HIVPhase 4RAPIDNCT02383355

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

A Phase 4 study testing Raltegravir and Continuation of own regimen in people with HIV, run by Radboud University Medical Center.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: HIV
What is being tested?: Raltegravir and Continuation of own regimen
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 40 participants
Where: No sites listed yet
Study dates: 1 Mar 2015to 1 Jul 2017
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Show all 9Show fewer

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

Who cannot join

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

Show all 11Show fewer

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

About this study

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

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.

Read the 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:

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:

Platelet-leukocyte aggregates (eg. PMA).
Activation markers on T cells and monocytes.
Soluble (plasma) markers of platelet and monocyte activation.

Conditions: HIV
Being tested: Raltegravir, Continuation of own regimen
Keywords: Persistent immune activation, Platelet hyperreactivity

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RaltegravirDrug
Also called Isentress
Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy
Continuation of own regimenDrug
Continuation of own antiretroviral medication during the 10 weeks follow-up

Study groups in NCT02383355
Study group	Role	What they receive
Switch group	Experimental	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks Receives: 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 Receives: Drug: Continuation of own regimen

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Baseline and week 10

Secondary outcomes (4)

Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)
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.
Measured: Baseline and week 10
T-cell Dysfunction (CD4-cells)
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.
Measured: Baseline and Week 10
Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)
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.
Measured: Baseline and week 10
Persistent Immune Activation - Monocyte Subsets
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.
Measured: Baseline and week 10

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Mar 20151 Jul 2017

First posted9 Mar 2015 (estimated)
Study start1 Mar 2015
Primary completion31 Mar 2016
Study completion1 Jul 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for HIVStudies of the same condition, open and under way.
More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 40 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02383355
Sponsor's protocol ID: NL50681.091.14
Other IDs: 2014-1320
Acronym: RAPID
Status last verified: Sep 2017
First submitted: 23 Jan 2015
Last updated: 10 Jan 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 25265076
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.
PubMed 30134289

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Study at a glance

From the registry record, last updated by the sponsor on 10 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT02383355
Acronym / sponsor ID: RAPID / NL50681.091.14
Conditions: HIV
Keywords: Persistent immune activation, Platelet hyperreactivity
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 40 participants (actual)
Lead sponsor: Radboud University Medical CenterUniversity, hospital or other
Collaborators: Merck Sharp & Dohme LLC
Study start: 1 Mar 2015 (actual)
Primary completion: 31 Mar 2016 (actual)
Study completion: 1 Jul 2017 (actual)
First posted: 9 Mar 2015 (estimated)
Results: Posted 10 Jan 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Rationale:

Objective:

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

Study population:

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:

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:

Platelet-leukocyte aggregates (eg. PMA).
Activation markers on T cells and monocytes.
Soluble (plasma) markers of platelet and monocyte activation.

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Switch group	Experimental	Drug: RaltegravirRaltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks
Continuation group	Active comparator	Drug: Continuation of own regimenIndividuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (9 listed)

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

Key exclusion criteria (11 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RaltegravirAlso: IsentressRaltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy	Drug	Switch group
Continuation of own regimenContinuation of own antiretroviral medication during the 10 weeks follow-up	Drug	Continuation group

Primary outcome

Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding
Time frame: 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.

4 secondary outcomes

Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)
Time frame: Baseline and week 10
T-cell Dysfunction (CD4-cells)
Time frame: Baseline and Week 10
Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)
Time frame: Baseline and week 10
Persistent Immune Activation - Monocyte Subsets
Time frame: Baseline and week 10

Results and safety

Results posted to the registry on 10 Jan 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Switch Group	19	17
Continuation Group	21	21

Primary outcome: Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding

Time frame: Baseline and week 10. Median (Full Range). Unit: Ratio

Measure	Switch Group n = 19	Continuation Group n = 21
ADP 125uM CD62p expression	0.9 (0.49 to 1.14)	0.96 (0.66 to 1.3)
ADP 125uM Fibrinogen binding	1 (0.37 to 2.8)	0.99 (0.66 to 1.95)
ADP 7.8uM CD62p expression	0.88 (0.46 to 1.11)	0.99 (0.690 to 1.32)
ADP 7.8uM fibrinogen binding	0.85 (0.39 to 2.13)	1.02 (0.57 to 1.53)
CRP (collagen) XL 655ng/ml CD62p expression	0.95 (0.87 to 1.2)	0.94 (0.68 to 1.28)
CRP (collagen) XL 655ng/ml fibrinogen binding	0.8 (0.48 to 1.77)	0.8 (0.64 to 1.38)
CRP (collagen) XL 27.33ng/ml CD62p expression	0.87 (0.41 to 2.14)	0.84 (0.33 to 1.84)
CRP (collagen) XL 27.33 ng/ml fibrinogen binding	0.88 (0.68 to 1.590)	1.04 (0.41 to 1.59)

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

4 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Switch Group	0 of 19 (0%)	2 of 19 (10.5%)	0 of 19
Continuation Group	0 of 21 (0%)	0 of 21 (0%)	0 of 21

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Jan 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 25265076Tunjungputri 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.
Derived from this study: PubMed 30134289van 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Quirijn de Mast, MD PhD principal investigator

Radboud University (Radboudumc)

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Raltegravir and Continuation of own regimen in people with HIV, run by Radboud University Medical Center.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jan 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding (time frame: Baseline and week 10). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02383355, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2019.