J.5.3 - Treatment Protocol Study 31.pdf

TBTC S31/A5349: Rifapentine-containing tuberculosis treatment shortening regimens Version 2.0 14 May 2015

TITLE

Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis:

A randomized, open-label, controlled phase 3 clinical trial

Consortium Identifiers:

Tuberculosis Trials Consortium Study 31

AIDS Clinical Trials Group A5349

Funding Agencies:

U.S. Centers for Disease Control and Prevention

U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health

Pharmaceutical Support Provided by:

Sanofi

IND Number:

46,954

IND Sponsor:

U.S. Centers for Disease Control and Prevention

ClinicalTrials.gov Identifier:

NCT02410772

Study Chairs:

Payam Nahid, M.D., M.P.H.

Susan Dorman, M.D.

Version Number: 2.0

IIE3

Typewritten Text Attachment J.5.3 - Solicitation 75D301-20-R-67869

TBTC S31/A5349: Rifapentine-containing tuberculosis treatment shortening regimens Version 2.0 ii

Statement of Compliance

This trial will be conducted in compliance with the protocol, International Conference on Harmonisation

Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations 45 CFR 46 and 21 CFR, and applicable site-specific regulatory requirements.

iii

Table of Contents

Statement of Compliance ............................................................................................................................... ii

Protocol Summary ........................................................................................................................................ vii

Study Schematic ...................................................................................................................................... x

1 Key Roles

2 Background Information and Scientific Rationale

2.1 Background Information

2.2 Rationale

2.3 Potential Harms and Benefits

2.3.1 Potential harms

2.3.2 Potential benefits

3 DESCRIPTIONS OF STUDY DRUGS

3.1 Rifapentine

3.2 Rifampin

3.3 Moxifloxacin

3.4 Isoniazid

3.5 Pyrazinamide

3.6 Ethambutol

3.7 Vitamin B6 (Pyridoxine)

4 Objectives

4.1 Primary:

4.2 Secondary:

5 Study Design

6 Study Population

6.1 Subject Inclusion Criteria

6.2 Criteria for Exclusion from Enrollment

6.3 Criteria for Exclusion after Enrollment (‘Late Exclusion’)

7 Enrollment, Randomization, and Masking Procedures

7.1 Enrollment Procedures

7.2 Randomization

8 Study Procedures

8.1 Clinical Evaluations

8.1.1 Interview for demographic and contact information

8.1.2 Obtaining a medical history

8.1.3 Obtaining sputum specimens

8.1.4 Performing visual acuity and color vision testing

8.1.5 Symptom assessment

8.1.6 Assessment for adverse events

8.1.7 Chest Radiograph

8.2 Concomitant Medications/Treatments

iv

8.3 Laboratory Evaluations

8.3.1 Sputum mycobacterial tests

8.3.2 Hematology

8.3.3 Biochemistry

8.3.4 HIV testing

8.3.5 CD4 testing

8.3.6 HIV viral load testing

8.3.7 Pregnancy testing

8.3.8 Diabetes screening

8.3.9 Pharmacokinetic sampling: Tuberculosis Drugs

8.3.10 Pharmacokinetic sampling: Efavirenz

8.3.11 Pharmacogenomic testing: Host Genetic Analysis

8.3.12 Storage of M. tuberculosis bacterial isolates

8.3.13 Samples for analyses to identify potential biomarkers of tuberculosis treatment response

8.4 Specimen preparation, handling and shipping

8.5 Loss to follow-up

8.6 Participants with a positive sputum culture for M. tuberculosis at or after week 17 42

8.7 Participants with a positive sputum smear at or after week 17

8.8 Participants with a possible poor treatment response

8.9 Management of a participant who is discontinued from study treatment

8.9.1 Management of a participant who is discontinued from study treatment because s/he is determined to be ineligible after enrollment (‘late exclusions’)

8.9.2 Management of participants who become pregnant during the study

8.9.3 Management of participants who are discontinued from study treatment in the setting of an adverse event or the investigator judges that discontinuation of study treatment is in the participant’s best interest

8.9.4 Management of a participant who requests premature discontinuation from study treatment

8.9.5 Management of a participant who is incarcerated after enrollment

8.10 Premature termination of the study or closure of a study stratum or a study site ... 44

9 Study Schedule

9.1 Screening

9.2 Baseline

9.3 Study Visits at Weeks 2, 4, 8, and 12

9.4 Week 17

9.5 Week 22

9.6 Week 26

9.7 Study Visits at Months 9, 12, 15, and 18

9.8 Study Procedures for Participants with Possible Poor Treatment Response v

9.9 Post Early Termination Visit (Visit after Early Termination) for Participants

Terminating before Completion of their Assigned Study Treatment

9.10 Early Termination Visit for Participants Stopping Study Participation after

Completion of their Assigned Study Treatment

9.11 Missed Visit

9.12 Unscheduled Visit

10 Study Intervention/Investigational DRUGS

10.1 Study Drugs

10.2 Study Drug Acquisition

10.3 Study Drug Storage and Stability

10.4 Administration and Dosage of Study Drugs

10.5 Dose Modifications for a Participant

10.5.1 Dose Modifications for a Change in Participant’s Weight

10.5.2 Drug Re-challenges

10.6 Criteria for Discontinuation of Study Drugs

10.7 Accountability Procedures for the Study Drugs

10.8 Assessment of Subject Compliance with Study Treatment

11 Assessment of Efficacy

11.1 Summary of Bacteriological Methods

12 Assessment of Safety

12.1 Specification of Safety Parameters

12.1.1 Primary Outcome Measure

12.1.2 Secondary Outcome Measure

12.2 Methods and Timing for Assessing, Recording, and Analyzing Safety

Parameters

12.2.1 Adverse Events and Serious Adverse Events

12.3 Recording and Reporting Procedures

12.3.1 Overview

12.3.2 Reporting Procedures

12.3.3 Pregnancy

12.4 Management of adverse events

12.4.1 Type and Duration of the Follow-up of Subjects after Adverse Events

12.5 Data and Safety Monitoring Board

12.6 Interim Monitoring and Analyses by the Data and Safety Monitoring Board

13 Statistical Considerations

13.1 Study Hypotheses

13.2 Study Outcome Measures

13.3 Definition of primary outcome status

13.4 Analysis Groups

13.5 Analysis Plan

13.5.1 Co-Primary efficacy analyses

13.5.2 Primary safety analysis

vi

13.5.3 Secondary efficacy analyses

13.5.4 Secondary safety analyses

13.5.5 Secondary Efavirenz PK analysis

13.6 Sample Size Considerations

14 Quality Control and Quality Assurance

14.1 Local quality control

14.2 External monitoring

15 Ethics/Protection of Human Subjects

15.1 Institutional Review Board

15.2 Informed Consent Process

15.3 Subject Confidentiality

15.4 Study Discontinuation

16 Data Handling and Record Keeping

17 Publications and Dissemination of Study Results

18 Literature References

APPENDICES

A: Schedule of Procedures/Evaluations

B: Abbreviations

Protocol Summary vii

Title: Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial

Hypotheses: A) Seventeen (17) week rifapentine-based regimen

In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus isoniazid, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen

In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and moxifloxacin, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

Phase: 3

Design: This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-inferiority trial.

Population: Patients with newly diagnosed, previously untreated pulmonary tuberculosis.

Number of Sites: Multiple international sites, primarily sites of the Tuberculosis Trials Consortium and the AIDS Clinical Trials Group.

Study Duration: Duration per participant is approximately 18 months.

viii

Description of Agent or Intervention: After written informed consent, participants will be randomly assigned to receive one of the following oral regimens:

Regimen 1 (control regimen): 2RHZE/4RH

Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by

Eighteen weeks of daily treatment with rifampin and isoniazid

Regimen 2 (investigational regimen): 2PHZE/2PH

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by

Nine weeks of daily treatment with rifapentine and isoniazid

Regimen 3 (investigational regimen): 2PHZM/2PHM

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by

Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin

Objectives:

Primary:

To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis

To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis

Secondary:

To evaluate the safety of the investigational regimens

To evaluate the tolerability of the investigational regimens

To collect and assess biospecimens from consenting participants for the purpose of research on discovery and validation of TB biomarkers ix

To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse.

To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters.

To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with

TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine

Endpoints:

Primary Endpoints:

Efficacy: TB disease-free survival at twelve months after study treatment assignment.

Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment

Secondary Endpoints:

TB disease-free survival at eighteen months after study treatment assignment

Time to stable sputum culture conversion (solid and liquid media considered separately)

Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection

Proportion of participants who are culture negative at completion of eight weeks of treatment (solid and liquid media considered separately)

Sensitivity analyses assuming all participants classified as ‘not assessable’ have a favorable outcome

Discontinuation of assigned treatment for a reason other than microbiological ineligibility

Estimated steady state efavirenz PK parameters including mid-dosing interval concentration x

Schematic of Study Design:

Screen for eligibility

Enroll

Randomize 1:1:1

Regimen 1

(control regimen)

2RHZE/4RH

(26 weeks)

Regimen 2

(investigational)

2PHZE/2PH

(17 weeks)

Regimen 3

(investigational)

2PHZM/2PHM

(17 weeks)

Participant follow-up:

18 months after treatment assignment

Analysis of Outcome Measures

Primary at 12 months; secondary at 18 months

1 KEY ROLES

Funding Agencies:

U.S. Centers for Disease Control and Prevention through the Tuberculosis Trials Consortium;

U.S. National Institute of Allergy and Infectious Diseases of the National Institutes of Health through the

AIDS Clinical Trials Group

IND Sponsor:

U.S. Centers for Disease Control and Prevention (IND# 46,954)

Pharmaceutical Support:

Sanofi

Protocol Chairs:

Payam Nahid, M.D., M.P.H.

University of California, San Francisco

1001 Potrero Ave, 5K1

San Francisco, CA 94110

Phone: 415-206-5464

Email: pnahid@ucsf.edu

Susan E. Dorman, M.D.

Johns Hopkins University School of Medicine

1550 Orleans Street, CRB2, 1M-12

Baltimore, Maryland, USA 21231

Phone 410-502-2717

Email: dsusan1@jhmi.edu

Project Officer:

Stefan Goldberg, M.D.

US Centers for Disease Control and Prevention

1600 Clifton Road, MS E-10

Atlanta, GA, USA 30333

Phone: 404-639-5339

Email: ssg3@cdc.gov

Central Study Clinician:

TB clinician(s), TBD mailto:pnahid@ucsf.edu mailto:DSUSAN1@JHMI.EDU mailto:ssg3@cdc.gov

Protocol Team

Name Institution

Janet Andersen Harvard School of Public Health, Boston, Massachusetts, USA

Richard Chaisson Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Kwok-Chiu Chang TB and Chest Service of Hong Kong, China

Michael Chen US Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Mark Cotton Stellenbosch University, Cape Town, South Africa

Dalene von Delft Community Research Advisory Group, Cape Town, South Africa

Kelly Dooley Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Melissa Engle University of Texas Health Science Center, San Antonio, Texas, USA

Pei-Jean Feng US Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Courtney Fletcher University of Nebraska Medical Center, Omaha, Nebraska, USA

Phan Ha National TB Program, Hanoi, Vietnam

Charles M Heilig US Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Daniel Johnson Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA

John L. Johnson Case Western Reserve University, Cleveland, Ohio, USA

Marilyn Maroni Sanofi, Paris, France

Cynthia Merrifield University of California, San Francisco, San Francisco, California, USA

Jose M. Miro Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain

Sachiko Miyahara Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Nguyen Viet Nhung National TB Program, Hanoi, Vietnam

April Pettit Vanderbilt University, Nashville, Tennessee, USA

Anthony Podany University of Nebraska Medical Center, Omaha, Nebraska, USA

Kathleen Robergeau Westat, Inc., Rockville, Maryland, USA

Wadzanai Samaneka Parirenyatwa Clinical Research Site, Harare, Zimbabwe

Erin Sizemore US Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Susan Swindells University of Nebraska Medical Center, Omaha, Nebraska, USA

Andrew Vernon Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Marc Weiner Audie L. Murphy Veterans Affairs Medical Center / University of Texas Health Science Center, San Antonio, Texas, USA

Lisa Wolf

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Suria Yesmin

Social & Scientific Systems, Inc., Silver Spring, Maryland, USA

2 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE

2.1 Background Information

Tuberculosis as a global health problem

Tuberculosis (TB) is one of the most important global health problems. According to recent estimates from the World Health Organization (WHO), 8.6 million new cases and 1.3 million deaths from TB occurred in 2012 (World Health Organization 2013). The vast majority of TB cases and TB deaths are in developing countries. The spread of HIV has fueled the TB epidemic, and TB is the leading cause of death among patients infected with HIV (Corbett et al., 2003). TB predominantly affects young adults in their most productive years of life and has substantial impact on economic development.

Need for new treatment regimens for tuberculosis

Although effective therapy for drug susceptible Mycobacterium tuberculosis is available, TB continues to cause significant morbidity and mortality worldwide, and rates of multi-drug resistant (MDR) and extensively-drug resistant (XDR) TB cases are on the rise. A major obstacle to the control of TB is poor adherence with lengthy (at minimum 6 months) and complicated treatment regimens. Incomplete TB treatment can lead to increased morbidity and mortality, prolonged infectiousness and transmission, and the development of drug resistance. The use of directly observed therapy (DOT) can improve patient adherence and reduce the emergence of resistant microorganisms, but is logistically difficult and expensive to implement (McDonald et al., 1982). The development of new treatment strategies with more potent antimycobacterial activity could lead to shorter and better tolerated regimens. A TB treatment regimen that allowed a decrease in treatment duration would potentially have important public health implications by facilitating DOT, increasing cure rates, potentially reducing transmission and preventing emergence of MDR TB. It is estimated that improved regimens that shorten treatment duration for drug-susceptible strains and are efficacious against resistant strains could reduce the incidence of TB by up to

27% by 2050 and reduce deaths by 25% from current global numbers of incident cases and deaths per year (Abu-Raddad et al, 2009).

Current standard treatment for pulmonary tuberculosis

Modern short course treatment for pulmonary tuberculosis is comprised of two treatment phases. The intensive phase is the initial 8 weeks of treatment, and typically is comprised of isoniazid, rifampin, pyrazinamide, and ethambutol. Continuation phase follows intensive phase, and continuation phase typically is comprised of isoniazid plus rifampin for an additional 18 weeks, to complete a total of 26 weeks (6 months) of treatment.

Rifamycins in tuberculosis treatment

Rifamycins are the key drugs in modern short-course TB chemotherapy of 6 months duration.

Rifamycins, including rifampin and rifapentine, have concentration-dependent activity against M.

tuberculosis. Rifamycins are considered critical for sterilization, that is, prevention of relapse after cessation of TB treatment. For rifapentine, the minimum inhibitory concentration (MIC)50 and MIC90 are one- to two-fold dilutions lower than those of rifampin (for the 7H10 agar system, rifapentine’s MIC50 and

MIC90 are 0.125 and 0.25 mg/L, compared with 0.5 and 1.0 mg/L for rifampin) (Bemer-Melchior et al., 2000). In addition, rifapentine’s half-life (t1/2) is five times longer than that of rifampin (14-18 hours vs. 2-

5 hours).

Preclinical studies of rifapentine

Murine model of tuberculosis treatment

The murine model of TB has been used for more than 50 years for the development and evaluation of new antituberculosis drugs and regimens (Veziris et al., 2005). Importantly, the mouse model of TB treatment has been shown to recapitulate human TB treatment with regard to treatment-shortening effects of rifampin and pyrazinamide. In the mouse model, the standard 6-month rifampin plus isoniazid plus pyrazinamide (RHZ)-based regimen cures mice in 6 months, followed by relapse rates of 0-10%. On the basis of its recapitulation of outcomes in humans, the murine TB treatment model is the reference standard against which new treatments are compared.

Preclinical studies of tuberculosis treatment regimens containing rifapentine

Pre-clinical studies suggest that improved antimycobacterial activity can be achieved with rifamycin exposure greater than that of the current standard regimen in which rifampin is used at a dose of 10 mg/kg/dose (almost always given as 600 mg) once daily. Increased rifamycin exposure can be achieved by using rifapentine. Of note, the pharmacokinetics of rifapentine have been shown to be similar in mice and in humans (Rosenthal et al., 2005). In the murine model of TB treatment, once-daily rifapentine administered during intensive phase has very potent antimycobacterial activity that results in durable cure after only 3 to 4 months of total treatment (Rosenthal et al., 2008). After aerosol infection, mice achieved a bacillary burden of 7.21 log10 cfu per lung. Treatment with a standard regimen of daily rifampin (10 mg/kg) plus isoniazid and pyrazinamide resulted in a decrease in bacillary burden of approximately 3 logs at completion of 4 weeks of treatment. However, treatment with a regimen of daily rifapentine (10 mg/kg) plus isoniazid and pyrazinamide was significantly more active at 4 weeks (mean lung cfu counts that were

1.00 log10 cfu lower than those for the standard regimen, p<0.001) and at 8 weeks (mean lung cfu counts that were >2 log10 cfu lower than those for the standard regimen, p<0.001). Furthermore, after 12 weeks of treatment, 100% (15/15) of mice treated with the standard regimen had bacteriological relapse, compared to 0/15 mice treated with the rifapentine regimen. In fact, the rifapentine regimen resulted in cure of 15/15 (100%) of mice after treatment for only 10 weeks.

Thus, murine studies indicate that rifapentine administered daily during combination intensive phase treatment has potent antimycobacterial activity that is associated with ability to achieve durable cure without relapse after about 3 months of total treatment.

Clinical trials of daily rifapentine

Phase I

Dooley and colleagues conducted a phase I dose-escalation study among healthy adult volunteers to determine the safety and pharmacokinetics of escalating daily doses of rifapentine (Dooley et al, 2012).

Participants received 5, 10, 15, or 20 mg/kg/dose rifapentine given once daily for 15 consecutive days; 20 mg/kg/dose was the pre-specified maximum dose; a cohort of additional participants received rifampin 10 mg/kg/dose. Of note, this study used strict weight-based dosing, such that the average rifapentine dose administered in the 20 mg/kg/dose cohort was 1650 mg daily. A total of 33 participants received study drugs. There were no grade 2 or higher clinical adverse events. Dose-limiting toxicities were observed in three participants, one each in the rifampin (grade 3 neutropenia), rifapentine 10 mg/kg (grade 3 serum liver transaminase elevation), and rifapentine 15 mg/kg (grade 3 lymphopenia) cohorts. In this study, the safety profile of rifapentine was similar to that of rifampin 10 mg/kg/dose, and it was concluded that rifapentine administered daily was tolerated and safe at doses as high as 20 mg/kg/dose. From a PK perspective, increases in rifapentine dosage resulted in less-than-dose proportional increases in single and multiple dose maximal concentrations.

Phase 2

The TBTC recently completed two phase 2 studies to assess the antimicrobial activity, safety, and tolerability of daily rifapentine administered with isoniazid, PZA, and ethambutol during the first eight weeks of pulmonary TB treatment. In TBTC Study 29, 531 adults with sputum smear positive pulmonary

TB were randomized to receive rifapentine approximately 10 mg/kg/dose or rifampin 10 mg/kg/dose administered 5 days per week for 8 weeks (intensive phase) with isoniazid, PZA, and ethambutol; study drugs were administered on an empty stomach (Dorman et al, 2012). The co-primary endpoints were negative sputum cultures on liquid and on solid media at the end of intensive phase; safety and tolerability were also assessed. This study demonstrated no significant difference between regimens in antimicrobial activity based on the surrogate marker of culture status at completion of intensive phase

(culture conversion on solid media 83.3% vs. 86.4% for the rifampin vs. rifapentine groups; and conversion in liquid media 65.1% vs. 67.9% in the rifampin vs. rifapentine groups). The rifapentine regimen was well tolerated based on similar proportions of participants discontinuing assigned treatment overall (15.7% in the rifampin group vs. 14.5% in the rifapentine group) or due to toxicity (1.2% in the rifampin group vs. 1.5% in the rifapentine group). There were no differences, by treatment group, in proportions of participants with a serious adverse event related to study treatment (0.4% in the rifampin group vs. 1.1% in the rifapentine group), or by type or severity of adverse events. Hepatitis occurred in

2.8% of rifampin group participants vs. 4.0% of rifapentine group participants (p=0.48). The investigators concluded that the rifapentine regimen administered on an empty stomach 5 days/week for 8 weeks was safe and well-tolerated but not significantly more active than the conventional rifampin regimen.

The TBTC subsequently conducted a randomized, multicenter, dose-ranging study to determine the optimal dose of daily rifapentine during the first 8 weeks of pulmonary TB treatment. In TBTC Study 29X, 334 adults with sputum smear positive pulmonary TB were randomized to receive rifampin (approximately

10 mg/kg/dose) or rifapentine (approximately 10, 15, or 20 mg/kg/dose, maximum dose 1500 mg) administered with a high fat meal once daily for 8 weeks, in addition to isoniazid, PZA, and ethambutol.

Rifapentine was well-tolerated across all treatment arms based on a pre-specified definition and also based on comparison with the rifampin group. Percentages of participants discontinuing assigned treatment were: rifampin 11/85 (12.9%; upper bound of 90% one-sided CI 19.0); rifapentine 10 mg/kg

5/87 (5.7%; 10.5); rifapentine 15 mg/kg 5/81 (6.2%; 11.3); and rifapentine 20 mg/kg 9/81 (11.1%; 17.1).

There were two deaths – one in the rifapentine 15 mg/kg group due to hematemesis, and one sudden death in the rifapentine 20 mg/kg group in a 61 year old male with untreated hypertension and diabetes mellitus and a strong family history of cardiac disease and sudden death. There were no differences between treatment groups in the percentages of participants with a serious adverse event associated with study treatment, or by type or severity of adverse events. Serious adverse events attributed to study treatment were as follows, by treatment assignment: two events among 85 participants in the rifampin group (one hepatitis, one drug allergy); one event among 87 in the rifapentine 10 mg/kg group

(leukocytosis); no events among 81 participants in the rifapentine 15 mg/kg group; one event among 81 participants in the rifapentine 20 mg/kg group (hepatitis). With respect to antimicrobial activity (efficacy), the rifapentine regimens were substantially more active than the standard rifampin regimen based on week 8 (end of intensive phase) culture status (Table 1) as well as time to stable culture conversion.

Antimicrobial activity was associated with rifapentine exposure (area under the concentration time curve

[AUC]) (Table 1B). The higher rifapentine exposures were associated with very high rates of sputum sterilization at two months, a very good indicator of overall efficacy of an anti-tuberculosis regimen.

Findings were consistent with a steep exposure-response relationship. Pharmacodynamic models were used to further elucidate the relationships between antimycobacterial activity and assigned rifapentine treatment arm, administered rifapentine dose, and rifapentine drug exposure. For efficacy outcomes of time to stable culture conversion in solid media and time to stable culture conversion in liquid media, there was a significant association with rifapentine AUC (p=0.0002 for solid media and p=0.001 for liquid media) but not for assigned rifapentine mg/kg group (p=0.6 for solid media and p=0.36 for liquid media) or for administered rifapentine dose in mg (p=0.17 for solid media and p=0.17 for liquid media). For rifapentine, the exposure-response relationship was best described by a sigmoidal Emax function (Figure

1), with the greatest change in effect per change in exposure occurring between exposures of approximately 200 mcg*h/L and 550 mcg*h/L, with a plateau in efficacy at higher exposures. In addition to identifying a target AUC of approximately 500 to 600 mcg*h/L, pharmacokinetic studies yielded additional information pertinent for rifapentine dosing. Specifically, the relationship between participant body weight and rifapentine clearance was examined, and clearance was not significantly affected by body weight, thereby supporting ‘flat’ dosing of rifapentine (i.e. rifapentine dose is not adjusted for body weight) (Figure 2). In addition, pharmacokinetic/pharmacodynamic modeling also predicted that a rifapentine dose of 1200 mg without food would yield an AUC of approximately the same as that of a rifapentine dose of 900 mg with a very high fat meal. Given that target rifapentine AUC lies somewhere between that achieved with a very high fat meal and rifapentine dose of 900 to 1200 mg, the strategy proposed in the current phase 3 trial is a rifapentine dose of 1200 mg with a modest food requirement, with the rationale that a very high fat meal is poorly feasible under phase 3 trial or routine TB care conditions whereas a more general recommendation of dosing with food is likely to be broadly feasible.

Table 1A. Percentages of participants with negative cultures at completion of intensive phase treatment, by treatment assignment, for the modified intention-to-treat analysis group, S29X

Rifampin Rifapentine

10 mg/kg

Rifapentine

15 mg/kg

Rifapentine

20 mg/kg

Solid culture medium

% (n/n) with negative cultures

% difference vs. Rifampin

(95% CI)

p-value

81.3 (52/64)

92.5 (62/67)

11.3

(-1.7, 24.3)

0.10

89.4 (59/66)

8.1

(-5.5, 21.8)

0.29

94.7 (54/57)

13.5

(0.6, 26.3)

0.05

Liquid culture medium

% (n/n) with negative cultures

% difference vs. Rifampin

56.3 (36/64)

74.6 (50/67)

18.4

(0.8, 35.9)

0.04

69.7 (46/66)

13.4

(-4.5, 31.4)

0.16

82.5 (47/57)

26.2

(8.9, 43.5)

<0.01

Table 1B. Percentages of participants with negative cultures at completion of intensive phase treatment, by rifapentine area under the concentration-time curve tertile, for the modified intention-to-treat analysis group, S29X

Rifampin Rifapentine

AUC < 323

mcg*h/L

Rifapentine

AUC 324 to 513 mcg*h/L

Rifapentine

AUC > 513

mcg*h/L

Solid culture medium

% (n/n) with negative cultures

% difference vs. Rifampin

81.3 (52/64)

83.9 (52/62)

2.6

(-12.2, 17.4)

0.88

100.0 (63/63)

18.8

(7.6, 29.9)

92.3 (60/65)

11.1

(-2.0, 24.2)

0.11

Liquid culture medium

% (n/n) with negative cultures

% difference vs. Rifampin

56.3 (36/64)

54.8 (34/62)

-1.4

(-20.4, 17.5)

1.00

90.5 (57/63)

34.2

(18.5, 50.0)

80.0 (52/65)

23.8

(6.6, 40.9)

Moxifloxacin for TB treatment

Moxifloxacin is a fluoroquinolone with potent activity against M. tuberculosis in vitro and in animal models, including sterilizing activity in animal models. In animal models, moxifloxacin’s potent activity is partly explained by the fact that it accumulates in granulomas and pulmonary lesions at higher concentrations than found in plasma and lung tissue (Kjellson et al., 2012; Prideaux et al., 2011). In humans, data on the long-term use of moxifloxacin have shown that it has an excellent safety profile. Three phase 2 TB clinical trials have shown that substitution of moxifloxacin for ethambutol during the intensive phase of pulmonary TB treatment increases the antimicrobial activity of the regimen, as assessed using surrogate markers (Burman et al., 2006; Rustomjee et al., 2008; Conde et al., 2009). A recently completed phase 3 trial found that treatment with a weekly regimen of rifapentine and moxifloxacin during the continuation phase of therapy (Rifaquin 6 month regimen, Jindani, 2014) was non-inferior to daily isoniazid plus rifampin; the efficacy of rifapentine plus moxifloxacin in this trial is significant because once-weekly rifapentine with isoniazid (instead of moxifloxacin) is associated with higher rates of relapse and treatment failure (Vernon et al., 1999). Two phase 3 treatment shortening studies using fluoroquinolone-based 4-month regimens administered daily have been completed recently. The Oflotub Trial was an open-label, Phase 3 multicenter trial evaluating the efficacy and safety of a 4-month gatifloxacin (G) containing regimen compared to the standard 6-month HRZE regimen (Merle et al, 2014). The Oflotub 4 month regimen consisted of a 2 month intensive phase of GHRZ, followed by a 2 month continuation phase of

GRH (2GRHZ/2GRH) versus a control arm of 2ERHZ/4RH, administered 6 days per week. The investigational 4 month regimen failed to achieve non-inferiority at a 6% margin: in a modified intention-to-treat analysis unfavorable outcomes at 24 months from end-of-treatment had occurred in 21.0%

(146/694) in the gatifloxacin-containing arm vs. 17.2% (114/662) in the control arm (difference +3.5%, 95% CI -0.7% to +7.7%). The REMox phase 3 study was a randomized placebo-controlled double-blind trial comparing two treatment shortening regimens, namely 2MHRZ/2MHR and 2EMRZ/2MR, with the standard control regimen 2EHRZ/4HR (Gillespie et al 2014). The primary end point was treatment failure or relapse within 18 months after randomization. In the REMox study, neither of the investigational moxifloxacin-containing regimens was shown to be non-inferior to the control. Specifically, of the 1931

Figure 1. Exposure-response relationship for rifapentine

8 AUC (mcg*h/L) ef fe ct

Median AUC, 1200 mg group

Median AUC, 900 mg group

Median AUC, 600 mg group

Body weight (kg)

C le ar an ce in d iv id u al d if fe re n ce

Figure 2. Rifapentine clearance is not meaningfully affected by body weight patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the 2MHRZ/2MHR group (85%) and the 2EMRZ/2MR group (80%) than in the control group (2EHRZ/4HR; 92%). A difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) was noted comparing to the 2MHRZ/2MHR group, and a difference favoring the control group of 11.4 percentage points (97.5% CI, 6.7 to 16.1) was noted when comparing to the 2EMRZ/2MR group. Overall the 2MHRZ/2MHR group performed slightly better than the

2EMRZ/2MR group, and achieved non-inferiority in certain sub-groups (e.g. females). In the REMox study the two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load as compared to the control group. As in the Oflotub Trial, however, overall the experimental moxifloxacin single-substitution regimen was also not shown to be non-inferior to the control. The fluoroquinolone-containing regimens were safe and well-tolerated in both the Oflotub (gatifloxacin) and the REMox

(moxifloxacin) studies. Overall, pre-clinical and clinical studies have shown that the single substitution of moxifloxacin for ethambutol increases antimicrobial activity of the regimen, but this increase is not sufficient to achieve acceptable cure rates after truncation of therapy to four months (Burman et al., 2006;

Rustomjee et al., 2008; Conde et al., 2009, Merle et al, 2014, Gillespie et al., 2014).

Quantitative capability of the Xpert MTB/RIF assay and its correlation with smear microscopy and culture.

The Xpert MTB/RIF Assay, endorsed by the WHO in 2010 and FDA approved for marketing in the US in

2013 for diagnosing TB, simultaneously detects the presence of M. tuberculosis in sputum and determines if genetic markers for rifampin resistance are present. Two studies have compared Xpert

MTB/RIF results with sputum smear results in newly suspected pulmonary TB (Blakemore et al, 2011;

Friedrich et al 2011). Medium and high qualitative readings from Xpert MTB/RIF correlate well with finding acid fast bacilli on sputum smears. The quantitative capability of the Xpert MTB/RIF assay will be used in this trial at baseline to permit participant randomization based on a medium or high semi-quantification of

M. tuberculosis copies on their Xpert test at screening. Drug susceptibility results as provided by the

Xpert MTB/RIF assay or the Hain MTBDRplus assay, will also be used as part of screening and enrollment procedures.

Efavirenz and Rifapentine Drug-Drug Interactions Rifamycin antibiotics such as rifapentine have the potential to cause significant drug-drug interactions with antiretroviral therapy. Rifapentine is a known inducer of various cytochrome P450 iso-enzymes. The nonnucleoside reverse transcriptase inhibitor efavirenz is a cytochrome P450 substrate, leading to concern for decreased efavirenz concentrations and an increased risk of virologic failure if dosed concurrently with rifapentine. Exposure-response relationships between efavirenz concentrations and virologic failure have been demonstrated. For example, Cohen et al. reported that in an evaluation of 142

HIV-infected persons, efavirenz mid-dosing interval concentrations <1 mg/L were strongly associated with an increased risk for virologic failure (odds ratio 12.5, 95% CI, 2.7-57.3) (Cohen, 2009). The collective data for efavirenz indicate an increased risk of virologic failure if mid-dosing interval (or trough) concentrations are less than 1 mg/L.

Clinical studies evaluating the effects of rifapentine co-administration on efavirenz pharmacokinetics and efficacy have shown mixed results. Among individuals with HIV infection enrolled in a clinical trial of treatment for latent TB infection, preliminary data recently presented by Podany et al. suggest no clinically relevant increase in efavirenz oral clearance when dosed together with isoniazid and rifapentine (10 mg/kg) once daily for four weeks. In this study of 87 patients, median mid-dosing interval efavirenz concentrations decreased in the presence of rifapentine (2588ng/mL vs 2460ng/mL), suggestive of an induction effect on efavirenz by rifapentine; however, the geometric mean ratio of efavirenz oral clearance increased by only 4%. Additionally, virologic suppression was maintained in 97% of the patients in the study (Podany, 2014). A second study, from Farenc et al. investigated the effect of repeated once weekly

900mg rifapentine dosing on efavirenz pharmacokinetics. In 12 HIV-infected, TB free adults, the authors found a minimal decrease in efavirenz exposure, as measured by a mean decrease in AUC0-24 of 14%

(Farenc, 2014). A third study investigated the effect of daily rifapentine dosing (15mg/kg) for 21 days in

HIV-infected, TB free adults receiving efavirenz based ART with baseline suppressed viral load (VL< 20 copies/mL). After a single dose of rifapentine efavirenz PK was unchanged (Cmax, AUC0-24, Cmin).

However, after 21 once-daily doses of 15 mg/kg rifapentine, decreases of 17%, 37% and 33% were seen in Cmax, AUC0-24 and Cmin respectively (Sanofi, 2014). All patients maintained viral suppression while taking RPT. While these studies are encouraging in that co-administration of rifapentine at daily doses of

10 and 15 mg/kg with EFV-based ART did not appear to increase risk of HIV treatment failure, further investigations of efavirenz PK and HIV treatment response when rifapentine is given at 1200 mg daily for a longer duration are needed.

The Tuberculosis Trials Consortium (TBTC)

The mission of the TBTC, funded by the U.S. Centers for Disease Control and Prevention, is to conduct programmatically relevant clinical, laboratory and epidemiologic research concerning the diagnosis, clinical management, treatment and prevention of tuberculosis infection and disease. The TBTC has sites in the United States, Spain, South Africa, Hong Kong, Kenya, Vietnam, Peru, and Uganda. All sites have close connections with the local TB control program; some sites are based in the TB control program. All sites work with experienced mycobacterial laboratories, and the CDC’s Mycobacteriology

Laboratory serves as the central laboratory for confirmation of drug-susceptibility testing, DNA fingerprinting, and further characterization of drug-resistant isolates. Since its inception in 1994 over

13,000 patients have been enrolled in TBTC clinical trials.

The AIDS Clinical Trials Group (ACTG)

The mission of the ACTG, established in 1987, is to develop and conduct scientifically rigorous translational research and therapeutic clinical trials, in the U.S. and internationally, related to HIV infection and its complications including tuberculosis. The ACTG is funded by the U.S. National Institutes of

Health through the National Institute of Allergy and Infectious Diseases. ACTG units and investigators serve their communities as major resources for HIV/AIDS research, treatment, care, and education. The

ACTG tuberculosis laboratory infrastructure consists of one international tuberculosis specialty laboratory as well as regional tuberculosis diagnostic laboratories.

2.2 Rationale

Rationale for regimen selection

The current standard six-month TB treatment regimen for drug-susceptible pulmonary tuberculosis is associated with unacceptably high rates of treatment default under program conditions, thereby contributing to individual morbidity and mortality, M. tuberculosis transmission, and drug resistance.

Highly potent regimens of shorter treatment duration may facilitate treatment completion and direct observation of treatment, thereby improving individual and public health. Studies using animal models of

TB chemotherapy have shown a clear relationship between rifamycin exposure and reduction of bacillary burden. Animal studies also indicate that rifapentine-based regimens are highly potent and can reduce overall tuberculosis treatment duration to approximately 3 months. In humans, phase 1 and 2 clinical trials support the safety and tolerability of rifapentine at daily doses up to 20 mg/kg. A phase 2 clinical trial has shown a strong drug exposure-response effect for rifapentine using a surrogate marker of time to stable culture conversion. These results provide rationale for a phase 3 clinical trial to determine the efficacy, using the definitive endpoint of durable cure, of a regimen containing rifapentine substituted for rifampin and administered in combination with other drugs for 17 weeks (approximately four months).

This trial will also assess the efficacy of a second investigational 17-week regimen that incorporates two strategies to enhance antimicrobial activity. The first strategy is optimization of rifamycin exposure through the single substitution of high dose rifapentine for rifampin throughout treatment as described above. The second strategy is a dual substitution approach that seeks to further enhance the potency of the regimen by also replacing ethambutol (which has relatively weak activity) with moxifloxacin, in the context of optimized rifamycin exposure. As described above, available evidence from animal models and in humans indicates that moxifloxacin, when substituted for ethambutol, will contribute to regimen bactericidal activity, even though that single substitution alone is insufficient to shorten treatment to four months. The investigational regimen that contains both rifapentine and moxifloxacin may well be the most potent regimen possible without new chemical entities. Therefore if both investigational regimens fail in the proposed study, then the implications are that new drugs are required for treatment shortening, and that treatment shortening cannot be achieved with existing drugs. Such a finding would push the drug-susceptible TB therapeutics field in a different direction.

Rationale for dosing strategy

With respect to rifapentine dose and dosing strategy, this trial will use a flat dose of 1200 mg with food dosed daily. This is based on 1) demonstration of safety of rifapentine at 1200mg in phase 1 and 2 trials,

2) demonstration that body weight does not significantly affect rifapentine clearance, 3) recognition of an effect of food in substantially increasing rifapentine absorption (Zvada et al., 2010) and 4) modeling predictions that the target rifapentine exposure (AUC of approximately 500 to 600 mcg*h/L) is achievable using this strategy.

For rifampin, administration with food slows the rate of absorption and decreases the maximal concentration (Cmax) by about 36% in healthy adults but to a lesser extent (5 to 15%) in TB patients, with little to no effect on AUC (reduction of 6% in healthy adults; reduction of 4% to increase of 8% in TB patients) (Peloquin et al., 1999; Zent et al., 1995). Overall the clinical consequences of these PK effects are unclear. As a consequence rifampin will not be dosed with food.

Rationale for an open-label (not blinded) study

This study will be open-label; participants, study staff, and clinical care providers will have knowledge of treatment assignment. While blinding is often incorporated into clinical trials as a strategy to reduce bias, blinding is not without cost. Besides logistic complexity, there are two main reasons to not incorporate blinding into this trial. First, if blinding through use of placebos were to be incorporated into this trial, the already substantial pill-burden would be further increased to approximately 20 pills per day, which will be difficult for participants to tolerate. Poor tolerability of the pill burden may result in diminished adherence to treatment and in turn efficacy. Besides tolerability, from a biological perspective the dissolution of pills in the gastrointestinal tract may be reduced with such a high pill burden, a situation that could result in diminished treatment efficacy and increased risk for acquisition of drug resistance. Reduced bioavailability due to the burden of added placebo pills also might reduce the generalizability of study findings to possible subsequent programmatic usage. As noted above, there may be a differential effect of food on rifampin and rifapentine such that different food advice is required so as to optimize regimen pharmacokinetics and potential efficacy. The study will minimize any impact of ascertainment bias through the use of objective laboratory measures for the primary efficacy endpoint as well as incorporation of a central study clinician (who is blinded as to individual participants’ treatment assignments) to be available to advise on protocol procedural issues. Co-intervention bias is unlikely during the active treatment in the first four months, and it is unlikely that the use of placebo can effectively avoid contamination bias in the last two months. Co-intervention bias is unlikely during active TB treatment, as site teams will closely monitor participants. Measures will be taken to evaluate participants equally, regardless of assigned study arm, such that timing of study visits and endpoints will be applied uniformly.

Rationale for CD4 testing before enrollment

HIV-infected individuals will be excluded from enrollment if, at the time of enrollment, their CD4 T cell count is known to be <100 cells/mm3. The rationale for doing so is the challenge of starting concomitant treatment for HIV-infection and TB within a short period of time as recommended by WHO guidelines, the potential for severe immune reconstitution when antiretroviral therapy is initiated early in the course of anti-TB therapy, an increased probability for the diagnosis of conditions that would require therapy with medications that have drug-drug interactions with study drugs, and the indication for primary antimicrobial prophylaxis against opportunistic infections (such as toxoplasmosis and Mycobacterium avium) with consequent increase in the probability of drug-drug interactions and adverse events. Additionally, treatment assignment is stratified by CD4 T cell count (Section 7.2).

Rationale for including adolescents

Inclusion of children in clinical trials of tuberculosis treatment increasingly has been called for to support the rational use and increased availability of anti-tuberculosis medications for children (Burman 2006, McKenna 2014). Tuberculosis disease characteristics, presentation, diagnosis, and treatment are similar for adults and adolescents.

Rifapentine currently is approved in the United States for use in persons as young as 12 years old

(Priftin® package insert). Rifapentine pharmacokinetic results have been found to be similar between adults and adolescents down to this age (Marshall 1999). Rifapentine 900 mg once weekly, with isoniazid for 12 weeks has been used to treat children for latent TB infection (LTBI) (Villarino 2015): the rifapentine-containing regimen was found to be as safe and effective as a 9-month daily isoniazid regimen, among 552 children age 2-17 years old treated with the rifapentine-containing regimen. Based on a large clinical trial that reported treatment of patients as young as 12 years old (Sterling 2011), CDC recommends use of this rifapentine-containing regimen “as an equal alternative to 9 months of daily self-supervised INH for treating LTBI in otherwise healthy patients aged ≥12 years.” (CDC 2011) Although the phase 2 trial of daily high-dose rifapentine enrolled 81 participants ≥ 18 years old (Dorman 2013), available animal and human data and a formal review by Sanofi support the safety of including adolescents in this clinical trial (Marilyn Maroni personal communication).

Moxifloxacin usage in children has been limited because of findings that treating juvenile dogs with doses higher than recommended for humans (≥ 30 mg/kg/day) resulted in arthropathy (Avelox® package insert).

Moxifloxacin has been recommended and used in children for treatment of multidrug resistant (MDR) TB although few safety data have been collected systematically (Bradley 2011). One recent report of a series of 9 children age 6 months to 13 years, treated with moxifloxacin for a range of 3-16 months, attributed side effects possibly to moxifloxacin in 2 patients (Garazzino 2014): A 6-year old girl developed arthritis of the ankle after 3 months, which “spontaneously resolved few days after drug cessation.” A 3-year old girl developed “grade three elevation of liver function tests after 9 months of treatment.” A more recent report of 23 children, median age 11.1 years (IQR 9.2-12.0 years), treated for MDR TB with moxifloxacin followed the children for a median of 236 days (IQR 142-541 days (Thee 2014). This group found lower exposures in children than in adults following an oral dose of 10 mg/kg and lower exposure with HIV infection.