Effects of Raltegravir Based Regimen on Platelet Reactivity, Platelet-monocyte Aggregation and Immune Activation

NCT02383355 | Completed Phase 4 Results DMC

• 2 other identifiers: NL50681.091.142014-1320
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

Brief Summary

Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in HIVinfected individuals. The precise mechanisms underlying this increased cardiovascular risk remain to be elucidated. Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIVinfectedpatients and may contribute to the excess cardiovascular risk as platelets play a key role in the onset and progression of atherosclerosis and in acute cardiovascular events. In addition, HIV-infected individuals frequently suffer from persistent immune activation and inflammation. In a crosssectional study the investigators recently showed that individuals using a regimen containing the integrase inhibitor raltegravir have reduced platelet hyperreactivity and PMA compared to other antiretroviral regimens. Other recent studies showed that raltegravir is associated with decreased immune activation. Due to the inherent limitations of cross sectional studies, the investigators aim to expand our findings in an intervention study. The investigators will conduct a randomized control trial where the investigators switch patients to a integrase containing treatment regimen to assay possible changes in platelet function and persistent immune activation. Knowledge gathered in the proposed study can help understand and prevent cardiovascular disease in patients treated for a HIV infection by reducing platelet hyperreactivity and persistent immune activation.

Conditions

HIV

Keywords

Persistent immune activation; Platelet hyperreactivity

Outcome Measures

Primary Outcomes (1)

• Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding

  Platelet expression of the platelet activation marker CD62P (P-selectin) and of the activated fibrinogen receptor (αIIbβ3) through fibrinogen binding following stimulation with two concentrations of the platelet agonists ADP (adenosine diphosphate) and CRP-XL (crosslinked collagen related peptide). Difference between week 0 and week 10. Primary outcome is CD62p expression upon stimulation with ADP (power calculation based on this measure). Expression of both markers are expressed as MFI (Median fluorescence intensity) and measured by flowcytometry. Change after 10 weeks was calculated as a ratio between baseline and week 10.

  Baseline and week 10

Secondary Outcomes (4)

• Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)

  Baseline and week 10

• T-cell Dysfunction (CD4-cells)

  Baseline and Week 10

• Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)

  Baseline and week 10

• Persistent Immune Activation - Monocyte Subsets

  Baseline and week 10

Study Arms (2)

Switch group

EXPERIMENTAL

Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks

Drug: Raltegravir

Continuation group

ACTIVE COMPARATOR

Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria

Drug: Continuation of own regimen

Interventions

Raltegravir DRUG

Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy

Also known as: Isentress

Switch group

Continuation of own regimen DRUG

Continuation of own antiretroviral medication during the 10 weeks follow-up

Continuation group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female
• Documented HIV-infection
• Age ≥ 18 years
• Willing to comply with the protocol requirements
• On stable antiretroviral therapy (ART) for ≥ 6 months at screening
• Undetectable plasma HIV viral load (\<50 copies/mL) for at least 6 months
• CD4 cell count \> 300 cells/mm3 at last measurement
• Current ART regimen at screening consisting of a backbone of two NRTI's (either TDF/FTC or ABC/3TC) with either a NNRTI (EFV or RPV) or a boosted PI (DRV/r, ATZ/r or LPV/r) and on this regimen for \> 3 months
• If female and of childbearing potential using effective birth control methods

You may not qualify if:

• Use of platelet function inhibitors, such as aspirin and adenosine diphosphate (ADP) receptor antagonists
• Known hypersensitivity to raltegravir or any other component of the formulation
• Using any concomitant therapy disallowed as per summary of product characteristics (SPC) for the study drug
• Signs of symptoms of an active (opportunistic) infection other than HIV
• Active hepatitis B or C
• Estimated glomerular filtration rate (by MDRD) \<50 ml/min
• Clinical or laboratory evidence of significantly decreased hepatic function, defined as alanine aminotransferase (ALAT) level \> 2 upper limit of normal (ULN)
• History of suspected or proven virologic failure since ART initiation (HIV-1 RNA "blips" less than 500 copies per milliliter with subsequent suppression are allowed)
• Known genotypic resistance to any current ART component
• Prior use of single or dual NRTI-only regimens, or history of any ART not considered highly active by current standards.
• In females, pregnancy or breast feeding

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Merck Sharp & Dohme LLC: collaborator

Related Publications (2)

• Tunjungputri RN, Van Der Ven AJ, Schonsberg A, Mathan TS, Koopmans P, Roest M, Fijnheer R, Groot PG, de Mast Q. Reduced platelet hyperreactivity and platelet-monocyte aggregation in HIV-infected individuals receiving a raltegravir-based regimen. AIDS. 2014 Sep 10;28(14):2091-6. doi: 10.1097/QAD.0000000000000415.

  PMID: 25265076 RESULT

• van der Heijden WA, van Crevel R, de Groot PG, Urbanus RT, Koenen HJPM, Bosch M, Keuter M, van der Ven AJ, de Mast Q. A switch to a raltegravir containing regimen does not lower platelet reactivity in HIV-infected individuals. AIDS. 2018 Nov 13;32(17):2469-2475. doi: 10.1097/QAD.0000000000001993.

  PMID: 30134289 DERIVED

MeSH Terms

Interventions

Raltegravir Potassium

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Even though our study was correctly powered for the primary outcome (platelet reactivity), the sample size gave us limited statistical power to explore all secondary objectives in detail and to include subanalyses exploring possible confounders.

Results Point of Contact

• Title: Wouter van der Heijden
• Organization: Radboudumc

wouter.vanderheijden@radboudumc.nl

0031 24 3616980

Study Officials

• Quirijn de Mast, MD PhD

  Radboud University (Radboudumc)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2015
• First Posted: March 9, 2015
• Study Start: March 1, 2015
• Primary Completion: March 31, 2016
• Study Completion: July 1, 2017
• Last Updated: January 10, 2019
• Results First Posted: January 10, 2019

Record last verified: 2017-09