TuberculosisPhase 3NCT00330304
Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children
A Phase 3 study testing Isoniazid and Cotrimoxazole in people with Tuberculosis, run by University of Cape Town at 2 sites in South Africa.
Trial summary
The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce mortality and infections in HIV-infected children and is currently the recommended standard of care. Read more about this study
- Who is it for?
- Ages 8 weeks to 15 years
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Isoniazid and Cotrimoxazole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 450 participants
- Where
- 2 sitesSouth Africa
- Study dates
- Jan 2003to 15 Nov 2011
- Phase
- Phase 3
- 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 8 weeks to 15 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- HIV-infected children
- Resident in Cape Town
- Informed consent obtainable
- weight > 2.5kg
- Access to transport
- HAART use for not less than 2 months but not more than 12 months with no significant demonstrated toxicity and good adherence
Who cannot join
- Chronic diarrhoea
- Current use of INH prophylaxis
- Prior hypersensitivity to INH prior history of allergy to sulphur drugs
- Prior history of allergy to sulphur drugs
- Severe anaemia (haemoglobin less than 7 gm/dl)
- Neutropenia (absoloute neutrophil count less than 400 cells)
Show all 10Show fewer
- Thrombocytopenia (platelet count < 50 000/uL)
- Non-reversible renal failure
- Clinical hepatitis
- Exposure to household TB contact, requiring INH prophylaxis
Trial locations and contacts
2 sites in 1 country.
South Africa2 sites
Red Cross Childrens Hospital
Cape Town, Western Cape, 7700
Tygerberg Hospital
Cape Town, Western Cape
About this study
Official title: Long Term Study of 2 Isoniazid (INH) Prophylactic Regimens With Concomitant Cotrimoxazole (CTX) in HIV-infected Children - Impact on Morbidity, Mortality, Bacterial Resistance and Incidence of Tuberculosis
The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce mortality and infections in HIV-infected children and is currently the recommended standard of care. However, isoniazid has only been studied in HIV-infected adults (in whom it has been shown to substantially reduce the incidence of tuberculosis). In a randomised controlled study of isoniazid in HIV-infected children, the investigators found that INH reduced mortality and tuberculosis incidence in excess of 50%; the data safety monitoring board recommended termination of the placebo arm given the beneficial effects of INH. The investigators therefore aim to follow-up these children to compare the long term impact of two different INH and CTX preventive regimens (daily versus thrice weekly) on morbidity, mortality, adherence and incidence of adverse reactions. The investigators also aim to investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART as the benefit in this group is unknown.
Read the detailed description
Tuberculosis (TB) and HIV are dual pandemics occurring in South Africa. Prevention of TB and the subsequent decline in immune function in HIV-infected children is an important strategy to reduce mortality. Isoniazid (INH) prophylaxis reduces TB incidence in HIV-infected adults, but the efficacy in HIV-infected children has not been studied. In 2003, the investigators therefore began a double blind placebo controlled trial to investigate the impact of INH prophylaxis on mortality, morbidity and TB incidence in HIV-infected children. Interim analysis found a striking reduction in mortality and TB with a decrease in mortality in excess of 50% and 60% respectively, in children on INH. Based on this, the placebo arm was terminated; the study continued as a trial of thrice versus daily INH and cotrimoxazole (CTX). Although the results indicate an important benefit in children on INH, it is unknown what the long term efficacy and safety of INH prophylaxis is, what the optimal regime is and whether this pertains to children on HAART (who formed a minority of the cohort but who are still at risk for TB).
Aim To investigate the efficacy, safety and tolerability of INH and CTX as prophylactic strategies for HIV-infected children in a high TB prevalence area.
Objectives
- To compare the long term impact of two different INH preventive regimens (daily versus thrice weekly) on TB incidence, occurrence of INH resistance in patients with culture-confirmed TB, mortality, incidence of adverse reactions and adherence
- To compare the long term impact of two different CTX prophylactic regimens (daily versus thrice weekly) on mortality, frequency and duration of hospitalization, type of serious infections, nasopharyngeal carriage of bacteria and development of antimicrobial resistance, adherence and incidence of adverse reactions
- To investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART
Methods A prospective randomized double blind placebo controlled study of INH versus placebo in newly recruited HIV-infected children who are stable on HAART. In addition, an extended follow-up study of children already randomised to thrice weekly or daily INH and CTX. Children will be followed for 2 years with regular clinical evaluation, adherence assessment and laboratory monitoring. Outcomes measured will be mortality, TB incidence, morbidity, adherence and tolerability.
- Conditions
- Tuberculosis
- Being tested
- Isoniazid, Cotrimoxazole, placebo
- Keywords
- Tuberculosis, Child, HIV, prophylaxis, mortality
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IsoniazidDrug
isoniazid 10mg/kg orally, daily, for study period
CotrimoxazoleDrug
Cotrimoxazole given 3 times a week or daily, orally, for study period
isoniazidDrug
Isoniazid, 10mg/kg daily for study period
placeboOther
Placebo tablet identicle in appearance to intervention: isoniazid table
| Study group | Role | What they receive |
|---|---|---|
| Isoniazid preventive therapy | Experimental | HIV infected children living in a high TB prevalence area receive isonaizid prophylaxis daily, together with cotrimoxazole prohpylaxis either 3 times a week or daily. Receives: Drug: Isoniazid; Drug: Cotrimoxazole |
| Placebo | Placebo comparator | HIV infected children living in a high TB prevalence area receive placebo once daily Receives: Drug: Cotrimoxazole; Other: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
TB incidence
Measured: Jan 2003 to July 2011
Mortality
Measured: Jan 2003 to July 2011
Secondary outcomes (4)
intercurrent infections
Measured: Jan 2003 to July 2011
adherence
Measured: Jan 2003 to July 2011
adverse events
Measured: Jan 2003 to July 2011
antimicrobial resistance
Measured: Jan 2003 to July 2011
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2006 (estimated)
- Study startJan 2003
- Primary completion15 Nov 2011
- Study completion15 Nov 2011
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.
- 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 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
- Enrolment
- 450 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cape Town
- Sponsor type
- University, hospital or other
- Collaborators
- University of Stellenbosch, Medical Research Council, Rockefeller Foundation
- Responsible party
- Principal investigator, Heather Zar, University of Cape Town
- Investigators
- Heather J Zar, MD PHd, Principal investigator, University of Cape TownMark Cotton, Md PhD, Principal investigator, University of Stellenbosch
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00330304
- Sponsor's protocol ID
- 299/2005
- Status last verified
- Apr 2019
- First submitted
- 24 May 2006
- Last updated
- 22 Apr 2019
- Results posted
- No
Publications
Amlabu V, Mulligan C, Jele N, Evans A, Gray D, Zar HJ, McIlleron H, Smith P. Isoniazid/acetylisoniazid urine concentrations: markers of adherence to isoniazid preventive therapy in children. Int J Tuberc Lung Dis. 2014 May;18(5):528-30. doi: 10.5588/ijtld.13.0730.
PubMed 24903787Gray DM, Workman LJ, Lombard CJ, Jennings T, Innes S, Grobbelaar CJ, Cotton MF, Zar HJ. Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study. Int J Tuberc Lung Dis. 2014 Mar;18(3):322-7. doi: 10.5588/ijtld.13.0354.
PubMed 24670570Frigati LJ, Kranzer K, Cotton MF, Schaaf HS, Lombard CJ, Zar HJ. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax. 2011 Jun;66(6):496-501. doi: 10.1136/thx.2010.156752. Epub 2011 Apr 2.
PubMed 21460373le Roux SM, Cotton MF, Golub JE, le Roux DM, Workman L, Zar HJ. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Med. 2009 Nov 3;7:67. doi: 10.1186/1741-7015-7-67.
PubMed 19886982Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.
PubMed 17085459
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long Term Study of 2 Isoniazid (INH) Prophylactic Regimens With Concomitant Cotrimoxazole (CTX) in HIV-infected Children - Impact on Morbidity, Mortality, Bacterial Resistance and Incidence of Tuberculosis
- ClinicalTrials.gov ID
- NCT00330304
- Acronym / sponsor ID
- 299/2005
- Conditions
- Tuberculosis
- Keywords
- Tuberculosis, Child, HIV, prophylaxis, mortality
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 450 participants (actual)
- Lead sponsor
- University of Cape TownUniversity, hospital or other
- Collaborators
- University of Stellenbosch, Medical Research Council, Rockefeller Foundation
- Study start
- Jan 2003 (actual)
- Primary completion
- 15 Nov 2011 (actual)
- Study completion
- 15 Nov 2011 (actual)
- First posted
- 26 May 2006 (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.
The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce mortality and infections in HIV-infected children and is currently the recommended standard of care. However, isoniazid has only been studied in HIV-infected adults (in whom it has been shown to substantially reduce the incidence of tuberculosis). In a randomised controlled study of isoniazid in HIV-infected children, the investigators found that INH reduced mortality and tuberculosis incidence in excess of 50%; the data safety monitoring board recommended termination of the placebo arm given the beneficial effects of INH. The investigators therefore aim to follow-up these children to compare the long term impact of two different INH and CTX preventive regimens (daily versus thrice weekly) on morbidity, mortality, adherence and incidence of adverse reactions. The investigators also aim to investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART as the benefit in this group is unknown.
Detailed description
Tuberculosis (TB) and HIV are dual pandemics occurring in South Africa. Prevention of TB and the subsequent decline in immune function in HIV-infected children is an important strategy to reduce mortality. Isoniazid (INH) prophylaxis reduces TB incidence in HIV-infected adults, but the efficacy in HIV-infected children has not been studied. In 2003, the investigators therefore began a double blind placebo controlled trial to investigate the impact of INH prophylaxis on mortality, morbidity and TB incidence in HIV-infected children. Interim analysis found a striking reduction in mortality and TB with a decrease in mortality in excess of 50% and 60% respectively, in children on INH. Based on this, the placebo arm was terminated; the study continued as a trial of thrice versus daily INH and cotrimoxazole (CTX). Although the results indicate an important benefit in children on INH, it is unknown what the long term efficacy and safety of INH prophylaxis is, what the optimal regime is and whether this pertains to children on HAART (who formed a minority of the cohort but who are still at risk for TB).
Aim To investigate the efficacy, safety and tolerability of INH and CTX as prophylactic strategies for HIV-infected children in a high TB prevalence area.
Objectives
- To compare the long term impact of two different INH preventive regimens (daily versus thrice weekly) on TB incidence, occurrence of INH resistance in patients with culture-confirmed TB, mortality, incidence of adverse reactions and adherence
- To compare the long term impact of two different CTX prophylactic regimens (daily versus thrice weekly) on mortality, frequency and duration of hospitalization, type of serious infections, nasopharyngeal carriage of bacteria and development of antimicrobial resistance, adherence and incidence of adverse reactions
- To investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART
Methods A prospective randomized double blind placebo controlled study of INH versus placebo in newly recruited HIV-infected children who are stable on HAART. In addition, an extended follow-up study of children already randomised to thrice weekly or daily INH and CTX. Children will be followed for 2 years with regular clinical evaluation, adherence assessment and laboratory monitoring. Outcomes measured will be mortality, TB incidence, morbidity, adherence and tolerability.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Isoniazid preventive therapy | Experimental | Drug: Isoniazid, Drug: CotrimoxazoleHIV infected children living in a high TB prevalence area receive isonaizid prophylaxis daily, together with cotrimoxazole prohpylaxis either 3 times a week or daily. |
| Placebo | Placebo comparator | Drug: Cotrimoxazole, Other: placeboHIV infected children living in a high TB prevalence area receive placebo once daily |
Who may qualify
- Ages
- 8 weeks to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- HIV-infected children
- Resident in Cape Town
- Informed consent obtainable
- weight > 2.5kg
- Access to transport
Key exclusion criteria (10 listed)
- Chronic diarrhoea
- Current use of INH prophylaxis
- Prior hypersensitivity to INH prior history of allergy to sulphur drugs
- Prior history of allergy to sulphur drugs
- Severe anaemia (haemoglobin less than 7 gm/dl)
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 |
|---|---|---|
| Isoniazidisoniazid 10mg/kg orally, daily, for study period | Drug | Isoniazid preventive therapy |
| CotrimoxazoleCotrimoxazole given 3 times a week or daily, orally, for study period | Drug | Isoniazid preventive therapy, Placebo |
| isoniazidIsoniazid, 10mg/kg daily for study period | Drug | Isoniazid preventive therapy |
| placeboPlacebo tablet identicle in appearance to intervention: isoniazid table | Other | Placebo |
Primary outcome
TB incidence
Time frame: Jan 2003 to July 2011
Mortality
Time frame: Jan 2003 to July 2011
4 secondary outcomes
intercurrent infections
Time frame: Jan 2003 to July 2011
adherence
Time frame: Jan 2003 to July 2011
adverse events
Time frame: Jan 2003 to July 2011
antimicrobial resistance
Time frame: Jan 2003 to July 2011
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 22 Apr 2019.
- Derived from this study: PubMed 24903787Amlabu V, Mulligan C, Jele N, Evans A, Gray D, Zar HJ, McIlleron H, Smith P. Isoniazid/acetylisoniazid urine concentrations: markers of adherence to isoniazid preventive therapy in children. Int J Tuberc Lung Dis. 2014 May;18(5):528-30. doi: 10.5588/ijtld.13.0730.
- Derived from this study: PubMed 24670570Gray DM, Workman LJ, Lombard CJ, Jennings T, Innes S, Grobbelaar CJ, Cotton MF, Zar HJ. Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study. Int J Tuberc Lung Dis. 2014 Mar;18(3):322-7. doi: 10.5588/ijtld.13.0354.
- Derived from this study: PubMed 21460373Frigati LJ, Kranzer K, Cotton MF, Schaaf HS, Lombard CJ, Zar HJ. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax. 2011 Jun;66(6):496-501. doi: 10.1136/thx.2010.156752. Epub 2011 Apr 2.
- Derived from this study: PubMed 19886982le Roux SM, Cotton MF, Golub JE, le Roux DM, Workman L, Zar HJ. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Med. 2009 Nov 3;7:67. doi: 10.1186/1741-7015-7-67.
- Derived from this study: PubMed 17085459Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.
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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.
Heather J Zar, MD PHd principal investigator
University of Cape Town
Mark Cotton, Md PhD principal investigator
University of Stellenbosch
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Isoniazid and Cotrimoxazole in people with Tuberculosis, run by University of Cape Town at 2 sites in South Africa.
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 6 inclusion and 10 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 22 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in South Africa. 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. Some participants in this study may receive a placebo. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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?
TB incidence (time frame: Jan 2003 to July 2011). The study lists 2 primary outcomes in all. 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 NCT00330304, 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 22 Apr 2019.