Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202007736854169 Date of Approval: 03/07/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Effect of N-acetylcysteine to reduce occurrence of adverse drug reactions in patients receiving multi drug resistant tuberculosis in Tanzania
Official scientific title Phase 2b open label randomized controlled trial to evaluate the adverse drug reaction protective efficacy, safety and tolerability of N-acetylcysteine in combination with second-line in adult subjects treated for multidrug-resistant tuberculosis in Tanzania.
Brief summary describing the background and objectives of the trial Background: Adverse drug reactions such as hearing loss or hepatotoxicity is one of the commonly unwanted and highly morbid events occurring in patients using second-line anti-TB medicine. In recent years, the number of multidrug resistant tuberculosis (MDR-TB) patients enrolling for treatment with second-line anti-TB regimen has increased gradually. Therefore, we anticipate that the number of individuals developing hearing loss or renal or hepatic failure post MDR-TB treatment will considerably increase in the foreseeable future, and that any form of prevention of with a currently approved accessible medication is highly relevant. Aims and Objectives: Investigate the use of a promising antidote, N-acetylcysteine (NAC), in combination with second line anti-TB regimen in slowing the rate of adverse drug events and protecting against the development of permanent and profound disability. NAC will be assessed at dose of 900mg daily or 900mg twice daily for safety and tolerability, efficacy in protecting the ototoxicity and interactions with second line anti-TB drugs. Furthermore, the effect of NAC in different parameters such as clinical and immunological responses, radiographic changes and clearance of Mycobacterium tuberculosis will also be evaluated.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) NAC TRIAL
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Other
Anticipated trial start date 30/06/2020
Actual trial start date 31/07/2020
Anticipated date of last follow up 15/07/2022
Actual Last follow-up date 31/07/2022
Anticipated target sample size (number of participants) 60
Actual target sample size (number of participants) 66
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Care giver/Provider,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group N acetylcysteine 900 mg twice daily 24 weeks Patients with MDR-TB patients will receive N acetylcysteine 900 mg twice daily 22
Experimental Group N acetylcysteine 900 mg of NAC (1-tablet) and Placebo (1-tablet) 24-weeks Patients will receive placebo and experimental drug (NAC) daily. The placebo will be taken am and the intervention ie NAC 900mg during the pm time 22
Control Group Placebo Placebo (1- tablet) twice daily 24-weeks Patients with MDR-TB will receive placebo 1 tablet a.m and placebo 1 tablet pm 22 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. A patient is able and willing to provide written informed consent prior to any trial procedure 2. Patient is aged between 18 – 65 years 3. Patient is a newly diagnosed with MDR-TB and not started MDR-TB treatment 4. Patient is eligible for aminoglycoside or bedaquiline based second-line anti-TB drugs 5. Karnofsky score of  50 6. Female patient should not be pregnant confirmed by urinary pregnant test (UPT) 1. Patient has pre-existing profound hearing loss at dB >90 2. Patient has a history of using secondline anti-TB drugs 3. Patient has previous or existing pathology of the external or middle ear which would preclude auditory testing 4. Patient has previous or existing pathology of the inner ear with or without hearing loss (i.e. sudden sensorineural hearing loss, Meniere's disease, autoimmune inner ear disease) 5. Patient has previous or existing pathology of the central nervous system with potential to impact auditory pathways (i.e. major head trauma, meningitis, encephalitis, brain metastasis, vestibular schwannoma) 6. Patient has mental disorder such as schizophrenia, schizoaffective disorder or psychotic disorder 7. Patient is pregnant as indicated by urinary pregnant test (UPT). 8. Patient has comorbid condition such as severe liver or renal diseases Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 21/05/2020 National Health Research Ethical Committee
Ethics Committee Address
Street address City Postal code Country
3 Barack Obama Drive Dar es Salaam 11101 United Republic of Tanzania
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Development of clinical or laboratory-based or both adverse events at any frequency during the first six month of MDR-TB treatment within 24 weeks of treatment
Secondary Outcome Efficacy • Occurrence of ototoxicity (Yes/No) or Hepatoxicity as defined by Common Terminology Criteria for Adverse Event (CTCAE). Hearing loss as defined as 20 dB or more change at any frequency compared to baseline or clinical ototoxicity at the end of 8 months of MDR-TB (conventional) treatment. • Proportion of MDR-TB patients requiring second-line anti-TB regimen modification modifications due to adverse drug events • TB Symptoms profile (Appendix 1) • Time to first negative culture on solid media • Proportion of patients converting to negative sputum culture on solid culture at 4 or 6 or 8 months after treatment initiation • Rate of change of sputum MTB RNA in MBL assay during treatment within 24 weeks of treatment
Secondary Outcome Pharmacokinetics endpoints of second-line anti-TB drugs • Area under the curve (AUC) • Observed Cmax • Volume of distribution • Elimination half life Week 2 and Week 8 of treatment
Secondary Outcome Mycobacteriological identification and characterizations • Identification of MTB complex from direct sputum specimen and susceptibility of first and second-line anti-TB drugs using Taqman Array Card rt-PCR for resistance determining regions in 10 genes • Minimum inhibitory concentration of 12 first and second-line anti-TB drugs using Sensititre MYCOTB plates • Whole Genome Sequence of discordant between TAC and MIC Baseline
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kibongoto Infeectious Diseases Hospital Mae Street, Lomakaa Road Moshi 0255 United Republic of Tanzania
FUNDING SOURCES
Name of source Street address City Postal code Country
EDCTP TMA 2016 1463 2509 AA The Hague 93015 Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Stellah Mpagama Mae Street, Lomakaa Road Moshi 0255 United Republic of Tanzania Hospital
COLLABORATORS
Name Street address City Postal code Country
Scott Heysell 1300 Jefferson Park Ave. Charlottesville 22903 United States of America
Gibson Kibiki Avenue Des Etats-Unis Bujumbura 0257 Burundi
Martin Boeree Radboudumc Nijmegen 6500 Netherlands
Patrick PJ Phillips 1001 Potrero Avenue San Francisco 94102 United States of America
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Stellah Mpagama sempagama@yahoo.com +255754860576 Mae Street, Lomakaa Road
City Postal code Country Position/Affiliation
Moshi 0255 Tanzania Senior Research Fellow
Role Name Email Phone Street address
Scientific Enquiries Peter Mbelele mbelelepeter@yahoo.com +255767902477 Mae Street, Lomakaa Road
City Postal code Country Position/Affiliation
Moshi 0255 United Republic of Tanzania Clinical Microbiologist
Role Name Email Phone Street address
Public Enquiries Alphonce Liyoyo liyoyo2010@gmail.com +255767134567 Mae Street, Lomakaa Road
City Postal code Country Position/Affiliation
Moshi 0255 United Republic of Tanzania Trial Manager
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and appendices). Study Protocol Beginning 9 months and ending 36 months following article publication. For individual participant data meta-analysis.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Reporting Plan to share IPD 02/07/2020 Address the comment according to the WHO recommendations No Yes
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 02/07/2020 Address the comment according to the WHO recommendations Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and appendices).
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD-Sharing time frame 02/07/2020 Address the comment according to the WHO recommendations Beginning 9 months and ending 36 months following article publication.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Key access criteria 02/07/2020 Address the comment according to the WHO recommendations For individual participant data meta-analysis.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Study protocol document 02/07/2020 Address the comment according to the WHO recommendations Study Protocol
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 02/07/2020 I overlooked the trial statistician Patrick PJ Phillips, 1001 Potrero Avenue, San Francisco, 94102, United States of America
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Official scientific title 23/11/2020 The manufacturer did not supply placebo Phase 2b double blind randomized controlled trial to evaluate the adverse drug reaction protective efficacy, safety and tolerability of N-acetylcysteine in combination with second-line in adult subjects treated for multidrug-resistant tuberculosis in Tanzania. Phase 2b open label randomized controlled trial to evaluate the adverse drug reaction protective efficacy, safety and tolerability of N-acetylcysteine in combination with second-line in adult subjects treated for multidrug-resistant tuberculosis in Tanzania.
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 23/11/2020 Recruitment has started Not yet recruiting Recruiting