING , I AM GOING TO PRESENT ON THE HIGH COHORT RETENTION IN A CLINICAL TRIAL OF THE DIAPHRAGM AND LUBRICANT GEL THAT WAS CONDUCTED IN SOUTHERN AFRICA

2. Methods for Improving Reproductive Health in Africa (MIRA)
Phase III randomized controlled trial to examine the effectiveness of the diaphragm and Replens gel in preventing HIV acquisition in women
THE METHODS OF IMPROVING REPRODUCTIVE HEALTH IN AFRICA WAS A PHASE III RANDOMISED CONTROLLED TRIAL THAT EXAMINED THE EFFECTIVENESS OF THE DIAPHRAGM AND REPLENS GEL IN PREVENTING HIV ACQUISITION AMONG WOMEN

3. Background: The MIRA Trial
UZ-UCSF = 2502
MRC = 1515
PHRU = 1028
Five study clinics in Zimbabwe (Harare) and South Africa (Durban & Soweto)
Sites were a mixture of rural, peri-urban and urban; with formal and informal settlements
A TOTAL OF 5045 WOMEN PARTICPATED IN THE STUDY ACROSS 3 SITES WITH 5 STUDY CLINICS. THE CLINIC SITES WERE BASED IN HARARE (ZIM), DURBAN AND SOWETO IN SOUTH AFRICA. THE SITES WERE A MIXTURE OF RURAL, PERI URBAN AND URBAN WITH FORMAL AND INFORMAL SETTLEMENTS

4. Baseline participant characteristics (n= 5045)
Average age = 28 (range 18 – 50)
44% high school educated
23% employed
56% earned income in the past year
59% married
68% living with partner
94% Christian
Average age at sexual debut = 18 (10-31)
22% had circumcised partner, 20% didn’t know
THE STUDY PARTICIPANTS WERE ON AVERAGE 28 YEARS OF AGE RANGING BETWEEN 18 AND 50 YEARS, 445 HAD HIGH SCHOOL EDUCATION AND 235 WERE EMPLOYED. 595 OF THESE WOMEN WERE MARRIED AND 685 WERE LIVING WITH A PARTNER. THE AVERAGE AGE OF SEXUAK DEBUT WAS 18 YEARS AND IT RANGED BETWEEN 10 AND 31 YEARS. 22% HAD CIRCUMCISED PARTNERS AND 20% DID NOT KNOW.

5. Retention and LTFU considerations
Protocol assumed 4-7% loss to follow-up (LTFU) per year over 3 years given an overall expected HIV incidence in the trial of 4%
Minimizing LTFU is essential in clinical trials to ensure the validity of trial results
Important not only to limit LTFU, but to ensure that LTFU is not different by study group
“LTFU” defined as no closing visit with HIV endpoint data
Sample size considerations - HIV incidence estimated as 4% across sites, therefore we aimed to limit LTFU to approximately this level
THE TRIAL DESIGN ASSUMED A 4.7% LOSS TO FOLLOW UP OVER A PERIOD OF 3 YEARS OVER AN ESTIMATED HIV INCIDENCE RATE OF 4 % ACROSS ALL SITES.
LTFU WAS DEFINED AS NO CLOSING VISIT WITH HIV END POINT DATA
IT IS ESSENTIAL TO LIMIT LTFU SO AS TO ENSURE VALIDITY OF RESULTS AND IT WAS IMPORTANT TO ENSURE LTFU WAS NOT DIFFERENT BY STUDY GROUP. WE

6. Follow-up schedule Screening visit
Enrollment visit (2 weeks after screening visit; repeat screening visit conducted if > 2 weeks since first screening visit)
Week 2 visit
Quarterly follow up visits during between 12 and 24 months, depending on date of enrollment
Closing visit at 12 – 24 months, depending on date of enrollment
A PARTICIPANT WAS ENROLLED INTO THE STUDY WITHIN TWO WEEKS AFTER THE SCREENING VISIT AND A REPAET SCREENING WAS DONE SHE IF SHE CAME BACK FOR ENROLLMENT TWO WEEKS AFTER THE FIRST SCREENING VISIT.
PARTICPANTS WERE THEN FOLLOWED UP QUARTELY FOR A PERIOD OF 12 TO 24 MONTHS DEPENDING ON THEIR DATE OF ENROLLMENT.
CLOSING VISITS WERE DONE BETWEEN 12 TO 24 MONTHS DEPENDING ON THEIR DATE OF ENROLLMENT

7. Concerns about LTFU prior to implementation
Migration
Long follow-up period (24 months)
Lack of perceived incentive to stay in study for control group?
Before the trial was implemented there were concerns about migration, long follow up periods which was a maximum of 24 months
There was also concern that those in the control group may perceive no benefit of staying in the study that long

8. Retention strategies prior to study implementation
Initiation training
Every staff member’s responsibility
Resources allocated and sites encouraged to hire many outreach workers
Outreach workers given space in clinic
Community launch activities
VERY DETAILED LOCATOR FORM
THE FOLLOWING STRATEGIES WERE THEREFORE IMPLEMENTED PRIOR TO IMPLEMENTATION OF THE STUDY
STAFF WAS TRAINED ON THE IMPORTANCE OF RETAINING PARTICIPANTS THROUGHOUT THE TRIAL AND ON HOW THIS COULD BE DONE
ADEQUATE RESOURCES FOR FOLLOW UP WERE ALLOCATED AND SITES WERE ENCOURAGED TO RECRUIT MANY OUTREACH WORKERS SO THAT THE OUTREACH:PARTICPANT RATIO WAS MANAGEABLE
OUTREACH WORKERS WERE ALLOCATED SPACE IN THE CLINICS , THIS ENABLE THEM TO HAVE ONE TO ONE CONTACT WITH PARTICPANT WHILE IN THE CLINIC AND ESTABLISH RAPPORT
COMMUNITY LAUNCH ACTIVITIES WERE DONE TO SENSITISE THE COMMUNITY
AND MOST IMPORTANTLTY STAFF WAS TRAINED TO OBTAIN VERY DETAILED LOCATOR INFORMATION FROM EACH PPT

9. Locator form information
Home address and phone number, space to draw map
Husband’s name, work address and phone number
School-going child’s name, school name and address
Parent or nearest relative’s name, address and phone number
Second contact after parent or relative
Rural address of the participant
For each, participant indicated and initialed whether it was okay to reach that contact person, by phone or by post, and whether it was okay to mention the study by name
VERY DETALIED LOCATOR INFORMATION WAS COLLECTED FROM EACH PPT FOR EFFICIENT TRACKING PURPOSES
INFORMATION OBTAINED INCLUDED THE PPT’S HOME ADDRESS, PHONE AND DIRECTION MAPS WERE DRAWN ON THE LOCATOR WHERE ADDRESSES WERE NON-EXISTENT
WE ALSO OBTAINED THE PPT’S SCHOOL GOING CHILD’S NAME, NAME OF THE SCHOOL AND ADDRESS.THIS WAS DONE TO ENSURE THAT IN THE EVENT THE PPT MOVED FROM HER CURRENT KNOWN ADDRESS THE CHILD WAS UNLIKELY TO CHANGE SCHOOLS THEREFORE WOULD REMAIN A RELAIBLE CONTACT
A SECOND CONTACT DETAILS WAS ALSO OBTAINED AFTER THE PARENT AND RELATIVE
FOR EACH OF THESE DETAILS THE PARTICIPANT WAS ASKED TO INDICATE AND INITIAL THAT IT WAS OKAY TO REACH THE CONTACT BY PHONE OR POST AND WHETHER IT WAS OKAY TO MENTION THE STUDY BY NAME

10. Retention strategies during study implementation: 1
Retention strategies during study implementation: 1. extensive follow-up
Reminder letters sent prior to visits
Phoning or home visits 24-hours after missed visits
Peer educators used for outreach (MRC site)
THE FOLLOWING STRATEGIES WERE USED DURING THE IMPLEMENTATION OF THE TRIAL
REMINDER LETTERS WERE SENT TO THE PPT’S BEFORE THE NEXT SCHEDULED VISIT WAS DUE
IF PPT MISSED HER SCHEDULED VISIT SHE WAS EITHER CONTACTED BY PHONE OR MAKING A HOME VISIT WITHIN 24 HOURS
PEER EDUCATORS WERE ALSO USED FOR OUTREACH

11. 2. improving customer service
Offered Saturday Clinics and evening hours
Created participant suggestion boxes
Provided transport
Appointed Client Liaison Officer to interface with participants regarding expected waiting periods
Played family movies and served refreshments in waiting areas
Provided childcare while women were in their visits
AS THE TRIAL PROGRESSED WE IMPROVED OUR CUSTOMER SERVICE TO TRY AND MEET THE PPT’S NEEDS AS FAR AS THEIR PARTICIPATION IN THE TRIAL WAS CONCERNED
WE OFFERED WEEKEND AND AFTER HOURS CLINICS FOR THOSE PPTS WHO WERE FINDING IT DIFFICULT TO GET TIME OFF FROM WORK
WE CREATED A SUGGESTION BOX FOR THE PPTS
PROVIDED TRANSPORT FOR THOSE WHO WERE LIVING IN AREAS WERE TRANSPORT WAS DIFFICULT TO ACCESS
A CLIENT LIASION OFFICER WAS APPOINTED AT EACH SITE TO INTERFACE WITH PARTICPANTS ABOUT THEIR WAITING PERIODS
PLAYED FAMILY MOVIES AND SERVED REFRESHMENTS IN WAITING AREAS
AND FOR THOSE PPTS WHO BROUGHT CHILDREN TO THE CLINIC CHILDCARE WAS PROVIDED WHILST THE PPT WAS HAVINGWERE IN THEIR VISITS

12. 3. small gifts and competitions
All IRB approved
Token gifts at visit milestones (all < R15 each) given at 6 month intervals:
Purse/ clock
Umbrella
Sewing Kit
Tupperware set
Participant lottery – one voucher for every visit attended and quarterly draw for winners. Prize = grocery voucher
Incremental reimbursement scale for every follow-up visit completed
TO ENCOURAGE OUR PPTS TO KEEP COMING FOR THEIR VISITS WE GAVE THEM TOKEN GIFTS AT VISIT MILESTONES E.G AT MONTH 6 VISITS( HALFWAY )
WE ALSO HELD A PARTICIPANT LOTTERY ,, THE DRAW WAS DONE QUARTELY FOR PREVIOUS VISITS THAT HAD ALREADY BEEN ATTENDED
AN INCREMENTAL REIMBURSEMENT WAS ALSO DONE AS THE VISTS ACCRUED
THESE SMALL GIFTS AND COMPETITIONS WERE ALL IRB APPROVED

13. 4. Focusing on hard to reach participants
Rural outreach trips
Closing visits done at homes
Coordinators/ PIs visiting participants who repeatedly were “difficult to bring to the clinic”
Fast-track provision for hard-to-reach or working participants
“Final push” for 2 months after last scheduled visit
We also focused on participants that we termed as Hard to reach. These participants were hard to reach for one reason or the other. They either relocated or kept promising to come for visit. For those who migrated to rural areas or other towns Rural Outreach trips were done to give these participants busfare to come to the clinics. For those who said they did not have time to come to the clinic a MIRA team visited them at home and did a closing visit in their home.
And for those participants who repeatedly were difficult to bring back to the clinic, a coordinator or PI visited them at home.
And a final push for participants who had not closed after the last scheduled visit was done for 2 months to try and bring them all back to the clinic for a closing visit

14. Results – Visit attendance # attended/ #expected

15. Results – final retention and LTFU
Intervention Arm
Control Arm
Followed
2521†
2518 †
Completed scheduled closing visit
2322 (92%)
2349 (93%)
Early withdrawals ††
57 (2.3%)
42 (1.7%)
Lost to follow up
142 (5.6%)
127 (5.0%)
- At last scheduled follow-up visit, on October 4, 2006, 89% of enrolled participants had a closing visit
- After another 2 months of intensive follow-up and tracking, 92.5% of participants had come for their scheduled visit
- Overall 5.3% of participants were classified as LTFU, meaning that they never returned to the clinic for a closing visit and a final endpoint (HIV) test. Some of these participants had some follow-up data and contributed some woman-months to the analysis, others were never seen after enrollment
† Baseline sample
†† Withdrawals include participants who were discontinued due to death (23) or
who came back to the study clinic and withdrew or were withdrawn early because of relocation (22), partner-related reasons (16), personal reasons (13), no time to participate (13) or other reasons (12)

16. Conclusions
Pre-emptive planning and continuous monitoring of retention rates, combined with additional tracking time ensured high return of participants
Achieving high retention is resource intensive and requires proper allocation of financial, administrative and human resources
Many of our successful strategies were staff-driven, therefore it’s important to involve all members of staff in retention discussions, and to share ideas across sites
In conclusion, pre-emptive planning and continuous monitoring of retention rates , combined with additional tracking time ensured high return of participants
Achieving high retention is resource intensive and requires proper allocation of financial, administrative and human resources
Many of our successful strategies were staff-driven, therefore it is important to involve all members of staff in retention discussions and to share ideas across all sites

17. Thank you!

18. Co-authors and Acknowledgements
This study was funded by the Bill and Melinda Gates foundation
UZ-UCSF Agnes Chidanyika
UCSF, Women’s Global Health Imperative Liz Montgomery
Mi Lam
Ariane van der Straten
Nancy Padian
Medical Research Council (MRC), Durban Sharika Gappoo
Perinatal HIV Research Unit (PHRU), Soweto Sinazo Pato
Ibis Reproductive Health Naomi Lince
The MIRA team