Improving Retreatment Success (IMPRESS) (IMPRESS)

An Open Label Randomized Controlled Clinical Trial Comparing a 24Week Oral Regimen Containing Moxifloxacin With a 24 Week Standard Drug Regimen for the Treatment of Smear-positive Pulmonary Tuberculosis in Patients Previously Treated for TB

This is an open label randomized controlled clinical trial comparing two regimens for treatment of smear-positive pulmonary TB, among patients previously treated for TB. The primary objective is to determine if a moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a control regimen of 24 weeks duration in improving treatment outcomes in patients with recurrent TB and shortens the duration of TB treatment.

Study Overview

• Status: Completed
• Conditions: Recurrent Tuberculosis
• Intervention / Treatment: Drug: moxifloxacin

Detailed Description

Intervention Arm :12 months (6 months treatment + 12 months post treatment follow up) Control Arm :12 months (6 months treatment + 12 months post treatment follow up) Total sample size is 330.

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• South Africa
  • KwaZulu Natal
    • Durban, KwaZulu Natal, South Africa, 4001
      • CAPRISA eThekwini Clinical Research Site (eCRS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults ≥ 18 years of age
• Previous history of anti-TB chemotherapy
• HIV status: HIV infected and uninfected patients are allowed in the study:
• All patients must agree to HIV testing to confirm HIV status.
• Patients already on ARVs will be allowed in the study provided that the ART regimen is not contraindicated with any of the study agents .
• HIV infected patients at any CD4 count irrespective of ART commencement and duration will be included in the study
• Smear positive or Gene Xpert positive pulmonary tuberculosis
• Rifampicin susceptible as determined by Gene Xpert at screening. Gene Xpert will be used to determine rifampicin resistance, hence the study team will made aware of resistance within 48 hours and prior to study enrolment.
• Karnofsky score greater than 70
• Female candidates of reproductive potential must agree to use two reliable methods of contraception while on study: a barrier method of contraception (condoms or cervical cap) together with another reliable form of contraceptive (condoms with a spermicidal agent, a diaphragm or cervical cap with spermicide, an Intrauterine Device (IUD), or hormone-based contraceptive)
• A negative pregnancy test

• Laboratory parameters done at, or 14 days prior to, screening:

  • Haemoglobin level of at least 7.0 g/dL
  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 times the upper limit of normal
  • Serum total bilirubin level less than 2.5 times upper limit of normal
  • Creatinine clearance (CrCl) level greater than 60 mls/min
  • Platelet count of at least 50 x109cells/L
  • Serum potassium greater than 3.0 mmol/L

Exclusion Criteria:

• Patients on a Nevirapine (NVP)-containing ART regimen at screening
• Pregnant or breastfeeding
• Received an antibiotic active against M. tuberculosis in the last 14 days (e.g. fluoroquinolones, macrolides, standard anti-tuberculosis drugs).
• Patients with known M. tuberculosis resistance to any of the study drugs at screening
• History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the intensive phase of tuberculosis treatment.
• Known allergies or intolerance to any of the study drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Moxifloxacin; A Moxifloxacin-containing oral regimen of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Moxifloxacin (M), substituting Moxifloxacin for Ethambutol, daily for 24 weeks, see information below. Intensive phase 7 days a week for 8 weeks Continuation phase - 7 days a week for 16 weeks RH(150,75mg), Z (500mg), M (400mg) Dosage and number of tablets dispensed is dependent on participants weight band.	Drug: moxifloxacin; [isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)]; Other Names: AVELON
Active Comparator: Ethambutol; An Ethambutol oral regimen of Isoniazid (H), Rifampicin(R), Pyrazinamide (Z), Ethambutol(E), daily for 24 weeks duration, substituting Ethambutol for Moxifloxacin. Intensive phase 7 days a week for 8 weeks Continuation phase - 7 days a week for 16 weeks.See details below. (150,75,400,275 mg) RHZE Dosage and number of tablets dispensed is dependent on participants weight band.	Drug: moxifloxacin; [isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)]; Other Names: AVELON

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation	The proportion of patients with negative sputum cultures at the end of the intensive phase (8 weeks) and the proportion of patients with negative sputum cultures at 6 months were compared between the two study arms. All participants with sputum culture results at week 8 and month 6 were included in the analysis.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Culture-conversion of the Moxifloxacin Regimen and the Ethambutol Regimen	To determine the time to culture-conversion of the moxifloxacin regimen and the ethambutol regimen.	Up to 2 years
Proportion of Patients With Any Grade 3 or 4 Adverse Reactions in the Two Study Arms	To compare the proportion of patients with any Grade 3 or 4 adverse reactions in the two study arms. Outcome measured in terms of number of participants with at least one grade 3 or 4 events, and not in number of events.	Up to 2 years
Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients	To compare adverse events and 8-week culture conversion rates among HIV-infected patients vs. HIV-uninfected patients. The proportion of participants with at least one grade 3 or 4 adverse event was measured.	up to 2 years for adverse events and 8 weeks for culture conversion rates
Proportion of Patients With Unfavourable Outcomes or Tuberculosis Recurrence in the Moxifloxacin and Control Arm.	A patient was defined as having an unfavourable outcome if he/she was not cured at the end of treatment or did not successfully complete treatment. Recurrence after completion of treatment was defined as two positive cultures within a period of four months without an intervening negative culture.	up to 2 years

Collaborators and Investigators

• Sponsor: Centre for the AIDS Programme of Research in South Africa
• Investigators: Principal Investigator: Nesri Padayatchi, MBChB, MSc, Centre for the AIDS Programme of Research in South Africa; Study Director: Kogieleum Naidoo, MBChB, Centre for the AIDS Programme of Research in South Africa

Publications and helpful links

General Publications

• Perumal R, Padayatchi N, Yende-Zuma N, Naidoo A, Govender D, Naidoo K. A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial. Clin Infect Dis. 2020 Jan 1;70(1):90-98. doi: 10.1093/cid/ciz152.
• Naidoo A, Chirehwa M, Ramsuran V, McIlleron H, Naidoo K, Yende-Zuma N, Singh R, Ncgapu S, Adamson J, Govender K, Denti P, Padayatchi N. Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis. Pharmacogenomics. 2019 Mar;20(4):225-240. doi: 10.2217/pgs-2018-0166. Epub 2019 Feb 15.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2013
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 17, 2017

Study Registration Dates

• First Submitted: January 29, 2014
• First Submitted That Met QC Criteria: April 14, 2014
• First Posted (Estimate): April 15, 2014

Study Record Updates

• Last Update Posted (Actual): August 5, 2019
• Last Update Submitted That Met QC Criteria: June 11, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: CAP 011