Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)

Tuberculosis, Pulmonary Clinical Trial

— TB-PRACTECAL  

Official title:

A Randomised, Controlled, Open-Label, Phase II-III Trial to Evaluate the Safety and Efficacy of Regimens Containing Bedaquiline and Pretomanid for the Treatment of Adult Patients With Pulmonary Multidrug Resistant Tuberculosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02589782
• Other study ID #: 1541
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: January 2017
• Est. completion date: December 2022

Study information

• Verified date: May 2021
• Source: Medecins Sans Frontieres, Netherlands
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

TB PRACTECAL is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multi drug-resistant TB (MDR-TB).

Description:

This is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multidrug-resistant TB (MDR-TB). The study will be divided into two stages, with a seamless transition between the stages, meaning recruitment into an arm will only stop after a decision has been taken following stage 1 primary end point data analysis. All recruited patients will be followed up to 108 weeks post randomisation unless they die or withdraw consent. The local standard of care (SOC) MDR-TB regimen will be used as the internal control for both safety and efficacy. The first stage corresponds to a Phase II trial of safety and preliminary efficacy in patients with MDR-TB. Patients will be recruited into 3 parallel B and Pa containing regimen arms plus a SOC control. The main objective of Stage 1 is to select drug regimens for evaluation in Stage 2 based on 8 week safety and efficacy endpoints. All stage 1 patients will be hospitalised for 8 weeks for intensive cardiological evaluations to establish the QT-specific liability of the regimens. Investigational arms that do not meet predefined safety and efficacy criteria (percentage culture conversion >40%; percentage discontinuation and death <45%) will not be considered for further evaluation. The regimens that do not meet these pre-defined safety and/or efficacy criteria will be eligible to be evaluated for long term safety, tolerability and efficacy in Stage 2. If less than two investigational arms are available for stage two assessment, the SAC will make recommendations on whether new arms should be introduced in the study. If more than two arms are available for the Stage 2 assessment, two regimens will be chosen. The SAC will make recommendations on which arms to take forward to the trial steering committee. The second stage corresponds to a phase III trial. Patients in this stage will be recruited into the arms chosen from stage 1 plus the SOC. The regimens will primarily be evaluated for safety and efficacy in comparison with the SOC arm at 72 weeks post randomisation. The primary efficacy outcome will be a composite endpoint of the percentage of unfavourable outcomes. The secondary outcomes will include safety outcomes and in particular the percentage of Grade 3 or 4 AEs and SAEs in the investigational regimens compared with the SOC.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 552
• Est. completion date: December 2022
• Est. primary completion date: September 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

Inclusion criteria:

Patients eligible for inclusion in the trial must fulfil all of the following criteria:

• Male or female subjects aged 15 years of age or above, regardless of HIV status;
• Microbiological test (molecular or phenotypic) confirming presence of M. tuberculosis;
• Resistant to at least rifampicin by either molecular or phenotypic drug susceptibility test;
• Completed informed consent form (ICF); Exclusion criteria: Patients will not be eligible for inclusion in the trial if they meet any of the following

criteria:

• Known allergies, hypersensitivity, or intolerance to any of the study drugs;
• Pregnant or breast-feeding; or unwilling to use appropriate contraceptive measures
• Liver enzymes >3 times the upper limit of normal (AST or ALT);
• Any condition (social or medical) which, in the opinion of the investigator, would make study participation unsafe;
• Taking any medications contraindicated with the medicines in the trial;
• QTcF > 450ms;
• One or more risk factors for QT prolongation (excluding age and gender) or other uncorrected risk factors for TdP;
• History of cardiac disease, syncopal episodes, symptomatic or asymptomatic arrhythmias (with the exception of sinus arrhythmia);
• Any baseline biochemical laboratory value consistent with Grade 4 toxicity.
• Moribund
• Known resistance to bedaquiline, pretomanid, delamanid or linezolid.
• Prior use of bedaquiline and/or pretomanid and/or linezolid and/or delamanid for one or more months.
• Patients not eligible to start a new course of MDR-TB/XDR-TB treatment according to

local protocol, including but not limited to:

• currently on MDR-TB treatment for more than 2 weeks (and not failing)
• unstable address
• loss to follow-up in previous treatment with no change in circumstance and motivation.
• Tuberculous meningoencephalitis, brain abscesses, osteomyelitis or arthritis.

PKPD inclusion/exclusion:

• Adult patients (aged 18 years or above) recruited into the investigational arms of the TB-PRACTECAL trial in the approved sites.
• Willing to sign the sub-study informed consent form after agreeing to the additional blood draws.

Related Conditions & MeSH terms

• Extensively Drug-Resistant Tuberculosis
• Tuberculosis
• Tuberculosis, Multidrug-Resistant
• Tuberculosis, Pulmonary

Intervention

Drug:
• Bedaquiline

• Pretomanid

• Moxifloxacin

• Linezolid

• Clofazimine

• Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.

Locations

Country	Name	City	State
Belarus	Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital	Minsk
South Africa	King DinuZulu Hospital	Durban	KwaZulu-Natal
South Africa	THINK Clinical Trial Unit, Hillcrest	Durban	KwaZulu-Natal
South Africa	Helen Jospeh Hospital	Johannesburg	Gauteng
South Africa	Doris Goodwin Hospital	Pietermaritzburg	KwaZulu Natal
Uzbekistan	Republican TB Hospital No. 2	Nukus	Karakalpakstan
Uzbekistan	Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital	Tashkent

Sponsors (15)

Lead Sponsor

Collaborator

Medecins Sans Frontieres, Netherlands

Drugs for Neglected Diseases, eResearch Technology, Inc., Global Alliance for TB Drug Development, London School of Hygiene and Tropical Medicine, Ministry of Health, Republic of Uzbekistan, Ministry of Public Health, Republic of Belarus, Rutgers, The State University of New Jersey, Swiss Tropical & Public Health Institute, THINK TB & HIV Investigative Network, University College, London, University of California, San Francisco, University of Liverpool, Wits Health Consortium (Pty) Ltd, World Health Organization

Countries where clinical trial is conducted

Belarus,  South Africa,  Uzbekistan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stage 1:Percentage of patients with culture conversion in liquid media at 8 weeks post randomisation.		8 weeks post randomisation
Primary	Stage 1: Percentage of patients who discontinue treatment for any reason or die		8 weeks post randomisation
Primary	Stage 2: Percentage of patients with an unfavourable outcome (failure, death, recurrence, loss to follow-up)		72 weeks post-randomisation
Secondary	Stage 1: Percentage of patients with grade 3 or higher QT prolongation		within 8 weeks post randomisation
Secondary	Stage 1: Percentage of patients experiencing at least one Serious Adverse Event (SAE)		within 8 weeks post randomisation
Secondary	Stage 1:Percentage of patients experiencing at least one new grade 3 or higher Adverse Event		within 8 weeks post randomisation
Secondary	Stage 2: Percentage of patients with culture conversion		12 weeks post randomisation
Secondary	Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up)		24 weeks post randomisation
Secondary	Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up, still on treatment at censure and recurrence)		108 weeks post randomisation
Secondary	Stage 2: Median time to culture conversion		108 weeks
Secondary	Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE		72 weeks post randomisation
Secondary	Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE		108 weeks post randomisation
Secondary	Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment	The percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment in the investigational arms (maximum of 24 weeks) and the SOC arm which varies in length (maximum 108 weeks).	24 weeks in investigational arms and 108 weeks in SOC arm
Secondary	Stage 2: Mean single ?QTcF		24 weeks post randomisation
Secondary	Stage 2: Percentage of patients experiencing recurrence		week 48 in investigational arms
Secondary	Stage 2: Plasma drug concentrations		In relation to dose intake and start of treatment over a 72 week period
Secondary	Stage 2: TB drug hair levels		In relation to dose intake and start of treatment over a 72 week period