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Modified BPaL Regimen for Managing Pre-XDR TB and MDR (TI/NR) TB in India (mBPaL)

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ClinicalTrials.gov Identifier: NCT05040126
Recruitment Status : Recruiting
First Posted : September 10, 2021
Last Update Posted : November 9, 2021
Sponsor:
Collaborators:
International Union Against Tuberculosis and Lung Diseases
Sarvodaya Charitable Trust Hospital, Ghatkopar, Mumbai
Shatabdi Centenary Hospital, Govandi, Mumbai
KGMU, Lucknow
SN Medical College, Agra
BJ Medical College, Ahmedabad
Govt. Medical College, Surat
NITRD, New Delhi
RBIPMT, Delhi
Information provided by (Responsible Party):
Dr C Padmapriyadarsini, Tuberculosis Research Centre, India

Brief Summary:

Existing problem with DR TB management:

Injectable regimens for longer duration with toxicity Poor adherence, treatment failures, continued transmission

Need of the study:

Oral regimens of shorter duration Improved treatment adherence Implementation of community-based models of care Reduction in direct costs and indirect costs of patients Improved treatment outcomes

Need for shorter, tolerable and effective regimen

Hence modified BPaL regimen is designed to study the newer shorter oral in varying doses of Linezolid for pre XDR Tb patients and MDR TI/NR patients


Condition or disease Intervention/treatment Phase
Pre-Extensively Drug-Resistant Pulmonary TB Treatment Intolerant Multidrug-Resistant Pulmonary TB Non-responsive Multidrug-Resistant Pulmonary TB Drug: Linezolid Drug: Bedaquiline Drug: Pretomanid Phase 3

Detailed Description:

The regimen proposed is based on the NIX-TB and ZeNIX trial regimen with modification in the Linezolid doses. The rationale is -

  1. While the EBA study showed that a modestly greater bactericidal effect over 14 days at the highest 1200 mg daily, this dose appears to be associated with a greater incidence of neuropathic and myelosuppressive effects than the 600 mg daily dose in the NIXTB trial.
  2. Linezolid EBA study showed similar bactericidal activity over 14 days irrespective of the single daily dose or twice-daily doses. A single daily dose will enhance patient adherence and will reduce the total time of exposure to the drug concentration that is greater than the calculated concentration associated with mitochondrial toxicity (likely mechanism for the toxicities of peripheral neuropathy and myelosuppression).
  3. While a full 6 months of linezolid therapy in the regimen may give greater culture conversion and avoid relapse, the mouse model found that linezolid dosing only for one or two months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free cure.
  4. More than 2 months of linezolid, when combined with B and Pa, does not increase relapse-free cure in the mouse model. Thus, the treatment arms in this study will give randomized comparative information about the optimal duration and dose of linezolid in the regimen relative to efficacy and toxicity.
  5. The ZeNIX study with consistent dosing of bedaquilline and pretomanid reported 93% success rate with linezolid 1200 mg for 6 months and 91% with linezolid 600mg for 6 months. However 2 months of 600mg linezolid showed a success rate of 84%. Adverse reactions were reported in 38 % of those receiving 1200mg linezolid for 6 months, 24% of those receiving 600mg of linezolid for 6 months and 13% of those receiving 600mg linezolid for 2 months.
  6. Interim analysis of BEAT study (personal communication/52nd UNION abstract) with 6 month regimen of bedaquilline, delaminid, clofazimine and linezolid (600mg daily for 6 months) reported 89.6% success rate at the end of 6 months of treatment. Adverse reactions such as peripheral neuropathy were reported in 39% and myelosuppression in 47% of the patients.

Learning from ZeNIX and BEAT study, a planned reduction of Linezolid along with BDQ and Pretomanid is planned as BDQ+Pa+LZD 600mg for 9 weeks followed by 300 mg for 17 weeks and BDQ+Pa+LZD 600mg for 13 weeks followed by 300mg for 13 weeks. This will help in deciding the effective dosing of Lzd to be combined with Bdq and Pa for drug resistant TB in the program.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Pragmatic Clinical Trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluate the Effectiveness, Safety and Tolerability of Various Doses of Linezolid in Combination With Bedaquiline and Pretomanid in Adults With Pre-Extensively Drug-Resistant (Pre-XDR), Or Treatment Intolerant/Non-responsive Multidrug-Resistant (MDRTI/NR) Pulmonary Tuberculosis in India
Actual Study Start Date : October 7, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : March 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Active Comparator: Arm 1 - 26 weeks of BDQ +Pa + LZD (600mg)

26 wks. of BDQ +Pa + LZD (600mg) Bedaquiline (available as 100 mg tablets) Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks.

Linezolid: (available as 600 mg tablets) - Linezolid will be administered as one 600 mg tablet once daily in Arm1.

Pretomanid: (Available as 200 mg tablets): Pretomanid is administered as one tablet once a day for 26 weeks along with Bedaquiline and Linezolid.

Drug: Linezolid

Participants will have a screening period of up to 14 days and will be randomized to one of the study arms in the ratio of 1:1:1, using an interactive web response system.

Each participant will receive 26 weeks of treatment. If the participant's 16th-week sample remains culture positive, treatment will be extended up to 39 weeks.

Participants will be followed for 48 weeks after the end of treatment


Drug: Bedaquiline
Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks in all three arms

Drug: Pretomanid
Pretomanid is administered as one tablet once a day for 26 weeks in all three arms

Experimental: Arm 2 - 9 weeks. of BDQ +Pa + LZD (600mg) followed by 17 wks. of BDQ +Pa+ LZD (300mg)

9 wks. of BDQ +Pa + LZD (600mg) followed by 17 wks. of BDQ +Pa+ LZD (300mg) Bedaquiline (available as 100 mg tablets) Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks.

Linezolid: (available as 600 mg tablets) - Linezolid will be administered as one 600 mg tablet once daily in IP of Arm 2 and ½ tablet of 600 mg once daily in CP of Arm 2 .

Pretomanid: (Available as 200 mg tablets): Pretomanid is administered as one tablet once a day for 26 weeks along with Bedaquiline and Linezolid.

Drug: Linezolid

Participants will have a screening period of up to 14 days and will be randomized to one of the study arms in the ratio of 1:1:1, using an interactive web response system.

Each participant will receive 26 weeks of treatment. If the participant's 16th-week sample remains culture positive, treatment will be extended up to 39 weeks.

Participants will be followed for 48 weeks after the end of treatment


Drug: Bedaquiline
Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks in all three arms

Drug: Pretomanid
Pretomanid is administered as one tablet once a day for 26 weeks in all three arms

Experimental: Arm 3 -13 weeks. of BDQ +Pa + LZD (600mg) followed by 13 wks. of BDQ +Pa+ LZD (300mg)

13 wks. of BDQ +Pa + LZD (600mg) followed by 13 wks. of BDQ +Pa+ LZD (300mg) Bedaquiline (available as 100 mg tablets) Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks.

Linezolid: (available as 600 mg tablets) - Linezolid will be administered as one 600 mg tablet once daily in IP of Arm 3 and ½ tablet of 600 mg once daily in CP of Arm 3.

Pretomanid: (Available as 200 mg tablets): Pretomanid is administered as one tablet once a day for 26 weeks along with Bedaquiline and Linezolid.

Drug: Linezolid

Participants will have a screening period of up to 14 days and will be randomized to one of the study arms in the ratio of 1:1:1, using an interactive web response system.

Each participant will receive 26 weeks of treatment. If the participant's 16th-week sample remains culture positive, treatment will be extended up to 39 weeks.

Participants will be followed for 48 weeks after the end of treatment


Drug: Bedaquiline
Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 24 weeks in all three arms

Drug: Pretomanid
Pretomanid is administered as one tablet once a day for 26 weeks in all three arms




Primary Outcome Measures :
  1. Sustained Treatment success [ Time Frame: 12 months after successful TB treatment ]
    Sustained Treatment success at 12 months after successful TB treatment, who is alive and free of TB. Successful TB treatment includes Cure and Treatment Completed.


Secondary Outcome Measures :
  1. Proportion of serious adverse events [ Time Frame: treatment and follow-up period - 18 months ]
    1. Proportion of serious adverse events occurring among patients in the study during the treatment and follow-up period

  2. proportion of patients died [ Time Frame: treatment and follow-up period - 18 months ]
    Died due to any cause during treatment

  3. proportion of patients with Treatment Failure [ Time Frame: treatment and follow-up period - 18 months ]
    Treatment terminated or need for permanent regimen change to a new regimen or treatment strategy because of lack of sputum culture conversion , • bacteriological reversion , clinical or radiological worsening

  4. proportion of patients with Lost-to-follow up [ Time Frame: treatment and follow-up period - 18 months ]
    After treatment initiation, treatment was interrupted continuously for 30-days


Other Outcome Measures:
  1. HRQoL scores [ Time Frame: baseline, end of treatment, and 48-weeks post-treatment - 18 months ]
    percentage change in score over the treatment period between the regimens



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adults aged between 18 years - 65 years
  2. Pulmonary Pre-XDR-TB, patients [with documented evidence of resistance to rifampicin with or without isoniazid resistance AND additional resistance to any fluoroquinolones by conventional DST (culture-based1) or rapid DST (Xpert MTB/RIF or Trunat MTB/RIF or LPA) from a certified laboratory] OR MDR-TBTI/NR patients [with documented treatment intolerance or non-response to MDR TB treatment regimen for 6-months or more when the participant was adherent to the treatment regimen]
  3. Bodyweight of ≥30 kg (in light clothing and no shoes)
  4. Provide written, informed consent before all study-related procedures
  5. Provide consent to HIV testing2 (if an HIV test was performed within 1 month before the study start, it should not be repeated as long as documentation can be provided [ELISA and/or Western Blot]).
  6. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) < 2.5 x ULN; Total bilirubin lesser than ULN when accompanied by an increase in other liver function tests.
  7. QTcF less than or equal to 450 at baseline
  8. Female patients should not be pregnant or should be using a birth control method. They should be willing to continue practicing birth control methods (barrier or non-barrier contraceptive methods including oral contraceptives) throughout the treatment period, or history of post-menopausal for the past 12 months.

Exclusion Criteria:

Non-DST based criteria

  1. Intolerance or risk of toxicity from medicine in the treatment regimens (e.g. drug-drug interactions)
  2. Patient who has received more than 2 weeks of Bedaquiline or Linezolid before the first dose of BPaL regimen
  3. Pregnancy or Lactating women
  4. All forms of Extrapulmonary TB (Lymph node TB associated with Pulmonary DR-TB and pleural effusion associated with pulmonary TB can be considered for inclusion )
  5. HIV infected patient having a CD4+ cell count of ≤ 50 cells/µL;
  6. Currently having an uncontrolled cardiac arrhythmia that requires medication
  7. Have any of the following QTcF interval characteristics at screening:

    1. QTcF ≥ 450 at baseline & normal electrolytes, ECG to be repeated after 6 hours and if both ECGs show QTc>450 then the patient should not be challenged with cardiotoxic drugs.
    2. History of additional risk factors for Torsade de Pointes, e.g. heart failure, hypokalaemia, family history of long QT syndrome;
  8. Any condition in the Investigator's opinion (i.e., an unstable disease such as uncontrolled diabetes on insulin3 or cardiomyopathy), where participation would compromise the well-being of the patient or prevent, limit or confound protocol-specified assessments.
  9. Very seriously ill patients (Karnofsky scores < 50 within last 30 days)
  10. If results of the serum chemistry panel or, hematology are outside the normal reference range (as given below), the patient may still be considered if the physician judges that the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable.

    • Hypokalaemia, hypomagnesemia, and hypocalcemia should be corrected before a patient receiving any cardiotoxic drugs. (hypothyroidism is not exclusion criteria, to be considered with simultaneous thyroxine replacement therapy and close monitoring)
    • Haemoglobin level of < 9.0 g/dl or Platelet count <1,00,000 /mm3
    • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >2.5 x ULN; Total bilirubin greater ULN when accompanied by an increase in other liver function tests
  11. Grade III or IV peripheral neuropathy

DST based criteria

a. if the result for DST (FQ, LZD)4 is not available and h/o more than 2 weeks consumption of drugs used in the study regimen


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): NCT05040126


Contacts
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Contact: Balaji Ramraj, MD 9790765215 ext +91 balaji.r@nirt.res.in

Locations
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India
S N Medical College Recruiting
Agra, Uttarpradesh, India
Contact: Santosh Kumar         
Sponsors and Collaborators
Tuberculosis Research Centre, India
International Union Against Tuberculosis and Lung Diseases
Sarvodaya Charitable Trust Hospital, Ghatkopar, Mumbai
Shatabdi Centenary Hospital, Govandi, Mumbai
KGMU, Lucknow
SN Medical College, Agra
BJ Medical College, Ahmedabad
Govt. Medical College, Surat
NITRD, New Delhi
RBIPMT, Delhi
Investigators
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Principal Investigator: Padmapriyadarsini Chandrasekharan Tuberculosis Research Centre, India
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr C Padmapriyadarsini, Director, Tuberculosis Research Centre, India
ClinicalTrials.gov Identifier: NCT05040126    
Other Study ID Numbers: 2021 004
First Posted: September 10, 2021    Key Record Dates
Last Update Posted: November 9, 2021
Last Verified: November 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
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Tuberculosis, Pulmonary
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Linezolid
Bedaquiline
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents