TuberculosisPhase 2NCT02684240
A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis
A Phase 2 study testing Nitazoxanide in people with Tuberculosis, run by Weill Medical College of Cornell University at 1 site in Haiti.
Trial summary
This research is being done to determine if Nitazoxanide (NTZ) will cause a significant decrease in the number of M. tuberculosis bacteria in sputum after 14 days of treatment. The study is being conducted at the GHESKIO Centers in Port au Prince Haiti Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Nitazoxanide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteHaiti
- Study dates
- Feb 2016to 11 Apr 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women ages 18 - 65
- Diagnosed with pulmonary tuberculosis via: sputum-microscopy smear-positive (2+ or 3+) within 14 days plus Sputum GeneXpert positive within 14 days plus Chest radiograph consistent with M. tuberculosis within 14 days
- TB treatment naïve at time of enrollment
- Bodyweight > 40kg
- Negative HIV test within 30 days
- Able to complete activities of daily living (ADLs)
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- All participants must agree not to participate in a conception process (i.e. active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization)
- All female participants must agree to use barrier methods such as condoms as well as hormonal contraception for dual prophylaxis.
- Able to give informed consent and demonstrate understanding of this study and willingness to participate in this study
- Willing to be hospitalized for 2 weeks
Who cannot join
- Pregnancy
- Evidence of complications of M. tuberculosis such as hemoptysis or shortness of breath
- Extrapulmonary manifestations of M. tuberculosis
- History of prior active tuberculosis
- Evidence of rifampin resistance via GeneXpert
- Previous diagnosis of diabetes or suggestion of impaired glucose metabolism via random plasma glucose
Show all 11Show fewer
- Previous diagnosis of HIV by any rapid HIV test or by ELISA
- Any of the following lab abnormalities: Creatinine > 1.5 times the ULN; Random glucose > 2 times the ULN; ALT, AST, or alkaline phosphatase > 2 times the ULN; Hemoglobin < 7.5 g/dL
- Any participant currently taking antimycobacterial therapy or within the past 30 days
- Any concomitant illness that could compromise patient safety in this trial such as renal failure, chronic liver disease or alcoholic dependency
- Enrolled in another clinical trial
Trial locations and contacts
1 site in 1 country.
About this study
This research is being done to determine if Nitazoxanide (NTZ) will cause a significant decrease in the number of M. tuberculosis bacteria in sputum after 14 days of treatment. The study is being conducted at the GHESKIO Centers in Port au Prince Haiti
Read the detailed description
This is a prospective randomized two-arm 14-day, early bactericidal activity study in treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis (TB). The study will be conducted at the GHESKIO Centers in Port au Prince Haiti. Twenty patients will be randomized to receive NTZ 1 gram orally twice daily for 14 days. Ten patients will be randomized as positive controls to receive standard 4 drug tuberculosis therapy with isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (PZA). Patients' sputum will be collected before and then every two days during 14 days of treatment, and the primary endpoint will be the change in the number of M. tuberculosis in patients' sputum. Our primary hypothesis is that NTZ will result in a significant decrease in the number of M. tuberculosis in sputum during14 days of treatment. The number of M. tuberculosis will be quantified by the time to positive (TTP) signal in hours in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson).
- Conditions
- Tuberculosis
- Being tested
- Nitazoxanide, Control
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitazoxanideDrug
Also called Nizonide, Alinia
nitazoxanide 1000 mg orally twice daily with food for 14 days
ControlOther
The control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol
| Study group | Role | What they receive |
|---|---|---|
| Nitazoxanide | Experimental | Participants with drug-sensitive tuberculous randomized to the NTZ arm will receive nitazoxanide 1000 mg po twice daily for 14 days. After this time point, participants will be switched to WHO standard tuberculosis therapy with isoniazid, rifampin, pyrazinamide and ethambutol. Receives: Drug: Nitazoxanide |
| Control | Other | Participants with drug-sensitive tuberculosis randomized to the standard therapy arm will receive WHO standard tuberculosis therapy involving isoniazid 300 mg po daily, rifampin 600 mg po daily, pyrazinamide 25 mg/kg po daily and ethambutol 15 mg/kg po daily. Receives: Other: Control |
What is being measured
The primary outcome is the main question the study is designed to answer.
time to positivity (TTP)
To assess the change in time in hours to positive (TTP) signal in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson) in participants receiving NTZ over 14 days
Measured: first 14 days of anti-tuberculosis therapy
Secondary outcomes (11)
Number of participants with treatment-related adverse events as determined by DAIDS toxicity tables
To assess the safety of 1000 mg twice daily dosing of NTZ in participants with drug-sensitive tuberculosis by grading each treatment-related adverse reaction according the DAIDS Toxicity tables (November 2014)
Measured: first 14 days of anti-tuberculosis therapy
Maximum plasma concentration of NTZ
To assess the maximum plasma concentration of NTZ via collection of whole blood samples at hours 2, 4, 6 after ingestion of 1000 mg NTZ on day 5 and day 14 of the study
Measured: first 14 days of anti-tuberculosis therapy
Most probable number of M tuberculosis in 1 ml of sputum
To quantify the number of M. tuberculosis (MTB) in sputum at baseline and at day 14 using most probable number (MPN) micro-plate assay with and without resuscitation factors added to media
Measured: first 14 days of anti-tuberculosis therapy
First-line drug susceptibility (DST) of Mycobacterium tuberculosis via Mycobacterial Growth Indicator System (MGIT)
To test for first-line drug susceptibility (DST) of Mycobacterium tuberculosis to isoniazid, rifampin, pyrazinamide and ethambutol via MGIT
Measured: first 14 days of anti-tuberculosis therapy
Quantification of change in urine metabolites and correlation with change in TTP
To quantify the change in urine metabolites by LC-MS technology and the correlation of this change with change in TTP.
Measured: first 14 days of anti-tuberculosis therapy
Minimum plasma concentration of NTZ
To assess the minimum plasma concentration of NTZ via collection of whole blood samples at 30 minutes prior to ingestion of 1000 mg of NTZ on day 5 and day 14 of the study
Measured: first 14 days of anti-tuberculosis therapy
Area under the curve of NTZ metabolites
To assess the area under the curve of NTZ metabolites (tizoxanide, tizoxanide glucuronide) via collection of whole blood samples at hour 2, 4, and 6 post-ingestion of 1000 mg of NTZ on day 5 and day 14
Measured: first 14 days of anti-tuberculosis therapy
Sputum concentration of NTZ
To assess the sputum concentration of NTZ via collection of spot sputum samples 4 hours post-ingestion of 1000 mg NTZ on day 5 and day 14 of study
Measured: first 14 days of anti-tuberculosis therapy
Change in Minimum inhibitory concentration (MIC) of NTZ against Tuberculosis over 14 days
To assess the MIC of NTZ against tuberculosis using microplate assay at baseline and again at day 14 to determine any change in the MIC over the course of treatment
Measured: first 14 days of anti-tuberculosis therapy
Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA
Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA over the course of 14 days and correlation of this change with change in TTP.
Measured: first 14 days of anti-tuberculosis therapy
Transcriptional signature of treatment response using whole blood transcriptional profiles
Determine the transcriptional signature of treatment response using whole blood transcriptional profiles obtained at baseline and day 14
Measured: first 14 days of anti-tuberculosis therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2016 (estimated)
- Study startFeb 2016
- Primary completion11 Apr 2018
- Study completion11 Apr 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Daniel W Fitzgerald, MD, Principal investigator, Weill Medical College of Cornell UniversityCarl Nathan, MD, Study chair, Weill Medical College of Cornell UniversityJean William Pape, MD, Study chair, Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02684240
- Sponsor's protocol ID
- 1302013616
- Status last verified
- Aug 2020
- First submitted
- 2 Feb 2016
- Last updated
- 5 Aug 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Data will be shared once the trial is complete. Data is currently being analyzed.
Publications
de Carvalho LP, Lin G, Jiang X, Nathan C. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance. J Med Chem. 2009 Oct 8;52(19):5789-92. doi: 10.1021/jm9010719.
PubMed 19736929Stockis A, De Bruyn S, Gengler C, Rosillon D. Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d. Int J Clin Pharmacol Ther. 2002 May;40(5):221-7. doi: 10.5414/cpp40221.
PubMed 12051574Shigyo K, Ocheretina O, Merveille YM, Johnson WD, Pape JW, Nathan CF, Fitzgerald DW. Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2834-7. doi: 10.1128/AAC.02542-12. Epub 2013 Mar 18.
PubMed 23507275Walsh KF, McAulay K, Lee MH, Vilbrun SC, Mathurin L, Jean Francois D, Zimmerman M, Kaya F, Zhang N, Saito K, Ocheretina O, Savic R, Dartois V, Johnson WD, Pape JW, Nathan C, Fitzgerald DW. Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e01956-19. doi: 10.1128/AAC.01956-19. Print 2020 Apr 21.
PubMed 32071052Wipperman MF, Bhattarai SK, Vorkas CK, Maringati VS, Taur Y, Mathurin L, McAulay K, Vilbrun SC, Francois D, Bean J, Walsh KF, Nathan C, Fitzgerald DW, Glickman MS, Bucci V. Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis. Nat Commun. 2021 Feb 18;12(1):1141. doi: 10.1038/s41467-021-21475-y.
PubMed 33602926
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis
- ClinicalTrials.gov ID
- NCT02684240
- Acronym / sponsor ID
- 1302013616
- Conditions
- Tuberculosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Study start
- Feb 2016
- Primary completion
- 11 Apr 2018 (actual)
- Study completion
- 11 Apr 2018 (actual)
- First posted
- 17 Feb 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This research is being done to determine if Nitazoxanide (NTZ) will cause a significant decrease in the number of M. tuberculosis bacteria in sputum after 14 days of treatment. The study is being conducted at the GHESKIO Centers in Port au Prince Haiti
Detailed description
This is a prospective randomized two-arm 14-day, early bactericidal activity study in treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis (TB). The study will be conducted at the GHESKIO Centers in Port au Prince Haiti. Twenty patients will be randomized to receive NTZ 1 gram orally twice daily for 14 days. Ten patients will be randomized as positive controls to receive standard 4 drug tuberculosis therapy with isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (PZA). Patients' sputum will be collected before and then every two days during 14 days of treatment, and the primary endpoint will be the change in the number of M. tuberculosis in patients' sputum. Our primary hypothesis is that NTZ will result in a significant decrease in the number of M. tuberculosis in sputum during14 days of treatment. The number of M. tuberculosis will be quantified by the time to positive (TTP) signal in hours in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitazoxanide | Experimental | Drug: NitazoxanideParticipants with drug-sensitive tuberculous randomized to the NTZ arm will receive nitazoxanide 1000 mg po twice daily for 14 days. After this time point, participants will be switched to WHO standard tuberculosis therapy with isoniazid, rifampin, pyrazinamide and ethambutol. |
| Control | Other | Other: ControlParticipants with drug-sensitive tuberculosis randomized to the standard therapy arm will receive WHO standard tuberculosis therapy involving isoniazid 300 mg po daily, rifampin 600 mg po daily, pyrazinamide 25 mg/kg po daily and ethambutol 15 mg/kg po daily. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Men and women ages 18 - 65
- Diagnosed with pulmonary tuberculosis via: sputum-microscopy smear-positive (2+ or 3+) within 14 days plus Sputum GeneXpert positive within 14 days plus Chest radiograph consistent with M. tuberculosis within 14 days
- TB treatment naïve at time of enrollment
- Bodyweight > 40kg
- Negative HIV test within 30 days
Key exclusion criteria (11 listed)
- Pregnancy
- Evidence of complications of M. tuberculosis such as hemoptysis or shortness of breath
- Extrapulmonary manifestations of M. tuberculosis
- History of prior active tuberculosis
- Evidence of rifampin resistance via GeneXpert
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NitazoxanideAlso: Nizonide, Alinianitazoxanide 1000 mg orally twice daily with food for 14 days | Drug | Nitazoxanide |
| ControlThe control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol | Other | Control |
Primary outcome
time to positivity (TTP)
Time frame: first 14 days of anti-tuberculosis therapy
To assess the change in time in hours to positive (TTP) signal in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson) in participants receiving NTZ over 14 days
11 secondary outcomes
Number of participants with treatment-related adverse events as determined by DAIDS toxicity tables
Time frame: first 14 days of anti-tuberculosis therapy
Maximum plasma concentration of NTZ
Time frame: first 14 days of anti-tuberculosis therapy
Most probable number of M tuberculosis in 1 ml of sputum
Time frame: first 14 days of anti-tuberculosis therapy
First-line drug susceptibility (DST) of Mycobacterium tuberculosis via Mycobacterial Growth Indicator System (MGIT)
Time frame: first 14 days of anti-tuberculosis therapy
Quantification of change in urine metabolites and correlation with change in TTP
Time frame: first 14 days of anti-tuberculosis therapy
Minimum plasma concentration of NTZ
Time frame: first 14 days of anti-tuberculosis therapy
Area under the curve of NTZ metabolites
Time frame: first 14 days of anti-tuberculosis therapy
Sputum concentration of NTZ
Time frame: first 14 days of anti-tuberculosis therapy
Change in Minimum inhibitory concentration (MIC) of NTZ against Tuberculosis over 14 days
Time frame: first 14 days of anti-tuberculosis therapy
Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA
Time frame: first 14 days of anti-tuberculosis therapy
Transcriptional signature of treatment response using whole blood transcriptional profiles
Time frame: first 14 days of anti-tuberculosis therapy
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2020.
- Background: PubMed 19736929de Carvalho LP, Lin G, Jiang X, Nathan C. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance. J Med Chem. 2009 Oct 8;52(19):5789-92. doi: 10.1021/jm9010719.
- Background: PubMed 12051574Stockis A, De Bruyn S, Gengler C, Rosillon D. Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d. Int J Clin Pharmacol Ther. 2002 May;40(5):221-7. doi: 10.5414/cpp40221.
- Background: PubMed 23507275Shigyo K, Ocheretina O, Merveille YM, Johnson WD, Pape JW, Nathan CF, Fitzgerald DW. Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2834-7. doi: 10.1128/AAC.02542-12. Epub 2013 Mar 18.
- Results publication: PubMed 32071052Walsh KF, McAulay K, Lee MH, Vilbrun SC, Mathurin L, Jean Francois D, Zimmerman M, Kaya F, Zhang N, Saito K, Ocheretina O, Savic R, Dartois V, Johnson WD, Pape JW, Nathan C, Fitzgerald DW. Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e01956-19. doi: 10.1128/AAC.01956-19. Print 2020 Apr 21.
- Derived from this study: PubMed 33602926Wipperman MF, Bhattarai SK, Vorkas CK, Maringati VS, Taur Y, Mathurin L, McAulay K, Vilbrun SC, Francois D, Bean J, Walsh KF, Nathan C, Fitzgerald DW, Glickman MS, Bucci V. Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis. Nat Commun. 2021 Feb 18;12(1):1141. doi: 10.1038/s41467-021-21475-y.
- Individual participant dataSharing planned: Yes. Data will be shared once the trial is complete. Data is currently being analyzed.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Daniel W Fitzgerald, MD principal investigator
Weill Medical College of Cornell University
Carl Nathan, MD study chair
Weill Medical College of Cornell University
Jean William Pape, MD study chair
Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitazoxanide in people with Tuberculosis, run by Weill Medical College of Cornell University at 1 site in Haiti.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Haiti. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
time to positivity (TTP) (time frame: first 14 days of anti-tuberculosis therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02684240, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2020.