Assessment of Physical Examination and Sexual Maturity Rating in HIV-Infected Children and Adolescents

1. IMPAACT 2017 Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected Children and AdolescentsMOCHAMore Options for Children and Adolescents

2. MOCHA study-specific training Self-Review module: IMPAACT 2017 Physical Examination and Sexual Maturity Rating (Tanner Staging)

3. Training Objectives To provide an overview and establish a common understanding of the following: • Timing and guidelines for performing a complete physical examination • Timing and guidelines for performing a symptom-directed (targeted) physical examination • Importance of sexual maturity rating (Tanner staging) • Guidelines and timing of performing Tanner staging

4. Protocol References See MOP Section 5.6, Physical Exams and Sexual Maturity Rating (Tanner Staging) for additional details and operational guidance on these topics

5. Physical examination

6. Physical Exam • A physical examination is required at each scheduled visit, either as a complete physical exam or as a symptom-directed physical exam, per the specified procedures for each visit • All exam findings should be source documented, with vital signs and any abnormal findings entered into eCRFs • Note that height and weight must be obtained on the same day as any PK sample collection, and must also be source documented and entered into eCRFs. Refer to the procedural tables in Protocol Section 6 and the SoEs for required PK sampling.

7. Physical Exam: Cohort 1

8. Physical Exam: Cohort 2

9. Physical Exam: LSFU

10. Complete Physical Exam • Protocol Section 6.11 outlines the visits when a complete physical exam is required; symptom-directed exams are required at all other scheduled visits. • Table 8. Visits Requiring Complete Physical Examination

11. Complete Physical Exam • Each complete physical exam must include the following: • Height and weight • Vital signs, including heart rate, temperature and blood pressure • Examination of: • General appearance • Head: eyes, ears, nose, mouth and throat • Neck • Lymph nodes • Chest: Lungs, heart • Abdomen • Musculoskeletal system • Skin • Neuro • Other body systems driven by other identified signs or symptoms • Should also include a Sexual Maturity Rating (SMR) at specific study visits

12. Symptom-DirectedExam • Each symptom-directed physical exam must include the following: • Height and weight • Vital signs, including heart rate, temperature and blood pressure • Examination of body systems driven by identified signs or symptoms • Additional assessments may be performed at the discretion of the examining site investigator.

13. Performing sexual maturity rating (SMR): Tanner Staging

14. Importance of Assessing Sexual Maturity • Drug metabolism is influenced by pubertal stage • CAB and RPV absorption are affected by muscle mass and adipose tissue • Adipose and muscle mass are influenced by stage of puberty • Most widely used method of assessing sexual maturity (SMR) is Tanner staging

15. SMR Timing • Sexual maturity rating should be conducted during the complete physical exam at the following study visits: • Cohort 1: Screening, Week 16 • Cohort 2: Screening, Week 24, Week 96 • LSFU: 48 Weeks Post-Last Injection/Early Termination visits

16. Performing SMR • During a complete physical exam, study staff should visually assess the participant to determine the corresponding rating of development • The following tool must be used to determine the Tanner stage and should be used across all participants

17. Tanner Stage

18. Tanner Stage Outcomes • All Tanner Staging data should be entered onto the Tanner Stage/Testicular Volume form (EVW10027). • The visual tool is available in the help text on the EVW10027 form • Note that menarche status will be collected separately on the EVW10042 form • For females, this includes: • Breast Tanner Stage • Pubic hair Tanner Stage • For males, this includes: • Genitalia Tanner Stage • Pubic Hair Tanner Stage

19. Boys and girls - pubic hair • Stage 1:Pre-pubertal (can see velus hair similar to abdominal wall) • Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia • Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes • Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs • Stage 5: Adult in type and quantity, with horizontal distribution ("feminine")

20. Boys - development of external genitalia • Stage 1: Pre-pubertal • Stage 2: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture • Stage 3: Enlargement of penis (length at first); further growth of testes • Stage 4: Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker • Stage 5: Adult genitalia

21. Girls - breast development • Stage 1: Pre-pubertal • Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola • Stage 3: Further enlargement of breast and areola; no separation of their contour • Stage 4: Areola and papilla form a secondary mound above level of breast • Stage 5 :Projection of papilla only, related to recession of areola

22. Thank you for viewing this self-review module! Please remember to document your completion of this training component Per the DAIDS policy on Requirements for Manual of Operational Procedures, all sites must establish and follow a standard operation procedure (SOP) for personnel training and certification documentation Each site is responsible for preparing attendance documentation for this self-review module in accordance with this SOP.