Immunomodulating Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in HIV-infected Patients (OUSCOX2)

May 29, 2017 updated by: Dag Kvale

Optional Immunomodulating Therapy and Improved Vaccination Responses by Adjuvant Administration of a Cyclooxygenase Type 2 Inhibitor in Antiretroviral naïve HIV-infected Patients and Patients on ART

Chronic immune activation is a central feature of HIV-infection, and the degree of activated T-cells is a better predictor of disease progression and mortality than plasma viral load. The study hypothesis is that the anti-inflammatory substance etoricoxib will dampen chronic immune activation and improve the effect of T-cell dependent vaccines in HIV-1 infected patients.

The aim of the present study is to explore the efficacy of the study drug on markers of immune activation and vaccine responses, as well as safety of the study drug, in HIV-infected patients not receiving antiretroviral therapy and in patients on long-term effective ART who had CD4 counts < 500.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The current trial was based on our observations that augmented levels of cyclic adenosine monophosphate (cAMP) contribute to the T cell dysfunction in HIV-infected patients. In T cells, cAMP triggers a protein kinase A (PKA) - Csk - Lck inhibitory pathway that inhibits the proximal T cell receptor (TCR) signaling events. This mechanism may also be involved in the inhibitory function of regulatory T cells.

The investigators have hypothesized that elevated levels of cAMP in T cells from HIV-infected individuals result from increased production of prostaglandin E2 (PGE2) following activation-induced expression of cyclooxygenase type 2 (COX-2) in lymphoid tissues. Although the investigators have identified even COX-2 positive T cells in HIV-infected individuals, activated monocytes may be the major source of PGE2; high levels of COX-2 are produced de novo after a number of stimuli, particularly lipopolysaccharide (LPS). Circulating LPS is indeed increased in untreated chronic HIV infection due to enhanced translocation of microbial material and correlates to chronic immune activation and disease progression.

In three preceding clinical explorative trials, the investigators have demonstrated that COX-2 inhibition by COX-2 inhibitors (COX-2i) improves the immune functions of HIV patients, the first two studies included patients on antiretroviral treatment (ART). In the third trial the investigators also showed for the first time that treatment with a COX-2i was able to downregulate chronic immune activation and improve T cell functions (efficacy of T cell-dependent vaccine) in asymptomatic HIV-infected patients who did not use ART. In these patients, chronic immune activation was dampened as demonstrated; CD38 density on CD8+ T cells (primary endpoint) decreased by 24% by study week 12. This reduction could be extrapolated to a possible improvement of CD4+ T cell loss with 30 CD4 cells per ul per year with an approximate mean CD4 loss of 60 per ul per year. These data founded the basis for further support to this study through the GLOBVAC call program under the Norwegian Research Council (granted application for the current study).

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Oslo, Norway, 0407
        • Department of Infectious Diseases, Oslo University Hospital
      • Oslo, Norway, 0407
        • The Biotechnology Centre, University of Oslo

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

ART- group: Confirmed diagnosis of HIV infection < 8 years prestudy

  • no HIV-related clinical manifestations including acute HIV infection
  • no current indication or use for antiretroviral treatment
  • CD4+ count > 350 x 10^6 /l
  • HIV RNA > 2000 copies/ml

ART+ group: Confirmed diagnosis of HIV infection

  • no HIV-related clinical manifestations including acute HIV infection
  • On stabile effective antiretroviral treatment (HIV RNA <50 copies/ml)
  • CD4+ count < 500 x 10^6 /l
  • HIV RNA > 2000 copies/ml

Exclusion Criteria:

  • concomitant or sporadic use of NSAID, corticosteroids or other immune modulating therapies including interferon-alpha
  • cholesterol > 7 M
  • under treatment for hypertension or antihypertensive treatment indicated at inclusion
  • cardiovascular events or stroke in parents, siblings or off-springs occurring < 55 years of age
  • elevated serum creatinine
  • diabetes type I or II
  • known hypersensitivity for etoricoxib, capsule substances or sulphonamides
  • active peptic ulcer or gastrointestinal haemorrhage
  • history of asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic reactions after taking acetyl salicylic acid or NSAID including COX-2 inhibitors
  • pregnancy or insufficient birth control for females
  • breastfeeding
  • seriously deranged liver function
  • creatine clearance < 30 ml/min
  • inflammatory bowel disease
  • heart failure (NYHA II-IV)
  • established ischaemic heart disease, peripheral arteriosclerosis and/or cerebrovascular disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Etoricoxib 90 mg qd for 25 weeks ART-
Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.
90 mg QD
Other Names:
  • Arcoxia
Active Comparator: Etoricoxib 90 mg qd for 2 weeks ART-
Etoricoxib for 2 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.
90 mg QD
Other Names:
  • Arcoxia
No Intervention: Control ART-
No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.
Active Comparator: Etoricoxib 90 mg qd for 25 weeks ART+
Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.
90 mg QD
Other Names:
  • Arcoxia
Active Comparator: Etoricoxib 90 mg qd for 2 weeks ART+
Etoricoxib for 2 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.
90 mg QD
Other Names:
  • Arcoxia
No Intervention: Control ART+
No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in progression markers and vaccine responses within and between ART groups
Time Frame: After 6 months
Changes in CD38 density (CD38 molecules per CD38+CD8+CD3+ T cells) and in humoral and cellular immune responses to study-specific vaccines.
After 6 months
Serious adverse events
Time Frame: During the 6 months study period
Reductions of etoricoxib dose or stop of drug, adverse events including cardiovascular events, blood pressure, clinical chemistry.
During the 6 months study period

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in HIV Gag CD8+ T cell responses within and between ART groups
Time Frame: 6 months
Changes in HIV Gag CD8+ T cell responses within and between ART groups
6 months
Changes in plasma markers of inflammation, coagulation and tryptophan metabolism within and between ART groups
Time Frame: 6 months
Changes in plasma markers of inflammation, coagulation and tryptophan metabolism
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: Dag Kvale, MD, PhD, Oslo University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2010

Primary Completion (Actual)

November 1, 2014

Study Completion (Actual)

November 1, 2014

Study Registration Dates

First Submitted

January 3, 2011

First Submitted That Met QC Criteria

January 3, 2011

First Posted (Estimate)

January 4, 2011

Study Record Updates

Last Update Posted (Actual)

May 31, 2017

Last Update Submitted That Met QC Criteria

May 29, 2017

Last Verified

May 1, 2017

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on HIV

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