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

NCT05040126 | Unknown Phase 3 DMC

• 1 other identifier: 2021 004
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 1

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

Conditions

Pre-Extensively Drug-Resistant Pulmonary TB; Treatment Intolerant Multidrug-Resistant Pulmonary TB; Non-responsive Multidrug-Resistant Pulmonary TB

Outcome Measures

Primary Outcomes (1)

• Sustained Treatment success

  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.

  12 months after successful TB treatment

Secondary Outcomes (4)

• Proportion of serious adverse events

  treatment and follow-up period - 18 months

• proportion of patients died

  treatment and follow-up period - 18 months

• proportion of patients with Treatment Failure

  treatment and follow-up period - 18 months

• proportion of patients with Lost-to-follow up

  treatment and follow-up period - 18 months

Other Outcomes (1)

• HRQoL scores

  baseline, end of treatment, and 48-weeks post-treatment - 18 months

Study Arms (3)

Arm 1 - 26 weeks of BDQ +Pa + LZD (600mg)

ACTIVE COMPARATOR

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; Drug: Bedaquiline; Drug: Pretomanid

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

EXPERIMENTAL

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; Drug: Bedaquiline; Drug: Pretomanid

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

EXPERIMENTAL

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; Drug: Bedaquiline; Drug: Pretomanid

Interventions

Linezolid DRUG

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

Arm 1 - 26 weeks of BDQ +Pa + LZD (600mg); Arm 2 - 9 weeks. of BDQ +Pa + LZD (600mg) followed by 17 wks. of BDQ +Pa+ LZD (300mg); Arm 3 -13 weeks. of BDQ +Pa + LZD (600mg) followed by 13 wks. of BDQ +Pa+ LZD (300mg)

Bedaquiline DRUG

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

Arm 1 - 26 weeks of BDQ +Pa + LZD (600mg); Arm 2 - 9 weeks. of BDQ +Pa + LZD (600mg) followed by 17 wks. of BDQ +Pa+ LZD (300mg); Arm 3 -13 weeks. of BDQ +Pa + LZD (600mg) followed by 13 wks. of BDQ +Pa+ LZD (300mg)

Pretomanid DRUG

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

Arm 1 - 26 weeks of BDQ +Pa + LZD (600mg); Arm 2 - 9 weeks. of BDQ +Pa + LZD (600mg) followed by 17 wks. of BDQ +Pa+ LZD (300mg); Arm 3 -13 weeks. of BDQ +Pa + LZD (600mg) followed by 13 wks. of BDQ +Pa+ LZD (300mg)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged between 18 years - 65 years
• 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 \[with documented treatment intolerance or non-response to MDR TB treatment regimen for 6-months or more when the participant was adherent to the treatment regimen\]
• Bodyweight of ≥30 kg (in light clothing and no shoes)
• Provide written, informed consent before all study-related procedures
• 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 \[ELISA and/or Western Blot\]).
• 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.
• QTcF less than or equal to 450 at baseline
• 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.

You may not qualify if:

• Non-DST based criteria
• Intolerance or risk of toxicity from medicine in the treatment regimens (e.g. drug-drug interactions)
• Patient who has received more than 2 weeks of Bedaquiline or Linezolid before the first dose of BPaL regimen
• Pregnancy or Lactating women
• HIV infected patient having a CD4+ cell count of ≤ 50 cells/µL;
• Currently having an uncontrolled cardiac arrhythmia that requires medication
• Have any of the following QTcF interval characteristics at screening:
• 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.
• History of additional risk factors for Torsade de Pointes, e.g. heart failure, hypokalaemia, family history of long QT syndrome;
• 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.
• Very seriously ill patients (Karnofsky scores \< 50 within last 30 days)
• 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.
• 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
• Grade III or IV peripheral neuropathy

Sponsors & Collaborators

• Tuberculosis Research Centre, India: lead
• International Union Against Tuberculosis and Lung Diseases: collaborator
• Sarvodaya Charitable Trust Hospital, Ghatkopar, Mumbai: collaborator
• Shatabdi Centenary Hospital, Govandi, Mumbai: collaborator
• King George's Medical College and Hospital, Lucknow: collaborator
• SN Medical College, Agra: collaborator
• Govt Medical College & Hospital, Bhavnagar: collaborator
• Govt. Medical College & Hospital, Surat: collaborator
• National Institute for Tuberculosis and Respiratory Diseases, New Delhi: collaborator
• Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, Delhi: collaborator
• Govt.Rajaji Medical college and hospital, Madurai: collaborator

Study Sites (1)

S N Medical College

Agra, Uttar Pradesh, India

Location

Related Publications (1)

• Padmapriyadarsini C, Devaleenal B, Ponnuraja C, Ramraj B, Singla R, Parmar M, Mattoo S, Mandal S. Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol. BMJ Open. 2022 Aug 29;12(8):e058606. doi: 10.1136/bmjopen-2021-058606.

  PMID: 36038181 DERIVED

MeSH Terms

Interventions

Linezolid; bedaquiline; pretomanid

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Padmapriyadarsini Chandrasekharan

  Tuberculosis Research Centre, India

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Model Details: Pragmatic Clinical Trial

Study Record Dates

• First Submitted: August 18, 2021
• First Posted: September 10, 2021
• Study Start: October 7, 2021
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: January 3, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)