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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2012 by Oslo University Hospital.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
The Research Council of Norway
Information provided by (Responsible Party):
Dag Kvale, Oslo University Hospital
ClinicalTrials.gov Identifier:
NCT01269515
First received: January 3, 2011
Last updated: May 11, 2012
Last verified: May 2012
  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.


Condition Intervention Phase
HIV
Drug: Etoricoxib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Oslo University Hospital:

Primary Outcome Measures:
  • Changes in progression markers and vaccine responses [ Time Frame: After 6 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    Reductions of etoricoxib dose or stop of drug, adverse events including cardiovascular events, blood pressure, clinical chemistry.


Secondary Outcome Measures:
  • Changes in progression markers [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Changes in CD38 density (molecules/cell) in CD8+PD-1+ or other T cell subsets, CD4+ T cell counts, HIV RNA, immunoglobulin levels, β2-microglobulin, CRP, D-dimer.

  • Clinical events [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    HIV-related clinical events, Indication for antiretroviral treatment.


Estimated Enrollment: 60
Study Start Date: October 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Etoricoxib 90 mg qd for 25 weeks
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
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
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

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 106 /l
  • HIV RNA > 2000 copies/ml

Exclusion Criteria:

  • On current antiretroviral treatment
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01269515

Locations
Norway
Department of Infectious Diseases, Oslo University Hospital Recruiting
Oslo, Norway, 0407
Contact: Dag Kvale, MD, PhD    +4795200709    dag.kvale@medisin.uio.no   
Principal Investigator: Dag Kvale, MD, PhD         
The Biotechnology Centre, University of Oslo Recruiting
Oslo, Norway, 0407
Contact: Kjetil Tasken, MD, PhD    +4790860759    kjetil.tasken@biotek.uio.no   
Principal Investigator: Kjetil Tasken, MD, PhD         
Sponsors and Collaborators
Dag Kvale
The Research Council of Norway
Investigators
Principal Investigator: Dag Kvale, MD, PhD Oslo University Hospital
  More Information

No publications provided

Responsible Party: Dag Kvale, Professor, Senior consultant, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT01269515     History of Changes
Other Study ID Numbers: OUSCOX2
Study First Received: January 3, 2011
Last Updated: May 11, 2012
Health Authority: Norway:National Committee for Medical and Health Research Ethics
Norway: Norwegian Medicines Agency
European Union: European Medicines Agency

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

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

ClinicalTrials.gov processed this record on October 16, 2014