Adjunctive NAC in Adult Patients With Pulmonary Tuberculosis (NAC-TB)

A Prospective Randomized Controlled Trial of Adjunctive N-acetylcysteine (NAC) in Adult Patients With Pulmonary Tuberculosis: a Sub-study of TB Sequel

To determine if adjunctive N-acetylcysteine 1200 mg twice a day (BID) accelerates sputum culture conversion and normalization of cellular glutathione in tuberculosis (TB), and to assess its potential effects on lung and immune function

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Drug: N-acetyl cysteine

Detailed Description

This is a randomized controlled, 2-arm, parallel group substudy of the TB-SEQUEL cohort study. It will enrol drug sensitive TB patients with moderately advanced or far advanced pulmonary disease by chest X-ray. Patients providing informed consent will undergo screening evaluations to establish eligibility. Patients meeting all the inclusion and none of the exclusion criteria will be randomized to receive standard TB treatment (2HRZE/4HR) plus NAC 1200 mg BID for months 1-4, or standard treatment alone. During the treatment period patients will undergo safety, efficacy, and biomarker assessments at specified time points. After a final evaluation at 6 months, patients will continue follow-up as a part of the main TB-SEQUEL cohort study.

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert Wallis; Phone Number: +27 (0) 10 590 1322; Email: rwallis@auruminstitute.org

Study Locations

• Tanzania
  • Mbeya, Tanzania
    • Recruiting
    • NIMR-Mbeya Medical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 18 to 65 years, male or female
2. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial related procedures.
3. Body weight (in light clothing without shoes) between 40 and 90 kg.
4. First episode of pulmonary tuberculosis
5. Positive sputum AFB smear with subsequent culture confirmation OR positive Xpert TB/RIF with Ct ≤27.1 [3].
6. RIF susceptibility diagnosed by Xpert TB/RIF OR Hain test
7. Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis [4]
8. If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment
9. HIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count >220/ul

Exclusion Criteria:

1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well being of the subject or prevent, limit or confound protocol specified assessments
2. Current or imminent (within 24 hr) treatment for malaria.
3. Pregnancy
4. Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow up period.
5. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
6. History of allergy or hypersensitivity to any of the trial therapies or related substances, including known allergy or suspected hypersensitivity to rifampin.
7. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
8. Prior TB treatment in the preceding 6 months.
9. Angina pectoris requiring treatment with nitroglycerin or other nitrates
10. Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
11. Random blood glucose >140 mg/dL, or history of unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.
12. Use of systemic corticosteroids within the past 28 days.
13. Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors

14. Subjects with any of the following abnormal laboratory values:

    1. creatinine >2 mg/dL
    2. haemoglobin <8 g/dL
    3. platelets <100x109 cells/L
    4. serum potassium <3.5
    5. aspartate aminotransferase (AST) ≥2.0 x ULN
    6. alkaline phosphatase (AP) >5.0 x ULN
    7. total bilirubin >1.5 mg/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAC; Patients will be randomized to receive standard TB treatment with N-acetylcysteine 1200 mg BID x 4 months, followed by 2 months of standard TB treatment alone	Drug: N-acetyl cysteine; NAC is listed by WHO as an essential medicine for its use in paracetamol (acetaminophen) poisoning, in which it protects against fatal liver injury. It also reduces the viscosity of sputum, thereby serving as an expectorant.; Other Names: NAC
No Intervention: No NAC; Patients will be randomized to receive 6 months standard TB treatment alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Median time to stable sputum culture conversion using liquid medium	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in mean concentration of reduced glutathione (GSH) in blood cells, expressed as the AUC during days 1-28	1-28 days
GSH concentrations and the ratio of GSH to GSSG (oxidized glutathione) measured at discrete time points during treatment	6 months
Whole blood bactericidal activity (WBA) prior and at intervals post dosing	24 hours

Collaborators and Investigators

• Sponsor: The Aurum Institute NPC
• Collaborators: National Institute for Medical Research, Tanzania
• Investigators: Principal Investigator: Robert Wallis, Chief Scientific Officer

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: October 4, 2018
• First Submitted That Met QC Criteria: October 9, 2018
• First Posted (Actual): October 11, 2018

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 18, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: N-acetylcysteine; Glutathione; Host-directed therapy
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: AUR1-1-219

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No