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

• Sponsor: Radboud University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02383355
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 40
• Arms: 2
• Actual Duration (Months): 28

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Raltegravir; Drug: Continuation of own regimen	Phase 4

Detailed Description

Rationale:

Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in HIV-infected individuals. The precise mechanisms underlying this increased cardiovascular risk remain to be elucidated . Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIV-infected patients 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 cross-sectional 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.

Objective:

Investigate whether switch from a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based regimen to a raltegravir-based regimen results in reduced platelet reactivity, reduced platelet-leukocyte aggregate formation and pro-inflammatory status of monocytes.

Study design: Investigator initiated, single-center, open-label, randomized controlled trial in HIV-infected patients using a NNRTI- or PI-based regimen.

Study population:

Adult HIV-infected study participants with undetectable (<40 copies/mL) viral load receiving a standard backbone of two NRTI's (either tenofovir (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC)) with either a NNRTI (efavirenz (EFV) or rilpivirine (RPV)) or a boosted PI (Darunavir (DRV/r), atazanavir (ATZ/r) or Lopinavir (LPV/r)). After Sample size calculation two groups of 20 subjects will be enrolled.

Intervention:

Participants will be randomized (1:1) to continue the same ART regimen ("Continuation group") or to switch their NNRTI or PI to raltegravir ("Switch group") during 10 weeks.

Main study parameters/endpoints:

Primary parameter:

1. Platelet reactivity: platelet expression of the platelet activation marker CD62P (P-selectin) and activated fibrinogen receptor (αIIbβ3) upon stimulation with different platelet agonists.

Secondary parameters:

1. Platelet-leukocyte aggregates (eg. PMA).

2. Activation markers on T cells and monocytes.

3. Soluble (plasma) markers of platelet and monocyte activation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Switch From an NNRTI or PI-based Regimen to a RAltegravir-based Regimen in Virologically Suppressed HIV-infected Patients: Effects on Platelet Reactivity, Platelet-monocyte Aggregation and the Inflammatory anD Thrombotic State of Monocytes
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Mar 31, 2016
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Switch group Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks	Drug: Raltegravir; Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy; Other Names: Isentress
Active Comparator: Continuation group 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; Continuation of own antiretroviral medication during the 10 weeks follow-up

Outcome Measures

Primary Outcome Measures

1. Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding [Baseline and week 10]

   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.

Secondary Outcome Measures

1. Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry) [Baseline and week 10]

   Platelet monocyte complex (PMCs) measured by flow-cytometry. % of CD61+ (platelet-marker) monocytes. Change after 10 weeks was calculated as a ratio between baseline and week 10.

2. T-cell Dysfunction (CD4-cells) [Baseline and Week 10]

   Markers of persistent immune activation measured by flow cytometry (% of CD4-cells positive for CD38HLA-DR cells). Change after 10 weeks was calculated as a ratio between baseline and week 10.

3. Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP) [Baseline and week 10]

   Plasma levels of hs-CRP (ng/mL) measured by ELISA . Change in concentration was calculated as a ratio between baseline (week 0) and week 10.

4. Persistent Immune Activation - Monocyte Subsets [Baseline and week 10]

   Monocyte subsets measured by flowcytometry. Classical monocytes (CD14+,CD16-), intermediate (CD14+CD16+), Non-classical (CD14dimCD16+). Reported values are change between baseline and week 10 and reported as ratio.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Radboud University Medical Center
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Quirijn de Mast, MD PhD, Radboud University (Radboudumc)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT02383355
• Other Study ID Numbers: NL50681.091.14; 2014-1320
• First Posted: Mar 9, 2015
• Last Update Posted: Jan 10, 2019
• Last Verified: Sep 1, 2017

• Keywords provided by Radboud University Medical Center: Persistent immune activation; Platelet hyperreactivity
• Additional relevant MeSH terms: Raltegravir Potassium

Study Results

Participant Flow

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Period Title: Overall Study
STARTED	19	21
COMPLETED	17	21
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Switch Group	Continuation Group	Total
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up	Total of all reporting groups
Overall Participants	19	21	40
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	48	49	48
Sex: Female, Male (Count of Participants)
Female	1 5.3%	0 0%	1 2.5%
Male	18 94.7%	21 100%	39 97.5%
Region of Enrollment (participants) [Number]
Netherlands	19 100%	21 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding
Description	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.
Time Frame	Baseline and week 10

Outcome Measure Data

Analysis Population Description

Intention to treat, if week 10 is not available, week 4 was used for these individuals (n=2)

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Measure Participants	19	21
ADP 125uM CD62p expression	0.9	0.96
ADP 125uM Fibrinogen binding	1	0.99
ADP 7.8uM CD62p expression	0.88	0.99
ADP 7.8uM fibrinogen binding	0.85	1.02
CRP (collagen) XL 655ng/ml CD62p expression	0.95	0.94
CRP (collagen) XL 655ng/ml fibrinogen binding	0.8	0.8
CRP (collagen) XL 27.33ng/ml CD62p expression	0.87	0.84
CRP (collagen) XL 27.33 ng/ml fibrinogen binding	0.88	1.04

2. Secondary Outcome

Title	Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)
Description	Platelet monocyte complex (PMCs) measured by flow-cytometry. % of CD61+ (platelet-marker) monocytes. Change after 10 weeks was calculated as a ratio between baseline and week 10.
Time Frame	Baseline and week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Measure Participants	19	21
Median (Full Range) [ratio]	0.95	0.932

3. Secondary Outcome

Title	T-cell Dysfunction (CD4-cells)
Description	Markers of persistent immune activation measured by flow cytometry (% of CD4-cells positive for CD38HLA-DR cells). Change after 10 weeks was calculated as a ratio between baseline and week 10.
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Measure Participants	19	21
Median (Full Range) [ratio]	1.314	1.016

4. Secondary Outcome

Title	Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)
Description	Plasma levels of hs-CRP (ng/mL) measured by ELISA . Change in concentration was calculated as a ratio between baseline (week 0) and week 10.
Time Frame	Baseline and week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Measure Participants	19	18
Mean (Standard Deviation) [ratio]	1.208 (0.895)	1.103 (1.007)

5. Secondary Outcome

Title	Persistent Immune Activation - Monocyte Subsets
Description	Monocyte subsets measured by flowcytometry. Classical monocytes (CD14+,CD16-), intermediate (CD14+CD16+), Non-classical (CD14dimCD16+). Reported values are change between baseline and week 10 and reported as ratio.
Time Frame	Baseline and week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switch Group	Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
Measure Participants	19	21
classical monocytes as % of total monocytes	0.98	0.998
intermediate monocytes as % of total monocytes	1.042	0.979
non-classical monocytes as % of total monocytes	1	1.089

Adverse Events

Arm/Group Title	Switch Group		Continuation Group
Arm/Group Description	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy		Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up
All Cause Mortality
	Switch Group		Continuation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/21 (0%)
Serious Adverse Events
	Switch Group		Continuation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Switch Group		Continuation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/19 (10.5%)		0/21 (0%)
Nervous system disorders
headache	1/19 (5.3%)	1	0/21 (0%)	0
insomnia	1/19 (5.3%)	1	0/21 (0%)	0

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.