ER Niacin/Laropiprant Impact on Cardiovascular Markers and Atheroprogression in HIV-infected Individuals on cART

HIV Clinical Trial

— NILACH  

Official title:

ER Niacin/Laropiprant Impact on Cardiovascular Markers and Atheroprogression in HIV-infected Individuals on cART

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01683656
• Other study ID #: NILACH 2012DR4097
• Status: Terminated
• Phase: Phase 4
• Start date: August 2012
• Est. completion date: July 2014

Study information

• Verified date: October 2019
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

HIV-infected patients are at increased risk for cardiovascular disease. Large investigations support an inverse correlation between HDL-C levels and coronary heart disease. Therefore a treatment lowering HDL-C such as niacin could reduce the risk of atheroprogression not only through its benefit in terms of lipid profile, but also by reducing atherosclerotic inflammation.

The study aims at showing that a therapy targeting HDL-C increase in HIV-infected patients on suppressive cART has the potential for reducing subclinical atherosclerotic inflammation associated with HIV itself in HIV-individuals on cART.

NILACH is a randomised, multicenter, double blind, placebo controlled, 48 weeks trial to test the effect of the newly marketed niacin/laropiprant on carotid intima-media thickness (IMT) in 90 subjects.

• Regimen 1: ER niacin/laropiprant 1g/20 mg for the first 4 weeks and 2g/40mg from week 5 to the end of the study (the titration aims to reduce adverse reactions)

• Regimen 2: ER niacin/laropiprant placebo p.m.

The primary end point is the change in mean common carotid intima-media thickness from baseline and 48 weeks, compared between the niacin/laropiprant group and the placebo group.

The proposed in vivo experiments should provide insights on the potential benefits of niacin treatment of cardiovascular disease in HIV patients. In addition, we will be able to further clarify the role of systemic inflammatory mediators in the development of early atherosclerosis of HIV-infected patients on antiretroviral therapy. Detection and treatment of non-infectious co-morbidities such as cardiovascular diseases have become essential for HIV-infected individuals exposed to lifelong antiretroviral therapy and go beyond mere management of opportunistic infections or virologic suppression.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Adult patients > 40 years;

• Women of childbearing potential must use two reliable contraceptive methods during the entire trial, from day 1 to one month after the end of the trial.

• Signing the study consent form;

• Stable cART since at least 3 months (ie no recent drug change);

• HIV-RNA below 100 copies for at least 6 months;

• HDL-cholesterol <1.29 mmol/l for men; <1.42 mmol/l for women

Exclusion Criteria:

• Pregnancy or lactation;

• Congestive Heart Failure;

• Malignant Hypertension;

• Acute or chronic coronary artery diseases;

• Any known cardiac arrhythmias;

• Diabetes;

• Concomitant cancer, rheumatologic disease or inflammatory bowel diseases;

• Concomitant renal or hepatic disease:

• Creatinine above 150 micromol/L

• Transaminases above 5 times upper normal limit

• Prothrombin time (Quick) value below 50%;

• Prior intolerance to niacin therapy (reported in a medical report);

• Cyclosporine, anti-inflammatory drugs (other than aspirin) or cytokine therapy in concomitant intake;

• Abnormal thyroid function;

• Excessive consumption of alcohol;

• Known severe lactose intolerance.

Related Conditions & MeSH terms

• Atherosclerosis
• HIV

Intervention

Drug:
• niacin/laropiprant

• Placebo
Procedures for the manufacturing and testing of the placebo are compiled in the IMP/study drug dossier and comply with local regulatory requirements (by GMP certified manufacturer).

Locations

Country	Name	City	State
Switzerland	University Hospital Basel	Basel	BS
Switzerland	University Hospital Berne Inselspital	Berne	BE
Switzerland	University Hospitals Genève	Geneva	GE
Switzerland	CHUV Cantonal University Hospital Vaud	Lausanne	VD
Switzerland	EOC Ente Ospedaliero Cantonale, civico	Lugano	TI
Switzerland	Kantonsspital St Gallen	St Gallen	SG
Switzerland	University Hospital Zurich	Zurich	ZH

Sponsors (5)

Lead Sponsor	Collaborator
Calmy Alexandra	Fondation Ernest Boninchi, Swiss Heart Foundation, Swiss National Science Foundation, University Hospital, Geneva

Country where clinical trial is conducted

Switzerland, 

References & Publications (25)

Baker J, Ayenew W, Quick H, Hullsiek KH, Tracy R, Henry K, Duprez D, Neaton JD. High-density lipoprotein particles and markers of inflammation and thrombotic activity in patients with untreated HIV infection. J Infect Dis. 2010 Jan 15;201(2):285-92. doi: 10.1086/649560. — View Citation

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Calmy A, Gayet-Ageron A, Montecucco F, Nguyen A, Mach F, Burger F, Ubolyam S, Carr A, Ruxungtham K, Hirschel B, Ananworanich J; STACCATO Study Group. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS. 2009 May 15;23(8):929-39. — View Citation

Chow DC, Stein JH, Seto TB, Mitchell C, Sriratanaviriyakul N, Grandinetti A, Gerschenson M, Shiramizu B, Souza S, Shikuma C. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010 Apr 24;24(7):1019-23. doi: 10.1097/QAD.0b013e3283383016. — View Citation

Currier JS, Kendall MA, Henry WK, Alston-Smith B, Torriani FJ, Tebas P, Li Y, Hodis HN. Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults. AIDS. 2007 May 31;21(9):1137-45. — View Citation

de Saint Martin L, Vandhuick O, Guillo P, Bellein V, Bressollette L, Roudaut N, Amaral A, Pasquier E. Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study). Atherosclerosis. 2006 Apr;185(2):361-7. Epub 2005 Aug 30. — View Citation

Dubé MP, Wu JW, Aberg JA, Deeg MA, Alston-Smith BL, McGovern ME, Lee D, Shriver SL, Martinez AI, Greenwald M, Stein JH; AIDS Clinical Trials Group A5148 Study Team. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. Antivir Ther. 2006;11(8):1081-9. — View Citation

Gotto AM Jr. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J. 2002 Dec;144(6 Suppl):S33-42. Review. — View Citation

Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21;352(16):1685-95. Review. — View Citation

Kush D, Hu DY, Ye P, Kim HS, Chen E, Sirah W, McCrary Sisk C, Paolini JF, Maccubbin D. Flushing profile of extended-release niacin/laropiprant at initiation of therapy in Asian lipid clinic patients. Cardiology. 2009;114(3):192-8. doi: 10.1159/000228585. Epub 2009 Jul 15. — View Citation

Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, Vernazza P, Sudre P, Flepp M, Furrer H, Francioli P, Weber R. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet. 1999 Mar 13;353(9156):863-8. — View Citation

Maggi P, Serio G, Epifani G, Fiorentino G, Saracino A, Fico C, Perilli F, Lillo A, Ferraro S, Gargiulo M, Chirianni A, Angarano G, Regina G, Pastore G. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS. 2000 Nov 10;14(16):F123-8. — View Citation

Mercié P, Thiébaut R, Lavignolle V, Pellegrin JL, Yvorra-Vives MC, Morlat P, Ragnaud JM, Dupon M, Malvy D, Bellet H, Lawson-Ayayi S, Roudaut R, Dabis F. Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement. Ann Med. 2002;34(1):55-63. — View Citation

Montecucco F, Mach F. Update on statin-mediated anti-inflammatory activities in atherosclerosis. Semin Immunopathol. 2009 Jun;31(1):127-42. doi: 10.1007/s00281-009-0150-y. Epub 2009 May 5. Review. — View Citation

Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD; HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006 Sep;43(1):27-34. — View Citation

Paolini JF, Bays HE, Ballantyne CM, Davidson M, Pasternak R, Maccubbin D, Norquist JM, Lai E, Waters MG, Kuznetsova O, Sisk CM, Mitchel YB. Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors. Cardiol Clin. 2008 Nov;26(4):547-60. Review. — View Citation

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Stein EA. Additional lipid lowering trials using surrogate measurements of atherosclerosis by carotid intima-media thickness: more clarity or confusion? J Am Coll Cardiol. 2008 Dec 16;52(25):2206-9. doi: 10.1016/j.jacc.2008.11.002. — View Citation

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Sterne JA, May M, Bucher HC, Ledergerber B, Furrer H, Cavassini M, Bernasconi E, Hirschel B, Egger M; Swiss HIV Cohort. HAART and the heart: changes in coronary risk factors and implications for coronary risk in men starting antiretroviral therapy. J Intern Med. 2007 Mar;261(3):255-67. — View Citation

Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26;361(22):2113-22. doi: 10.1056/NEJMoa0907569. Epub 2009 Nov 15. — View Citation

Thoenes M, Oguchi A, Nagamia S, Vaccari CS, Hammoud R, Umpierrez GE, Khan BV. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract. 2007 Nov;61(11):1942-8. — View Citation

van Vonderen MG, Hassink EA, van Agtmael MA, Stehouwer CD, Danner SA, Reiss P, Smulders Y. Increase in carotid artery intima-media thickness and arterial stiffness but improvement in several markers of endothelial function after initiation of antiretroviral therapy. J Infect Dis. 2009 Apr 15;199(8):1186-94. doi: 10.1086/597475. — View Citation

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	change in mean common carotid intima-media thickness	mean of maximal IMT value will be calculated over three cardiac cycles and for left and right carotid artery at baseline and week 48. The primary endpoint will be assessed by a single investigator in a blinded and anonymized fashion at cIMT Core Facility, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada Responsible: Pr Jean-Claude Tardif.	48 weeks
Secondary	Mean hs-CRP plasma concentration changes		12, 24, 48 weeks
Secondary	Mean Total Cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, apolipoprotein, triglycerides, and apolipoprotein (apo) Al, B and E levels		12, 24, 48 weeks
Secondary	Mean biomarkers of inflammatory process (fibrinogen, S-VCAM-1, adiponectin, CCL2, CCL3, d-dimer, IL-6, TNF-alpha, Lp-PLA2) changes		12, 24, 48 weeks
Secondary	Clinical MACE: cardiovascular mortality, stroke, acute coronary syndromes, any cardiac arrhythmias, hospitalisation for cardiovascular causes, peripheral artery disease, revascularization.		one year