A Pragmatic Trial With Optimized Dose of Rifampicin and Moxifloxacin for the Treatment of Drug Susceptible Pulmonary Tuberculosis

NCT05575518 | Recruiting Phase 3 DMC

• 1 other identifier: OptiRiMoxTB-01
• Study Type: interventional
• Target: 414
• Locations: 1 country
• Sites: 1

Brief Summary

Tuberculosis (TB) remains a major global public health problem, particularly in low- and middle-income countries (LMICs) in Africa, Asia, and Eastern Europe. Approximately 10 million people fall sick with TB, causing up to 2 million deaths, worldwide per year. Considerable progress was made in TB control from 1990-2015, motivating the World Health Organization (WHO) to launch an ambitious EndTB strategy. However, the effect of the ongoing Coronavirus Disease 2019 (Covid-19) pandemic has been devastating and the last two years have seen the first year-on-year increases (of 5.6%) in TB mortality since 2005 . In order to regain lost ground, and re-establish progress towards elimination of TB, innovation is needed in all aspects of TB control, including development of shorter treatment regimens for drug susceptible (DS) and multi-drug resistant / rifampicin resistant (MDR/RR) forms of the disease. This protocol seeks to conduct the TB clinical trial combining the 8-methoxyfluroquinolone and optimised dose of rifamycing to address two questions. The first is to confirm the non-inferiority of a four-month optimised dose rifamycin and moxifloxacin-based regimen amongst African TB patient populations with high rates of co-incident HIV. Secondly, we seek to establish that the rifamycin of choice in potent 4-month anti-TB treatments could be rifampicin as this will be more rapidly up-scalable for public health impact.

Conditions

Tuberculosis; Human Immunodeficiency Virus

Keywords

TB/HIV; Phase III; Randomised

Outcome Measures

Primary Outcomes (2)

• Bacteriological cure, absence of either TB treatment failure or relapse

  Treatment failure, defined as submitting two sputum samples with positive culture for M tuberculosis on different visits, when the first of these samples was collected at or after two weeks prior to the scheduled end of treatment. TB relapse, defined as submitting two sputum samples with positive culture for M tuberculosis on different visits, when the first of these samples was collected after completion of scheduled TB therapy and where at least one of the M tuberculosis isolates is genetically similar to the baseline strain.

  Participant survival, free of tuberculosis 12 months after randomisation

• Proportional of adverse events (AE) of grade 3 severity or higher

  The severity of all AEs will be classified according to the U.S. National Institutes of Health Common Terminology Criteria for Adverse Events 5.0 (CTCAE).

  4 or 6 months of treatment

Secondary Outcomes (4)

• Proportional of clinically significant adverse events related to the intervention

  4 or 6 months of treatment

• Clinical improvement of TB symptoms

  12 month after randomisation

• Clinical improvement of body mass index (BMI)

  12 month after randomisation

• Clinical improvement of participant reported health status

  12 month after randomisation

Other Outcomes (1)

• Participant survival free of TB

  12 months after completing TB treatment

Study Arms (3)

No intervention

NO INTERVENTION

Standard of care according to the National TB Programmes which is a weight-banded rifampicin, isoniazid, pyrazinamide, and ethambutol for weeks 0-8 followed by rifampicin and isoniazid for weeks 9-26.

Experimental Arm 1

EXPERIMENTAL

Optimised dose of rifampicin. The rifampicin 35mg/kg alongside standard weight-banded doses of isoniazid, pyrazinamide, and ethambutol, once daily

Drug: Optimised rifamycin

Experimental Arm 2

EXPERIMENTAL

Optimised dose of rifampicin and moxifloxacin. The rifampicin 35mg/kg and moxifloxacin 400mg alongside standard weight-banded doses of isoniazid and pyrazinamide, once daily.

Drug: Optimised rifamycin

Interventions

Optimised rifamycin DRUG

optimised dose rifampicin with or without moxifloxacin

Also known as: 8-methoxy-fluoroquinolone

Experimental Arm 1; Experimental Arm 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient has given fully informed, signed written or witnessed oral informed consent for study participation prior to all trial-related procedures, including HIV testing if HIV status is not known.
• The patient has a diagnosis of pulmonary TB established by Xpert MTB/RIF® result which confirms "low" "medium" or "high" level detection of M tuberculosis and does not detect rifampicin resistance.
• If the patient has been referred from a clinic at which the pre-screening clinical diagnostic test for TB was an Xpert MTB/RIF® assay done at the trial laboratory, and the full read-out of that result is available, the test does not need to repeated to confirm eligibility.
• If the patient has been referred from a clinic at which the pre-screening clinical diagnostic test for TB was an Xpert MTB/RIF® assay done at a non-trial laboratory, but the full read-out of that result is available, the test does not need to repeated to confirm eligibility.
• If the patient has been referred to the study from a clinic from which the full pre-screening clinical diagnostic Xpert MTB/RIF® test result is unavailable, a repeat Xpert MTB/RIF® assay should be performed by the study laboratory to confirm eligibility before recruitment.
• The patient should be aged ≥ 18 years on the day of providing informed consent.
• The patient has a body weight in light clothing and without shoes of at least 35kg.
• Female patients of child-bearing potential must have a negative urine or serum pregnancy test ≤ 7 days prior to screening, and consent to practice an effective method of contraception until completion of therapy.
• The patient must have a verifiable residence location and telephone number that is accessible if necessary for contact during follow-up.

You may not qualify if:

• Patients for whom one of the following criteria is met will be excluded from the trial:
• There is concern about any circumstances that raise concern about free, informed consent to study participation.
• The patient's pre-screening or screening Xpert MTB/RIF® assay result is "negative","trace", or "very low" positive.
• The patient is in poor general condition where delay in treatment cannot be tolerated, or death within three months is likely, as assessed by the investigator.
• The patient had a nose/throat swab which was positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), on Polymerase Chain Reaction (PCR) or a rapid diagnostic test ≤ 14 days preceding study recruitment.
• The patient is pregnant or breast-feeding (female patients only).
• The patient is unable to take oral medications.
• The patient has received any investigational drug in the past three months.
• The patient has received more than five days of treatment directed against active tuberculosis ≤ 6 months preceding initiation of study drugs.
• The patient has known intolerance to any of the study drugs, or conditions for which they are contra-indicated.
• The patient is unwilling, or unable to adhere to requirements regarding restricted use of other medications during the study. Restricted medications will include medications which prolong the QTc interval, and CYP450 inhibitors or inducers.
• The patient is due to initiate, or requires continuation of, non-efavirenz, non-dolutegravir-based anti-retroviral therapy for HIV infection.
• The patient has decompensated liver disease and/or aminotransaminases \>3x upper limit of normal (ULN), serum total bilirubin level \>1.5x ULN or serum/plasma creatinine level \>x2 ULN.
• The patient has a baseline QTc interval of \>450ms.
• The patient is being, or about to be, treated for malaria.

Sponsors & Collaborators

• Stellah Mpagama: lead
• University of St Andrews: collaborator
• Radboud University Medical Center: collaborator

Study Sites (1)

Kibong'oto Infectious Diseases Hospital

Moshi, Kilimanjaro, 25401, Tanzania

RECRUITING

Related Publications (9)

• World Health Organization. Global Tuberculosis Report 2021. World Health Organisation 2021.https://www.who.int/publications/i/item/9789240037021

  BACKGROUND

• World Health Organisation. WHO End TB Strategy: Global strategy and targets for tuberculosis prevention, care and control after 2015. World Health Organization 2021. https://www.who.int/tb/strategy/End_TB_Strategy.pdf

  BACKGROUND

• Pai M, Kasaeva T, Swaminathan S. Covid-19's Devastating Effect on Tuberculosis Care - A Path to Recovery. N Engl J Med. 2022 Apr 21;386(16):1490-1493. doi: 10.1056/NEJMp2118145. Epub 2022 Jan 5. No abstract available.

  PMID: 34986295 BACKGROUND

• Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, Phillips PP, Gillespie SH, McHugh TD, Hoelscher M, Heinrich N, Rehal S, van Soolingen D, van Ingen J, Magis-Escurra C, Burger D, Plemper van Balen G, Aarnoutse RE; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058-65. doi: 10.1164/rccm.201407-1264OC.

  PMID: 25654354 BACKGROUND

• Te Brake LHM, de Jager V, Narunsky K, Vanker N, Svensson EM, Phillips PPJ, Gillespie SH, Heinrich N, Hoelscher M, Dawson R, Diacon AH, Aarnoutse RE, Boeree MJ; PanACEA Consortium. Increased bactericidal activity but dose-limiting intolerability at 50 mg.kg-1 rifampicin. Eur Respir J. 2021 Jul 8;58(1):2000955. doi: 10.1183/13993003.00955-2020. Print 2021 Jul.

  PMID: 33542056 BACKGROUND

• Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26.

  PMID: 28100438 BACKGROUND

• Dorman SE, Nahid P, Kurbatova EV, Phillips PPJ, Bryant K, Dooley KE, Engle M, Goldberg SV, Phan HTT, Hakim J, Johnson JL, Lourens M, Martinson NA, Muzanyi G, Narunsky K, Nerette S, Nguyen NV, Pham TH, Pierre S, Purfield AE, Samaneka W, Savic RM, Sanne I, Scott NA, Shenje J, Sizemore E, Vernon A, Waja Z, Weiner M, Swindells S, Chaisson RE; AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021 May 6;384(18):1705-1718. doi: 10.1056/NEJMoa2033400.

  PMID: 33951360 BACKGROUND

• WHO consolidated guidelines on tuberculosis: Module 4: Treatment - Drug-susceptible tuberculosis treatment [Internet]. Geneva: World Health Organization; 2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK581329/

  PMID: 35727905 BACKGROUND

• Mlyuka HJ, Liyoyo A, Nyaulingo B, Mpolya E, Kaswaga OL, Semvua H, Lwambura S, McHugh TD, Wildner L, Sabiiti W, Adegbite BR, Nliwasa M, Khosa C, Mbelele P, Mbeya B, Jeremiah K, Boeree MJ, Gillespie SH, Sloan DJ, Mpagama SG; SimpliciTB Consortium. A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: a study protocol for open-label, randomized phase III trial (OptiRiMoxTB). Trials. 2026 Jan 30. doi: 10.1186/s13063-026-09466-0. Online ahead of print.

  PMID: 41612490 DERIVED

MeSH Terms

Conditions

Tuberculosis; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Central Study Contacts

Stellah Mpagama, PhD

CONTACT

+255754860576; sempagama@yahoo.com

Alphonce Liyoyo, M.D

CONTACT

+255767134567; liyoyo2010@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of Research

Study Record Dates

• First Submitted: October 6, 2022
• First Posted: October 12, 2022
• Study Start: August 11, 2023
• Primary Completion: December 31, 2025
• Study Completion: March 31, 2026
• Last Updated: August 25, 2023

Record last verified: 2023-08

Locations

TA (1)