Economic Evaluation of New MDR TB Regimens (PRACTECAL-EE)

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ClinicalTrials.gov Identifier: NCT04207112

Recruitment Status : Unknown

Verified May 2021 by Medecins Sans Frontieres, Netherlands.
Recruitment status was: Recruiting

First Posted : December 20, 2019

Last Update Posted : May 14, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

London School of Hygiene and Tropical Medicine

Ministry of Health, Republic of Uzbekistan

Ministry of Public Health, Republic of Belarus

THINK TB & HIV Investigative Network

University of Liverpool

Wits Health Consortium (Pty) Ltd

LSHTM Clinical Research Department

Information provided by (Responsible Party):

Medecins Sans Frontieres, Netherlands

Study Description

Brief Summary:

The current treatment regimen for MDR-TB has poor outcomes and costs of treating MDR-TB are greater than treating drug susceptible TB, both in terms of health service and patient-incurred costs. Urgent action is needed to Identify short, effective and tolerable treatments for people with MDR-TB. The PRACTECAL economic evaluation sub-study (PRACTECAL-EE) will take place alongside the TB PRACTECAL trial, aiming to assess the costs to patients and providers of such regimens and to estimate the cost-effectiveness and poverty impact of an introduction of new MDR-TB regimens in the three countries participating in the main study.

Condition or disease	Intervention/treatment	Phase
Multi-drug Resistant Tuberculosis Extensively Drug-Resistant Tuberculosis Pulmonary Tuberculoses	Drug: Bedaquiline Drug: Pretomanid Drug: Moxifloxacin Drug: Linezolid Drug: Clofazimine Drug: Standard Drugs	Phase 2 Phase 3

Show detailed description

Detailed Description:

Multidrug resistant tuberculosis (MDR TB), tuberculosis (TB) that does not respond to at least isoniazid and rifampicin, is currently a public health issue. The current treatment regimen for MDR-TB has poor outcomes and costs of treating MDR-TB are greater than treating drug susceptible TB, both in terms of health service and patient-incurred costs. (1, 2). Key changes to recommendations for MDR-TB treatment regimens were published recently by the World Health Organization after an assessment of new evidence(3). In this rapid communication, three main changes to the standard MDR regimen were recommended: firstly, the withdrawal of injectable antibiotics; secondly, the inclusion of bedaquiline in a recommended longer regimen (ie 20 months); and thirdly, the recommendation of use for a shorter regimen only for specific conditions. It also highlights the urgent need for evidence to inform better optimal treatment choices for MDR-TB patients. Economic evaluations of such bedaquiline-containing regimens will provide additional important information for decision makers who need to consider its economic value along with clinical efficacy when planning for introduction.

TB PRACTECAL is a randomised, controlled trial to evaluate the safety and efficacy of investigational regimens containing bedaquiline and pretomanid for the treatment of MDR-TB in adults. It has been designed in two stages: stage 1 is a phase II trial aiming to identify two regimens containing bedaquiline and pretomanid for further evaluation based on safety and efficacy outcomes after 8 weeks of treatment. Stage 2 is a phase III trial to evaluate the safety and efficacy of the two investigational regimens containing bedaquiline and pretomanid selected in stage 1 compared with the standard of care at 72 weeks post-randomisation (Clinical trial protocol, study number: NCT02589782). This economic evaluation sub-study (PRACTECAL EE) will take place alongside TB PRACTECAL aiming to assess the costs to patients and providers of such regimens and to estimate the cost-effectiveness and poverty impact of an introduction of new MDR-TB regimens in the three countries participating in the main study.

The decision problem is stated as the evaluation of the new treatment regimen for MDR TB patients to inform the GRADE process at a global level, and health technology assessments (HTA) in the trial host countries, as applied to regimens for drug-resistant TB. During these processes (both at global level, GRADE, and at country level, HTA), the review of economic evidence produced alongside clinical trials focuses around patient outcomes and then on resources needed to answer the question of whether a new regimen should be considered for introduction. Population level considerations can also be included, especially in a second stage where the decision problem has advanced from whether to recommend a new regimen, to how to introduce it to achieve maximum health at a limited budget.

The overall aim of this sub study is to estimate the probability that new MDR-TB regimens containing bedaquiline and pretomanid will be cost-effective from a societal as compared to the standard of care for MDR-TB patients in three settings: Uzbekistan, South Africa, and Belarus.

A secondary aim is to assess the costs from a provider perspective of treating patients with these new regimens (new MDR-TB regimens containing bedaquiline and pretomanid), and estimate the impact of new regimens on prevalence of catastrophic costs due to TB.

The specific objectives of this sub-study are, in each setting:

to assess the costs from a provider's perspective for selected facilities in the intervention and control arms;
to assess the costs from a patient's perspective for a sample of patients seeking care in study facilities in the intervention and control arms;
To estimate the prevalence of catastrophic costs in the intervention and control arms;
to assess the probability of new regimens being cost-effective at different willingness-to-pay thresholds from a societal perspective using a Markov model.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	200 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Health Services Research
Official Title:	Economic Evaluation of New MDR TB Regimens (PRACTECAL EE)
Actual Study Start Date :	October 20, 2020
Estimated Primary Completion Date :	July 30, 2022
Estimated Study Completion Date :	July 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Moxifloxacin: 400 mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Drug: Bedaquiline Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria. This in turn blocks the ATP production required for cellular energy production and leading to cell death.	Drug: Bedaquiline Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria. This in turn blocks the ATP production required for cellular energy production and leading to cell death. Other Names: Sirturo R207910 TMC207 Drug: Pretomanid Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria. It may have other mechanisms of action as well in non-replicating mycobacteria. Other Name: PA-824 Drug: Moxifloxacin Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria Other Names: Avelox BAY 12-8039 Drug: Linezolid Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis. It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease. Other Name: Zyvox
Experimental: Regimen 2: Bedaquiline, Pretomanid, Linezolid, Clofazimine Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Clofazimine: 50 mg (less than 33 kg), 100 mg (more than 33 kg) for 24 weeks	Drug: Bedaquiline Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria. This in turn blocks the ATP production required for cellular energy production and leading to cell death. Other Names: Sirturo R207910 TMC207 Drug: Pretomanid Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria. It may have other mechanisms of action as well in non-replicating mycobacteria. Other Name: PA-824 Drug: Linezolid Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis. It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease. Other Name: Zyvox Drug: Clofazimine Clofazimine (Cfz) is a lipophilic riminophenazine licensed for treatment of leprosy. Its mechanism(s) of action remains unclear, but existing evidence suggests production of reactive oxygen species within Mycobacterium tuberculosis is one mechanism. Other Name: Lamprene
Experimental: Regimen 3: Bedaquiline, Pretomanid, Linezolid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated)	Drug: Bedaquiline Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria. This in turn blocks the ATP production required for cellular energy production and leading to cell death. Other Names: Sirturo R207910 TMC207 Drug: Pretomanid Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria. It may have other mechanisms of action as well in non-replicating mycobacteria. Other Name: PA-824 Drug: Linezolid Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis. It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease. Other Name: Zyvox
Active Comparator: Control regimen Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB	Drug: Standard Drugs Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.

Outcome Measures

Primary Outcome Measures :

Incremental cost incurred per disability adjusted life year (DALY) averted: Societal Perspective [ Time Frame: 108 weeks post randomisation ]
Incremental cost incurred per disability adjusted life year (DALY) averted with the intervention regimen compared to the standard of care from societal perspective. DALYs will be modelled up to a life time horizon using a markov model.
Incremental cost per disability adjusted life year (DALY) averted: Provider Perspective [ Time Frame: 108 weeks post randomisation ]
Incremental cost per disability adjusted life year (DALY) averted with the intervention regimen compared to the standard of care from provider perspective. DALYs will be modelled up to a life time horizon using a markov model.

Secondary Outcome Measures :

Mean cost per month of treatment [ Time Frame: 108 weeks post randomisation ]
Mean cost per month of treatment for different regimens and type of patient (MDR-TB, pre-XDR-TB (resistant to fluoroquinolone) and XDR-TB)
Mean cost per course of treatment for different types of patients [ Time Frame: 108 weeks post randomisation ]
Mean cost per course of treatment for different types of patients (MDR-TB, pre-XDR-TB (resistant to fluoroquinolone), XDR-TB) and by category (training, monitoring, service delivery and drugs)
Incremental total cost of intervention for the trial population [ Time Frame: 108 weeks post randomisation ]
Incremental total cost of intervention for the trial population, over the trial duration
Incremental total cost of intervention for the modelling cohort [ Time Frame: 108 weeks post randomisation ]
Incremental total cost of intervention for the modelling cohort, over a life time horizon

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

adults with Mycobacterium tuberculosis resistant to at least rifampicin by either molecular or phenotypic drug susceptibility test.

Exclusion Criteria:

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04207112

Contacts

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Contact: Nicola James, MSc	+44 (0) 207 0674 255	nicola.james@london.msf.org
Contact: Charlotte Batts		Charlotte.Batts@london.msf.org

Locations

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Belarus
Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital	Recruiting
Minsk, Belarus
Contact: Ernest Nshimiyimana, MD +375336486008 minsk-ct-mtl@oca.msf.org
Principal Investigator: Varvara Solodovnikova, MD
South Africa
Helen Joseph Hospital	Recruiting
Johannesburg, Gauteng, South Africa, 2092
Contact: Sharon Motlhako +27 11 276 8800 smotlhako@witshealth.co.za
Principal Investigator: Mohammed Rassool Rassool, MBChB
Doris Goodwin Hospital	Recruiting
Pietermaritzburg, KwaZulu Natal, South Africa
Contact: Odette van Amsterdam 033 398 0054 O.Amsterdam@think.org.za
Principal Investigator: Ronelle Moodliar, MBBS, MMed
THINK Clinical Trial Unit, Hillcrest	Recruiting
Durban, KwaZulu-Natal, South Africa, 3650
Contact: Seshni Moorgas 0317771009 s.moorgas@think.org.za
Principal Investigator: Ronelle Moodliar, MBBS,MMed
King DinuZulu Hospital	Recruiting
Durban, KwaZulu-Natal, South Africa, 4091
Contact: Londiwe Luthuli +27 87 702 2581 lluthuli@witshealth.co.za
Principal Investigator: Nosipho Ngubane, MBChB
Uzbekistan
Republican TB Hospital No. 2	Recruiting
Nukus, Karakalpakstan, Uzbekistan
Contact: Soe Moe, MD +998939200344 NukusCT-med2@oca.msf.org
Principal Investigator: Tigay N Zinaida, MD
Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital	Recruiting
Tashkent, Uzbekistan
Contact: Pei Sun Aw, MD +998 933881121 tashkent-crc@oca.msf.org
Principal Investigator: Irina Liverko, MD

Sponsors and Collaborators

Medecins Sans Frontieres, Netherlands

London School of Hygiene and Tropical Medicine

Ministry of Health, Republic of Uzbekistan

Ministry of Public Health, Republic of Belarus

THINK TB & HIV Investigative Network

University of Liverpool

Wits Health Consortium (Pty) Ltd

LSHTM Clinical Research Department

Investigators

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Principal Investigator:	Sedona Sweeny	London School of Hygiene and Tropical Medicine

More Information

Publications:

Sweeney S, Gomez G, Kitson N, Sinha A, Yatskevich N, Staples S, Moodliar R, Motlhako S, Maloma M, Rassool M, Ngubane N, Ndlovu E, Nyang'wa BT. Cost-effectiveness of new MDR-TB regimens: study protocol for the TB-PRACTECAL economic evaluation substudy. BMJ Open. 2020 Oct 10;10(10):e036599. doi: 10.1136/bmjopen-2019-036599.

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Responsible Party:	Medecins Sans Frontieres, Netherlands
ClinicalTrials.gov Identifier:	NCT04207112
Other Study ID Numbers:	PRACTECAL-EE
First Posted:	December 20, 2019 Key Record Dates
Last Update Posted:	May 14, 2021
Last Verified:	May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Medecins Sans Frontieres, Netherlands:


Bedaquiline Pretomanid Linezolid Clofazimine	Moxifloxacin Economic Evaluation Pharmacoeconomics

Additional relevant MeSH terms:

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Tuberculosis Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Extensively Drug-Resistant Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Respiratory Tract Infections Lung Diseases Respiratory Tract Diseases Moxifloxacin	Linezolid Bedaquiline Clofazimine Anti-Bacterial Agents Anti-Infective Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Protein Synthesis Inhibitors Antitubercular Agents Anti-Inflammatory Agents Leprostatic Agents

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