Impact of Malnutrition on Pharmacokinetic or Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in TB-HIV Co-infected Children

Tuberculosis Clinical Trial

— TB-Speed TB-PK  

Official title:

Impact of Malnutrition on Pharmacokinetic or Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in TB-HIV Co-infected Children

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04972903
• Other study ID #: C20-17
• Status: Not yet recruiting
• Start date: August 2021
• Est. completion date: December 2022

Study information

• Verified date: July 2021
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: Aurelia Vessière, PhD
• Phone: +33 (0)5 57 57 15 35
• Email: aurelia.vessiere[@]u-bordeaux.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

TB-Speed TB-PK is a cross-sectional PK study of anti-TB treatment nested in the TB-Speed HIV and TB-Speed SAM studies aiming at assessing the impact of malnutrition on PK of rifampicin, isoniazid, pyrazinamide, and ethambutol in TB-HIV co-infected children in Uganda and Zambia.

Description:

Tuberculosis can worsen malnutrition and in turn malnutrition increases the risk of TB. HIV infection is prevalent in children with TB and SAM and is often associated with poor outcomes when present. TB alone is the leading cause of death of among HIV-infected children worldwide accounting for a third of all the death in this group.

In 2010, the WHO recommended increased dose for rifampicin (+50%), isoniazid (+100%), and pyrazinamide (+33%) based on PK data showing that plasma drug concentrations in children using standard adult dosages did not reach target levels. In children that are TB/HIV co-infected, drug-drug interactions between anti-TB drugs and antiretroviral drugs are of concern.

The investigators hypothesize that HIV-infection and SAM, each one on its own, may have an impact on TB drugs concentrations. Furthermore, SAM is frequent in children with HIV, and may affect the metabolism of anti-TB drugs and consequently result in low serum concentration.

TB-Speed TB-PK is a cross-sectional PK study of anti-TB treatment nested in the TB-Speed HIV and TB-Speed SAM studies aiming at assessing the impact of malnutrition on PK of rifampicin, isoniazid, pyrazinamide, and ethambutol in TB-HIV co-infected children. It will be implemented in Uganda and Zambia. Children will also be enrolled from routine care for TB outside of the TB- Speed HIV and TB-Speed SAM studies.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 5 Years

Eligibility

INCLUSION CRITERIA:

• Gr1. HIV-infected children with SAM

• Age 6 months to 5 years

• Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion

• HIV-infection

• SAM as defined by WHO at the time of starting TB treatment

• Weight-for-height z-score (WHZ) < -3 SD,

• OR MUAC <11.5 cm or

• OR presence of bilateral pitting oedema of nutritional origin

• Ability to take drugs orally during the planned PK day

• Signed informed consent from parents or guardian

• Gr2. HIV-infected children without SAM

• Age 6 months to 5 years

• Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion

• HIV-infection

• Absence of SAM as defined by WHO at the time of starting TB treatment

• Weight-for-height z-score (WHZ) > -3 SD,

• AND MUAC >11.5 cm or

• AND absence of bilateral pitting oedema of nutritional origin

• Ability to take drugs orally during the planned PK day

• Signed informed consent from parents or guardian

• Gr3. HIV-negative children with SAM

• Age 6 months to 5 years

• Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion

• HIV-negative

• SAM as defined by WHO at the time of starting TB treatment

• Weight-for-height z-score (WHZ) < -3 SD,

• OR MUAC <11.5 cm or

• OR presence of bilateral pitting oedema of nutritional origin

• Ability to take drugs orally during the planned PK day

• Signed informed consent from parents or guardian

• Gr4. HIV-negative children without SAM

• Age 6 months to 5 years

• Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion

• HIV-negative

• Absence of SAM as defined by WHO at the time of starting TB treatment

• Weight-for-height z-score (WHZ) > -3 SD,

• AND MUAC >11.5 cm or

• AND absence of bilateral pitting oedema of nutritional origin

• Ability to take drugs orally during the planned PK day

NON INCLUSION CRITERIA:

• Very ill or moribund children unable to take drugs orally or requiring nasogastric drug intake

• Severe anaemia (Hb < 6 g/dl),

• Severe renal impairment (DAIDS grade 3 and above)

• Severe hepatic impairment (DAIDS grade 3 and above)

• Children on second line TB drugs

Related Conditions & MeSH terms

• Malnutrition
• Tuberculosis

Locations

Country	Name	City	State
Uganda	Mulago National Referral Hospital	Kampala
Uganda	Mbarara Regional Hospital	Mbarara
Zambia	The University Teaching Hospital	Lusaka
Zambia	Arthur Davison Children Hospital	Ndola

Sponsors (2)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France	National Agency for Research on AIDS and Viral Hepatitis (ANRS)

Countries where clinical trial is conducted

Uganda,  Zambia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect of SAM on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB	Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol peak concentration (Cmax)	6 months
Primary	Effect of SAM on minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB	Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol minimum concentration (Cmin or C trough)	6 months
Primary	Effect of SAM on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB	Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol exposure (Area Under the Curve - AUC)	6 months
Secondary	Effect of HIV-infection and antiretroviral treatment on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM	Cmax of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection	6 months
Secondary	Effect of HIV-infection and antiretroviral treatment on Minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM	Cmin of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection	6 months
Secondary	Effect of HIV-infection and antiretroviral treatment on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM	AUC of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection	6 months
Secondary	WHO-based dosages will achieve rifampicin, isoniazid, pyrazinamide, and ethambutol drug concentrations above the target therapeutic concentrations in HIV-TB co-infected children with and without SAM	Proportion of children with AUC24 and Cmax above the recommended threshold for Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol	6 months
Secondary	Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on CL/F of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	CL/F(Apparent total clearance of the drug from plasma) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Secondary	Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on V/F of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	V/F (Apparent volume of distribution after administration) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Secondary	Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on Ka of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	Ka (Absorption rate constant) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Secondary	Relationship between all-cause mortality in children with TB and SAM, and Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best Cmax plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Secondary	Relationship between all-cause mortality in children with TB and SAM, and the minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best Cmin plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Secondary	Relationship between all-cause mortality in children with TB and SAM, and Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best AUC plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Secondary	Rifampicin protein binding in relation with malnutrition and albuminemia	Proportion of protein bound rifampicin in children with SAM and association with albuminemia	6 months

External Links

•   TB-Speed project official website