Improving Retreatment Success (IMPRESS)

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Recurrent Tuberculosis

Intervention / Treatment
-----------------
* Drug: moxifloxacin


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Moxifloxacin<br>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<br>* [isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)]<br>* Other names: AVELON;|
| Active Comparator: Ethambutol<br>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<br>* [isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)]<br>* 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 |