J.5.2 - Treatment Protocol Study 37.pdf

Attachment J.5.2 - Solicitation 75D301-20-R-67869

Six weeks of daily rifapentine vs. a comparator arm of 12-16 week rifamycin-based treatment of latent M. tuberculosis infection:

assessment of safety, tolerability and effectiveness

Version 2.0

July 24, 2019

ASTERoiD

Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine given Daily for LTBI

U.S. Public Health Service Study 37

Tuberculosis Trials Consortium (Centers for Disease Control and Prevention; CDC)

TB Epidemiologic Studies Consortium (CDC)

University College London (British Medical Research Council; BMRC)

Protocol Team:

Protocol co-chairs

Timothy Sterling, Vanderbilt University Medical Center (TBTC)

Bob Belknap, Denver Public Health (TBESC)

Ibrahim Abubakar, University College London (BMRC)

Rosanna Boyd, CDC Project Officer (TBTC)

Amina Ahmed, Carolinas (TBESC)

Bert Arevalo, Westat

Kristian Atchley, Metro Nashville Public Health (TBESC)

Angela Crook, University College London (BMRC)

Mascha Elskamp, Columbia University (TBTC)

Pei-Jean Feng, CDC (TBESC)

David Horne, University of Washington (TBESC)

Dolly Katz, CDC (TBESC)

Russell Kempker, Emory (TBESC)

Amy Kerrigan, Vanderbilt University Medical Center (TBTC)

Renuka Khurana, Maricopa (TBESC)

Marc Lipman, University College London (BMRC)

Gina Maltas, Johns Hopkins Medical Institutions (TBESC)

Payam Nahid, University of California at San Francisco (TBTC)

Andrew Nunn, University College London (BMRC)

Patrick Phillips, University of California at San Francisco (TBTC)

Neil Schluger, Columbia University (TBTC)

Nigel Scott, CDC (TBTC)

Erin Sizemore, CDC (TBTC)

Amber Coyne, Metro Nashville Public Health (Community Research Advisory Group (CRAG))

Yoseph Sorri, Seattle King County Health Department (TBESC)

Contents

ABBREVIATIONS

PROTOCOL SYNOPSIS

I. Background

Epidemiology and Pathogenesis of Tuberculosis

Treatment of Latent Tuberculosis Infection (LTBI, or Preventive Therapy)

Shorter LTBI Treatment Regimens

Animal Studies and Previous Human Studies using Shorter LTBI Treatment Regimens

Rationale

II. Aims of the Study

Hypothesis

Primary Objectives

Secondary Objectives

III. Study Agents

Isoniazid

Rifampin

Rifapentine

D. Use of study agents (INH, RIF, RPT) in the pediatric population (children and adolescents).

IV. Methodology

Study Design

Eligibility Criteria

1. Inclusion Criteria

2. Exclusion Criteria

Outcome Measures

Sample Size and Statistical Analysis

1. Sample size estimates for safety

2. Sample size estimates for effectiveness

3. Tolerability

4. Statistical analysis

Study Procedures

1. Pre-Enrollment Screening

2. Enrollment/Randomization

3. Administration of Study Drugs

4. Participant Evaluations

5. Assessment of Endpoints

Risks and Benefits

1. Risks

2. Benefits

Participant Reimbursement of Costs

V. Clinical Management Issues

Concomitant Medications during Study Treatment Phase

Study Drug Adverse Events

Adverse Event Reporting

Criteria for Discontinuation of Study Drug

VI. Administrative Management Issues

Randomization Process

Supply of Study Drug

Drug Accountability and Record Keeping

Ethics Committee and Informed Consent

1. Ethics Committee (EC) or Institutional Review Board (IRB)

2. Informed Consent Process

Monitoring

Data Reporting

Management and Retention of Study Records

VII. Appendices

Appendix A. Schedule of Events

Appendix B. Common Terminology Criteria for Adverse Events (Version 5)

Appendix C. List of Drug Interactions with Study Medications

Appendix D. High TB Incidence Countries (TB rate of >150 cases per 100,000 population). 53

Appendix E. List of Participating Sites

Appendix F. Definitions and Scales Used in Reporting Adverse Events

Appendix G. Participant Wallet Card

VIII. References

ABBREVIATIONS

12H 12 months of daily isoniazid

3HP 12 weeks of once-weekly isoniazid and rifapentine

3HR 12 weeks of daily isoniazid and rifampin

4R 16 weeks of daily rifampin

6H 6 months of daily isoniazid

6wP 6 weeks of daily rifapentine

9H 9 months of daily isoniazid

ACE Angiotensin-converting enzyme

ACTG AIDS Clinical Trials Group

ADR Adverse drug reaction

AE Adverse event

AFB Acid-fast bacilli

ALT Alanine aminotransferase

ARB Angiotensin receptor blockers

ART Antiretroviral therapy

AST Aspartate aminotransferase

ASTERoiD Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine given

Daily for LTBI

ATS American Thoracic Society

BMRC British Medical Research Council

CAGE Alcohol intake questionnaire (each letter stands for one of the four questions)

CBC Complete blood count

CDC U.S. Centers for Disease Control and Prevention

CFR Code of Federal Regulations

CI Confidence interval

CRAG Community Research Advisory Group

CTCAE Common Terminology Criteria for Adverse Events

CYP Cytochrome

DNA Deoxyribonucleic acid

DOT Directly observed therapy

DSMB Data & Safety Monitoring Board

DTBE Division of TB Elimination

EC Ethics committee

ELISA Enzyme-linked immunosorbent assay

FDA Food and Drug Administration

HAV IgM Hepatitis A virus immunoglobulin M

HbsAg Hepatitis B surface antigen

HCV Ab Hepatitis C virus antibody

HIV Human immunodeficiency virus

ICH-GCP International Conference on Harmonization Good Clinical Practice

IDSA Infectious Diseases Society of America

IGRA Interferon gamma release assay

INH Isoniazid

INR International normalized ratio

IRB Institutional review board

ITT Intention-to-treat

LAN Local-area network

LFT Liver function test

LTBI Latent M. tuberculosis infection mITT Modified intention-to-treat

MOOP Manual of operating procedures

NAAT Nucleic acid amplification test

NAT2 N-acetyltransferase enzyme

NCHHSTP National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

NI Non-inferiority

NNRTI Non-nucleoside reverse transcriptase inhibitors

NOAC Novel oral anticoagulants

NRTI Nucleoside reverse transcriptase inhibitors

NSAID Nonsteroidal anti-inflammatory drug

PP Per protocol

PT Prothrombin time

RIF Rifampin

RNA Ribonucleic acid

RPT Rifapentine

SAE Serious adverse event

SAT Self-administered therapy

SGOT Serum glutamic oxaloacetic transaminase

SGPT Serum glutamic-pyruvic transaminase

SOC Standard of care

TAF Tenofovir alafenamide

TB Tuberculosis

TBESC Tuberculosis Epidemiologic Studies Consortium

TBTC Tuberculosis Trials Consortium

TDF Tenofovir disoproxil fumarate

TNF- Tumor necrosis factor alpha

TST Tuberculin skin test

WBC White blood cell

WHO World Health Organization

Statement of Compliance

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

Harmonization Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations (CFR)

45 CFR 46 and 21 CFR, and applicable site-specific regulatory requirements.

PROTOCOL SYNOPSIS

The primary objectives of this open-label Phase III clinical trial are to compare the safety and effectiveness of a six week regimen of daily rifapentine (6wP, the experimental arm) with a comparator arm of 12-16 weeks of rifamycin-based treatment of latent M. tuberculosis infection

(LTBI). The latter will be the local standard of care rifamycin-based regimen. This trial will be conducted among persons with LTBI living in low to moderate tuberculosis (TB) incidence settings who are at increased risk of progression to TB and require treatment of LTBI.

Hypothesis

The safety and effectiveness of 6wP is non-inferior to a comparator arm of 12-16 weeks of rifamycin-based treatment of LTBI. The comparator arm’s regimens will include 12 weeks of once-weekly isoniazid (INH) + rifapentine (3HP), 12 weeks of daily INH + rifampin (3HR), and

16 weeks of daily rifampin (4R).

Primary Objectives

1. Compare the safety of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.

2. If safe, compare the effectiveness of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.

Primary Endpoints

1. Safety: Drug discontinuation due to adverse drug reaction (ADR) associated with 6wP and the rifamycin-based comparator arm (3HP, 3HR, or 4R).

• Attribution of an adverse event (AE) to study drugs will be initially determined by the local site investigator, with final attribution determined by the sponsor.

2. Effectiveness: Culture-confirmed TB in participants > 18 years old and culture-confirmed or clinical TB in participants < 18 years old.

• Diagnosis of culture-confirmed TB will be performed using liquid and/or solid media.

The use of nucleic acid amplification tests (NAATs; e.g., GeneXpert) is not required, but

NAATs should be used if available.

Secondary Objectives

Among those treated with 6wP vs. the comparator arm (3HP, 3HR, or 4R), compare the:

1. Proportion who complete assigned treatment (tolerability).

• Treatment completion will be assessed by both participant self-report and pill counts for those receiving self-administered therapy and by medication administration records for those receiving directly-observed therapy.

2. Proportion with drug discontinuation for any reason.

3. Proportion with any grade 3, 4, or 5 (i.e., death) adverse event during the time period of 9 months after enrollment

4. Proportion with any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug

(ADR).

5. Proportion who have died for any reason

6. Proportion with hepatitis and non-hepatotoxic systemic drug reactions.

7. Proportion with culture-confirmed or clinical TB regardless of age.

8. Proportion with TB among those who complete assigned therapy (efficacy).

9. Safety, tolerability, and effectiveness among participants with human immunodeficiency virus (HIV) infection.

10. Safety, tolerability, and effectiveness in participants < 18 years old.

Among those treated with 6wP, compare the:

11. Safety, tolerability, and effectiveness to each regimen in the comparator arm: 3HP, 3HR, 4R.

12. Treatment completion with an alternative regimen after discontinuation of study therapy

13. Proportion with resistance to rifamycins or isoniazid among persons who develop TB to each regimen in the comparator arm: 3HP, 3HR, 4R.

Secondary Endpoints

1. Treatment completion

2. Discontinuation of therapy for any reason. The reasons for discontinuation will be collected.

3. Development of any grade 3, 4, or 5 (i.e., death) adverse event during the time period of 9 months after enrollment

4. Development of any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug

(ADR)

5. Death (from any cause)

6. Hepatitis and non-hepatotoxic systemic drug reactions (see definition below in Section 5.

Assessment of endpoints).

7. Culture-confirmed and clinical TB regardless of age.

8. TB among all participants who completed therapy (efficacy).

9. Safety, tolerability and effectiveness in HIV-infected participants.

10. Safety, tolerability and effectiveness in participants < 18 years old.

Among those treated with 6wP, compare:

11. Proportions of: (a) drug discontinuation due to adverse drug reactions (safety), (b) treatment completion (tolerability), and (c) culture-confirmed or clinical TB (effectiveness) to each regimen in the comparator arm: 3HP, 3HR, 4R.

12. Treatment completion with an alternative regimen after discontinuation of study therapy

Study Design

The study will be an open label, multi-center, phase III randomized controlled non-inferiority clinical trial with 2 arms. Participants will receive daily 6wP (the experimental arm) or a 12-16 week rifamycin-based regimen (3HP, 3HR, or 4R, the comparator arm) for the prevention of TB in persons > 12 years old with LTBI and at increased risk of progression to TB. The study will be conducted in the United States, the United Kingdom, and other countries with low to moderate TB incidence (< 100 TB cases per 100,000 population)1 that have treatment of LTBI as their standard of care and offer 12-16 week rifamycin-based therapy.

Participants will be randomly assigned to one of the two study arms. Trial randomization will be computer-generated by the CDC TBTC Data and Coordinating Center (DCC). Enrollment will be through the CDC’s web-based study management system. Demographic data without identifying information will be collected about individuals who decline study enrollment and recorded in a decline log. Individuals who decline participation and are willing to respond will be asked about their reason(s) for declining participation in the study.

Participants will be prescribed:

Rifapentine (RPT) 600 mg daily x 6 weeks (6wP)

OR

A 12-16 week rifamycin-based regimen available at the participant’s site. The specific regimen will be determined by the local site investigator; it will be one of the following:

• RPT 900 mg and INH 900 mg once-weekly x 12 weeks (3HP)

• Rifampin (RIF) 600 mg and INH 300 mg daily x 12 weeks (3HR)

• RIF 600 mg daily x 16 weeks (4R)

Weight-based dosing will be used (see IV.A. Study Design).

Eligibility Criteria

▪ Inclusion Criteria

• Males or non-pregnant, non-breastfeeding females > 12 years old. Women of child-bearing potential who are not surgically sterilized must agree to practice an adequate method of contraception (barrier method or non-hormonal intrauterine device) or abstain from heterosexual intercourse during study drug treatment.

• Persons with LTBI who do not have evidence of TB disease and are at increased risk of progression to TB. M. tuberculosis infection may be demonstrated by either a positive tuberculin skin test (TST) or a positive interferon gamma release assay (IGRA; e.g., QuantiFERON or T.SPOT.TB).

Persons with LTBI at increased risk of progression to TB are those with one of the following:

1. Household and other close contacts (> 4 hours of exposure in a one week period) within 2 years prior to enrollment, of persons with culture-confirmed TB

▪ A positive nucleic acid amplification test (NAAT)/GeneXpert in the source case may be used for enrollment prior to culture confirmation

2. Recent M. tuberculosis infection, defined as converting from a documented negative to positive TST or IGRA within 2 years prior to enrollment. Persons without known close contact to someone with active pulmonary TB who have a conversion by IGRA may require additional evaluation to rule out a false conversion.

3. HIV co-infection.

4. ≥ 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray and no prior history of treatment for TB or LTBI.

5. Recent (within 2 years prior to enrollment) immigration to the United

States, United Kingdom, or other country with low to moderate TB incidence, with abnormal chest X-ray, and no evidence of active TB.

6. Recent (within 2 years prior to enrollment) immigration to the United

States, United Kingdom, or other country with low to moderate TB incidence, from a country with an estimated incidence rate of TB >

150 per 100,000 (see Appendix D).

7. An increased risk of TB due to medical conditions such as end-stage renal disease, or due to use of immunosuppressive medications such as chronic steroids or TNF- inhibitors.

• HIV-infected persons who are close contacts of a TB case, regardless of TST or IGRA result.

• Willingness to provide signed informed consent, or parental permission and participant assent.

▪ Exclusion Criteria

• Current confirmed culture-positive or clinical TB.

• Suspected current TB. Includes cases in which active TB cannot be eliminated as a possibility (by the site investigator)

• TB resistant to any rifamycin in the source case

• A history of treatment for > 7 consecutive days with a rifamycin or > 30 consecutive days with INH within 2 years prior to enrollment.

• A documented history of completing an adequate course of treatment for TB disease or LTBI in a person who is HIV-seronegative.

• History of allergy or intolerance to rifamycins.

• Serum alanine aminotransferase (ALT; SGPT) or serum aspartate aminotransferase (AST; SGOT) > 5x upper limit of normal among persons in whom baseline ALT or AST is determined+.

• HIV-seropositive and on antiretroviral therapy that cannot be given with rifampin or rifapentine due to drug-drug interactions.

• Receiving concomitant medications that are known to be contraindicated with any study drug.

• Females who are currently pregnant, breastfeeding, or intend to become pregnant within 120 days of enrollment.

• Weight < 25 kg.

Interim Monitoring and Analysis

The Data & Safety Monitoring Board (DSMB) will review safety and effectiveness data at least annually after commencement of recruitment.

After the first 560 participants in each arm are enrolled and eligible to have completed study treatment (see Section E5a: Completion of Therapy) the DSMB will assess the incidence of study treatment discontinuation due to adverse drug reaction and review other safety parameters

(including laboratory - LFTs, bilirubin, etc.) in each study arm. Based on the review of safety data, the DSMB will then make recommendations on whether the study enrollment should be continued or stopped, changes to the protocol are required (e.g. continue baseline hepatic enzymes testing and continued monitoring in all patients, etc.), or other action is recommended.

Enrollment rates, percentage of participants enrolled in clusters, risk categories of participants enrolled, and pooled TB rates among those enrolled will be assessed to determine whether the study sample size or enrollment criteria should be modified.

Sample Size

The sample size for this study will be 560 participants per arm (1,120 total) for the evaluation of safety and 1,700 participants per arm (3,400 total) for the evaluation of effectiveness. Therefore, the total expected sample size for the study is 3,400.

Study Visit Schedule (Also see Appendix A for a chart of all study visits and calls)

Study Treatment Phase

The study treatment evaluations will be conducted as follows:

• Participants on 6wP will have treatment evaluations at weeks 2, 4, 6

• Participants on 3HP or 3HR will have treatment evaluations at weeks 2, 4, 8, 12

• Participants on 4R will have treatment evaluations at weeks 2, 4, 8, 12, 16

All study treatment evaluations will be conducted in person, except the week 2 evaluation, which may be conducted by telephone or in person.

All study treatment evaluations prior to the end of treatment evaluation will be within (-/+3) calendar days of the scheduled visit. End of study treatment evaluations will be within (-3/+7) calendar days of the scheduled visit. The target end of treatment evaluations will be as follows

(also see Section E5a: Completion of Therapy):

• Participants on 6wP: week 6

• Participants on 3HR and 3HP: week 12

• Participants on 4R: week 16

Follow-up Phase

Participants on all regimens will be assessed in person or by phone for delayed ADRs 2 weeks

(14 days) after their last study dose.

The follow-up phase study evaluations will be conducted to assess for adverse events (Grade 3, 4 or 5) as follows:

• Participants on 6wP will have evaluations at months 4, 6 and 9 from the date of enrollment

• Participants on 3HR, 3HP, and 4R will have evaluations at months 6 and 9 from the date of enrollment

The follow-up phase study evaluations will be conducted to assess for TB disease as follows:

• Participants on 6wP will have evaluations at months 4, 6, 9, 12, 18 and 24 from the date of enrollment

• Participants on 3HR, 3HP, and 4R will have evaluations at months 6, 9, 12, 18 and 24 from the date of enrollment

Evaluations at months 4 (only for 6wP), 6, 9, 12, and 18 will be within (+/-7) calendar days of the scheduled visit, in person or by telephone. Evaluations at month 24 will be within (+/-14) calendar days of the scheduled visit, in person or by telephone, but preferably in person.

I. Background

Epidemiology and Pathogenesis of Tuberculosis

Approximately 1.4 million people die of tuberculosis (TB) each year,2 making it the most common infectious cause of death in the world. In 2015, there were 10.4 million new cases of

TB disease globally.2 Of these new cases, more than 40% (> 4 million) were smear-positive and at high risk for transmitting TB to their close contacts. The contacts infected with latent

Mycobacterium tuberculosis become the source of new TB cases in the future.

The epidemiology of TB is influenced by two important factors. Infection with M. tuberculosis in the environment usually occurs through contact with a person with untreated pulmonary TB via droplet nuclei that are expelled by coughing and sneezing. After close contact with a patient with infectious TB, 30-50% of exposed susceptible persons acquire the infection, as determined by the TST.3-5 The second factor that contributes to TB incidence is progression to active disease among infected persons. Conditions that alter host cellular immunity increase the risk of developing TB disease. These conditions include HIV infection, extremes of age, diabetes, smoking, severe malnutrition and anti-tumor necrosis factor alpha (TNF-) treatment.6, 7

Although TB disease can occur immediately after the initial infection in a small proportion of patients, M. tuberculosis infection remains clinically silent and microbiologically latent in most persons. However, approximately 5-10% of otherwise healthy M. tuberculosis -infected persons will progress to active clinical disease, becoming the source of infection for others.8-11

Therefore, preventing patients with LTBI from developing active TB disease is an important step to break the cycle of transmission and decrease the overall burden of TB worldwide.12, 13

The global burden of LTBI is enormous, with approximately one-quarter to one-third of the world’s population infected.14, 15 Modeling studies have demonstrated that widespread use of effective LTBI treatment would have a profound effect on decreasing the global TB burden.16, 17

A 9-month course of isoniazid (9H) is highly efficacious in preventing LTBI from progressing to

TB disease, but its effectiveness is limited by treatment completion rates of 30-64%.18-21 .

Treatment of LTBI in low and medium TB burden countries is an essential component of the

World Health Organization (WHO)’s End TB Strategy.22Given the efficacy plus high treatment completion rates of current short-course regimens, they are highlighted in WHO guidelines for treatment of LTBI.23 To improve TB control worldwide, even shorter treatment for LTBI that is affordable, effective, safe, and well-tolerated is a global priority.

Treatment of Latent Tuberculosis Infection (LTBI, or Preventive Therapy)

Candidates for LTBI treatment are those persons with a positive TST or IGRA, particularly if they also have risk factors for progressing to active TB disease, including individuals likely to be recently infected.24 LTBI treatment effectiveness varies primarily according to patient adherence. Among close contacts of TB cases who subsequently develop LTBI, isoniazid (INH) reduces the risk of active disease by 60-90%. The effectiveness of a 6-month course of INH among Eastern European persons with fibrotic lung lesions was 65%.18 The U.S. Public Health

Service trials showed that INH effectiveness was 55-83% among all patients who took treatment for 12 months as a preventive therapy.25 An average effectiveness of 68% has been suggested for a 9 to 12 month course of INH.26 INH is highly efficacious and inexpensive, but the long duration of therapy hinders effectiveness due to poor adherence. Therefore, the development of an alternative, shorter regimen has become a priority.6

In a recent large clinical trial conducted among primarily HIV-negative persons living in low and medium TB incidence countries (the Prevent TB study), a 12 week course of once-weekly INH and rifapentine (3HP) was as effective as 9 months of INH in preventing TB, and was also well-tolerated.27 In another study conducted among HIV-seropositive adults in South Africa, the regimen had similar effectiveness and tolerability as 6 months of INH.28 However, the 12 week

RPT + INH regimen was given under direct observation, which could be prohibitively costly for public health programs and less acceptable to patients. There have also been reports of a possible hypersensitivity or flu-like syndrome with the 12-week regimen, which could be due at least in part to its intermittent dosing frequency and higher dosing of INH and rifapentine.27, 29

Alternative rifamycin-based regimens include a 3-month regimen of daily, self-administered RIF and INH (3HR) which is widely use in Europe as a standard treatment option, and four months of daily RIF (4R), which has tolerability similar to that of 3HP and 3HR. Though the regimens are widely used in clinical practice, to date there are no published phase III randomized clinical trials that have been conducted to evaluate efficacy of the 4R regimen, and there are limited data on the 3HR regimen. However, two network meta-analyses of published trials showed similar efficacy between 3-4HR, 4R, and 3HP.30, 31 Three studies included in the 2014 meta-analysis assessed the risk of TB disease with 6-month INH daily treatment regimen (6H) compared to 3 or 4-month RIF (3-4R),32-34 six compared 6H to 3-4HR,28, 33, 35-38 three compared 9H to 4R,39-41 and one compared 12 months of daily INH (12H) to 3HR.42 Some of these studies had no TB outcomes in the relevant arms, including all of the 9H versus R comparisons.

In a Cochrane review, trials comparing 3 or 4 months of RIF to 6 or 9 months of INH found the regimens comparable in preventing TB disease, with less toxicity and better adherence to rifampin.43 Cost-effectiveness modeling has shown that even if the efficacy of RIF were slightly less than INH, RIF would still be more effective based on the higher adherence rates.44

Shorter LTBI Treatment Regimens

Treatment duration has long been recognized as an important factor affecting adherence and treatment completion with INH.19 The recommendation for 9 months of INH to treat LTBI was originally extrapolated from the higher efficacy with 12 months but lower adherence compared to 6 months of treatment. The Prevent TB study demonstrated the safety and efficacy of the shorter once-weekly 3HP regimen, and also showed that 3HP had significantly higher treatment completion rates than the standard 9 INH regimen (81% vs. 69%, p< 0.001).27 The iAdhere study was a follow-up to Prevent TB that compared 3HP by directly observed therapy (DOT) versus self-administered therapy (SAT) with or without text message reminders. Treatment completion by 3HP SAT was lower than DOT but was comparable to the reported treatment completion using 4R and higher than 9H in the Prevent TB study.27, 45, 46

An AIDS Clinical Trials Group (ACTG) study (5279) compared daily self-administered RPT plus INH for 4 weeks with daily self-administered INH for 9 months among HIV-seropositive persons.47 This study differed from the proposed study in that the ACTG study enrolled only

HIV-seropositive persons, it was conducted in high TB incidence countries (where there is a high risk of re-infection with M. tuberculosis after completion of treatment), and evaluates a shorter regimen, but one that includes INH . Moreover, most persons in this study did not have evidence of LTBI; the majority were TST negative. In contrast, our study will evaluate a slightly longer

(6-week) non-INH containing treatment regimen, be conducted primarily among HIV-seronegative persons, enroll only persons with evidence of LTBI, and take place only in countries with low-medium incidence of TB (where the risk of re-infection with M. tuberculosis is low).

The optimal length of treatment and the risk/benefits of monotherapy versus combination therapy are unknown. The animal studies described below show that 6 weeks of daily RPT appears to be a very effective regimen in preventing TB disease.

Animal Studies and Previous Human Studies using Shorter LTBI Treatment Regimens

In a murine model of LTBI 6wP for was as effective as RIF plus pyrazinamide for 8 weeks; both regimens cured all mice (cure defined as having stably negative M. tuberculosis cultures).48 The latter regimen is highly effective in humans, but its use has been precluded by severe hepatotoxicity.49, 50 Relapse rates 3 months after treatment completion were also comparable between the 6-week and 8-week murine study regimens: 1 / 15 (7%) mice who received 6wP vs.

0 / 15 (0%) mice who received 8 weeks of RIF plus pyrazinamide.48 In another murine study, daily RPT for 4 weeks resulted in relapse rates comparable to once-weekly RPT plus INH for 12 weeks.51 However, the relapse rates were high with both regimens: 67% and 47%, respectively.

No relapses occurred among the mice who received 8 weeks of daily RPT; 6 weeks was not studied. Relapse risk appears to be an important endpoint to assess the effectiveness of preventive therapy regimens in the murine model. Of note, this murine model has predicted efficacy in human trials of 8 weeks of RIF and pyrazinamide and 12 weeks of once-weekly RPT and INH.49, 52, 53

Rationale

Given the promising results regarding the effectiveness of 6wP in preventing TB disease in a murine model that has predicted the effectiveness in humans of other short-course regimens, we wish to evaluate the safety, tolerability, and effectiveness of 6wP in humans. A simple, safe and effective regimen that is significantly shorter than current therapy (e.g., 6 weeks instead of 12-16 weeks) would likely improve the willingness of providers to recommend therapy and patients to accept and complete treatment. Additionally, RPT given alone should have less toxicity and be better tolerated than when given with INH, which is hepatotoxic.18, 40, 54 Daily administration of

RPT alone could also decrease the risk of the flu-like syndrome compared to higher, more intermittent dosing of rifamycins plus INH.29, 55, 56 Lastly, this trial’s test regimen of short-course daily RPT could be prescribed as SAT, significantly decreasing the burden to patients and the cost to health departments compared to DOT.

The rationale for a combined comparator arm that includes three 12-16 week rifamycin-based treatment regimens includes the following points. First, two network meta-analyses concluded that the three regimens had similar effectiveness and safety.30, 31 Second, they can be readily incorporated into a single arm of a large pragmatic trial, with only minimal increases in sample size to account for the three component regimens. Third, the high treatment completion rates associated with such short-course regimens have prompted the WHO to recommend them for treatment of LTBI.23 Patients are much less likely to accept a 9-month course of INH now that 3-

4 month regimens are available. Fourth, the short-course regimens for treatment of LTBI that are offered vary across the U.S. and other countries. Thus, a large pragmatic trial which includes the different 12-16 week rifamycin-based regimens would allow enrollment of participants not only in many states in the U.S., but also in other countries (e.g. U.K).

The safety and tolerability of RPT at doses of 600 mg daily and higher (up to 1,200 mg) have been evaluated in a phase II clinical trial.57 However, in that trial, RPT was administered as part of combination therapy, and the trial was conducted in adults with TB disease. There are no phase II trials that have evaluated the safety and tolerability of rifapentine 600 mg administered daily (alone) for 6 weeks in patients with TB or LTBI. The ACTG trial noted above demonstrated the safety of a 4-week daily regimen of isoniazid and rifapentine 600 mg in persons with HIV coinfection. Acceptable thresholds for safety of LTBI treatment regimens are generally higher than for TB disease regimens because persons with LTBI are asymptomatic.

Therefore, a strong rationale exists for an assessment of the safety and tolerability of a daily RPT regimen for LTBI as the first step in assessing the regimen’s effectiveness.

We propose a large pragmatic trial to assess the safety, tolerability, and effectiveness of 6wP.

The trial is designed as an effectiveness study, with an early assessment of safety and tolerability. We predict that 6wP will be as safe, well-tolerated and effective as (i.e., non-inferior

to) current rifamycin-based regimens of 12-16 weeks’ duration.

II. Aims of the Study

Hypothesis

The safety and effectiveness of 6wP is non-inferior to a comparator arm of 12-16 weeks of rifamycin-based treatment of LTBI. The comparator arm’s regimens will include 12 weeks of once-weekly isoniazid (INH) + rifapentine (3HP), 12 weeks of daily INH + rifampin (3HR), and

16 weeks of daily rifampin (4R).

Primary Objectives

1. Compare the safety of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.

2. If safe, compare the effectiveness of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.

Secondary Objectives

Among those treated with 6wP vs. the comparator arm (3HP, 3HR, or 4R), compare the:

1. Proportion who complete assigned treatment (tolerability).

• Treatment completion will be assessed by both participant self-report and pill counts for those receiving self-administered therapy and by medication administration records for those receiving directly-observed therapy.

2. Proportion with drug discontinuation for any reason.

3. Proportion with any grade 3, 4, or 5 (i.e., death) adverse event during the time period of 9 months after enrollment

4. Proportion with any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug

(adverse drug reaction; ADR).

5. Proportion who have died for any reason

6. Proportion with hepatitis and non-hepatotoxic systemic drug reactions.

7. Proportion with culture-confirmed or clinical TB regardless of age.

8. Proportion with TB among those who complete assigned therapy (efficacy).

9. Safety, tolerability, and effectiveness among participants with human immunodeficiency virus (HIV) infection.

10. Safety, tolerability, and effectiveness in participants < 18 years old.

Among those treated with 6wP, compare the:

11. Safety, tolerability, and effectiveness to each regimen in the comparator arm: 3HP, 3HR, 4R.

12. Treatment completion with an alternative regimen after discontinuation of study therapy

III. Study Agents

Isoniazid

Isoniazid (INH) has been used for the treatment of TB since the 1950s. INH is a prodrug that is activated by the mycobacterial enzyme KatG and is selective for mycobacterial species. INH has the greatest early bactericidal activity of any anti-TB drug. The primary mechanism of INH activity is the inhibition of mycolic acid synthesis; mycolic acids are essential to mycobacterial cell walls. Orally administered INH is 90% absorbed, with peak serum concentrations at ½ to 2 hours after ingestion. INH is generally well absorbed, but food and antacids decrease absorption.

INH is metabolized in the liver and excreted by the kidneys. The hepatic elimination rate and differences in serum INH concentrations between individuals taking daily INH are primarily due to acetylation rates determined by polymorphic variation in the N-acetyltransferase enzyme

(NAT2) gene. Differences in acetylation status are seen between ethnicities: approximately 50% of whites and blacks are rapid acetylators, whereas 80 to 90% of Asian individuals are rapid acetylators. INH dosing is not changed based on acetylation status, or the presence of renal or hepatic disease. INH is not considered a teratogen and is safe in breast-feeding patients.

Although INH is generally well-tolerated, it has well recognized adverse effects. INH interferes with pyridoxine (vitamin B6) functions and may lead to dose-related neurologic side effects including peripheral neuropathy and paresthesias. In otherwise healthy persons, this adverse effect is uncommon (<0.2%) at conventional doses.58 The risk is increased in individuals with nutritional deficiency, diabetes, renal failure, and alcoholism; people living with HIV; and pregnant and breastfeeding women. Individuals at risk for neurologic side effects should receive pyridoxine supplementation (25-50 mg/day) to minimize the risk of neuropathy.

INH may cause asymptomatic elevations in ALT levels in 10-20% of individuals receiving INH as a single drug for LTBI treatment. In this benign process, termed hepatic adaptation, enzyme concentrations usually normalize even with continued administration of INH and is a reason that routine monitoring of liver function tests in low-risk individuals is not recommended.59

Hepatic injury occurred in 0.1-0.15% of individuals receiving INH alone as treatment for LTBI under programmatic conditions.60 Continued administration of INH despite signs and symptoms of hepatotoxicity may lead to fulminant hepatic failure. The incidence of hepatotoxicity increases with older age, the co-administration of other potentially hepatotoxic drugs, increased doses of

INH, liver disease, and heavy alcohol use. A meta-analysis estimated the rate of clinical hepatitis to be 0.6% with INH alone, and 2.6% when INH was administered with rifampin.61

Less common adverse effects related to INH include drug-induced lupus syndrome (<1%), and central nervous system effects such as headaches, difficulties with concentration, seizures, optic neuritis, and depression. INH also inhibits the cytochrome (CYP) system and may cause increases in serum concentrations of concomitant medication such as phenytoin, carbamazepine, clopidogrel, and warfarin. Rare hematologic reactions include agranulocytosis, thrombocytopenia, eosinophilia, and hemolytic, sideroblastic, or aplastic anemia.

Hypersensitivity reactions include fever, skin eruptions, lymphadenopathy, and vasculitis. A rheumatic syndrome and a systemic lupus erythematosus syndrome have also been reported.

Metabolic and endocrine reactions include pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.

INH decreases the clearance of some medications that are metabolized in the liver. Patients who take INH and the following medications should have appropriate serum drug levels measured to prevent toxicity: carbamazepine (Tegretol), phenytoin (Dilantin), theophylline (Theodur, etc.), and valproic acid (Depakote). For further information, see Appendix C and the INH package insert (West-Ward Pharmaceuticals Corp, 2016).

Rifampin

Rifampin (RIF) is a semi-synthetic rifamycin derivative that is highly active against mycobacteria, most gram-positive bacteria, and some gram-negative bacteria. It is bactericidal for both intracellular and extracellular microorganisms. By inhibiting prokaryotic DNA-dependent RNA polymerase, it suppresses the early elongation of the nucleotide chain in RNA synthesis.

RIF is normally absorbed completely when taken orally, but food delays absorption. After 1.5 to

2 hours, a 600 mg dose yields a peak blood level of 8-20 mcg/ml. The half-life of rifampin varies from 2 to 5 hours, and it is shortened by approximately 20-40% after the first week of daily treatment because of the induction of hepatic microsomal enzymes. The half-life is unaffected by renal impairment but is increased by liver disease or biliary obstruction. RIF is deacetylated to an enterohepatically-recirculated active metabolite, and 50% to 60% is excreted in the feces.

Up to 30% of a dose is excreted in the urine. Approximately 85% of circulating rifampin is bound to plasma proteins, and is widely distributed throughout the body.

RIF is a potent inducer of a number of hepatic enzymes involved in the metabolism of drugs and some hormones.62 This enzyme induction causes more rapid elimination (and potential loss of efficacy) of many drugs. For some medications, this loss in pharmacological activity effect is dramatic, and rifampin cannot be used if one of these medications is essential. Medications with which concomitant rifampin should not be used include: HIV-1 protease inhibitors, delavirdine, cyclosporine, tacrolimus, itraconazole, and ketoconazole. For many other medications, the dose can be increased to compensate for the effect of RIF (see Appendix C).

In the usual daily doses of 10 mg/kg (maximum 600 mg), RIF is well tolerated. It often causes harmless but disconcerting red-orange discoloration of tears, sweat, saliva, feces, and urine. Less than 4% of TB patients experience significant adverse reactions to RIF. Gastrointestinal adverse effects are the most common, and they include epigastric distress, anorexia, nausea, vomiting, cramps, and diarrhea. Hepatitis rarely occurs in persons who have normal baseline hepatic function. The incidence of hepatitis may be increased for older persons and those who have chronic liver disease or alcoholism, but remains substantially lower than that for pyrazinamide or

INH.

Rifamycins have been associated with several types of immune-mediated allergic reactions termed hypersensitivity. A common presentation for rifamycin hypersensitivity reactions is a flu-like syndrome with non-specific symptoms including fever, chills, malaise, headaches, dizziness, and/or bone pain. No consensus definition or validated diagnostic classification of a rifamycin hypersensitivity reaction has been published. The syndrome has been associated in some studies with the development of anti-rifampin antibodies or with complement activation.63

Hypersensitivity reactions have been associated with intermittent rifampin administration, particularly at doses higher than 600 mg. Such reactions are uncommon using the 600 mg rifampin dose given daily. In a very small proportion of patients the flu-like syndrome is associated with interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia, dyspnea, and shock. (see Rifadin [rifampin] package insert).64

RIF can occasionally cause thrombocytopenia and thrombocytopenic purpura, with or without other symptoms of abnormal bleeding. Thrombocytopenia has usually occurred during intermittent chemotherapy but has also been reported with daily treatment. No permanent abnormality of platelet production or function has been reported, and fatalities, attributed to cerebral hemorrhage, have been reported only when RIF administration was continued or resumed after the appearance of purpura. If purpura occurs during RIF administration, the RIF should be terminated immediately and never given again. If this policy is adopted, the risk to the patient is very small.

Rifapentine

Rifapentine (RPT) is a rifamycin-S derivative with antimicrobial activity similar to rifampin

(RIF), but with a longer half-life. Like RIF, RPT inhibits bacterial RNA synthesis and most likely has the same target site as RIF, prokaryotic DNA-dependent RNA polymerase.

Bioavailability of coated tablets is around 70% and is increased if taken with food. Peak plasma levels are achieved 5 to 7 hours post dose. RPT is metabolized to form a microbiologically active metabolite, 25-Desacetyl-RPT. RPT has a prolonged terminal half-life of about 15 hours and is

97% bound to plasma proteins. Tissue distribution is broader and tissue levels higher for RPT than for RIF. The major route of elimination for RPT and its metabolites is through biliary excretion and elimination in feces. Urinary excretion accounts for 17% of clearance. No dose adjustment is recommended in elderly patients or those with hepatic impairment. See the Priftin

[rifapentine] package insert for further details.65

In the Prevent TB trial, medication-related adverse events occurred in 8.2% of study participants receiving once weekly RPT/INH.27 The majority of adverse events were Grade 1 or 2 in severity. Permanent drug discontinuations ascribed to adverse effects were more common for

RPT/INH than INH alone (4.9% vs. 3.7%; p<0.01). RPT/INH-related hepatotoxicity occurred in

0.5% of participants, and 0.3% discontinued therapy. Other adverse events attributable to

RPT/INH occurred rarely in the trial but in general the potential toxicities are thought to be similar to those observed with RIF.

No episodes of RPT-associated flu-like syndrome were observed in TBTC Study 22 or in a study from Hong Kong.66, 67 In the Prevent TB Trial, a possible hypersensitivity reaction, including flu-like syndrome, was reported in 3.8% of patients receiving RPT/INH versus 0.5% receiving INH only, and treatment discontinuation occurred in 2.9% vs. 0.4% ( p<0.01), respectively. Six of

152 possible RPT/INH hypersensitivity reactions included hypotension.27, 29

Like RIF, RPT can cause tears, sweat, saliva, feces, and urine to turn orange. This can stain contact lenses. RPT is an inducer of CYP P4503A4 and P4502C8/9. Therefore, RPT may increase the metabolism of other co-administered drugs that are metabolized by these enzymes.

Induction of hepatic enzymes by RPT occurs within four days of the first dose. Enzyme activity returns to baseline 14 days after discontinuing RPT. In addition, the magnitude of enzyme induction is dependent on dose and dosing frequency; less enzyme induction occurs when a 600 mg oral dose of RPT is given once every 72 hours versus daily. In vitro and in vivo enzyme induction studies have suggested RPT induction potential may be less than RIF but more than rifabutin. RIF has been reported to accelerate the metabolism and may reduce the activity of many drugs; hence, RPT may also increase the metabolism and decrease the activity of these drugs. Dosage adjustments of drugs metabolized by CYP P450 3A4 or P450 2C8/9 may be necessary if they are given concurrently with RPT.

Drugs whose activity may be reduced or metabolism accelerated by co-administration of RIF or

RPT include: anticonvulsants (e.g., phenytoin) anti-arrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), antibiotics (e.g., chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones), oral anticoagulants (e.g., warfarin), antifungals (e.g. fluconazole, intraconazole, ketoconazole), barbiturates, benzodiazepines, beta-blockers, calcium channel blockers, corticosteroid, cardiac glycoside preparations, clofibrate, oral and other systemic hormonal contraceptives, haloperiodol, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, oral hypoglycemic agents, immunosuppressants (e.g., cyclosporine, tacrolimus), levothyroxine, narcotic analgesics including methadone, progestins, quinine, sildenafil, theophylline, tricyclic antidepressants (see Appendix C).

D. Use of study agents (INH, RIF, RPT) in the pediatric population (children and adolescents).

INH: Extensive evidence suggests that INH is well-tolerated by children and adolescents, and the frequency of INH-induced hepatotoxicity in this population is low, even when INH is administered daily for 9-12 months.68 Advantages of the currently used rifamycin-containing regimens, with or without INH (4R, 3HR, and 3HP), in children and adolescents include shorter treatment duration and higher adherence.68

4R: A recently published randomized clinical trial of 4R in pediatric patients demonstrated safety of this regimen.69 An observational study with 395 children treated with 4R and 779 children treated with 9H demonstrated that completion rates overall were significantly higher for

4R than 9H (83.5% vs 68.8%; p<0.001) and drug toxicity leading to treatment discontinuation was low in both groups (1.5% in 4R; 0.7% in 9H; p=0.23).70Based on clinical trials conducted in adults, and considering the improved adherence with this shorter regimen, 4R is being used in clinical practice for LTBI treatment in children.

3HR: Studies comparing 3HR to 6-12 months of INH reported similar or lower frequency of serious adverse effects, including hepatotoxicity, in the 3HR arm. One pediatric study conducted in Greece reported significantly higher completion rates (78%–90%) with both 4HR and 3HR compared to the completion rate (66%) with 9H; no serious drug-related adverse events were detected in 926 participants.71

3HP: A large (1058 children enrolled) international randomized clinical trial demonstrated that treatment with 3HP is as effective as 9H for the prevention of TB in children aged 2 to 17 years.

None of the 471 evaluable participants in the 3HP group developed TB (versus 3 participants of

434 evaluable in the 9H group): a difference of -0.74%, which met the trial’s pre-defined non-inferiority criterion. The 3HP arm had a higher treatment completion rate than the 9H group, and was safe. 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 analysis population, 3 of 539 participants (0.6%) in the 3HP group had a grade 3 AE vs. 1 of 493 (0.2%) on 9H. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death.72

Hepatotoxicity, peripheral neuropathy, gastrointestinal upset (including nausea, vomiting, abdominal pain), and rash are the most common AEs seen in children and adolescents receiving

INH. Gastrointestinal upset, hepatotoxicity, rash, and thrombocytopenia are the most common

AEs seen in children and adolescents receiving RIF or RPT. The most common AEs seen in children and adolescents are similar to AEs seen in adults. Overall, tolerability of the anti-TB medications in children is high, and the frequency of AEs in children is similar, or lower, than the frequency of AEs in adults.68

IV. Methodology

Study Design

The study will be an open label, multi-center, phase III randomized controlled clinical trial with

2 arms. Participants will receive daily 6wP or a 12-16 week rifamycin-based regimen (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.

The primary objective is to compare the safety and effectiveness of daily 6wP to a 12-16 week rifamycin-based regimen (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI and at increased risk of progression to TB. The study will be conducted in the United

States, the United Kingdom, and other countries with low to moderate TB incidence (< 100 TB cases per 100,000 population)1, 2 which have treatment of LTBI as their standard of care, and offer 12-16 week rifamycin-based therapy.

Participants will be randomly assigned to one of the two study arms. Trial randomization will be computer-generated by the CDC TBTC Data and Coordinating Center.