Tuberculosis, PulmonaryPhase 2RIPENACTBNCT03281226
RIPE vs RIPE Plus N-acetylcysteine in Patients With HIV/TB Co-infection
A Phase 2 study testing RIPE (2m) and RI (4m) and RIPE+NAC (2m) and RI (4m) in people with Tuberculosis, Pulmonary and HIV/AIDS, run by Fundação de Medicina Tropical Dr. Heitor Vieira Dourado at 1 site in Brazil.
Trial summary
Although tuberculosis is a treatable disease, it is currently the infectious disease with the highest mortality in the world. It is estimated that one-third of the world's population is infected. HIV is the main predisposing factor for TB development. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, Pulmonary, HIV/AIDS
- What is being tested?
- RIPE (2m) and RI (4m) and RIPE+NAC (2m) and RI (4m)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteBrazil
- Study dates
- 7 Dec 2016to Dec 2019
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age greater than or equal to 18 years;
- Acceptance of the HIV test;
- Forecast of hospital stay of more than twenty-four hours;
- Clinical and laboratory indication of RIPE;
- Conditions for puncture of venous access;
Who cannot join
- Brazilian indigenous people;
- People the refuse to perform HIV test;
- Pregnant women, nursing mothers or pregnant women,
- Extra pulmonary TB, without pulmonary involvement;
- Not be able to perform the collection of sputum or tracheal aspirate for microbiological confirmation;
- No MGIT® positive for Mtb;
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- Resistance to Mtb, detected by professional sensitivity;
- Individuals under treatment for bronchospasm secondary to bronchial asthma, according to the decision of the assistant team or researcher of the study;
- Clinical suspicion of gastric or duodenal ulcer, as decided by the assistant team or study investigator; or evidence by upper digestive endoscopy;
- Alanine aminotransferase (ALT) greater than three times normal;
- Need to suspend the RIPE treatment, according to the decision of the assistant team or researcher of the study;
- Lack of adherence to the proposed treatment for more than seven consecutive days.
Trial locations and contacts
1 site in 1 country.
Brazil1 site, 1 recruiting
- Recruiting
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Manaus, Amazonas, 69040000
Izabella P Safe, MD, (+55 92) 2127 3498, izabellasafe@gmail.com
Marcelo C dos Santos, MD, PhD
About this study
Official title: An Open Label Randomized Phase 2 Clinical Trial to Assess Safety and Tolerability of RIPE vs RIPE Plus N-acetylcysteine in Patients With HIV/Aids and Pulmonary Tuberculosis
Although tuberculosis is a treatable disease, it is currently the infectious disease with the highest mortality in the world. It is estimated that one-third of the world's population is infected. HIV is the main predisposing factor for TB development. The Brazilian Ministry of Health and the World Health Organization recommends that patients should initially be treated orally with RIPE - rifampicin (R), isoniazid (I), pyrazinamide (P) and ethambutol (E). The N-acetylcysteine (NAC) first benefit was reported during the 1960s, when it proved to be an effective mucolytic agent in individuals with cystic fibrosis. Later, a new role arose when investigating its therapeutic potential in acetaminophen intoxication. Cleavage of the acetyl group makes cysteine available for later incorporation into glutathione synthesis, decreased in hepatic injury caused by acetaminophen. This mechanism causes NAC to have an indirect antioxidant effect, which aroused an interest in studying the effect in diseases that occur with oxidative stress. TB and HIV/Aids are also diseases with chronic inflammation. The present study aims to evaluate the effects of NAC as a adjuvant therapy in the treatment of TB. This is a phase II randomized clinical trial in which the safety and tolerability of NAC as adjunctive therapy for TB treatment will be assessed. Fifty-six patients will be randomized into two groups. The first group will receive the standard tuberculosis treatment as recommended by the Brazilian Ministry of Health (RIPE); the second will receive in addition to this treatment 1200mg of NAC per day for two months. In this way, microscopy and culture conversion rate to mycobacteria at 8 weeks, levels of glutathione and biomarkers of immune activation and inflammation in case of TB with or without NAC will be monitored.
Read the detailed description
TB and AIDS are also diseases that occur with a chronic inflammatory stimulus, with constant formation of excessive free radicals, leading to cellular and systemic oxidative stress. The effects of NAC in both populations are studied. A study demonstrated that HIV-positive individuals have low levels of glutathione in CD4+ T lymphocytes when compared to healthy controls, these levels being restored after in vivo supplementation with NAC, favoring the production of cytokines involved in Th1 response. They also observed that glutathione depletion in lymphocytes was correlated with increased levels of tumor necrosis factor and free radicals. Some authors suggested that the immune system's inability of HIV-positive individuals (or not) in containing Mycobaterium tuberculosis (Mtb) may be a consequence of low levels of glutathione in macrophages. The same occurred in a model of animals infected with Mtb, suggesting that oxidative stress was partly due to the poor antioxidant defense of the host. NAC supplementation decreases the bacterial load on the spleen and the severity of necrosis in the lung. The balance between oxidative and antioxidant substances plays a critical role in the induction of IL-12 production involved in the Th1 response and suggests that the use of NAC may be useful for better immune control of TB. Additional benefits of NAC in individuals with TB are related to the possible protective effect of hepatic to tuberculostatic drugs and to the direct antimicrobial effect demonstrated in vitro. Some authors suggest that the restoration of glutathione levels reversed the loss of innate immunity functions, pointing to a new mechanism of control of Mtb and a possible complement to antiretroviral treatment. This clinical trial will be undertaken in the Amazonas State (Western Brazilian Amazon), in Manaus, at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. It is a prospective, open-label, 2-arm, randomized clinical trial. Twenty-five patients will be enrolled in each treatment arm. A total number of 50 patients should be enrolled. Patients hospitalized in the ICU, in the wards or emergency room of the tertiary unit care will be invited to participate in this study. The assessment schedule will be done in days 1, 7, 14, 28, 42, 56, 120 and 180 (in addition, patient will be asked to come back to the health centre if symptoms occurs at any time). Sputum and blood collection and medical evaluation will be performed.
- Conditions
- Tuberculosis, Pulmonary, HIV/AIDS
- Being tested
- RIPE (2m) and RI (4m), RIPE+NAC (2m) and RI (4m)
- Keywords
- Pulmonary tuberculosis, HIV/AIDS, Glutathione, N-acetylcysteine, Oxidative stress
- Medical subject headings
- Tuberculosis, Pulmonary, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RIPE (2m) and RI (4m)Drug
Rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months
RIPE+NAC (2m) and RI (4m)Drug
Rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) plus oral N-acetylcysteine (NAC) 1200 mg (600mg twice daily) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months
| Study group | Role | What they receive |
|---|---|---|
| RIPE (2m) and RI (4m) | Active comparator | The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (combined fixed dose tablet according to the weight) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. Receives: Drug: RIPE (2m) and RI (4m) |
| RIPE+NAC (2m) and RI (4m) | Experimental | The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (combined fixed dose tablet according to the weight) plus N-acetylcysteine (NAC) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. The NAC is administered by means of effervescent tablet 1200 mg (two sachets of 600 mg) to be diluted in 200ml of water and administered in a 12-hour interval. Receives: Drug: RIPE+NAC (2m) and RI (4m) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with any biological intolerability or adverse event
This evaluation will be done by the physician along all the follow-up of the study
Measured: 6 months
Secondary outcomes (3)
Number of patients in the NAC treatment arm with shorter sputum smear conversion time and culture
This outcome will be monitored by culture of solid (Löwenstein Jensen) and liquid (MGIT) sputum
Measured: Until week 8
Number of patients presenting tuberculostatic drug-related hepatotoxicity
This outcome will be monitored by hepatic transaminases and bilirubins levels
Measured: 6 months
Dosage of inflammatory cytokines
This outcome will be evaluate immunological assays in the two groups
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2017
- Study start7 Dec 2016
- Primary completionJun 2019 (estimated)
- Study completionDec 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Tuberculosis, PulmonaryStudies of the same condition, open and under way.
- 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
- None (open label)
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Marcelo C dos Santos, MD, PhD, Principal investigator, Fundação de Medicina Tropical Dr. Heitor Vieira DouradoBruno B Andrade, MD, PhD, Principal investigator, Fundação Osvaldo Cruz Bahia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03281226
- Sponsor's protocol ID
- CAAE: 60219916.5.0000.0005
- Acronym
- RIPENACTB
- Status last verified
- Feb 2019
- First submitted
- 11 Sep 2017
- Last updated
- 15 Feb 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label Randomized Phase 2 Clinical Trial to Assess Safety and Tolerability of RIPE vs RIPE Plus N-acetylcysteine in Patients With HIV/Aids and Pulmonary Tuberculosis
- ClinicalTrials.gov ID
- NCT03281226
- Acronym / sponsor ID
- RIPENACTB / CAAE: 60219916.5.0000.0005
- Conditions
- Tuberculosis, Pulmonary, HIV/AIDS
- Keywords
- Pulmonary tuberculosis, HIV/AIDS, Glutathione, N-acetylcysteine, Oxidative stress
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Fundação de Medicina Tropical Dr. Heitor Vieira DouradoUniversity, hospital or other
- Study start
- 7 Dec 2016 (actual)
- Primary completion
- Jun 2019 (estimated)
- Study completion
- Dec 2019 (estimated)
- First posted
- 13 Sep 2017 (actual)
- 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.
Although tuberculosis is a treatable disease, it is currently the infectious disease with the highest mortality in the world. It is estimated that one-third of the world's population is infected. HIV is the main predisposing factor for TB development. The Brazilian Ministry of Health and the World Health Organization recommends that patients should initially be treated orally with RIPE - rifampicin (R), isoniazid (I), pyrazinamide (P) and ethambutol (E). The N-acetylcysteine (NAC) first benefit was reported during the 1960s, when it proved to be an effective mucolytic agent in individuals with cystic fibrosis. Later, a new role arose when investigating its therapeutic potential in acetaminophen intoxication. Cleavage of the acetyl group makes cysteine available for later incorporation into glutathione synthesis, decreased in hepatic injury caused by acetaminophen. This mechanism causes NAC to have an indirect antioxidant effect, which aroused an interest in studying the effect in diseases that occur with oxidative stress. TB and HIV/Aids are also diseases with chronic inflammation. The present study aims to evaluate the effects of NAC as a adjuvant therapy in the treatment of TB. This is a phase II randomized clinical trial in which the safety and tolerability of NAC as adjunctive therapy for TB treatment will be assessed. Fifty-six patients will be randomized into two groups. The first group will receive the standard tuberculosis treatment as recommended by the Brazilian Ministry of Health (RIPE); the second will receive in addition to this treatment 1200mg of NAC per day for two months. In this way, microscopy and culture conversion rate to mycobacteria at 8 weeks, levels of glutathione and biomarkers of immune activation and inflammation in case of TB with or without NAC will be monitored.
Detailed description
TB and AIDS are also diseases that occur with a chronic inflammatory stimulus, with constant formation of excessive free radicals, leading to cellular and systemic oxidative stress. The effects of NAC in both populations are studied. A study demonstrated that HIV-positive individuals have low levels of glutathione in CD4+ T lymphocytes when compared to healthy controls, these levels being restored after in vivo supplementation with NAC, favoring the production of cytokines involved in Th1 response. They also observed that glutathione depletion in lymphocytes was correlated with increased levels of tumor necrosis factor and free radicals. Some authors suggested that the immune system's inability of HIV-positive individuals (or not) in containing Mycobaterium tuberculosis (Mtb) may be a consequence of low levels of glutathione in macrophages. The same occurred in a model of animals infected with Mtb, suggesting that oxidative stress was partly due to the poor antioxidant defense of the host. NAC supplementation decreases the bacterial load on the spleen and the severity of necrosis in the lung. The balance between oxidative and antioxidant substances plays a critical role in the induction of IL-12 production involved in the Th1 response and suggests that the use of NAC may be useful for better immune control of TB. Additional benefits of NAC in individuals with TB are related to the possible protective effect of hepatic to tuberculostatic drugs and to the direct antimicrobial effect demonstrated in vitro. Some authors suggest that the restoration of glutathione levels reversed the loss of innate immunity functions, pointing to a new mechanism of control of Mtb and a possible complement to antiretroviral treatment. This clinical trial will be undertaken in the Amazonas State (Western Brazilian Amazon), in Manaus, at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. It is a prospective, open-label, 2-arm, randomized clinical trial. Twenty-five patients will be enrolled in each treatment arm. A total number of 50 patients should be enrolled. Patients hospitalized in the ICU, in the wards or emergency room of the tertiary unit care will be invited to participate in this study. The assessment schedule will be done in days 1, 7, 14, 28, 42, 56, 120 and 180 (in addition, patient will be asked to come back to the health centre if symptoms occurs at any time). Sputum and blood collection and medical evaluation will be performed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| RIPE (2m) and RI (4m) | Active comparator | Drug: RIPE (2m) and RI (4m)The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (combined fixed dose tablet according to the weight) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. |
| RIPE+NAC (2m) and RI (4m) | Experimental | Drug: RIPE+NAC (2m) and RI (4m)The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (combined fixed dose tablet according to the weight) plus N-acetylcysteine (NAC) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. The NAC is administered by means of effervescent tablet 1200 mg (two sachets of 600 mg) to be diluted in 200ml of water and administered in a 12-hour interval. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age greater than or equal to 18 years;
- Acceptance of the HIV test;
- Forecast of hospital stay of more than twenty-four hours;
- Clinical and laboratory indication of RIPE;
- Conditions for puncture of venous access;
Key exclusion criteria (12 listed)
- Brazilian indigenous people;
- People the refuse to perform HIV test;
- Pregnant women, nursing mothers or pregnant women,
- Extra pulmonary TB, without pulmonary involvement;
- Not be able to perform the collection of sputum or tracheal aspirate for microbiological confirmation;
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 |
|---|---|---|
| RIPE (2m) and RI (4m)Rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months | Drug | RIPE (2m) and RI (4m) |
| RIPE+NAC (2m) and RI (4m)Rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) plus oral N-acetylcysteine (NAC) 1200 mg (600mg twice daily) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months | Drug | RIPE+NAC (2m) and RI (4m) |
Primary outcome
Number of participants with any biological intolerability or adverse event
Time frame: 6 months
This evaluation will be done by the physician along all the follow-up of the study
3 secondary outcomes
Number of patients in the NAC treatment arm with shorter sputum smear conversion time and culture
Time frame: Until week 8
Number of patients presenting tuberculostatic drug-related hepatotoxicity
Time frame: 6 months
Dosage of inflammatory cytokines
Time frame: 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2019.
- Individual participant dataSharing planned: No
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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.
Marcelo C dos Santos, MD, PhD principal investigator
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Bruno B Andrade, MD, PhD principal investigator
Fundação Osvaldo Cruz Bahia
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 RIPE (2m) and RI (4m) and RIPE+NAC (2m) and RI (4m) in people with Tuberculosis, Pulmonary and HIV/AIDS, run by Fundação de Medicina Tropical Dr. Heitor Vieira Dourado at 1 site in Brazil.
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 5 inclusion and 12 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: status not confirmed, as of the sponsor's last update on 15 Feb 2019. 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 Brazil. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Izabella P Safe, MD ((+55 92) 2127 3498, izabellasafe@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with any biological intolerability or adverse event (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 15 Feb 2019.