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

Sponsor

Dag Kvale (Other)

Overall Status

Completed

CT.gov ID

NCT01269515

Collaborator

The Research Council of Norway (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
HIV	Drug: Etoricoxib	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

60 participants

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

Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

Nov 1, 2014

Actual Study Completion Date :

Nov 1, 2014

Arms and Interventions

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.	Drug: Etoricoxib 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.	Drug: Etoricoxib 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.	Drug: Etoricoxib 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.	Drug: Etoricoxib 90 mg QD Other Names: Arcoxia
No Intervention: Control ART+ No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

Outcome Measures

Primary Outcome Measures

Changes in progression markers and vaccine responses within and between ART groups [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 [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 [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 [6 months]
Changes in plasma markers of inflammation, coagulation and tryptophan metabolism

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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