Short-course Rifamycin-based Regimens for Latent Tuberculosis in Patients With End-stage Kidney Disease

Study Overview
=================
Brief Summary
-----------------
Objective To determine if treatment completion with a 4-month rifampin (4R) or 3-month rifapentine (P) + isoniazid (H) weekly for 12 weeks (3HP) regimens is better than with a 3-month (3HR) regimen for treatment of latent tuberculosis (TB) infection (LTBI) in patients with end stage kidney disease. Methods Design: Multicenter, prospective, parallel-group, open-label, controlled clinical trial. Study population: All adult patients with ESKD in who treatment for LTBI is prescribed at 7 hospitals. Interventions: Patients who accept participation, will be randomly assigned to one of the 3 arms: 3HR (control) (90 doses), 4R (120 doses) or 3HP (12 doses). Outcome: Proportion of participants who discontinue permanently the assigned treatment. Follow-up: Periodic assessment for permanent or temporary discontinuation, and adverse events of the assigned treatment. Sample size: 225 subjects (75 per arm) will be needed to demonstrate, if exists, a 0.16 decrease in permanent discontinuation rates in the experimental arms (4R and 3HP) with respect to the control arm (3HR), with α= 0.025, β= 0.20, and 5% expected losses, and assuming a 0.25 proportion of permanent discontinuation in the control.

Official Title
-----------------
Comparison of 3-month Once-weekly Isoniazid Plus Rifapentine, 4-month Daily Rifampicin, and 3-month Daily Isoniazid Plus Rifampicin for the Treatment Latent Tuberculosis in Patients With End-stage Kidney Disease: A Randomised Clinical Trial

Conditions
-----------------
Latent Tuberculosis, Kidney Failure

Intervention / Treatment
-----------------
* Drug: Rifampicin plus Isoniazid
* Drug: Rifapentine plus Isoniazid
* Drug: Rifampicin alone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 years or older Stage 5 kidney disease (glomerular filtrate rate <15 mL/minute or under substitutive renal therapy Informed written consent Exclusion Criteria: Prior allergy/intolerance to rifamycins or isoniazid Pregnancy or breastfeeding Pre-treatment transaminases (ALT and/or AST) >5-fold of normality titer Concomitant drugs contraindicated with rifamycins Having received rifamycins or isoniazid within the two previous weeks Weigh <32 Kgs Inability to understand the nature of the study or to give written consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 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: 3-month Isoniazid plus Rifampicin<br>Daily isoniazid 300 mg plus rifampicin 600 mg for three months | Drug: Rifampicin plus Isoniazid<br>* Administration of rifampicin plus isoniazid for latent tuberculosis<br>|
| Experimental: 3-month Isoniazid plus Rifapentine<br>Weekly isoniazid 900 mg plus rifapentine 900 mg for 12 weeks | Drug: Rifapentine plus Isoniazid<br>* Administration of rifapentine plus isoniazid for latent tuberculosis<br>|
| Experimental: 4-month Rifampicin<br>Daily rifampicin 600 mg for four months | Drug: Rifampicin alone<br>* Administration of rifampicin alone for latent tuberculosis<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment completion | Proportion of participants who complete the treatment assigned at randomization, defined as: 1) 90 doses within a maximum of 16 weeks, without interruptions longer than 2 weeks, and no more than in 2 occasions, for 3HR (control arm); 2) 12 doses within a maximum of 14 weeks, without interruptions longer than 10 days, for 3HP (experimental arm 1), and 3) 120 doses within a maximum of 20 weeks, without interruptions longer than 2 weeks, and no more than in two occasions, for 4R (experimental arm 2). | From date of randomization until the date of completion of the assigned treatment, or date of lost to follow-up, or date of death, whichever came first, assessed up to 16 weeks for the 3HR arm, 14 weeks for the 3HP arm, and 20 weeks for the 4R arm. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Permanent discontinuation because of adverse events | Proportion of participants who permanently discontinue the treatment assigned, because of adverse events, regardless the relationship of the event/s to the study treatment. Permanent discontinuation defined as: 1) not completion of 90 doses within a maximum of 16 weeks, without interruptions longer than 2 weeks, and no more than in 2 occasions, for 3HR (control arm); 2) not completion 12 doses within a maximum of 14 weeks, without interruptions longer than 10 days, for 3HP (experimental arm 1), and 3) not completion of 120 doses within a maximum of 20 weeks, without interruptions longer than 2 weeks, and no more than in two occasions, for 4R (experimental arm 2). | From date of randomization until the date of completion of the assigned treatment, or date of lost to follow-up, or date of death, whichever came first, assessed up to 16 weeks for the 3HR arm, 14 weeks for the 3HP arm, and 20 weeks for the 4R arm. | 
| Permanent discontinuation because of adverse events related to the treatment | Proportion of participants who permanently discontinue the treatment assigned, because of adverse events related to he study treatment Permanent discontinuation defined as: 1) not completion of 90 doses within a maximum of 16 weeks, without interruptions longer than 2 weeks, and no more than in 2 occasions, for 3HR (control arm); 2) not completion 12 doses within a maximum of 14 weeks, without interruptions longer than 10 days, for 3HP (experimental arm 1), and 3) not completion of 120 doses within a maximum of 20 weeks, without interruptions longer than 2 weeks, and no more than in two occasions, for 4R (experimental arm 2). | From date of randomization until the date of completion of the assigned treatment, or date of lost to follow-up, or date of death, whichever came first, assessed up to 16 weeks for the 3HR arm, 14 weeks for the 3HP arm, and 20 weeks for the 4R arm. | 
| Death | Number of participants who die while on the study, regardless of its relationship to the treatment assigned at randomization | From date of randomization until four weeks after completing the assigned treatment, or lost to follow-up, assessed up to 17 weeks for the 3HR arm, 15 weeks for the 3HP arm, and 21 weeks for the 4R arm. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rifamycins, Tuberculosis, Rifampicin, Rifapentine, Kidney failure