J.5.1 - Treatment Protocol Study 35.pdf

Attachment J.5.1 - Solicitation 75D301-20-R-67869

TBTC S35: Phase I/II Dose Finding and Safety Study of Rifapentine in Children with LTBI Version 2.0

14 April 2019

TITLE

Phase I/II Dose Finding and Safety Study of Rifapentine and Isoniazid in HIV-Infected and HIV-Uninfected Children with Latent Tuberculosis Infection

Consortium Identifiers:

Tuberculosis Trials Consortium Study 35 (TBTC Study 35)

Funding Agency:

U.S. Centers for Disease Control and Prevention (CDC), and CDC Foundation

Pharmaceutical Support Provided by:

Sanofi U.S.

IND Number:

141932

Sponsor:

U.S. Centers for Disease Control and Prevention (CDC)

Study Chairs:

Anneke C. Hesseling, MD, PhD

Deron Burton, MD, JD, MPH Rada Savic, PhD

Kelly Dooley, MD, Pharm D

Version Number: 2.0

Statement of Compliance

This trial will be conducted in compliance with the protocol, International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), the U.S. Code of Federal Regulations 45 CFR 46 and 21 CFR, and applicable site-specific including South African regulatory requirements including SA-GCP.

To comply with conditions of receiving donated study drug product, Clinical Trial Sites will adhere to the following, throughout the implementation of this study:

− The clinical trial sites will take reasonable precautions to protect the confidential nature of proprietary information related to the drug product used for this study, at least as stringent as those observed by their own organizations to protect their own confidential information.

− The drug product supplied by the manufacturer will not be used for any purpose other than the conduct of this study, as outlined in the protocol. The drug product will not be transferred to anyone other than research personnel or participants and will not undergo any analysis (compositional, structural, functional or other) without written permission from the manufacturer.

TABLE of Contents

1. Overview

1.1 Protocol Summary

1.2 Study Schematic

1.3 Abbreviations

1.4 Key Roles

2 Background Information and Scientific Rationale

2.1 Background Information

2.1.1 Treatment of latent TB infection (LTBI)

2.1.2 Pharmacokinetics of TB drugs in children

2.1.3 Rifapentine for the prevention of tuberculosis

2.1.4 Pharmacokinetics of rifapentine in adults

2.1.5 Pharmacokinetics of rifapentine in children

2.1.6 Effect of HIV co-infection on the pharmacokinetics of rifapentine

2.1.7 Safety and tolerability of rifapentine

2.1.8 Safety of higher dose isoniazid in children

2.1.9 Formulation development

2.2 Relevance to the Global Scientific Agenda and Global Child Health

2.3 Summary of rationale and aims

3 Study Objectives

4 Study Design

5 Study Population

5.1 Inclusion criteria

5.2 Exclusion criteria

6 Recruitment/Enrolment

7 Study Procedures

7.1 Clinical evaluations

7.2 Cohort management (overview of enrolment plan, interim analyses, and rules for rifapentine dosing adjustment)

7.3 Starting dose and dose adjustment

7.4 Concomitant medications

7.5 Adherence assessment

7.6 Collection, processing and storage of PK samples

7.7 Analyses of study drug concentrations

7.7.1 Pharmacokenetic laboratories

7.8 Pharmacogenomic assessments

7.8.1 Pharmacogenomic laboratories

7.9 Tolerability and safety assessment

7.9.1 Safety laboratories

7.10 Palatability assessments

7.11 Management of a participant who is discontinued from study drug

8 Study Schedule

8.1 Screening/Enrolment

8.2 Study visits

9 Study Intervention/Investigational Drugs

9.1 Study drugs and dosing

9.2 Study drug acquisition

9.3 Study drug stability/storage

9.4 Allowable treatment period

9.5 Accountability procedures for study drug

10 Assessment of Safety/Clinical Management Issues

10.1 Specification of safety parameters and management of adverse events

10.1.1 Adverse event (AE) definition and grading

10.1.2 Suspected adverse reaction (SAR) definition

10.1.3 Adverse reaction (AR) definition

10.1.4 Definition of unexpected AE or SAR

10.1.5 Definition of serious adverse event (SAE) or serious SAR

10.1.6 Definition and reporting of serious and unexpected suspected adverse reaction (SUSAR)

10.1.7 Overview of management of participants

10.1.7.1 Suspected TB Disease

10.1.7.2 Rifamycin hypersensitivity syndrome (RHS)

10.1.7.3 Gastrointestinal

10.1.7.4 Cutaneous

10.1.7.5 Drug-Associated Fever

10.1.7.6 Peripheral Neuropathy

10.1.7.7 Asymptomatic Elevation in ALT

10.1.7.8 Hepatotoxicity (Symptomatic Hepatitis)

10.1.7.9 General Management of Adverse Events (Not Otherwise Specified Above)

10.2 Reporting procedures for adverse events and serious adverse events

10.2.1 Overview

10.2.2 Reporting procedures

10.3 Other diseases

10.4 Pregnancy

10.5 Data and Safety Monitoring Board

11 Statistical Considerations

11.1 Study hypotheses

11.2 Study endpoints

11.2.1 Primary endpoints

11.2.2 Secondary endpoints

11.3 Disposition of participants

11.4 Analysis plan

11.4.1 Population PK analysis

11.4.2 Safety and tolerability analyses

11.5 Sample size considerations

12 Feasibility of Study

13 Quality Control and Quality Assurance

13.1 Local quality control

13.2 External monitoring

14 Ethics/Protection of Human Subjects

14.1 Institutional review board

14.2 Informed consent process

14.3 Subject (Participant) confidentiality

14.4 Study discontinuation

15 Data Handling and Record Keeping

16 Publication and Dissemination of Study Results

APPENDIX 1. RECOMMENDED FIRST-LINE ARV REGIMENS IN CHILDREN; SOUTH

AFRICAN NATIONAL DEPARTMENT OF HEALTH GUIDELINES, 2015

APPENDIX 2. SCHEDULE OF STUDY EVALUATIONS

APPENDIX 3. INFORMED CONSENT, ASSENT, PHARMACOGENETIC TESTING CONSENT

AND PHARMACOGENETIC TESTING ASSENT FORMS (GENERIC VERSIONS). NOTE

THAT ADDITIONAL SITE-SPECIFIC CONSENTS MAY BE REQUIRED

I. PARTICIPANT INFORMATION LEAFLET AND INFORMED CONSENT FORM FOR

PARENTS/LEGAL GUARDIANS

II. GENETIC TESTING AND LONG-TERM STORAGE PARTICIPANT INFORMATION LEAFLET

AND CONSENT FORM FOR USE BY PARENTS/LEGAL GUARDIANS

III. INFORMATION LEAFLET AND ASSENT FORM FOR CHILDREN OLDER THAN 7 YEARS

IV. GENETIC TESTING AND LONG-TERM STORAGE PARTICIPANT INFORMATION

LEAFLET AND ASSENT FORM FOR OLDER CHILDREN

APPENDIX 4. PALATABILITY AND ACCEPTABILITY QUESTIONNAIRE

REFERENCES

1. Overview

1.1 Protocol Summary

Title: Phase I/II Dose Finding and Safety Study of Rifapentine and Isoniazid in HIV-Infected and HIV-Uninfected Children with Latent

Tuberculosis Infection

Hypotheses: Rifapentine (given as water-dispersible monolayer and/or fixed dose combination with isoniazid) dosing in HIV-infected and uninfected children ≤ 12 years of age with latent TB infection (LTBI) or with exposure to Mycobacterium tuberculosis (M. tuberculosis) will require higher mg/kg rifapentine dosing than adults to achieve adult exposures which are correlated with efficacy of rifapentine in trials of TB prevention. We further hypothesize that rifapentine will be safe and well-tolerated in HIV-infected and uninfected children who require treatment for LTBI.

Design: Tuberculosis Trials Consortium Study 35 (TBTC S35) is a Phase I/II, open-label, single arm, exposure-controlled dose finding study using an adaptive design. S35 will evaluate the pharmacokinetics (PK), safety and tolerability of rifapentine given in a new, water-dispersible fixed dose combination formulation with isoniazid once-weekly, for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The study utilizes a modified age de-escalation approach given the extensive PK and safety data already available in children older than 2 years of age. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.

Sample Size: Approximately 72 participants will be required to ensure a minimum number of 60 evaluable participants.

Participants will be enrolled in 4 age cohorts:

Cohort 1: ≥ 4 to ≤ 12 years Cohort 2: ≥ 24 months to < 4 years Cohort 3: ≥ 12 to < 24 months Cohort 4: 0 to <12 months

There will be a minimum of 12 participants each in cohorts 1 and 2, and 18 participants each in cohorts 3 and 4, respectively, to allow for

36 participants in the age group below 2 years, given the importance of developmental pharmacology in this youngest age group (Table 1) and the lack of historical data in this age group. Cohorts 3 and 4 will be enrolled once week 1 PK data and safety data through week 12 are available in cohorts 1 and 2.

Up to 18 HIV-infected children overall will be enrolled (all cohorts) with a minimum target of 12 HIV-infected children overall. It is expected that most HIV-infected children will be > 3 years of age given current international recommendations regarding the use of efavirenz in children in international settings, where the study will be conducted. However, it is expected that integrase inhibitors (e.g.

raltegravir and dolutegravir) would become more routinely available during the study period, allowing for younger HIV-infected children (<3 years of age) to also be enrolled on study.

Population: HIV-infected and uninfected children aged 0-12 years who could benefit from chemotherapy for LTBI to prevent the development of active tuberculosis, who have documented close recent exposure to a bacteriologically positive drug sensitive adult pulmonary TB source case, or who have proof of M. tuberculosis infection (positive test of

M.tuberculosis infection). HIV-infected children will be established on anti-retroviral therapy for at least 12 weeks prior to enrolment.

Table 1. Minimum evaluable number of participants per age group and by HIV status.

Cohort Age Total number

Number HIV-infected*

Number HIV-uninfected

1 ≥ 4 to ≤ 12 years 12 6 6

2 ≥ 24 months to < 4 years

12 6 6

3 ≥ 12 to < 24 months 18 - 18

4 0 to < 12 months 18 - 18

Total 60 12 48

*The availability of integrase inhibitors during the study implementation may affect the age distribution of

HIV-infected children enrolled (i.e. inclusion of children < 3 years)

Sites: TBTC Site 33, Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, South Africa

TBTC Site 34, Baragwaneth, Perinatal HIV Research Unit (PHRU), Wits Health Consortium, Soweto, Johannesburg, South Africa

Study Duration: Child participants will be on study for a total of 24 weeks, including a

12-week rifapentine and isoniazid dosing period, with an additional follow-up period of 12 weeks. The overall study accrual period will be approximately 12-18 months and the total study duration will be approximately 36 months.

Description of Agent or Intervention:

Participants will receive 12 once-weekly doses of water-dispersible rifapentine and isoniazid; the initial rifapentine dose in each age cohort will be determined based on historical population models, results of relative bioavailability evaluation of the new formulations to be tested and will be adjusted as data become available in paediatric cohorts in this study. Cohorts 1 and 2 will open up with a pre-selected modeled dose. Dose selection for cohorts 3 and 4 will be modeled from data emerging from cohorts 1 and 2 and historical data. Doses in cohorts will be adjusted as required based on interim PK and safety analyses. Isoniazid will be given at doses of up to 25 mg/kg, once weekly, in combination with pyridoxine (Vitamin B6) 25 mg/kg given to participants as clinically indicated.

Objectives

In HIV-infected and HIV-uninfected children aged 0-12 years receiving a new water-dispersible formulation of rifapentine in combination with isoniazid for the prevention of

TB:

Primary

1. To establish, through population PK modeling, the dose(s) of rifapentine that will achieve the target adult exposures [median area under the curve24 (AUC 0-24) no more than 25% lower than, and no more than 75% higher than, the target adult AUC of 522 mcg*h/L] from TBTC Study 26, when rifapentine was given once-weekly, in a fixed dose combination with isoniazid, for 12 weeks.

Secondary

1. To document the safety of rifapentine given in combination with isoniazid once-weekly over 12 weeks.

2. To document the tolerability of rifapentine given in combination with isoniazid once-weekly for 12 weeks.

3. To characterize the PK of rifapentine, given in model-predicted doses, in combination with isoniazid once-weekly for 12 weeks, taking into account covariates that may influence the PK of rifapentine, such as age, weight, sex, HIV status, nutritional status and pharmacogenomics (e.g. SLCO1B1).

4. To document the palatability and acceptability of rifapentine given in combination with isoniazid once-weekly for 12 weeks.

5. To characterize incident TB over a total of 24 weeks follow-up from enrolment in children treated for TB exposure or infection.

6. To characterize the PK of isoniazid given once weekly in combination with rifapentine, taking into account N-acetyltransferase 2 (NAT2) metabolizer genotype.

Exploratory

1. In HIV-infected children, to characterize the effects of once-weekly rifapentine and isoniazid on efavirenz taking into account CYP2B6 efavirenz metabolizer status. In addition, the potential effects of once-weekly rifapentine and isoniazid on dolutegravir/raltegravir PK parameters will be studied if dolutegravir/raltegravir are routinely used in the trial population during the study.

End points

1. Dosing algorithm derived by simulation of optimal rifapentine doses (based on the target adult AUC levels from TBTC Study 26) in children, using nonlinear mixed effects models, using an age and/or weight banding approach.

1. The cumulative number and proportion of children with grade 3 and 4 adverse events over the 12 week dosing period.

2. The cumulative number and proportion of children who discontinue study drug due to an adverse event during the 12 week dosing period.

3. Primary population PK parameters including absorption rate constant (ka), volume of distribution (Vd), and oral clearance (Cl/F) and between-subject variability terms;

post-hoc Bayesian predictions of secondary PK parameters of rifapentine including

(Cmax), time to Cmax (Tmax), area-under-the-curve (AUC0-24) and t ½ for rifapentine (and its 25-desacetyl metabolite).

4. Palatability scores and acceptability over the 12 week rifapentine dosing period.

5. Frequency of incident tuberculosis over 24 weeks’ follow-up from enrollment.

6. PK parameters of isoniazid, taking into account NAT2 genotype.

PK parameters of efavirenz in HIV-infected children when taking concomitant rifapentine versus not taking rifapentine, taking into account the CYP2B6 genotype. PK parameters of other

ART will be explored, including dolutegravir/raltegravir, if they are routinely used in the trial population during the study.

1.2 Study Schematic

Figure 1 a. Cohort management for cohort 1: ≥ 4 to ≤ 12 years

Median AUC more than 25% lower than target AUC and safety target met

PK and safety targets met

Median AUC more than 25% lower than target AUC and safety target not met

No change in rifapentine dose

Decrease rifapentine dose based on modeled estimates

Increase rifapentine dose based on modeled estimate

STOP ENROLMENT

• Continue enrolment into cohort 1 up to the total of 12 in the cohort

• Complete final PK and PK safety analysis through week 12

• Continue parallel enrolment of cohort 2 (n=12 total; refer to figure 1 b)

• Proceed with enrolment of cohorts 3 and 4 after completion of enrolment into cohorts 1 and 2 (figure 1 c and d)

Interim analysis: PK through week 1 and safety data through Week 12 in 6 participants . Week 12 PK is not required for interim analysis.

PK: Estimate rifapentine PK parameters (median clearance, relative bioavailability, and AUC) from week 1.

Safety: Number and proportion of children with grade 3 or 4 adverse events (AEs)***

Repeat enrolment of up to 6 children in cohort 1 using the new modeled Rifapentine dose.

Pause enrolment after 6 participants have been enrolled in cohort 1 and have completed week 1 PK and safety evaluation through week 12.

• Enroll eligible children into cohorts 1 and 2 in parallel using once-weekly rifapentine at a preselected modeled dose for each of the cohorts, given in combination with isoniazid

• Cohort 1: ≥ 4 to ≤ 12 years (N=12 total). For cohort 2, refer to figure 1 b.

• Use an initial preselected rifapentine dose of 25 mg/kg (range: 20-25 mg/kg)

* HIV-infected children will have additional PK sampling performed at 12 weeks following completion of 12 weeks’ rifapentine and isoniazid to investigate potential drug-drug interactions between rifapentine and ART **Additional assessment as clinically indicated.

***AEs considered in interim analysis must meet criteria for suspected adverse reaction (i.e., reasonable possibility that the AE was caused by rifapentine).

• PK: Complete PK sampling at Week 1 (intensive sampling) and Week 12 (sparse sampling)*

• Safety: Complete weekly safety monitoring visits** through Week 12

Review and adjust rifapentine dose based on pre-established PK and safety targets:

• PK target: Median AUC no more than 25% lower or 75% higher than the adult target AUC of 522 mcg h/L

• Safety target: No more than one grade 3 or 4 AEs (of 6 participants)

PK target met but safety target not met

Median AUC more than 75% higher than target AUC (regardless of safety target met)

Figure 1 b. Cohort management for cohort 2: ≥ 24 months to < 4 years

AUC and safety target met

PK and safety targets met

Median AUC more than 25% lower than target AUC and safety target not met

No change in

RIFAPENTINE

dose

Decrease rifapentine dose based on modeled estimates

Increase rifapentine dose based on modeled estimate

STOP ENROLMENT

• Continue enrolment into cohort 2 up to the total of 12 in the cohort

• Complete final PK and safety analysis through week 12

• Continue parallel enrolment of cohort 1 (n=12 total; see figure 1 a).

• Proceed with enrolment of cohorts 3 and 4 after completion of enrolment into cohorts 1 and 2 (figure 1 c and d)

Interim analysis: PK through week 1 and safety data through Week 12 in 6 participants.. Week 12 PK is not required for interim analysis

• PK: Estimate rifapentine PK parameters (median clearance, relative bioavailability, and AUC)

• Safety: Number and proportion of children with grade 3 or 4 adverse events (AEs)***

Repeat enrolment of up to 6 children in cohort 2 using the new modeled rifapentine dose.

Pause enrolment after 6 participants have been enrolled in cohort 2 and have completed week 1 PK and safety evaluation through week 12

• Enroll eligible children into cohorts 1 and 2 in parallel using once-weekly rifapentine at a preselected modeled dose for each of the cohorts, given in combination with isoniazid

• Cohort 2: ≥ 24 months to < 4 years (N=12 total)

• Use a preselected dose of 25 mg/kg (range: 20-25 mg/kg)

• PK: Complete PK sampling at Week 1 (intensive sampling) and Week 12 (sparse sampling)*

• Safety: Complete weekly safety monitoring visits** through Week 12

Review and adjust rifapentine dose based on pre-established PK and safety targets:

• PK target: Median AUC no more than 25% lower or 75% higher than the adult target AUC of 522 mcg h/L

• Safety target: No more than one grade 3 or 4 AEs (of 6 participants)

PK target met but safety target not met

Median AUC more than 75% higher than target AUC (regardless of safety target met)

* HIV-infected children will have additional PK sampling performed at 12 weeks following completion of 12 weeks’ rifapentine and isoniazid to investigate potential drug-drug interactions between rifapentine and ART **Additional assessment as clinically indicated.

***AEs considered in interim analysis must meet criteria for suspected adverse reaction (i.e., reasonable possibility that the AE was caused by rifapentine).

Figure 1 c. Cohort management for cohort 3: ≥ 12 to < 24 months

AUC and safety target met

PK and safety targets met

Median AUC more than 25% lower than target AUC and safety target not met

No change in

RIFAPENTINE

dose

Decrease rifapentine dose based on modeled estimates

Increase rifapentine dose based on modeled estimate

STOP ENROLMENT

• Continue enrolment into cohort 3 up to the total of 18 in the cohort

• Complete final PK and safety analysis through week 12

• Continue parallel enrolment of cohort 4 (n=18 total; refer to figure 1 d)

Interim analysis: PK through week 1 and safety data through Week 12 in 6 participants. Week 12 PK is not required for

• PK: Estimate rifapentine PK parameters (median clearance, relative bioavailability, and AUC)

• Safety: Number and proportion of children with grade 3 or 4 adverse events (AEs)***

Repeat enrolment of up to 6 children in cohort 3 using the new modeled RIFAPENTINE dose.

Pause enrolment after 6 participants have been enrolled in cohort 3 and have completed week 1 PK and safety evaluation through week 12

• Enroll eligible children into cohorts 3 and 4 in parallel using once-weekly rifapentine at a preselected modeled dose for each of the cohorts, given in combination with isoniazid, based on findings from cohorts 1, 2.

• Cohort 3: ≥ 12 to < 24 months (N=18 total). For cohort 4, refer to figure 1 d.

• Use a preselected modeled dose (to be determined)

• PK: Complete PK sampling at Week 1 (intensive sampling) and Week 12 (sparse sampling)*

• Safety: Complete weekly safety monitoring visits** through Week 12

Review and adjust rifapentine dose based on pre-established PK and safety targets:

• PK target: Median AUC no more than 25% lower or 75% higher than the adult target AUC of 522 mcg h/L

• Safety target: No more than one grade 3 or 4 AEs (of 6 participants)

PK target met but safety target not met

Median AUC more than 75% higher than target AUC (regardless of safety target met)

* HIV-infected children will have additional PK sampling performed at 12 weeks following completion of 12 weeks’ rifapentine and isoniazid to investigate potential drug-drug interactions between rifapentine and ART **Additional assessment as clinically indicated.

***AEs considered in interim analysis must meet criteria for suspected adverse reaction (i.e., reasonable possibility that the AE was caused by rifapentine).

Figure 1 d. Cohort management for cohort 4: 0 to <12 months

AUC and safety target met

PK and safety targets met

Median AUC more than 25% lower than target AUC and safety target not met

No change in rifapentine dose

Decrease rifapentine dose based on modeled estimates

Increase rifapentine dose based on modeled estimate

STOP ENROLMENT

• Continue enrolment into cohort 4 up to the total of 18 in the cohort.

• Complete final PK and safety analysis through week 12.

• Continue parallel enrolment of cohort 3 (n=18 total; refer to figure 1 c).

Interim analysis: PK through week 1 and safety data through Week 12 in 6 participants. Week 12 PK is not required for

• PK: Estimate rifapentine PK parameters (median clearance, relative bioavailability, and AUC)

• Safety: Number and proportion of children with grade 3 or 4 adverse events (AEs)***

Repeat enrolment of up to 6 children in cohort 4 using the new modeled Rifapentine dose.

Pause enrolment after 6 participants have been enrolled in cohort 4 and have completed week 1 PK and safety evaluation through week 12

• Enroll eligible children into cohorts 3 and 4 in parallel using once-weekly rifapentine at a preselected modeled dose for each of the cohorts, given in combination with isoniazid, based on findings from cohorts 1, 2.

• Cohort 4: 0 to < 12 months (N=18 total).

• Use a preselected modeled dose

• PK: Complete PK sampling at Week 1 (intensive sampling) and Week 12 (sparse sampling)*

• Safety: Complete weekly safety monitoring visits** through Week 12

Review and adjust rifapentine dose based on pre-established PK and safety targets:

• PK target: Median AUC no more than 25% lower or 75% higher than target AUC of 522 mcg h/L

• Safety target: No more than one grade 3 or 4 AEs (of 6 participants)

PK target met but safety target not met

Median AUC more than 75% higher than target AUC (regardless of safety target met)

* HIV-infected children will have additional PK sampling performed at 12 weeks following completion of 12 weeks’ rifapentine and isoniazid to investigate potential drug-drug interactions between rifapentine and

ART

**Additional assessment as clinically indicated.

***AEs considered in interim analysis must meet criteria for suspected adverse reaction (i.e., reasonable possibility that the AE was caused by rifapentine).

1.3 Abbreviations

AE

AESI

Adverse Event/Adverse Experience Adverse Event of Special Interest

ALT Alanine Transaminase ARV Antiretroviral

ART

AST

Antiretroviral therapy Aspartate Transaminase

AUC Area Under the Curve BMI Body Mass Index BR Bilirubin CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations Cmax Maximum Concentration CRF Case Report Form

DAIDS

Division of AIDS, U.S. National Institute of Allergy and Infectious Diseases

DLT Dose limiting toxicity DOT Directly Observed Therapy DSMB Data Safety and Monitoring Board E Ethambutol EFV Efavirenz EMA European Medicines Agency FDA Food and Drug Administration FDC Fixed dose combination

FWA Federal-Wide Assurance GCP Good Clinical Practice H Isoniazid HIV Human Immunodeficiency Virus HPLC High Performance Liquid Chromatography IB Investigator’s Brochure IRB Institutional review board ICF Informed Consent Form IGRA Interferon gamma release assay IND Investigational New Drug INH Isoniazid IQR Interquartile range IRB Institutional Review Board ISM Independent Safety Monitor kg Kilograms LTBI Latent tuberculosis infection MCC Medicine Control Council MDR-TB Multi-Drug Resistant Tuberculosis mg Milligrams

MIC Mean Inhibitory Concentration MOOP Manual of Operations and Procedures MTB Mycobacterium tuberculosis N Number (typically refers to subjects) NIAID National Institute of Allergy and Infectious Diseases, NIH NIH National Institutes of Health P Rifapentine PCR Polymerase chain reaction PI Principal Investigator PK Pharmacokinetics QA Quality Assurance QC Quality Control QD Daily R Rifampicin RHS Rifamycin hypersensitivity syndrome RIF Rifampicin RIFAPENTINE Rifapentine

SAE

SAHPRA

Serious Adverse Event/Serious Adverse Experience South African Health Products Regulatory Authority

SAR Suspected adverse reaction SUSAR Suspected Unexpected Serious Adverse Reaction t 1/2 Half-life Tmax Time to maximal concentration TB Tuberculosis TBTC Tuberculosis Trials Consortium TST Tuberculin skin test ULN Upper limit of normal WHO World Health Organization Z Pyrazinamide

1.4 Key Roles

Funding Agencies U.S. Centers for Disease Control and Prevention (CDC) and CDC Foundation

Pharmaceutical Support Sanofi U.S.

Protocol Chair

Anneke Hesseling, MD, PhD

Desmond Tutu TB Centre

Department of Paediatrics and Child Health

Faculty of Medicine and Health Sciences

Stellenbosch University

P.O. Box 241

Cape Town 8000

South Africa

Phone: (27) 21 9389062

Email: annekeh@sun.ac.za

Study Officer

Rosanna Boyd, PhD

US Centers for Disease Control and Prevention

1600 Clifton Road NE, MS E-10

Atlanta, GA 30329, USA

Phone: 404-553-7434

Email: icg7@cdc.gov

Protocol Pharmacometrician

Rada Savic, PhD

University of San Francisco School of Pharmacy

1550 4th Street, Building 19B

San Francisco, CA 94158, US

Phone: (415) 502-0640

Email: rada.savic@ucsf.edu

Protocol Clinical Pharmacologist Kelly Dooley, MD, Pharm D Divisions of Clinical Pharmacology & Infectious Diseases Johns Hopkins University School of Medicine 600 N. Wolfe Street, Osler 527 Baltimore, MD 21287 Phone: 410-955-3100 Fax: 410-614-9978 E-Mail: kdooley1@jhmi.edu

Protocol Statistician

TBD

US Centers for Disease Control and Prevention

1600 Clifton Road NE, MS E-10

Atlanta, GA 30329, USA

Phone: TBD mailto:annekeh@sun.ac.za mailto:icg7@cdc.gov mailto:rada.savic@ucsf.edu mailto:kdooley1@jhmi.edu

Email: TBD

Protocol Investigators Jana Winckler, MD, MPhil Desmond Tutu TB Centre (TBTC Site 33) Department of Paediatrics and Child Health

Faculty of Medicine and Health Sciences

Stellenbosch University

P.O. Box 241

Cape Town 8000

South Africa

Phone (27) 21-5087409 Email: jwinckler@sun.ac.za

Neil Martinson, MBBCh, MPH Site Co-PI PHRU Site 35 Soweto Johannesburg Phone +27119899862 Fax +27119899862 South Africa Neil. Martinson@phru.co.za

Avy Violari, MD Site Co-PI PHRU Site 35 Soweto Johannesburg South Africa violari@mweb.co.za

Sanjay Lala, MBBCh, FCPaed, MMed, PhD Associate Professor and Head of Clinical Unit Department of Paediatrics and Child Health School of Clinical Medicine, Faculty of Health Sciences University of Witwatersrand and Chris Hani Baragwanath Academic Hospital P O Bertsham 2013 South Africa Tel: +27 (0)11 933 0188 (Office - no answerphone) Fax: +27 (0)865 534 599 Sanjay.Lala@wits.ac.za mailto:jnn6@cdc.gov mailto:Martinson@phru.co.za mailto:violari@mweb.co.za

Marc Weiner, MD Audie L. Murphy VA Hospital Medical Service (111F) 7400 Merton Minter Boulevard, Room E703 San Antonio, TX 78229, US Phone: (210) 617-5300 x 16060 Email: weiner@uthscsa.edu

Laboratory Pharmacologist Lubbe Wiesner, PhD Division of Clinical Pharmacology, Department of Medicine University of Cape Town, Laboratory Main Road Observatory K45, Old Main Building Groote Schuur Hospital Observatory Cape Town 7925 South Africa Phone: (27) 21-406-6289 E-mail: lubbe.wiesner

Laboratory Pharmacology Manager Jennifer Norman, MSc University of Cape Town, Laboratory

K50.30 Division of Clinical Pharmacology Old Main Building Groote Schuur Hospital Observatory Tel. +27 21 404 7695 UCT ext. X 7695 Fax. +27 86 669 1348 Email: Jennifer.norman@uct.ac.za

Protocol Data Manager Erin Sizemore, MPH US Centers for Disease Control and Prevention

1600 Clifton Road NE, MS E-10

Atlanta, GA 30329, USA

Phone: 404-639-8869 Email: ddq9@cdc.gov

Protocol Data Analyst Kit Whitworth, MPH US Centers for Disease Control and Prevention mailto:weiner@uthscsa.edu mailto:Jennifer.norman@uct.ac.za mailto:ddq9@cdc.gov

1600 Clifton Road NE, MS E-10

Atlanta, GA 30329, USA

Phone: 404-639-8876 Email: wcw2@cdc.gov

Community representative Lindsay McKenna, MPH

Treatment Action Group (TAG)

261 Fifth Avenue, Suite 2110 New York, NY 10016 Phone: 631-258-0808 Email: Lindsay.McKenna@treatmentactiongroup.org

Pharmaceutical representatives (advisory capacity) Andrew Hockey, MBBS Tuberculosis Medical Lead Global Health Sanofi One Onslow Street, Guildford, Surrey, GU1 4YS, UK Email: andrew.hockey@sanofi.com Mobile: +44 (0) 7714 429142

Isabelle Cieren-Puiseux Tuberculosis Program Head Global Health Program Sanofi 82, Avenue Raspail 94255

GENTILLY

Cedex France Tel.: +33 (0) 1 41 24 59 48 Cell.: +33 (0) 6.86 38 86 06 Email: Isabelle.cieren-puiseux@sanofi-aventis.com mailto:wcw2@cdc.gov mailto:andrew.hockey@sanofi.com mailto:Isabelle.cieren-puiseux@sanofi-aventis.com

2 Background Information and Scientific Rationale

2.1 Background Information

Childhood tuberculosis (TB) represents 10-15% of the total disease burden in developing countries and is also a serious problem amongst paediatric subpopulations in developed countries.(1, 2) The World Health Organization (WHO) estimated that there were a million cases globally of TB in children < 15 years of age in 2014 (3), the majority preventable. Young children have a high risk of developing active TB disease and a propensity to develop severe and disseminated forms of disease following exposure and infection with Mycobacterium tuberculosis (M. tb) in the absence of adequate TB preventive therapy.(4) However, since young children typically have paucibacillary pulmonary TB disease, there is emerging international consensus amongst researchers and regulatory agencies that phase 3 trials are not necessary to assess the efficacy of new antituberculosis compounds or regimens if these are shown to be effective as treatment or preventive strategies in adults.(5) A critical need however remains for the generation of data to guide the appropriate drug dosing in children to reach exposures associated with clinical efficacy and safety in adults, thus ensuring access to appropriate preventive TB therapy for children. These efforts must also be supported by the development of appropriate paediatric formulations.

2.1.1 Treatment of latent TB infection (LTBI)

Prevention of TB in children through post-exposure preventive therapy using short-course effective strategies is an important public health strategy to reduce the burden of TB amongst children, who have a high risk of disease progression and developing severe forms of TB following exposure to and infection with M. tb. (4) The use of anti-tuberculosis medications to prevent the development of TB among individuals with known LTBI or household contacts of TB participants is effective, but adherence to long courses (e.g. 6-9 months of isoniazid) of preventive therapy is generally low and is particularly poor in children, especially in high-burden settings (6, 7), limiting the effectiveness of this strategy at TB programme level.

Shorter duration combination chemoprophylaxis is therefore a feasible and highly attractive strategy to improve adherence and outcomes in children in both high- and low-burden settings.

2.1.2 Pharmacokinetics of TB drugs in children

There are major gaps in our knowledge of the pharmacokinetics (PK) of many first-line and second-line antituberculosis drugs in children despite the fact that most were approved more than 30 years ago; similarly, data on mostnovel antituberculosis agents are still lacking in children. (8) Similar mg/kg doses in adults and children of different ages may result in very different drug exposures. The PK of antituberculosis drugs is modulated by several factors.

Age is an important variable as young children may achieve lower serum levels for some first line antituberculosis drugs compared to adults, even at the same weight-adjusted (mg/kg) dose. In young children (<2 years of age), the group with the highest risk of progression to active TB disease following M. tb infection, (4) body composition, renal function, and metabolizing enzyme and transporter expression change rapidly and significantly, and thus, developmental pharmacology, or ‘ontogeny’, may play an important role in drug disposition.

Data regarding the PK of TB drugs are particularly limited in very young infants (<3 months of age), a group with a high risk of TB exposure early in life, especially in settings with high prevalence of maternal HIV infection.(9) Determining appropriate doses of drugs for children must thus take into account age-dependent changes in organ function and body composition which affect drug absorption, distribution, metabolism, and excretion.(10) Other important potential determinants of PK in children include HIV infection, concomitant medications, nutritional status and genetics.

2.1.3 Rifapentine for the prevention of tuberculosis

Rifamycins are the key drugs in modern “short-course” TB chemotherapy. Rifamycins, including rifampicin and rifapentine, have concentration-dependent activity against M. tb and are considered critical for “sterilization,” that is, prevention of relapse after cessation of TB treatment. These drugs have been under investigation as agents that may help improve the treatment of latent TB infection (LTBI) by increasing the intermittency of dosing, and decreasing the duration of therapy. Rifapentine is a new rifamycin with prolonged half-life and lower minimum inhibitory concentration (MIC) against M. tb than rifampicin, and is a promising drug for the treatment of both LTBI and TB disease. A regimen of once-weekly rifapentine plus isoniazid for 12 weeks had potent activity in an animal model of latent TB(11). A large phase 3 trial comparing this regimen to 9 months of daily isoniazid, regarded as the gold-standard regimen for treatment of LTBI, TBTC Study 26 (n ~ 8000, “Prevent TB”, NCT00023452) found that this 12 week combined rifapentine and isoniazid weekly regimen given by directly observed therapy was at least as effective as self-administered isoniazid taken daily for 9 months for preventing TB disease.(12)

In a follow-up to Study 26, the efficacy and safety of the 12-dose weekly rifapentine and isoniazid regimen was assessed in a paediatric cohort nested within study 26, in 29 study sites in the United States, Canada, Brazil, Hong Kong, and Spain. Participants were children (aged 2- 17 years) who were eligible for treatment of LTBI, supported through supervision by a health care professional. Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness.

Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs. 351 of 434 (80.9%) in the isoniazid-only group (p = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range.

In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 adverse event (AE) vs. 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed TB vs. 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the non-inferiority criterion. Treatment with the combination of rifapentine and isoniazid was therefore as effective as isoniazid-only treatment for the prevention of TB in children aged 2 to 17 years. In addition the combination-therapy group had a higher treatment completion rate than did the isoniazid-only group.(13, 14)

Rifapentine (trade name: Priftin®) was approved by the USA FDA in November 2014 for the treatment of LTBI and has been available on the market in the USA since 1999. Priftin is currently indicated in adults and children 2 years and older for the treatment of LTBI caused by M. tb in participants at high risk of progression to TB (including those in close contact with active TB participants, recent conversion to a positive tuberculin skin test, HIV-infected participants, or those with pulmonary fibrosis on radiograph) and is being increasingly accessed in high-burden TB settings.

2.1.4 Pharmacokinetics of rifapentine in adults

Rifapentine is well absorbed, reaching a peak concentration approximately 5 hours after ingestion. Absorption of rifapentine is improved when ingested with food, particularly with fatty foods. (15) In addition, rifapentine’s half-life (t1/2) is five times longer than that of rifampicin (11-18 hours vs. 2-5 hours), therefore measurable concentrations are generally present at and beyond 24 hours post-ingestion. (16) Rifampicin, a similar rifamycin antibiotic, induces its own metabolism such that half-life and AUC decrease substantially (~ 33%) with repeat dosing. Rifapentine does induce its own metabolism when it is given daily or thrice-weekly, but weekly dosing does not result in auto-induction. (17)

2.1.5 Pharmacokinetics of rifapentine in children

In an initial Phase I single-dose study among 24 children aged 2-11 years, participants were given either 150 mg or 300 mg (average dose of 8.5 mg/kg).(18) Compared to concentration-time profiles of adults, dose-normalized AUC was lower in children, and oral clearance (Cl/F) (per kg) highest amongst children who received the 150 mg dose (average age 4). Higher doses of rifapentine (in mg/kg) were thought to be required to achieve the PK of the 15 mg/kg (maximum 900mg) dose used among adults (Figure 2). In TBTC Study 26PK substudy (NCT00164450), PK information was used to determine appropriate doses of rifapentine to evaluate among children ages 2-12 for the treatment of LTBI. In brief, 80 children aged 2 to 11 years and 77 adult controls (19-63 years) were enrolled. Children younger than 12 years of age received isoniazid 25 mg/kg weekly (900 mg maximum), together with their assigned dose of rifapentine which was doses based on weight. Only sparse sampling was completed.

Crushed tablets were administered to children who could not swallow tablets and food intake was documented. PK sampling was performed among study participants after they had received at least three once-weekly doses of study medications. Rifapentine plasma concentrations 24 hours after drug administration (C24) were used as a surrogate for exposure, and data among children and adults were compared.

Doses of rifapentine in the children studied to date (≥ 2 years of age) have ranged from 300 to 900 mg (15-32 mg/kg, mean 22.8 mg/kg), and all adults received 900 mg (range 5-17 mg/kg, mean 10.7 mg/kg; Table 1). The geometric mean of rifapentine C24 was 10.9 mcg/mL in all children versus 8.5 mcg/mL in adults. The geometric mean of the 25-Desacetyl-Rifapentine Metabolite C24 was 15.1 mcg/mL in children versus 10.4 mcg/mL in adults (Table 2).

The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 22.8 mg/kg; adults, 10.7 mg/kg).Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The relatively higher rifapentine doses in children were well tolerated.

(19)

There are however no data available on the PK of rifapentine in children < 2 years, including in infants or neonates; these youngest children were excluded from Study 26 because there was no data in these children <2 years old and an appropriate formulation was not available then.

To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by nonlinear mixed effects methods were developed. The use of higher weight adjusted (mg/kg) rifapentine doses for young children are warranted to achieve systemic exposures that were associated with successful treatment of LTBI in adults.

Table 2. Rifapentine and metabolite concentrations in adults and children in Study 26

PK

Based on these data together with what we know about drug handling in the very young and experience with rifampicin among children 0-2 years, we estimate that a dose of at least 25 mg/kg will be required to achieve equivalent exposures in children 0-2 years of age (See Figure 3). Doses as high as 20 mg/kg daily have been given to adults (Study 29 X), and doses as high as 25 mg/kg daily have been given to children and have been shown to be safe and tolerable.(12, 19) In the proposed study, S35, optimal rifapentine doses will be derived through modeling of the existing data from Study 26 PK, as well as ongoing analysis and modelling of PK data from groups of children, using an adaptive design. Selection of isoniazid dose will be based on the doses used in S26 in children, but will not exceed a dose of 25 mg/kg. Thus, the final drug ratio of rifapentine and isoniazid in the fixed dose combination remains to be determined.

Figure 2. Area under the curve concentration-time curve (AUC 0-inf) in groups of participants in Study 26 PK derived by 1) dose from the weights bands used and in the treatment algorithm and 2) by rifapentine integrity (whole vs. crushed). The 25th, 50th and 75th percentiles are indicated by the bottom, middle and top of the box plots, and the whiskers are drawn at either the maximum (minimum) or 1.5 times the IQR above (below) the 75th (25th) percentile depending on which of the two is closer to the median. The geometric mean (+ SD) and 90% CI are also indicated for each group.

Figure 3. Predicted dose (mg/kg) of rifapentine in children required to match the AUC achieved with the 15 mg/kg dose in adults

R if a p e n ti n e d o s e m g

/k g

Age (years)

2.1.6 Effect of HIV co-infection on the pharmacokinetics of rifapentine Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, specifically, the CYP3A4, CYP2C8, and CYP2C9 isoenzymes, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of concurrently-delivered antiretrovirals (ARVs). The relative potency as inducers is as follows: rifampicin, 1; rifapentine, 0.85; and rifabutin, 0.40.

(16). Therefore, interaction of rifapentine and drugs that are metabolized by these enzymes, including protease inhibitors, are anticipated to be clinically significant. (20) Concomitant use of rifamycins to treat or prevent TB can result in sub therapeutic concentrations of antiretroviral drugs. In a study of the interaction of efavirenz with daily rifapentine plus isoniazid in HIV-infected individuals receiving a 4-week regimen to prevent TB, participants received daily rifapentine and isoniazid with efavirenz and had PK evaluations at baseline and weeks 2 and 4 of concomitant therapy. Eighty-seven participants were evaluable. The numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable at week 8. The authors concluded that four weeks of daily rifapentine plus isoniazid can be co-administered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression. (21) Sanofi conducted a DDI study in HIV infected participants receiving EFV (600mg) with rifapentine 900 mg weekly for 3 weeks. Another study found that once-weekly co-administration of 900 mg Rifapentine with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected participants did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir. A 15% decrease in efavirenz Cmin and AUC and a 13% decrease in tenofovir Cmin were observed with repeated weekly doses of rifapentine. No clinically significant change in CD4 cell counts or viral loads were noted.(22)

Co-administration of raltegravir (400 mg 12 hourly) with rifapentine was evaluated at a dose of 900 mg once weekly compared with raltegravir alone in healthy adult volunteers (NCT00809718). In 16 subjects who completed the study, co-administration of raltegravir with rifapentine (900 mg once week) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC 0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Co-administration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir co-administered with rifapentine in this short-term study was generally well tolerated. Once-weekly rifapentine can therefore be used with raltegravir to treat latent tuberculosis infection in participants who are infected with HIV.(23) Given limited expected drug-drug interactions between rifapentine once-weekly and efavirenz-containing regimens in children, and the burden of TB in HIV-infected children, Study 35 will include HIV-infected children on efavirenz-containing regimens used in international settings where S35 will be conducted. As integrase inihibitors (e.g. dolutegravir, raltegravir) will be recommended and will become more readily available to children in these settings as part of routine care, these ARTs may also be studied in children on rifapentine and isoniazid for TB prevention in this protocol.

2.1.7 Safety and tolerability of rifapentine

Rifapentine, like other rifamycins, causes red-orange discoloration of body fluids. In trials where rifapentine was combined with isoniazid and other antituberculosis drugs, rates of adverse reactions were similar with rifampicin and rifapentine, with hepatotoxicity in between 0.59% (HIV-uninfected) and 1.4%(12) in HIV-infected participants on Rifapentine and isoniazid In sub-analysis of Study 26, the risk of hepatotoxicity associated with 3HP compared to 9H, and factors associated with hepatotoxicity, were evaluated. Hepatotoxicity was defined as aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST > 5 x ULN. Risk factors were analyzed among adults who took at least 1 dose of their assigned treatment. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic.

Hepatotoxicity was seen in 1.8% (61/3317) of those on 9 months’ isoniazid (9H) and 0.4% (15/3545) of those taking 3 months’ isoniazid and rifapentine (3HP; P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, Hepatitis C infection was associated with hepatotoxicity when controlling for other factors. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. (24)

In Study 26, flu-like and other Systemic Drug Reactions (SDR) appeared to be more common amongst participants receiving the 3HP vs. the 9H regimen. Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose;

median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009).