Targeting Platelets in Chronic HIV Infection

NCT02578706 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: GCO 14-1374R56HL127995-01
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Advances in antiretroviral therapy (ART) have resulted in increased survival of the HIV-infected population; however, this gain in longevity is associated with an increased risk of cardiovascular disease (CVD). Although ART and traditional risk factors contribute to CVD in this population, heightened markers of immune activation, inflammation, and coagulation independently predict morbidity and mortality, suggesting that dysregulation of these systems plays a significant role in the increased risk of CVD. The investigators believe that platelet activation is an important driver in HIV-associated immune activation, inflammation, and coagulation, leading to an increased CVD pathophysiology and risk. Platelets initiate thrombus formation and also play a key role in vascular inflammation by releasing pro-inflammatory mediators and cross-talking with other relevant cell types including leukocytes. Researchers have described platelet hyperreactivity in chronic HIV infection. Importantly, the investigators demonstrated that one week of anti-platelet therapy (aspirin) decreased platelet activation and immune activation, with an improved trend in inflammation and immune parameters. The overall hypothesis is that platelet activation is a major driver of immune activation, inflammation, and thrombosis in ART-treated HIV infected patients. The purpose of the proposed proof-of-concept study is to understand the mechanism(s) by which anti-platelet therapy improves immune and inflammatory parameters in chronic HIV infection. To test this, the immune modulating and anti-inflammatory effects of 24 weeks of the anti-platelet drug aspirin as compared to the anti-platelet drug clopidogrel will be evaluated. Given their different mechanisms of action and inhibitory potency, the investigators can differentiate whether the potential benefits are mediated via inhibition of arachidonic acid (aspirin) or inhibition of ADP (clopidogrel) or by the antithrombotic activity. A secondary goal is to perform multidimensional assays of platelet activity and thrombogenicity alongside immune activation assays and careful assessments of traditional risk factors and medication regimens, to understand which parameters are highly associated with thrombogenicity.

Conditions

HIV-1 Infection

Keywords

HIV; Aspirin; Clopidogrel; Platelet; Inflammation; Cardiovascular disease; Arachidonic acid; Cyclooxygenase inhibitor; ADP inhibitor; Immune activation; Monocyte; Coagulation; Thrombogenicity

Outcome Measures

Primary Outcomes (1)

• Change in sCD14 From Baseline to Week 24

  Soluble CD14 (sCD14) levels in blood. sCD14 is a nonspecific maker of monocyte activation.

  baseline and 24 weeks

Secondary Outcomes (23)

• Number of Subjects With at Least One Grade 3 or Higher Sign/Symptom or Laboratory Abnormality

  24 weeks

• Change in Classical Monocyte Subsets From Baseline to Week 24

  baseline and 24 weeks

• Change in Intermediate Monocyte Subsets From Baseline to Week 24.

  Baseline and 24 weeks

• Change in Non-classical Monocyte Subsets From Baseline to Week 24

  baseline and 24 weeks

• Change in Monocyte Activation sCD163 From Baseline to Week 24

  baseline and 24 weeks

Study Arms (3)

Aspirin and placebo

ACTIVE COMPARATOR

At week 0, participants will be administered aspirin 81mg (one tablet) and placebo for clopidogrel 75 mg (one tablet) once daily. At week 24, participants will stop both study product tablets.

Drug: Aspirin; Drug: Placebo

Clopidogrel and placebo

ACTIVE COMPARATOR

At week 0, participants will be administered clopidogrel 75 mg (one tablet) and placebo for aspirin 81 mg (one tablet) once daily. At week 24, participants will stop both study product tablets.

Drug: Clopidogrel; Drug: Placebo

Placebos only

PLACEBO COMPARATOR

At week 0, participants will be administered placebo for aspirin 81 mg (one tablet) and placebo for clopidogrel 75mg (one tablet) once daily. At week 24, participants will stop both study product tablets.

Drug: Placebo

Interventions

Clopidogrel DRUG

Clopidogrel 75mg

Also known as: Plavix

Clopidogrel and placebo

Aspirin DRUG

81 mg

Aspirin and placebo

Placebo DRUG

Aspirin and placebo; Clopidogrel and placebo; Placebos only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection
• Currently on continuous ART for ≥48 weeks prior to study entry. NOTE: This is defined as continuous active therapy with no treatment interruption longer than 7 consecutive days and a total duration off-treatment of no more than 14 days during the 48 weeks prior to entry.
• No change in ART regimen within the 12 weeks prior to study entry (except as noted below).
• NOTE: Modifications of ART dosing during the 12 weeks prior to entry are permitted. In addition, the change in formulation (eg, from standard formulation to fixed dose combination or single tablet regimen) or dosing (eg, from once a day to twice a day) is allowed within 12 weeks prior to entry. Within-class single drug substitution (eg, switch from nevirapine to efavirenz or from atazanavir to darunavir), are not allowed within 12 weeks prior to entry. No other changes in ART in the 12 weeks prior to entry are permitted.
• Screening HIV-1 RNA must be \<50 copies/mL and performed by any FDA-approved assay at any US laboratory that has a CLIA certification or its equivalent within 45 days prior to study entry.
• Maintain ART-mediated viral suppression for at least 48 weeks prior to study entry defined as:
• A. At least one HIV-1 RNA test result obtained at any time point greater than 48 weeks prior to study entry must be BLQ and must be performed by any FDA-approved assay at a CLIA-certified laboratory.
• AND B. All HIV-1 RNA tests reported during the 48 weeks prior to study entry must be BLQ and must be performed by any FDA-approved assay at a CLIA-certified laboratory.
• NOTE: A single RNA "blip" of ≤500 copies/mL is permissible if RNA levels most recent before and after (may include the screening HIV-1 RNA test) are BLQ for the assay.
• The following laboratory values obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent.
• Absolute neutrophil count (ANC) ≥750/mm3
• Hemoglobin ≥9.0 g/dL for female subjects and ≥10.0 g/dL for male subjects
• Platelet count \>100,000/mm3
• Prothrombin time (PT) \<1.2 x upper limit normal (ULN)
• Partial thromboplastin time (PTT) \<1.5 x ULN

You may not qualify if:

• Current malignancy (except non-melanoma cancer of the skin not requiring systemic chemotherapy or radiation therapy).
• Prior history of malignancy if the subject is not disease free for 24 or more weeks prior to study entry.
• Current use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin that cannot be interrupted for clinical reasons. Examples of clinical reasons include, but are not limited to, known and documented cardiovascular disease (history of MI, coronary artery bypass graft surgery, percutaneous coronary intervention, stroke, transient ischemic attack, peripheral arterial disease with ABI \<0.9 or claudication).
• Current diagnosis of diabetes with HbA1c ≥8% at screening.
• Use of lipid-lowering medications including: statins, fibrates, niacin (dose ≥250 mg daily), and fish-oil/omega 3 fatty acids (dose \>1000 mg of marine oils daily).
• Known cirrhosis
• Known chronic active hepatitis B NOTE: Active hepatitis B is defined as hepatitis B surface antigen positive and hepatitis B DNA positive within 24 weeks prior to study entry; subjects with hepatitis B virus (HBV) DNA BLQ for greater than 24 weeks prior to study entry are eligible.
• Known chronic active hepatitis C NOTE: Active hepatitis C is defined as a detectable plasma HCV RNA level within 24 weeks prior to study entry; subjects with HCV RNA BLQ for greater than 24 weeks prior to study entry are eligible.
• Known inflammatory conditions, such as, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, inflammatory bowel disease (IBD), chronic pancreatitis, autoimmune hepatitis, Adult Stills disease, Rheumatic heart disease, bursitis.
• Breastfeeding or pregnant
• Previous intolerance or allergy to aspirin or any aspirin products or clopidogrel.
• Frequent use of aspirin or aspirin products (NSAIDs), defined as an average of 2 or more times per week in the last 12 weeks prior to study entry.
• Immunosuppressant use, such as, but not limited to, systemic or potentially systemic glucocorticoids (including injected, ie, intra-articular, nasal or inhaled steroids), azathioprine, tacrolimus, mycophenolate, sirolimus, rapamycin, methotrexate, or cyclosporine within 45 days prior to study entry.
• Use of any systemic antineoplastic or immunomodulatory treatment, investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry.
• NOTE: Routine standard of care, including hepatitis A and/or B, human papilloma virus, influenza, pneumococcal, and tetanus vaccines are permitted if administered at least 7 days before study entry and before biomarker/peripheral blood mononuclear cell (PBMC) blood collections.

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Related Publications (5)

• O'Brien M, Montenont E, Hu L, Nardi MA, Valdes V, Merolla M, Gettenberg G, Cavanagh K, Aberg JA, Bhardwaj N, Berger JS. Aspirin attenuates platelet activation and immune activation in HIV-1-infected subjects on antiretroviral therapy: a pilot study. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):280-8. doi: 10.1097/QAI.0b013e31828a292c.

  PMID: 23406976 BACKGROUND

• Miller EA, Gopal R, Valdes V, Berger JS, Bhardwaj N, O'Brien MP. Soluble CD40 ligand contributes to dendritic cell-mediated T-cell dysfunction in HIV-1 infection. AIDS. 2015 Jul 17;29(11):1287-96. doi: 10.1097/QAD.0000000000000698.

  PMID: 26091297 BACKGROUND

• Viswanathan GN, Marshall SM, Balasubramaniam K, Badimon JJ, Zaman AG. Differences in thrombus structure and kinetics in patients with type 2 diabetes mellitus after non ST elevation acute coronary syndrome. Thromb Res. 2014 May;133(5):880-5. doi: 10.1016/j.thromres.2014.01.033. Epub 2014 Feb 1.

  PMID: 24582462 BACKGROUND

• Hutter R, Speidl WS, Valdiviezo C, Sauter B, Corti R, Fuster V, Badimon JJ. Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1alpha activation: a novel aspect of angiogenesis in atherosclerosis. J Cardiovasc Transl Res. 2013 Aug;6(4):558-69. doi: 10.1007/s12265-013-9469-9. Epub 2013 May 10.

  PMID: 23661177 BACKGROUND

• Arazi HC, Badimon JJ. Anti-inflammatory effects of anti-platelet treatment in atherosclerosis. Curr Pharm Des. 2012;18(28):4311-25. doi: 10.2174/138161212802481264.

  PMID: 22236116 BACKGROUND

MeSH Terms

Conditions

Inflammation; Cardiovascular Diseases; Thrombosis

Interventions

Clopidogrel; Aspirin

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Embolism and Thrombosis; Vascular Diseases

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Limitations and Caveats

This study was powered assuming that 40 study participants would be assigned per arm, however less than 10 participants were assigned per arm, therefore more participants would be needed to observe significant differences.

Results Point of Contact

• Title: Dr. Meagan O'Brien
• Organization: Icahn School of Medicine at Mount Sinai

Meagan.O'Brien@mssm.edu

Study Officials

• Meagan O'Brien, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

• Juan Badimon, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 15, 2015
• First Posted: October 19, 2015
• Study Start: October 1, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: February 28, 2018
• Results First Posted: February 28, 2018

Record last verified: 2018-01

Locations

US (1)