Rifapentine-Based Regimens for Latent Tuberculosis

(ASTERoiD Trial)

Recruiting at 20 trial locations

Overseen By TBTC Research Administrator

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Centers for Disease Control and Prevention

Must not be taking: Antiretrovirals, Contraindicated drugs

Disqualifiers: Current TB, Rifamycin resistance, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-16 weeks

3400 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is conducted to compare the safety and effectiveness of a novel short 6-week regimen of daily rifapentine (6wP, experimental arm) with a comparator arm of 12-16 weeks of rifamycin-based treatment (standard of care, control arm) of latent M. tuberculosis infection (LTBI). This trial is conducted among persons who are at increased risk of progression to tuberculosis (TB) and require treatment of LTBI. The study will be conducted in low, medium and high TB incidence settings that have treatment of LTBI as their standard of care and offer 12-16 week rifamycin-based therapy as standard of care. The hypothesis of this study is that the safety and effectiveness of the experimental treatment (6wP arm) is non-inferior to a comparator arm of 12-16 weeks of rifamycin-based treatment of LTBI (control arm). Participants are enrolled and randomly assigned to one of the two study arms: experimental 6wP or control. The comparator (control) arm's treatment regimens include 12 weeks of once-weekly isoniazid (INH) and rifapentine (3HP), 12 weeks of daily INH and rifampin (3HR), and 16 weeks of daily rifampin (4R). A total of 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 will be enrolled, given treatment as per randomization assignment, and followed for 24 months from the date of enrollment. After completion of data collection, statistical analyses will be conducted to compare proportions of drug discontinuation due to adverse drug reaction (ADR) and proportions of newly diagnosed tuberculosis between 6wP and control arm.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on medications that cannot be taken with rifampin or rifapentine, you may not be eligible to participate. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Rifapentine for treating latent tuberculosis?

Research shows that using Rifapentine with isoniazid once a week for 3 months or daily for 1 month can effectively treat latent tuberculosis. In a study, this combination had an 85% treatment completion rate, which is much higher than the standard 9-month treatment with isoniazid alone. ^{1 2 3 4 5}

Is rifapentine safe for humans?

Rifapentine has been studied for safety in humans, including healthcare workers with latent tuberculosis, and is generally considered safe, though some adverse events (unwanted side effects) have been reported. It has been used in combination with other drugs like isoniazid for shorter treatment courses, which may reduce potential side effects compared to longer regimens. ^{2 3 6 7 8}

How is the drug Rifapentine unique for treating latent tuberculosis?

Rifapentine is unique because it allows for shorter treatment durations for latent tuberculosis, with regimens like once weekly for 3 months or daily for 1 month, compared to traditional longer treatments. It can be used alone or with isoniazid, and studies suggest it may be as effective or better than other regimens without the added toxicity of isoniazid. ^{1 2 3 8 9}

Research Team

Timothy Sterling, MD

Principal Investigator

Vanderbilt University Medical Center, USA

Robert Belknap, MD

Principal Investigator

Denver Public Health (USA)

Amber Robinson, PhD

Principal Investigator

Centers for Disease Control and Prevention

Rosanna M Boyd, PhD

Principal Investigator

Centers for Disease Control (USA)

Dick Menzies, MD

Principal Investigator

McGill University

Eligibility Criteria

This trial is for people over 12 years old with latent TB infection at high risk of developing active TB, including recent immigrants from high-incidence countries and those in close contact with TB patients. Participants must not be pregnant or breastfeeding, agree to use contraception if applicable, have no history of TB treatment, and not be on certain conflicting medications.

Inclusion Criteria

I have lung scarring seen on an X-ray but have never been treated for TB.

I am HIV positive with a CD4 count over 100.

I agree to use contraception or abstain from sex during the study if I can have children and am not surgically sterilized.

Exclusion Criteria

I have been treated with rifamycin for more than 7 days or INH for more than 30 days within the last 2 years.

I am not on any medications that conflict with the study drugs.

My TB is resistant to rifamycin antibiotics.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 6 weeks of daily rifapentine or 12-16 weeks of rifamycin-based treatment

6-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Rifapentine

Trial Overview The study compares a new short-term (6 weeks) daily treatment using Rifapentine against the standard longer-term (12-16 weeks) treatments for latent TB that include various combinations of Rifapentine, Isoniazid, and Rifampin. The goal is to see if the shorter regimen is just as safe and effective.

Participant Groups

Group I: 6 weeks of daily rifapentine (6wP) Experimental Treatment 1 Intervention

Rifapentine daily for 6 weeks: 600 mg of Rifapentine (RPT) given once daily for 6 weeks

Group II: 12-16 week rifamycin-based regimen Active Control 3 Interventions

A 12-16 week rifamycin-based regimen available at the participant's site: "Rifapentine and Isoniazid weekly for 12 weeks" (3HP) or "Rifampin and Isoniazid daily for 12 weeks" (3HR) or "Rifampin daily for 16 weeks" (4R)

Rifapentine is already approved in United States, European Union for the following indications:

Approved in United States as Priftin for:

• Active tuberculosis
• Latent tuberculosis

Approved in European Union as Priftin for:

• Tuberculosis

Who Is Running the Clinical Trial?

Centers for Disease Control and Prevention

Lead Sponsor

Trials

902

Recruited

25,020,000+

British Medical Research Council

Collaborator

Trials

13

Recruited

2,127,000+

Findings from Research

In a study of 399 household contacts of TB patients, the weekly treatment of rifapentine and isoniazid was found to be well tolerated, with significantly lower rates of hepatotoxicity (1%) compared to the daily rifampin and pyrazinamide regimen (10%).

Both treatments showed similar efficacy in preventing active TB, with slightly more cases in the rifapentine/isoniazid group, suggesting that rifapentine/isoniazid could be a promising alternative for latent TB infection therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Schechter, M., Zajdenverg, R., Falco, G., et al.[2022]

Daily rifapentine-based regimens showed comparable efficacy to the standard rifampin+pyrazinamide regimen in treating latent tuberculosis infection (LTBI) in a mouse model, suggesting they could potentially shorten treatment duration to 6 to 8 weeks.

Existing regimens like isoniazid and rifampin were less effective, with many mice remaining culture-positive after 8 weeks, highlighting the improved effectiveness of rifapentine-based treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Zhang, T., Zhang, M., Rosenthal, IM., et al.[2021]

A 600-mg daily dose of rifapentine for 6 weeks (6wP) is predicted to be more effective in reducing bacterial loads in latent tuberculosis infection (LTBI) compared to the standard 3-month (3HP) and 1-month (1HP) regimens.

The study suggests that 6wP may achieve equal or better efficacy than 1HP and 3HP without the added toxicity associated with isoniazid, indicating a potentially safer treatment option for LTBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Rifapentine Alone and in Combination with Isoniazid for Latent Tuberculosis Infection: a Translational Pharmacokinetic-Pharmacodynamic Modeling Study. Radtke, KK., Ernest, JP., Zhang, N., et al.[2022]

In an urban jail population, a 3-month treatment regimen of isoniazid and rifapentine (3HP) led to an impressive 85% completion rate for latent tuberculosis infection treatment, significantly higher than the 18% completion rate for the standard 9-month isoniazid treatment.

Only 2 out of 91 patients on the 3HP therapy discontinued treatment due to adverse drug reactions, indicating that this shorter regimen is not only more effective but also relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail. Juarez-Reyes, M., Gallivan, M., Chyorny, A., et al.[2020]

A Markov model analysis showed that both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months are more cost-effective and effective than longer treatment options for latent tuberculosis infection (LTBI).

The daily regimen of isoniazid/rifapentine for one month was identified as the least expensive and most effective treatment option, suggesting it should be prioritized for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection. Holland, DP., Sanders, GD., Hamilton, CD., et al.[2021]

The once-weekly isoniazid and rifapentine (3H1P1) regimen for latent tuberculosis infection showed a higher treatment completion rate (92.9%) compared to the standard isoniazid plus rifampin (3HR) regimen (86.7%).

While the 3H1P1 group experienced more adverse events overall (75.2% vs 56.7%), it had significantly lower rates of hepatotoxicity (7.5% vs 20.0%) and no fatalities, although some cases of flu-like syndrome and anaphylaxis were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse event and treatment completion rates of a 12-dose weekly isoniazid and rifapentine course for South Korean healthcare workers. Jo, KW., Kim, JS., Kwon, HS., et al.[2020]

In a study of 531 adults with pulmonary tuberculosis, rifapentine was found to be safe and showed similar efficacy to rifampin, with 86.4% of rifapentine patients achieving negative sputum cultures compared to 83.3% for rifampin after 8 weeks of treatment.

Both rifapentine and rifampin had similar rates of treatment discontinuation (15.7% for rifampin vs. 14.5% for rifapentine), indicating that rifapentine is a tolerable option for tuberculosis treatment, though further research on higher doses is suggested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. Dorman, SE., Goldberg, S., Stout, JE., et al.[2015]

Rifapentine (RPT) and rifampicin (RMP) show similar efficacy and safety for treating pulmonary tuberculosis (PTB) in HIV-negative patients, based on a systematic review of nine randomized controlled trials.

However, using RPT once a week or less frequently increases the risk of bacteriological relapse compared to more frequent RMP dosing, and there are concerns that RPT may lead to rifamycin resistance in HIV-positive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review. Gao, XF., Li, J., Yang, ZW., et al.[2018]

In a phase 3 trial with 2516 participants, a 4-month rifapentine regimen combined with moxifloxacin was found to be as effective as the standard 6-month treatment for drug-susceptible pulmonary tuberculosis, demonstrating noninferiority in preventing unfavorable outcomes.

The rifapentine-only regimen did not meet the noninferiority criteria compared to the standard treatment, indicating that moxifloxacin is crucial for maintaining efficacy in shorter treatment courses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. Dorman, SE., Nahid, P., Kurbatova, EV., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Rifapentine Alone and in Combination with Isoniazid for Latent Tuberculosis Infection: a Translational Pharmacokinetic-Pharmacodynamic Modeling Study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Adverse event and treatment completion rates of a 12-dose weekly isoniazid and rifapentine course for South Korean healthcare workers. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. [2015]

8. France pubmed.ncbi.nlm.nih.gov

Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. [2022]