Economic Evaluation of New MDR TB Regimens

NCT ID: NCT04207112

Last Updated: 2024-04-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-20
• Study Completion Date: 2022-08-25

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.

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:

1. to assess the costs from a provider's perspective for selected facilities in the intervention and control arms;

2. 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;

3. To estimate the prevalence of catastrophic costs in the intervention and control arms;

4. to assess the probability of new regimens being cost-effective at different willingness-to-pay thresholds from a societal perspective using a Markov model.

Conditions

Multi-drug Resistant Tuberculosis; Extensively Drug-Resistant Tuberculosis; Pulmonary Tuberculoses

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Bedaquiline

Intervention Type: DRUG

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.

Pretomanid

Intervention Type: DRUG

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.

Moxifloxacin

Intervention Type: DRUG

Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria

Linezolid

Intervention Type: DRUG

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.

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

Group Type: EXPERIMENTAL

Bedaquiline

Intervention Type: DRUG

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.

Pretomanid

Intervention Type: DRUG

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.

Linezolid

Intervention Type: DRUG

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.

Clofazimine

Intervention Type: DRUG

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.

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)

Group Type: EXPERIMENTAL

Bedaquiline

Intervention Type: DRUG

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.

Pretomanid

Intervention Type: DRUG

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.

Linezolid

Intervention Type: DRUG

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.

Control regimen

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

Group Type: ACTIVE_COMPARATOR

Standard Drugs

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Moxifloxacin

Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Standard Drugs

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

Intervention Type: DRUG

Other Intervention Names

Sirturo; R207910; TMC207; PA-824; Avelox; BAY 12-8039; Zyvox; Lamprene

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

-

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

Ministry of Health, Republic of Uzbekistan

OTHER_GOV

Sponsor Role: collaborator

Ministry of Public Health, Republic of Belarus

OTHER_GOV

Sponsor Role: collaborator

THINK TB & HIV Investigative Network

NETWORK

Sponsor Role: collaborator

University of Liverpool

OTHER

Sponsor Role: collaborator

Wits Health Consortium (Pty) Ltd

OTHER

Sponsor Role: collaborator

Medecins Sans Frontieres, Netherlands

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sedona Sweeny

Role: PRINCIPAL_INVESTIGATOR

London School of Hygiene and Tropical Medicine

Locations

Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital

Minsk, , Belarus

Helen Joseph Hospital

Johannesburg, Gauteng, South Africa

THINK Clinical Trial Unit, Hillcrest

Durban, KwaZulu-Natal, South Africa

King DinuZulu Hospital

Durban, KwaZulu-Natal, South Africa

Doris Goodwin Hospital

Pietermaritzburg, KwaZulu-Natal, South Africa

Republican TB Hospital No. 2

Nukus, Karakalpakstan, Uzbekistan

Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital

Tashkent, , Uzbekistan

Countries

Belarus; South Africa; Uzbekistan

References

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.

Reference Type: BACKGROUND

PMID: 33039989 (View on PubMed)

Other Identifiers

PRACTECAL-EE

Identifier Type: -

Identifier Source: org_study_id