Evaluation of 8 Weeks of Treatment With the Combination of Moxifloxacin, PA-824 and Pyrazinamide in Patients With Drug Sensitive and Multi Drug-Resistant Pulmonary Tuberculosis (TB) (NC-002)

NCT01498419 | Completed Phase 2 Results DMC

• 1 other identifier: NC-002-(M-Pa-Z)
• Study Type: interventional
• Target: 207
• Locations: 2 countries
• Sites: 8

Brief Summary

The purpose of this study is to assess the mycobactericidal activity of the moxifloxacin plus PA-824 plus pyrazinamide regimen after 8 weeks of treatment.

Conditions

Pulmonary Tuberculosis

Keywords

Tuberculosis; Serial Sputum Colony Counts; Colony Forming Units; Time to Sputum Culture Positivity; PA824; pretomanid

Outcome Measures

Primary Outcomes (1)

• The Rate of Change in Colony Forming Units (CFUs) Using Non-linear Mixed Effects Modeling of the Serial Sputum Colony Counts (SSCC) Over 8 Weeks of Treatment.

  The primary efficacy endpoint was bactericidal activity characterized by the daily rate of change in mean log10CFU counts during 8 weeks of treatment (bactericidal activity assessed by CFU on solid media for days 0-56).

  8 weeks

Secondary Outcomes (6)

• Time to Sputum Conversion Using Data From Weekly Cultures Through 8 Weeks on Liquid Media

  8 weeks

• Percentage of Patients With Sputum Culture Conversion at 8 Weeks on Solid Media

  Day 57 after eight weeks of daily treatment

• The Rate of Change in Time to Sputum Culture Positivity (TTP) Through 8 Weeks in the MGIT System in Sputum Over 8 Weeks in Participants as Derived From a Non-linear Regression Model.

  8 weeks

• Percentage of Participants Who Discontinue Due to an Adverse Event in Each Experimental Arm.

  8 weeks

• Time to Sputum Conversion Using Data From Weekly Cultures Through 8 Weeks on Solid Media

  8 weeks

Study Arms (4)

Drug Sensitive: M (400 mg) Pa (100 mg) Z (1500 mg)

EXPERIMENTAL

Drug Sensitive Participants: One moxifloxacin (M) 400 mg tablet plus one Pretomanid (PA-824) 100 mg tablet plus three pyrazinamide 500 mg tablets taken once daily for 8 weeks

Drug: Moxifloxacin (M); Drug: Pretomid (Pa); Drug: Pyrazinamide (Z)

Drug Sensitive: M (400 mg) Pa (200 mg) Z (1500 mg)

EXPERIMENTAL

Drug Sensitive Participants: One moxifloxacin (M) 400 mg tablet plus one Pretomanid (PA-824) 200 mg tablet plus three pyrazinamide 500 mg tablets taken once daily for 8 weeks

Drug: Moxifloxacin (M); Drug: Pretomid (Pa); Drug: Pyrazinamide (Z)

Drug Sensitive: Rifafour

ACTIVE COMPARATOR

Drug Sensitive Participants: Rifafour was administered orally once daily for 8 weeks according to weight: 30 kg to 37 kg: two tablets; 38 kg to 54 kg: three tablets; 55 kg to 70 kg: four tablets; ≥71 kg: five tablets

Drug: Rifafour

Multi Drug-Resistant: M (400 mg) Pa (200 mg) Z (1500 mg)

EXPERIMENTAL

Multi Drug-Resistant Participants: One moxifloxacin (M) 400 mg tablet plus one Pretomanid (PA-824) 200 mg tablet plus three pyrazinamide 500 mg tablets taken once daily for 8 weeks

Drug: Moxifloxacin (M); Drug: Pretomid (Pa); Drug: Pyrazinamide (Z)

Interventions

Moxifloxacin (M) DRUG

Drug Sensitive: M (400 mg) Pa (100 mg) Z (1500 mg); Drug Sensitive: M (400 mg) Pa (200 mg) Z (1500 mg); Multi Drug-Resistant: M (400 mg) Pa (200 mg) Z (1500 mg)

Pretomid (Pa) DRUG

Also known as: PA-824

Drug Sensitive: M (400 mg) Pa (100 mg) Z (1500 mg); Drug Sensitive: M (400 mg) Pa (200 mg) Z (1500 mg); Multi Drug-Resistant: M (400 mg) Pa (200 mg) Z (1500 mg)

Pyrazinamide (Z) DRUG

Drug Sensitive: M (400 mg) Pa (100 mg) Z (1500 mg); Drug Sensitive: M (400 mg) Pa (200 mg) Z (1500 mg); Multi Drug-Resistant: M (400 mg) Pa (200 mg) Z (1500 mg)

Rifafour DRUG

Rifafour e-275 once daily for 8 weeks. Daily dose dependent on weight as follows: 30-37kg: 2 tablets, 38-54 kg: 3 tablets, 55-70 kg: 4 tablets: 71 kg and over: 5 tablets

Drug Sensitive: Rifafour

Eligibility Criteria

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

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures including HIV testing (if an HIV test was performed within 1 month prior to trial start, it should not be repeated as long as documentation can be provided \[ELISA and/or Western Blot\]).
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Sputum smear-positive pulmonary TB (at trial appointed laboratory). For Drug Sensitive TB treatment arms, subjects should be newly diagnosed and previously untreated. Exception: Participants can be included in the trial if they were diagnosed and treated for TB greater than 5 years prior to screening and can provide documentation of cure for that episode. Additionally, participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial. Drug sensitive status to be confirmed with fluoroquinolone, rifampicin and isoniazid susceptibility testing at screening using Hain Plus rapid sputum test.
• For the MDR-TB treatment arm only: Subjects with smear-positive MDR infection, defined as confirmed resistance to at least both R and H confirmed at screening for entry into this trial. Resistance to R and H will be determined using the rapid screen test (Hain Plus). If the first spot sputum shows an indeterminate result, the test must be repeated on freshly collected spot sputum or overnight sputum and that result may be used.
• Subjects with newly diagnosed MDR-TB are defined as a) subjects with MDR-TB who have never been treated for TB before, or b) subjects with MDR-TB who have previously been treated with only one course of first-line TB drugs (H, R, E, Z and/or S) and that treatment is/was discontinued at least 7 days prior to randomization into this trial. Additionally, MDR-TB participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.
• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• Sputum positive (at site laboratory) on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).
• Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
• Females may participate if they are: 1) of non-childbearing potential (have had a bilateral oophorectomy, tubal ligation and/or hysterectomy or have been postmenopausal for at least 12 consecutive months), 2) if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or 3) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either: 1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraceptive measures until one week after the last dose of study medication or one week after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).
• Male participants who are having heterosexual intercourse with females of child-bearing potential are required to use one of the following birth control methods during their participation in the trial and for 12 weeks after their last dose of study medication to prevent pregnancy:
• a double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or
• a barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.
• The use of the above mentioned birth control method does not apply if the male participant has been vasectomised or has had a bilateral orchidectomy minimally three months prior to screening, or is not heterosexually active, or practices sexual abstinence or if the female sexual partner has had a bilateral oophorectomy, tubal ligation and/or hysterectomy or has been postmenopausal for at least 12 consecutive months.

You may not qualify if:

• Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including myasthenia gravis and malaria.
• End stage liver failure (class Child Pugh C).
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
• Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
• History of allergy or hypersensitivity to any of the study IMP or related substances, including a known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifamycin antibiotics.
• Resistance to fluoroquinolones (Hain plus rapid test) and/or pyrazinamide. Participants may be included in the study prior to receipt of the susceptibility test results for fluoroquinolones or pyrazinamide, however once these are received after a participant has entered into the study and if the results show the participant is resistant to fluoroquinolones and/or pyrazinamide, such a participant should be removed from the trial. DS participants will not be replaced, but MDR-TB participants taking part in the EBA Sub-Study could be replaced after consultation and written approval with the sponsor.
• Known (positive urine drug screen) or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
• For HIV infected participants:
• having a CD4+ count \<200 cells/µL;
• or having received intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• Having participated in other clinical study/ies with investigational agent/s within 8 weeks prior to trial start.
• Significant cardiac arrhythmia requiring medication.
• Participants with the following at screening (per measurements and reading done by Central ECG):
• Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF (Fridericia correction) or QTcB (Bazett correction) interval \>450 ms at screening;

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (8)

Task Applied Science, Karl Bremer Hospital

Cape Town, 7531, South Africa

Location

University of Cape Town Lung Institute (Pty) Ltd

Cape Town, 7700, South Africa

Location

KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH)

Durban, 4013, South Africa

Location

CHRU Themba Lethu Clinic

Johannesburg, South Africa

Location

Klerksdorp Tshepong Hospital

Klerksdorp, 2570, South Africa

Location

The Aurum Institute: Tembisa Hospital

Tembisa, 1736, South Africa

Location

Ifakara Health Institute

Bagamoyo, Tanzania

Location

Mbeya Medical Research Programme

Mbeya, Tanzania

Location

Related Publications (1)

• Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, Schall R, Spigelman M, Conradie A, Eisenach K, Venter A, Ive P, Page-Shipp L, Variava E, Reither K, Ntinginya NE, Pym A, von Groote-Bidlingmaier F, Mendel CM. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015 May 2;385(9979):1738-1747. doi: 10.1016/S0140-6736(14)62002-X. Epub 2015 Mar 18.

  PMID: 25795076 RESULT

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

Moxifloxacin; pretomanid; Pyrazinamide

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Daniel E. Everitt, MD, Vice President and Senior Medical Officer
• Organization: Global Alliance for TB Drug Development

Dan.Everitt@tballiance.org

(212) 227-7540

Study Officials

• Rodney Dawson, MD

  University of Cape Town

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2011
• First Posted: December 23, 2011
• Study Start: March 1, 2012
• Primary Completion: April 1, 2013
• Study Completion: July 1, 2013
• Last Updated: June 28, 2018
• Results First Posted: December 12, 2016

Record last verified: 2017-01

Locations

ZA (6); TA (2)