MTN003 Study Specific Training Randomization Overview 1 Why

MTN-003 Study Specific Training Randomization Overview 1

Why Randomize? • Ensures that all study groups in a clinical trial are comparable with regard to factors that could affect study outcomes (e. g. , risk of HIV infection) – Age and other demographics – Past medical history and pre-existing conditions – Sexual behaviors and condom use • Ensures that the study team will be able to clearly interpret the final study results – E. g. If the study drug has an effect in reducing HIV, the effect of the drug is due to the drug itself and not some other factor 2

What Randomization Achieves Mean Age (yrs) Mean Education (yrs) Ever Pregnant Married Vaginal sex acts in last 7 days Condom use in last 7 days 3 Active Drug 21 Placebo 22 11 11 85% 84% 5% 5% 5 5 89%

MTN-003 Randomization Scheme All Participan ts (4200) Blinded 4 Not Blinded Oral Tablet (2520) Truvada Tablet (840) Tenofovir Tablet (840) Vaginal Gel (1680) Placebo Tablet (840) Tenofovir Gel (840) Placebo Gel (840)

How Will the Randomization Process Work? • Envelope randomization will be used • SCHARP will provide two sets of envelopes to each site 1) Clinic Randomization Envelopes 2) Pharmacy Randomization Envelopes 5 • Each set of envelopes will be numbered sequentially • Each clinic envelope will have a matching pharmacy envelope (matched by envelope number)

How Will the Randomization Process Work? 6 • Each participant will be assigned a clinic randomization envelope and the matching pharmacy randomization envelope (e. g. , a participant assigned clinic envelope 0100 will be assigned pharmacy envelope 0100, etc. ) • Assignment of the clinic envelope is the effective act of enrollment in MTN-003 · Once a clinic envelope is assigned, the participant is considered officially enrolled in the study

Importance of Sequential Clinic Envelope Assignment • It is critical to the integrity of the study that clinic randomization envelopes are assigned in sequential order – If not assigned in proper order (even just one), this could have a serious impact on validity of study results. • SCHARP will provide clinic and pharmacy envelope tracking records to document envelope assignments – This will help ensure that envelopes are assigned sequentially 7

Clinic Envelope Tracking Record 8

Randomization Envelopes • Clinic envelopes sent to site clinics • Pharmacy envelopes sent to site pharmacies • Envelope specifications: – – Large enough to contain A 4 size paper Opaque: manila folder inside each envelope Tamper evident: sealed with blue tape Labeled as “Clinic” or “Pharmacy” with site information, study number, envelope number • All envelopes assembled and reviewed for at SCHARP before shipment to sites 9

Clinic Randomization Envelopes • Maintained by clinic staff CLINIC MTN 003 -Randomization Envelope DAIDS Site ID: 30302 CRS Name: R. K. Khan Hospital CRS Location: Durban, South Africa Envelope Number: 0001 10

Pharmacy Randomization Envelopes • Maintained by pharmacy staff • Look exactly like clinic envelopes, except labeled as “PHARMACY” PHARMACY MTN-003 Randomization Envelope DAIDS Site ID: 30302 CRS Name: R. K. Khan Hospital CRS Location: Durban, South Africa Envelope Number: 0001 11

12

13

Clinic Randomization Envelopes • Contain one MTN-003 prescription: – Two-part, no carbon required (NCR) form • original (top part) is white • copy (bottom part) is yellow – 14 Assignment to “Oral Tablets” or “Vaginal Gel” • Authorized prescriber or other designated clinic staff should complete information on prescription (e. g. , PTID, Date Assigned) • Signature of authorized prescriber is required • Dispensing instructions for pharmacy staff • Once completed, white (original) goes to pharmacy, yellow (copy) is filed, along with opened envelope, in the participant study notebook

Gel Prescription 15

Tablet Prescription 16

Pharmacy Randomization Envelopes • Contain study product dispensing records that will be completed by pharmacy staff • Dispensing records are linked to prescriptions by envelope number – The prescription from the clinic envelope will have the clinic envelope number pre-printed on it – The pharmacy will receive the prescription and assign the pharmacy envelope with this same number to the participant – Pharmacy staff will then dispense the assigned study product to the participant and record this information on the dispensing record. 17

Before You Randomize…. . • Confirm participant’s eligibility for the study • Complete the enrollment informed consent process • Administer the Baseline Behavior Assessment CRF and Baseline ACASI questionnaire • Obtain blood for plasma archive • If applicable, administer Hepatitis B vaccine 18

SCHARP Monitoring of Randomization • Both clinic and pharmacy staff will record randomization information on CRFs and fax these CRFs to SCHARP • Based on these CRFs, SCHARP will verify sequential assignment of clinic envelopes and proper random assignment to either oral tablets or vaginal gel • SCHARP will also verify that the correct product was dispensed at the Enrollment Visit – SCHARP will monitor on-study dispensing as well 19

SCHARP Monitoring of Randomization • If CRF data indicate a randomization error, SCHARP will contact the site clinic and/or pharmacy immediately to verify the information recorded on the CRF • If it is determined that a randomization error has occurred, the Protocol Team will be notified and the site will be provided guidance on how to address the error 20

Operational Considerations • Each site must establish an MTN-003 SOP for randomization (clinic procedures only) to specify: – Who will receive clinic randomization envelopes from SCHARP – Where clinic randomization envelopes and tracking record will be kept (secure location) – How clinic envelopes will be assigned and who will assign them – Who will complete prescriptions – Where opened envelopes and yellow (clinic) copies of prescriptions will be filed – Who will QA/QC randomization documentation and how often this will occur 21

If the site identifies a randomization error… • Immediately contact the MTN-003 SCHARP Project Managers and FHI Clinical Research Managers and explain the situation – mtn 003 mgmt@mtnstopshiv. org • Follow guidance provided by SCHARP and the Protocol Team – randomizations may need to be halted during this time 22

Questions? ? ? 23