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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01269515
First Posted: January 4, 2011
Last Update Posted: May 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
The Research Council of Norway
Information provided by (Responsible Party):
Dag Kvale, Oslo University Hospital
  Purpose

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.


Condition Intervention Phase
HIV Drug: Etoricoxib Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Dag Kvale, Oslo University Hospital:

Primary Outcome Measures:
  • 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.

  • 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.


Secondary Outcome Measures:
  • 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

  • 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


Enrollment: 60
Study Start Date: October 2010
Study Completion Date: November 2014
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Etoricoxib 90 mg qd for 25 weeks ART-
Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.
Drug: Etoricoxib
90 mg QD
Other Name: 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.
Drug: Etoricoxib
90 mg QD
Other Name: 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.
Drug: Etoricoxib
90 mg QD
Other Name: 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.
Drug: Etoricoxib
90 mg QD
Other Name: Arcoxia
No Intervention: Control ART+
No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

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).

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01269515


Locations
Norway
Department of Infectious Diseases, Oslo University Hospital
Oslo, Norway, 0407
The Biotechnology Centre, University of Oslo
Oslo, Norway, 0407
Sponsors and Collaborators
Dag Kvale
The Research Council of Norway
Investigators
Principal Investigator: Dag Kvale, MD, PhD Oslo University Hospital
  More Information

Publications:
Responsible Party: Dag Kvale, Professor, Senior consultant, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT01269515     History of Changes
Other Study ID Numbers: OUSCOX2
First Submitted: January 3, 2011
First Posted: January 4, 2011
Last Update Posted: May 31, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Dag Kvale, Oslo University Hospital:
Cox-2 inhibitor
HIV
immune activation
immune modulating
progression markers
vaccine

Additional relevant MeSH terms:
Vaccines
Etoricoxib
Cyclooxygenase 2 Inhibitors
Immunologic Factors
Physiological Effects of Drugs
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents


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