Intracellular boosting of human immunodeficiency virus (HIV) protease inhibitors

ISRCTN	ISRCTN76548641
DOI	https://doi.org/10.1186/ISRCTN76548641
Clinical Trials Information System (CTIS)	2008-002627-90
Protocol serial number	3589
Sponsor	Royal Liverpool and Broadgreen University Hospitals Trust (UK)
Funder	National Institute of Health Research (NIHR) Biomedical Research Centre at Royal Liverpool and Broadgreen University Hospitals Trust (UK)

Submission date: 15/09/2008
Registration date: 13/11/2008
Last edited: 21/05/2014

Recruitment status: Stopped
Overall study status: Stopped
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

http://www.nres.nhs.uk/researchsummaries/?entryid29=177620&q=0~intracellular+boosting~

Contact information

Dr Saye Khoo
Scientific

University of Liverpool
Pharmacology Research Labs
1st Floor, Block H
70 Pembroke Place
Liverpool
L69 3GF
United Kingdom

Study information

Primary study design	Interventional
Study design	A single centre, prospective, randomised open-labelled crossover study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Intracellular boosting of human immunodeficiency virus (HIV) protease inhibitors through inhibition of transport: a novel strategy for potentiating HIV therapy
Study objectives	The intracellular accumulation of the HIV protease inhibitor lopinavir may be pharmacologically enhanced in-vivo through inhibition of drug transporters using dipyridamole and furosemide.
Ethics approval(s)	Liverpool (Adult) Research Ethics Committee, 07/07/2008, ref: 08/H1005/64
Health condition(s) or problem(s) studied	Human immunodeficiency virus (HIV) pharmacology
Intervention	During the study period, patients will continue to take their normal antiretroviral therapy including lopinavir. Following screening subjects will attend at study visit 1 for a 12 hour pharmacokinetic assessment. Subjects will return the next day for study visit 2 and receive a stat dose of either furosemide 40 mg or dipyridamole modified release (Persantin®; Retard) 200 mg followed by a 12 hour pharmacokinetic assessment. After a 7 day washout period, subjects will return for study visit 3 and receive a stat dose of either furosemide 40 mg or dipyridamole MR 200 mg followed by a 12 hour pharmacokinetic assessment. After a 7 day washout period subjects will return for study visit 4 and receive stat doses of both furosemide 40 mg and dipyridamole MR 200 mg followed by a 12 hour pharmacokinetic assessment. Following a 7 day washout period subjects will attend for a clinical assessment (study visit 4). Updated 21/05/2014: this trial was stopped early on 29/02/2012 due to slow recruitment and safety concerns.
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Lopinavir, furosemide, dipyridamole
Primary outcome measure(s)	A change in cellular accumulation ratio (CAR) of lopinavir following treatment with dipyridamole and/or furosemide. CAR will be calculated as a ratio of intracellular and plasma area under curve (AUC) of lopinavir. The outcomes will be measured at the study visits 1, 2, 3 and 4 by pharmacokinetic assessment. Serial blood specimens will be obtained at trough, 1, 2, 4, 8, 12 hours post lopinavir dose.
Key secondary outcome measure(s)	1. Absolute change in plasma AUC 2. Absolute change in intracellular AUC 3. Safety and tolerability of furosemide and dipyridamole 4. Correlation between drug transporter expression on peripheral blood mononuclear cells (PBMCs) at baseline and 4.1. Intracellular drug exposure 4.2. Intracellular boosting effect of furosemide and/or dipyridamole 4.3. Polymorphisms in host genotype of transporter The outcomes will be measured at the study visits 1, 2, 3 and 4 by pharmacokinetic assessment. Serial blood specimens will be obtained at trough, 1, 2, 4, 8, 12 hours post lopinavir dose.
Completion date	01/10/2010
Reason abandoned (if study stopped)	Participant recruitment issue

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	18
Key inclusion criteria	1. The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements 2. Male or female patients 3. Aged 18 years and above 4. HIV positive
Key exclusion criteria	1. History of drug sensitivity or drug allergy to lopinavir, ritonavir, furosemide or dipyridamole 2. Aged less than 18 years 3. Pregnant or lactating women 4. CD4 less than 100 x 10^6 L 5. Viral load greater than 5000 copies 6. Anaemia (haemoglobin [Hb] less than 10.0 g/dl) 7. Severe coronary artery disease 8. Unstable angina 9. Recent myocardial infarction or haemodynamic instability 10. Hypovolaemia or dehydration 11. Renal dysfunction (estimated glomerular filtration rate [eGFR] less than 70 ml/min/1.73 m^2) 12. Severe hypokalaemia (K+ less than 3.0 mmol/l) 13. Severe hyponatraemia (Na+ less than 130 mmol/l) 14. Men with symptomatic urinary outflow obstruction 15. Severe hypotension (systolic less than 100 mmHg or diastolic less than 60 mmHg) 16. Women of childbearing age unless using appropriate contraception 17. Any known bleeding disorders 18. International normalised ratio (INR) less than 1.5 19. Platelets less than 100 x 10^9 L
Date of first enrolment	01/10/2008
Date of final enrolment	01/10/2010

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

University of Liverpool

Liverpool
L69 3GF
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes