Pilot Clinical Trial of PRS TB Regimen I - Phase II

NCT03561753 | Completed Phase 4

• 1 other identifier: K18-103
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 4

Brief Summary

Tuberculosis is the current leading cause of death due to an identifiable infectious agent worldwide. The current standard regimen for tuberculosis requires a patient to take drug combination (isoniazid, rifampicin, ethambutol, and pyrazinamide) for six to eight month periods. The purpose of this study is to compare tuberculosis treatment therapy between the current standard regimen and PRS derived combinatorial regimen. PRS derived regimen may potentially allow for a shorter course of treatment, which may reduce problems associated with adherence, toxicity, and development of drug resistance.

Conditions

Pulmonary Tuberculosis TB in Sputum: (+) Microscopy

Keywords

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• The rate of sputum smear/culture negative conversion

  The primary efficacy outcome is the proportion of the rate of sputum smear and culture(MGIT and LJ) negative conversion from samples collected at the end of treatment.

  Group A (the standard 2HRZE/4HR regimen)：at the end of Sixth months after treatment. Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz) ：at the end of Fourth months after treatment.

Secondary Outcomes (3)

• Radiological manifestation change of lung TB lesions or cavity

  Group A (the standard 2HRZE/4HR regimen)：at the end of Sixth months after treatment. Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz) ：at the end of Fourth months after treatment.

• Number of Patients with Grade 3 or 4 Adverse Events

  Group A (the standard 2HRZE/4HR regimen)：6 months from the beginning of clinical trials. Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz) ：4 months from the beginning of clinical trials.

• Number of Patients with TB recurrence/relapse

  24 months after treatment completion for 2 groups.

Study Arms (2)

Group A (the standard 2HRZE/4HR regimen)

ACTIVE COMPARATOR

Group A, Standard Regimen (2EHRZ/4HR): Control group, use the standard six-month regimen with eight weeks of daily treatment with isoniazid, rifampin, ethambutol, and pyrazinamide followed by sixteen weeks of isoniazid and rifampin.

Drug: Group A (the standard 2HRZE/4HR regimen）

Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz)

EXPERIMENTAL

Group B, PRS Regimen (4EZ \[high dose\] Cfz Pto): Experience group，use the PRS regimen is 4 months of daily Cfz, Emb, Pto, and high dose pyrazinamide, dosed by weight.

Drug: Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz)

Interventions

Group A (the standard 2HRZE/4HR regimen） DRUG

The standard six-month regimen is eight weeks of daily treatment with isoniazid, rifampin, ethambutol, and pyrazinamide followed by sixteen weeks of isoniazid and rifampin. The six-month regimen is the standard regimen for the treatment of drug-susceptible tuberculosis recommended by WHO.

Also known as: The control group

Group A (the standard 2HRZE/4HR regimen)

Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz) DRUG

The PRS regimen I（new short course PRS regimen） is 4 months of daily Cfz, Emb, Pto, and high dose pyrazinamide, dosed by weight.Comparison of Standard Regimen：The standard six-month regimen is eight weeks of daily treatment with isoniazid, rifampin, ethambutol, and pyrazinamide followed by sixteen weeks of isoniazid and rifampin.

Also known as: The experimental group

Group B (New short course PRS regimen, 4EZ(high dose)PtoCfz)

Eligibility Criteria

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

You may qualify if:

• Newly diagnosed and untreated sputum smear positive tuberculosis patient
• Pulmonary lesion consistent with TB by radiological examination
• Positive sputum culture, identification of bacterial type confirmed Mycobacterium tuberculosis. MGIT drug sensitivity test (DST) results are sensitive of the first-line drugs (isoniazid, streptomycin, rifampicin and ethambutol).
• Age 18 years-65 years old
• Males or non-pregnant, non-nursing females
• Women of child-bearing potential who are not surgically sterilized must agree to practice a barrier method of contraception or abstain from heterosexual intercourse during study drug treatment.
• a.Effective birth control methods: i.A double contraceptive method should be used as follows: ii.Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or iii.Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female subject/partner; iv.and are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation.
• Laboratory parameters done at or within 14 days prior to screening:
• Serum or plasma aminotransferases (AST, ALT) less than 3 times the upper limit of normal
• Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal
• Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal
• Serum or plasma potassium level greater than or equal to 3.5 meq/L
• Hemoglobin level of 7.0 g/dL or greater
• Platelet count of 100,000/mm3 or greater
• For women of childbearing potential, a negative pregnancy test is required during screening

You may not qualify if:

• Tuberculosis resistant to any of the study drugs (isoniazid, rifampin, EMB, PZA, CFZ, Pto)
• Unable to take oral medications.
• History of allergy or intolerance to any of the study drugs
• Serum aminotransferase (AST or ALT) 3x upper limit of normal or higher
• Pregnant or nursing females, or plan to become pregnant or nurse during the study period
• Males planning to conceive a child during the study or within 6 months of cessation of treatment.
• Any treatment directed against active tuberculosis within 6 months preceding initiation of study drugs.
• Suspected or documented tuberculosis involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis.
• HIV infected
• HBV infected or HCV infected (these increase the risk of TB-drug induced hepatotoxicity)
• Weight less than 40.0 kg.
• Known allergy or intolerance to any of the study medications.
• Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any of the study drugs.
• QTcF \> 500 msec
• Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest.

Sponsors & Collaborators

• Shanghai Pulmonary Hospital, Shanghai, China: lead
• Shanghai Center for Disease Control and Prevention: collaborator
• No.85 Hospital, Changning, Shanghai, China: collaborator
• Shanghai Public Health Clinical Center: collaborator
• Bill and Melinda Gates Foundation: collaborator
• University of California, Los Angeles: collaborator

Study Sites (4)

Eighty-fifth Hospital of PLA

Shanghai, 200000, China

Location

Shanghai Public Health Clinical Center Shanghai, China

Shanghai, 200000, China

Location

Shanghai Center for Disease Control and Prevention

Shanghai, 200336, China

Location

Shanghai Pulmonary Hospital, Shanghai, China

Shanghai, 200433, China

Location

Related Publications (8)

• Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov. 2013 May;12(5):388-404. doi: 10.1038/nrd4001.

  PMID: 23629506 BACKGROUND

• Zumla A, Chakaya J, Centis R, D'Ambrosio L, Mwaba P, Bates M, Kapata N, Nyirenda T, Chanda D, Mfinanga S, Hoelscher M, Maeurer M, Migliori GB. Tuberculosis treatment and management--an update on treatment regimens, trials, new drugs, and adjunct therapies. Lancet Respir Med. 2015 Mar;3(3):220-34. doi: 10.1016/S2213-2600(15)00063-6. Epub 2015 Mar 9.

  PMID: 25773212 BACKGROUND

• Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects in chemotherapy of tuberculosis. Respirology. 2010 Jul;15(5):764-78. doi: 10.1111/j.1440-1843.2010.01775.x. Epub 2010 Jun 4.

  PMID: 20546189 BACKGROUND

• Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet. 2010 Jun 12;375(9731):2100-9. doi: 10.1016/S0140-6736(10)60359-9. Epub 2010 May 18.

  PMID: 20488518 BACKGROUND

• Silva A, Lee BY, Clemens DL, Kee T, Ding X, Ho CM, Horwitz MA. Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2172-9. doi: 10.1073/pnas.1600812113. Epub 2016 Mar 28.

  PMID: 27035987 BACKGROUND

• Lee BY, Clemens DL, Silva A, Dillon BJ, Maslesa-Galic S, Nava S, Ding X, Ho CM, Horwitz MA. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time. Nat Commun. 2017 Jan 24;8:14183. doi: 10.1038/ncomms14183.

  PMID: 28117835 BACKGROUND

• Handbook of anti-tuberculosis agents. Introduction. Tuberculosis (Edinb). 2008 Mar;88(2):85-6. doi: 10.1016/S1472-9792(08)70002-7. No abstract available.

  PMID: 18486036 BACKGROUND

• Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52. doi: 10.1164/rccm.200510-1666ST.

  PMID: 17021358 BACKGROUND

Related Links

• WHO. 2015. Global Tuberculosis Report 2015.

MeSH Terms

Conditions

Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• sha wei

  Shanghai Pulmonary Hospital, Shanghai, China

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Head of Tuberculosis Department,Shanghai Pulmonary Hospital, Principal Investigator, Clinical Professor

Study Record Dates

• First Submitted: May 21, 2018
• First Posted: June 19, 2018
• Study Start: December 1, 2017
• Primary Completion: December 31, 2019
• Study Completion: January 31, 2020
• Last Updated: November 9, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (4)