Follow-up Medical History and Clinical Considerations MTN 025 Training

Outline  Medical Menstrual History Update  Specific Clinical Management Considerations

Follow-Up Medical/Menstrual History  An updated participant self reported medical/menstrual history is required at each scheduled visit  Two objectives of the follow-up history Determine whether previously documented conditions have changed Determine whether new AEs have occurred since the last history was obtained  History should also be obtained at interim visits, as clinically indicated

Possible Approaches  General questions about current health How are you feeling today? Have you had any issues since your last visit?  Targeted gynecologic questions Any gynecologic problems since your last visit- like abnormal discharge or irregular bleeding?  Targeted questions about ongoing baseline medical conditions and previously reported AEs At your last visit you reported X. Is this still ongoing?

Follow-Up Medical/Menstrual History Documentation  “How have things changed since your last visit with us?” Chart note  Review Baseline Medical History Log CRF Follow-up on ppt-reported baseline symptoms/conditions still ongoing Document resolution of ppt-reported items by updating form  Review AE and GAE CRFs Follow up on and update, as needed, ppt-reported conditions on AE and GAE CRFs that are continuing; add new events as needed  Cross-check with Con Meds Log as needed

Follow-up Medical History Documentation and Considerations  Documentation of review is required in a chart note, even if nothing has changed Example: “Ppt reported no changes in conditions or symptoms since last visit”  Participants will see a number of staff members throughout the visit and may report different or varying symptoms during the visit How will the team ensure that documentation is consistent in the chart notes? How will discrepancies be addressed?

Baseline Condition Identified  If a baseline condition is identified in follow-up (That is, the participant did not report it at screening or enrollment), add the information to the Baseline Medical History Log CRF  Explain the addition in a chart note

Last Menstrual Period  Last menstrual period will be recorded on the Pregnancy Test Result CRF. Menstrual-like bleeding Use clinical discretion to determine if bleeding is menstrual like  LMP recording does not need to be consistent with AE reporting terms.  Genital bleeding that is not considered to be menses, should not be documented on the Pregnancy Test Result CRF. Record on other source documents as applicable (e.g. chart notes) as well as AE Log CRF, if AE reporting requirements are met.

Self-Collection of Vaginal Fluid  At Enrollment and all scheduled follow-up visits, participants will collect vaginal fluid for biomarker analysis (**instructions on website) Collect PRIOR to removal of the last month’s ring Collect even if the participant chose not to wear the ring or had a hold Collect even during menses The participant or clinician can collect

AEs, SAEs, and EAEs – An Overview MTN 025 Training

Layers of Safety  Study participants  Study site staff team  Clinical affairs staff at SCHARP  MTN-025 Protocol Safety Review Team (PSRT)

Any untoward medical occurrence in a clinical research participant administered an investigational product that does not necessarily have a causal relationship with the investigational product. An AE can therefore be an unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. ICH E6, Glossary 1.2 Definition: Adverse Event

Any medical condition, problem, sign, symptom, or finding identified as ongoing in a study participant at the time of enrollment Baseline Medical conditions are not AEs. However, if a baseline condition worsens in severity and/or frequency after enrollment, the worsened condition is an AE. If a baseline condition resolves after enrollment, but then recurs at a later date, the recurrence is considered an AE. Definition: Baseline Medical Condition

Case 1  A participant reports that she has asthma during her baseline medical history  Has an AE occurred? No Yes Not enough information to determine

Case 2  A participant reports a migraine headache occurring two weeks before her Month 3 visit.  Has an AE occurred? No Yes Not enough information to determine

Case 3  A participant has a positive pregnancy test result at her Month 6 visit.  Has an AE occurred? Yes No Not enough information

Case 4  A participant reports new vulvar erythema at her Month 3 visit. You note erythema on pelvic exam that covers approximately 30% of her vulva.  Is this an AE? Yes No Not enough information  What if the vulvar erythema had not been seen on exam – does this change your answer?

An AE that meets study protocol criteria for reporting on adverse event case report forms For MTN 025, this means reportable on an Adverse Experience (AE) Log CRF AEs that do not meet the protocol criteria for reporting on adverse event forms will be recorded on the Grade 1 AE Log CRF (GAE Log) Definition: Reportable Adverse Event

Reportable Adverse Events There are six types of AEs that are reportable in MTN 025. Can you name them?

Reportable AEs  All genital, genitourinary, and reproductive system AEs except Fetal losses Expected genital bleeding per clinical assessment  All AEs of severity Grade 2 or higher  All serious AEs  All AEs that results in product hold  All lab test abnormalities not otherwise associated with a reported clinical AE  AEs that meet expedited reporting requirement  Any AE not covered above will go on a Grade 1 AE Log form

AE Log or Grade 1 AE Log CRF?  Grade 1 vaginal erythema  Grade 3 headache  Grade 1 diarrhea  Grade 1 urinary tract infection  Grade 1 weakness prompting hospital admission to rule out stroke  Grade 1 allergic reaction to the vaginal ring

Pelvic Exam Finding AEs  Report any and all new abnormal findings as AEs Specify anatomical location (e.g., vulvar, vaginal, cervical) Use finding term as it appears in FGGT or Pelvic Exam CRF, whichever is more specific For example, do not report “genital sore.” Instead, report “vaginal ulcer.” Describing AEs

Pelvic Exam Terminology

Well-Defined Terms  Makes communication between investigators easier  Can be used to double- check what is recorded regarding intactness of the epithelium and blood vessels

Pelvic Exam Terminology  To document findings, use terms from the pelvic exam case report form or FGGT  These terms largely match the FGGT Ecchymosis is listed on CRF but not on FGGT Petechiae is listed neither place but is referenced in protocol  Always grade 1 per SSP Use routine QC/QA opportunities to help ensure consistency of terminology across staff and exams

Common Pelvic Finding Terms  Erythema  Edema  Petechiae  Ecchymosis  Peeling  Ulceration  Abrasion  Laceration

Pelvic Exam Findings Review Epithelial Disruption Erythema Edema ALL IMPACT PRODUCT USE

Epithelial Disruption  Extent of epithelial disruption helps to distinguish between findings  Superficial epithelial disruption Does not penetrate into the subepithelial tissue  Deep epithelial disruption Penetrates into and exposes subepithelial tissue and possibly vessels

Epithelial Disruption  If bleeding from finding is present, disruption should be recorded as deep when in doubt  Assessment of disruption depth is subjective, even with magnification of colposcopy

Normal Cervix  Mucosa Typically uniformly pink Epithelium intact Vessels intact  Normal variants are not lesions Ectropion Gland openings Scarring from cone biopsies

Normal Findings  Ectopy

Normal Findings  Nabothian cysts

Erythema  Reddened areas Margins may or may not be clearly defined Epithelium intact Vessels intact

Edema  Epithelium Intact Swollen  Vessels Intact  Color Normal or pale white

Petechiae  Punctate red areas  Individual or group  Epithelium intact  Vessels disrupted  Diameter ≤3mm  Color of finding is red or purple

Ecchymosis  Epithelium intact  Vessels disrupted  Size >3mm  Color is red or purple

Peeling  Epithelium disrupted but superficially  Vessels intact  Fragment may remain attached to area of peeling  Generally well- demarcated  Underlying epithelium appears normal

Ulceration  Disrupted epithelium Superficial or deep  Vessels intact or disrupted  May include sloughing  Sharply demarcated outline

Abrasion  Epithelium disrupted Superficial or deep  Vessels intact or disrupted  Diffuse or poorly demarcated outline

Laceration  A “cut” or “fissure”  Epithelium disrupted Superficial or deep  Vessels intact or disrupted  Appears to be linear “pulling apart” or wearing away of tissue

Reporting Recurring Events  If an AE previously reported within an AE log CRF resolves and then recurs at a later date, the second occurrence must be reported as a new AE on a new AE or GAE Log CRF  Regular occurrences of the same adverse event that are expected are not considered separate adverse events Headaches, for example

 The severity of all AEs must be graded as Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Potentially Life-Threatening Grade 5 = Death  Assign grades based on the DAIDS Female Genital Grading Table (FGGT) and DAIDS Table for Grading Adult and Pediatric Adverse Events (Toxicity Table) AE Severity

Severity Grading of Vaginal Candidiasis  Normal = absence of symptoms regardless of candida test results  Grade 1 = positive wet mount or other laboratory test for yeast, with mild symptoms  Grade 2 = positive wet mount or other laboratory test for yeast, with moderate to severe symptoms  Grade 3: Not applicable  Grade 4: Not applicable

 The relationship of each AE to study product must be assessed as: Related Not Related Relationship to Study Product

 Pre-clinical and clinical profile of the study products: protocol, package inserts, investigators brochures, other published information  Timing of product use relative to onset, resolution, and/or recurrence of the AE  Likelihood of observing the AE in the study population in the absence of product use  Presence of other conditions or exposures that could have caused the AE  Clinical judgment, including judgment of biologic plausibility Factors to Consider

 Sites must include text in the “Comments” field to explain why the AE has been judged “related” or “not related“  “No other explanation” is not adequate Relationship Rationale

 All AEs – reportable and not reportable – must be followed clinically until the AE resolves or stabilizes  Resolution = return to baseline severity grade  Stabilization = persistence at a severity grade above baseline for 3 consecutive months AE Outcome

 At each visit, an authorized study clinician should review all previously reported ongoing AEs to evaluate their current status  Oftentimes the outcome of an AE will not be available when the AE is first documented  In such cases, documentation should be updated when the final outcome becomes available AE Outcome

 If an AE increases in severity or frequency, the higher grade AE must be documented (and reported) as a new AE  If an AE completely resolves and then recurs at a later date, the second occurrence must be documented (and reported) as a new AE AE Outcome

Any untoward medical occurrence that at any dose:  Results in death  Is life-threatening  Requires inpatient hospitalization or prolongation of existing hospitalization  Results in persistent or significant disability/ incapacity  Is a congenital anomaly/birth defect Definition: Serious Adverse Event Important medical events that may not be immediately life- threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of the above-listed outcomes, also may be considered serious.

 Seriousness ≠ severity  SAEs are a subset of all AEs  All SAEs are reportable on AE Log forms  All AEs must be assessed by authorized study staff to determine whether they meet the definition of serious  source document and record on AE Log form Seriousness of Adverse Events

AE that meets criteria in the study protocol for additional reporting for rapid review and assessment by DAIDS Reporting period begins once the participant is enrolled and continues through the final study visit (Study Exit/Termination Visit) For MTN 025 the “SAE (Serious Adverse Event) Reporting Category” will be used to report EAEs. Expedited Adverse Event

Let’s Discuss More Adverse Events Suppose a participant has a grade 3 decreased hemoglobin at her PUEV Is this an adverse event? 1. Yes 2. No 3. Not enough information to determine

Let’s Discuss More Adverse Events Suppose a participant has a grade 4 decreased hemoglobin at her PUEV Is this serious? 1. Yes 2. No 3. Not enough information to determine

Let’s Discuss Adverse Events Suppose a participant is in a car accident. As a result of the accident she suffers a broken arm and a head laceration. She is taken to the emergency room where she receives a cast for her arm. Because the treating doctor is concerned that the participant might have suffered a concussion, the doctor admits the participant to the hospital. How many AEs have occurred? 1. One 2. Two 3. None

Let’s Discuss Adverse Events Suppose a participant is in a car accident. As a result of the accident she suffers a broken arm and a head laceration. She is taken to the emergency room where she receives a cast for her arm. Because the treating doctor is concerned that the participant might have suffered a concussion, the doctor admits the participant to the hospital. How many AEs are EAEs? 1. One 2. Two 3. None

Let’s Discuss Adverse Events Suppose a participant has a positive pregnancy test at her Month 6 visit. At her Month 9 visit, her pregnancy test is negative. She reports having no symptoms between visits and is surprised that she is no longer pregnant. Is this an adverse event? 1. Yes 2. No 3. Not enough information to determine

A Few Extra Reporting Tips  Only symptomatic BV confirmed by wet mount should be reported as an AE  Only symptomatic candida infections confirmed by wet mount should be reported as an AE  Chlamydia should be “genitourinary chlamydia infection”  Gonorrhea should be “genitourinary gonorrhea infection”  Suspected herpes lesions should be captured as “ulcers”

Specific Reporting Issues (and a little bit of management)

Pap Smear  Whether an abnormal pap smear in follow-up is an AE depends on the cervical dysplasia history  If the pap smear is a HIGHER grade than baseline, submit an AE  If the pap smear is the SAME grade as baseline, no AE

Cytology vs Histology  In general, replace histology with cytology when available and equal grade  If histology is higher grade than cytology, submit an AE

For Example:  A participant has a LSIL pap smear result during screening Where is this documented?  Once enrolled she has a colposcopy with a biopsy If the biopsy shows CIN 1 (same grade) If the biopsy shows CIN 2 (higher grade)

Pap Clinical Follow-Up  Pap smears should be managed per local standard of care as specified in SOP  If a colposcopy is required Participant should be advised to remove the ring on the day of the colposcopy Duration of the ring outage will depend on what happens at the colposcopy  If a biopsy or treatment is NOT performed, reinsert following the colposcopy (no product hold)  If a biopsy or treatment IS performed complete PH CRF and hold until adequate healing is confirmed

STI/RTI Management  STIs/RTIs should be treated per WHO guidelines Except for asymptomatic candidiasis and asymptomatic bacterial vaginosis neither require treatment per HOPE  WHO guidelines are minimum standard; if local guidelines set higher standard, follow local guidelines  Document all treatments taken on Con Meds Log

STI/RTI Management  Syndromic Management is acceptable per site SOP  STI/RTI are considered resolved when treatment has been completed and symptoms, if any, have resolved No test of cure is required or result needed on CRF

Syphilis  Clinical management of syphilis should include repeat serology (RPR) at six-month intervals to confirm treatment effectiveness If RPR titre does not decrease four-fold or revert to seronegative within six months after treatment, consult the PSRT

Vaginal Discharge  Abnormal vaginal discharge is common and may be participant reported or clinician observed  Evaluation is per clinician discretion and should be the same regardless of identifying source  Treatment, however, may differ If underlying diagnosis is STI, treat If asymptomatic BV or yeast, no treatment required  Record AE Verbatim term should be underlying diagnosis (trichomonas, for example) UNLESS asymptomatic BV or yeast is uncovered In that case, record “vaginal discharge per ppt report” or “vaginal –discharge-clinician observed” If discharge is both participant reported and clinician observed, record “per ppt report”

Urinary Tract Infections  In HOPE, UTI may be diagnosed by symptoms  Other methods of diagnosis (culture, dipstick) may be performed per site standard of care per site SOP  If urine culture or urinalysis are used, UTI should be graded per the UTI row of FGGT  If only symptoms are used, grade per the estimating Severity Grade for Parameters Not Identified in the Grading Table row

 Report only bleeding that is different from baseline and NOT attributable to a contraceptive Use appropriate term FGGT  Menorrhagia, metrorrhagia, menometrorrhaghia, post coital bleeding Use separate terms for pregnancy-related bleeding If bleeding associated with pelvic exam finding, report finding as the AE The bleeding is a sign of the finding - comment on in Comments field Genital Bleeding

 Shorter than expected menses are not AEs  New events of infrequent bleeding for UNKNOWN reasons or delay of menses for more than one month delay should be documented as an AE For missed menses events of 1-3 months in duration, use the term “missed menses” For missed menses events of 4-5 months in duration, use the term “oligomenorrhea” For missed menses events of 6 months or longer, use the term “amenorrhea ”  Infrequent Bleeding

Bleeding during pregnancy prior to the onset of labor (regardless of trimester) will be graded per the table below: Antepartum Bleeding

 Weight loss is reportable as an AE ONLY if it considered potentially deleterious to the participant’s health by either the participant or the site clinician Use the term “weight loss abnormal” Add to the comments section that the AE is considered deleterious Weight Loss

 “HIV Infection” should not be captured as an AE as it is a study endpoint  However, seroconversion illness SHOULD be captured as often the participant is symptomatic Use the term “seroconversion illness” In the comments describe each HIV-related symptom and sign In the comments, note the alternate etiology as due to “acute HIV” Reporting HIV Infection

 Social Harm - non-medical adverse social consequence of study participation  Ex: stigma/discrimination from members of community or family, difficulties in personal relationships with partners, family, or friends  Ppts will be specifically asked about social harms every 3 months and at PUEV (via BA CRF), but can report (and site to document) a social harm at any time during the study  Care, counseling, follow-up provided per SSP guidance in Section 11.9  Documented on Social Impact Log Social Harms

Intimate Partner Violence (IPV) Complete Social Impact Log if “yes” and event was related to study participation Complete AE Log, if indicated (criteria defined in SSP Section 11.1) and report as EAE, if required (criteria defined in SSP Section 11.2) Regardless of whether IPV meets criteria for reporting as a Social Harm or AE, always provide appropriate support, counseling, and referrals to the participant.

 Any physical sequelae that result from a sexual assault reported during the study and that meet AE reporting criteria should be reported on an AE log CRF  Each physical sequela should be reported as its own AE In the AE text due not mention sexual assault but rather reference “sexual assault” in the Comments section DO NOT complete a separate AE log form for “sexual assault” as the AE term  These participants need to be offered immediate support, care and referrals  Emergency contraceptive and STI prophylaxis/treatment should be offered  PEP should be considered Reporting Sexual Assault

Questions?