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Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes (SOUTH)

Primary Purpose

AIDS With Tuberculosis

Status

Unknown status

Phase

Phase 4

Locations

Uganda

Study Type

Interventional

Intervention

Rifampicin, Isoniazid, Ethambutol, Pyrazinamide

About this trial

This is an interventional treatment trial for AIDS With Tuberculosis focused on measuring HIV, Tuberculosis, Antituberculosis drugs

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Evidence of a personally signed and dated informed consent
Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Age of ≥18 years
First episode of pulmonary TB i.e. proven or highly suspected TB considered for TB treatment qualifying for 6 months anti-Tb drugs regimen
Confirmed HIV-1 infection

Exclusion Criteria:

Unable to provide informed consent
Documented or highly suspected TB infection of any organs/systems other than the lung requiring TB treatment longer than 6 months
Previously treated for a mycobacterial infection (TB or atypical mycobacterial infection, active or latent)
Pregnancy or planned pregnancy within the next year
Unwillingness to perform pregnancy test
Decompensated liver disease and/or aminotransferases >5x ULN
GFR < 50 ml/min
Co-morbidities reducing life expectancy to <1 year (e.g. cancer)
Patient wishes to take part in another interventional study

Sites / Locations

Infectious Diseases InstituteRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

anti-tuberculosis drugs

Arm Description

Rifampicin, Isoniazid, Ethambutol, Pyrazinamide tablets 3 to 5 tablets once daily for 2 months followed by Rifampicin, Isoniazid 3 to 5 tablets once daily for 4 months

Outcomes

Primary Outcome Measures

clinical outcome

To investigate the association between serum concentrations of antituberculosis drugs and tuberculosis treatment response in HIV-TB-co-infected individuals.

Secondary Outcome Measures

Cmax

To investigate the steady-state pharmacokinetic parameters of anti-TB drugs at different time-points over the course of TB-treatment

Number of adverse events

To assess the safety and tolerability of anti-TB drugs based on the WHO guidelines

ART trough levels

To correlate the effect of anti-TB drugs on plasma concentrations of efavirenz or protease inhibitors and vice versa.

Isoniazid Cmax

To evaluate the effect of acetylator geno-and phenotype (NAT-2 gene) on isoniazid plasma concentrations and toxicity

Full Information

NCT ID

NCT01782950

First Posted

January 9, 2013

Last Updated

April 10, 2015

Sponsor

Makerere University

1. Study Identification

Unique Protocol Identification Number

NCT01782950

Brief Title

Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes

Acronym

SOUTH

Official Title

Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes in HIV-tuberculosis Co-infected Ugandan Adults

Study Type

Interventional

2. Study Status

Record Verification Date

April 2015

Overall Recruitment Status

Unknown status

Study Start Date

February 2013 (undefined)

Primary Completion Date

March 2016 (Anticipated)

Study Completion Date

March 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Makerere University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Tuberculosis (TB) is a leading cause of death in HIV-infected individuals. There are insufficient data correlating concentrations of anti-TB drugs with treatment response. We hypothesize that sub-therapeutic concentrations of anti-TB drugs are associated with inadequate TB treatment response to Mycobacterium tuberculosis.

Detailed Description

During the study periodic monitoring will be conducted to ensure that the protocol and Good Clinical Practices (GCPs) are being followed.The monitors may review source documents to confirm that the data recorded on CRFs is accurate. The study site may be subject to review by the Institutional Review Board (IRB) and/or appropriate regulatory authorities. A CRF will be completed for each included subject and will be signed by the investigator or by an authorized staff member to attest that the data is true. Any corrections to entries made in the CRFs, source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry. Qualit assurance will as also be performed regularly on the CRFs. The primary end point will be analyzed using Time to event (cure, death, relapse etc)analysis and failure rates and hazard ratios will be calculated accordig to categorical drug concentrations with proposed cutt offs. Secondary end points will be analysed using time to event for occurence of toxicities which will also be corelated to the drug concentrations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

AIDS With Tuberculosis

Keywords

HIV, Tuberculosis, Antituberculosis drugs

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

anti-tuberculosis drugs

Arm Type

Other

Arm Description

Rifampicin, Isoniazid, Ethambutol, Pyrazinamide tablets 3 to 5 tablets once daily for 2 months followed by Rifampicin, Isoniazid 3 to 5 tablets once daily for 4 months

Intervention Type

Drug

Intervention Name(s)

Rifampicin, Isoniazid, Ethambutol, Pyrazinamide

Other Intervention Name(s)

Forecox Trac, and Montozid

Intervention Description

Rifampicin, Isoniazid, Ethambutol, Pyrazinamide: 3, 4 or 5 tablets daily for weight below 55kg, above 55kg or above 70kg respectively for first 2 months followed by Rifampicin, Isoniazid: 3, 4 or 5 tablets daily for patients' weight below 55kg, above 55kg or above 70kg respectively for 4 months

Primary Outcome Measure Information:

Title

clinical outcome

Description

To investigate the association between serum concentrations of antituberculosis drugs and tuberculosis treatment response in HIV-TB-co-infected individuals.

Time Frame

At the end of treatment (6 months after enrolmet)

Secondary Outcome Measure Information:

Title

Cmax

Description

To investigate the steady-state pharmacokinetic parameters of anti-TB drugs at different time-points over the course of TB-treatment

Time Frame

At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation

Title

Number of adverse events

Description

To assess the safety and tolerability of anti-TB drugs based on the WHO guidelines

Time Frame

2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation

Title

ART trough levels

Description

To correlate the effect of anti-TB drugs on plasma concentrations of efavirenz or protease inhibitors and vice versa.

Time Frame

At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation

Title

Isoniazid Cmax

Description

To evaluate the effect of acetylator geno-and phenotype (NAT-2 gene) on isoniazid plasma concentrations and toxicity

Time Frame

At 2 weeks, 8 weeks and 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Evidence of a personally signed and dated informed consent Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Age of ≥18 years First episode of pulmonary TB i.e. proven or highly suspected TB considered for TB treatment qualifying for 6 months anti-Tb drugs regimen Confirmed HIV-1 infection Exclusion Criteria: Unable to provide informed consent Documented or highly suspected TB infection of any organs/systems other than the lung requiring TB treatment longer than 6 months Previously treated for a mycobacterial infection (TB or atypical mycobacterial infection, active or latent) Pregnancy or planned pregnancy within the next year Unwillingness to perform pregnancy test Decompensated liver disease and/or aminotransferases >5x ULN GFR < 50 ml/min Co-morbidities reducing life expectancy to <1 year (e.g. cancer) Patient wishes to take part in another interventional study

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Andrew Kambugu, MMED

Phone

+256-414-307000

Ext

227

akambugu@idi.co.ug

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Barbara Castelnuovo, MD, PhD

Organizational Affiliation

Infectious Diseases Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Infectious Diseases Institute

City

Kampala

ZIP/Postal Code

256

Country

Uganda

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christine Sekaggya, MMed

Phone

+256312307000

Ext

370

csekaggya@idi.co.ug

First Name & Middle Initial & Last Name & Degree

Barbara Castelnuovo, MBChB, PhD

12. IPD Sharing Statement

Citations:

PubMed Identifier

19432554

Citation

Chideya S, Winston CA, Peloquin CA, Bradford WZ, Hopewell PC, Wells CD, Reingold AL, Kenyon TA, Moeti TL, Tappero JW. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis. 2009 Jun 15;48(12):1685-94. doi: 10.1086/599040.

Results Reference

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PubMed Identifier

15844071

Citation

Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B, Silva-Trigo C, Zhao Z, Hodge T; Tuberculosis Trials Consortium. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis. 2005 May 15;40(10):1481-91. doi: 10.1086/429321. Epub 2005 Apr 14.

Results Reference

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PubMed Identifier

15504887

Citation

Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran A, Ravichandran N, Paramesh P. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004 Nov;48(11):4473-5. doi: 10.1128/AAC.48.11.4473-4475.2004.

Results Reference

background

PubMed Identifier

11170964

Citation

Narita M, Hisada M, Thimmappa B, Stambaugh J, Ibrahim E, Hollender E, Ashkin D. Tuberculosis recurrence: multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis. 2001 Feb 1;32(3):515-7. doi: 10.1086/318490. Epub 2001 Jan 25.

Results Reference

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PubMed Identifier

17724157

Citation

Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, Drusano GL. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother. 2007 Nov;51(11):3781-8. doi: 10.1128/AAC.01533-06. Epub 2007 Aug 27.

Results Reference

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PubMed Identifier

30910890

Citation

Sekaggya-Wiltshire C, Chirehwa M, Musaazi J, von Braun A, Buzibye A, Muller D, Gutteck U, Motta I, Calcagno A, Fehr JS, Kambugu A, Castelnuovo B, Lamorde M, Denti P. Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines? Antimicrob Agents Chemother. 2019 May 24;63(6):e02174-18. doi: 10.1128/AAC.02174-18. Print 2019 Jun. Erratum In: Antimicrob Agents Chemother. 2020 Mar 24;64(4):

Results Reference

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PubMed Identifier

29514175

Citation

Sekaggya-Wiltshire C, von Braun A, Lamorde M, Ledergerber B, Buzibye A, Henning L, Musaazi J, Gutteck U, Denti P, de Kock M, Jetter A, Byakika-Kibwika P, Eberhard N, Matovu J, Joloba M, Muller D, Manabe YC, Kamya MR, Corti N, Kambugu A, Castelnuovo B, Fehr JS. Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. Clin Infect Dis. 2018 Aug 16;67(5):708-716. doi: 10.1093/cid/ciy179.

Results Reference

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PubMed Identifier

29162063

Citation

Kwizera R, Parkes-Ratanshi R, Page ID, Sekaggya-Wiltshire C, Musaazi J, Fehr J, Castelnuovo B, Kambugu A, Denning DW. Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis. BMC Pulm Med. 2017 Nov 21;17(1):149. doi: 10.1186/s12890-017-0500-9.

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Citation

Sekaggya-Wiltshire C, Castelnuovo B, von Braun A, Musaazi J, Muller D, Buzibye A, Gutteck U, Henning L, Ledergerber B, Corti N, Lamorde M, Fehr J, Kambugu A. Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study. BMJ Open. 2017 Sep 18;7(9):e014679. doi: 10.1136/bmjopen-2016-014679.

Results Reference

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Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes

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