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High Dose Oral Rifampicin to Improve Survival from Adult Tuberculous Meningitis: a pharmacokinetic substudy (HARVEST-PK)

Award Number: R01AI177101
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/22/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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High Dose Oral Rifampicin to Improve Survival from Adult Tuberculous Meningitis: a pharmacokinetic substudy (HARVEST-PK) - PROJECT SUMMARY Tuberculous meningitis (TBM) causes death or neurological disability in up to 50% of those affected and is particularly devastating in people living with HIV (PLHIV). There is an urgent need to improve therapy as current first-line TBM treatment, including standard dose rifampin (10 mg/kg daily), results in low concentrations in the Central Nervous System (CNS). In HARVEST, a phase III trial in Uganda, South Africa, and Indonesia, we currently test whether high dose (35 mg/kg) rifampin will reduce mortality and disability compared to standard dose (10 mg/kg) rifampin in people with TBM. HARVEST will answer key clinical research questions, but important knowledge gaps are not directly addressed. There is scanty data on exposure to first-line TB drugs in the CNS and the extent to which this is influenced by brain injury and inflammation and drug transport mechanisms. Optimal targets for drug exposure are lacking and it is unknown whether patient subgroups, such as PLHIV, critically ill patients or pediatric patients, require tailored doses of TB drugs. It is also unknown whether higher doses of rifampin require a change in dose of co-administered antiretroviral drugs in PLHIV. We propose HARVEST-PK to test our central hypothesis that plasma and CNS concentrations of TB drugs are the key intermediary link between administered doses and disease outcome. We will measure concentrations of TB/HIV drugs as well as inflammatory and brain injury markers in carefully timed and collected samples from HARVEST and apply state-of-the-art modelling and simulation techniques to build a comprehensive exposure- response model that will fill aforementioned knowledge gaps. More specifically, we will define the relationship between administered doses and concentrations achieved (pharmacokinetics, PK), identify predictors of TB drug exposure and CNS drug entry, and elucidate the relationship between TB drug concentrations achieved and response (pharmacodynamics, PD). HARVEST-PK will determine critical exposure thresholds associated with improved TBM survival and identify corresponding optimal drug doses in adult TBM patients and patient subgroups. Finally, HARVEST-PK aims to demonstrate that high dose rifampin compared to standard dose rifampin does not significantly compromise exposure to anti-retroviral drugs, and does not impact virological outcomes in TBM patients living with HIV. HARVEST-PK uniquely leverages our existing phase III TBM trial to gain key pharmacological insight in the PK-PD of TB drugs in TBM treatment. This will result in the identification of optimal exposure targets for high dose rifampin and other drugs in adults and children with TBM. Members of our consortium have studied TBM in Asia and Africa for more than 15 years and we have a longstanding interest in optimization of TBM treatment based on PK and PD principles. HARVEST-PK will enable optimal dosing recommendations based on PK and PK-PD evaluations, which seeks to impact U.S. and international treatment guidelines.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $560,902 )
2026	2026	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	000	3	1/2/2026	NON-COMPETING CONTINUATION	$560,902
														Subtotal = $560,902

Issue Date FY: 2025 ( Subtotal = $561,023 )
2025	2025	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	001	2	8/11/2025	NON-COMPETING CONTINUATION	$561,023
2025	2024	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	000	1	10/11/2024	NEW	$0
														Subtotal = $561,023

Issue Date FY: 2024 ( Subtotal = $561,021 )
2024	2024	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	000	1	1/22/2024	NEW	$505,774
2024	2024	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	003	1	9/4/2024	NEW	$55,247
2024	2024	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	002	1	3/11/2024	NEW	$505,774
2024	2024	STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	GEERT GROOTEPLEIN ZUID, 10	NIJMEGEN				NLD	Allergy and Infectious Diseases Research	001	1	2/29/2024	NEW	-$505,774
														Subtotal = $561,021

Grand Total All Awards = $1,682,946

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High Dose Oral Rifampicin to Improve Survival from Adult Tuberculous Meningitis: a pharmacokinetic substudy (HARVEST-PK)

Award Number: R01AI177101

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/22/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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