Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes

AIDS With Tuberculosis Clinical Trial

— SOUTH  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01782950
• Other study ID #: IDI
• Status: Recruiting
• Phase: Phase 4
• First received: January 9, 2013
• Last updated: April 10, 2015
• Start date: February 2013
• Est. completion date: March 2016

Study information

• Verified date: April 2015
• Source: Makerere University
• Contact: Andrew Kambugu, MMED
• Phone: +256-414-307000
• Email: akambugu[@]idi.co.ug
• Is FDA regulated: No
• Health authority: Uganda: National Council for Science and TechnologyUganda: National Drug AuthorityUganda: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• AIDS With Tuberculosis
• Tuberculosis

Intervention

Drug:
• Rifampicin, Isoniazid, Ethambutol, Pyrazinamide
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

Locations

Country	Name	City	State
Uganda	Infectious Diseases Institute	Kampala

Sponsors (1)

Lead Sponsor	Collaborator
Makerere University

Country where clinical trial is conducted

Uganda, 

References & Publications (5)

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. — View 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. Epub 2007 Aug 27. — View 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. — View 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. Epub 2001 Jan 25. — View 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. Epub 2005 Apr 14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	clinical outcome	To investigate the association between serum concentrations of antituberculosis drugs and tuberculosis treatment response in HIV-TB-co-infected individuals.	At the end of treatment (6 months after enrolmet)	No
Secondary	Cmax	To investigate the steady-state pharmacokinetic parameters of anti-TB drugs at different time-points over the course of TB-treatment	At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation	No
Secondary	Number of adverse events	To assess the safety and tolerability of anti-TB drugs based on the WHO guidelines	2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation	Yes
Secondary	ART trough levels	To correlate the effect of anti-TB drugs on plasma concentrations of efavirenz or protease inhibitors and vice versa.	At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation	No
Secondary	Isoniazid Cmax	To evaluate the effect of acetylator geno-and phenotype (NAT-2 gene) on isoniazid plasma concentrations and toxicity	At 2 weeks, 8 weeks and 24 weeks	Yes