Clinical trial NCT01543958: Sevelamer for Reducing Endotoxemia and Immune Activation
Official title: Sevelamer Carbonate for Reducing Endotoxemia and Immune Activation: A Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-03-05
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: HIV-infected people can have an increase in inflammation in their body organs, even after taking anti-HIV medicines.

Sevelamer carbonate is used to bind phosphate in dialysis patients. It can also bind endotoxin in the gut and lowers endotoxin levels in the blood of dialysis patients. Sevelamer carbonate decreases the inflammation endotoxin causes in dialysis patients.

A5296 is a phase II, single-arm study to evaluate the effect of 8 weeks of sevelamer carbonate administration on markers of microbial translocation and T-cell activation in the blood in chronically HIV-infected subjects not receiving ART.

Detailed description: HIV-infected people can have an increase in inflammation in their body organs, even after taking anti-HIV medicines. Inflammation is a normal body reaction to any infection. However, if inflammation lasts a long time like in HIV infection, it may lead to complications, such as heart disease, cancer, liver disease, and problems with thinking. Also, HIV-infected people with high inflammation have lower CD4+ T-cell counts (cells that fight infection). Many HIV researchers are studying the harmful effects of this prolonged inflammation and possible ways to prevent these complications.

The increase in inflammation in HIV-infected people may be caused by HIV or by other factors such as parts of bacteria. These bacterial pieces, called endotoxins, do not cause harm in the intestine (gut). However, in HIV infection, there is damage to the gut that allows endotoxins to cross from the gut into the blood. These endotoxins then cause inflammation in the body. New research is focusing on strategies to reduce the levels of endotoxin as a way to decrease inflammation.

A drug called sevelamer carbonate is used to bind phosphate in dialysis patients. However, sevelamer carbonate also binds endotoxin in the gut and lowers endotoxin levels in the blood of dialysis patients. Sevelamer carbonate also decreases the inflammation endotoxin causes in dialysis patients. This study will see if sevelamer carbonate can have the same effects in HIV-infected patients.

A5296 is a phase II, single-arm study to evaluate the effect of 8 weeks of sevelamer carbonate administration on markers of microbial translocation as well as monocyte and T-cell activation in the blood in chronically HIV-infected subjects with CD4+ T-cell count ≥ 400 cells/mm3 not receiving ART. This study enrolled 40 subjects. To assess whether there is a persistent effect of study drug, subjects were observed for an additional 8 weeks off sevelamer carbonate and changes in biomarkers were monitored.

As A5296 is a phase II study of biologic activity, the primary and secondary analyses are as-treated, limited to subjects who have data for baseline and week 8 and who remain on study treatment through week 8. For any subject who initiated antiretroviral treatment (ART), analyses only included data collected prior to the time ART was started.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection
* No plans to initiate ART during the course of the proposed study.
* Screening CD4+ T-cell count ≥ 400 cells/mm3 performed in a laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
* HIV-1 RNA \>50 copies/mL within the last 180 days prior to entry.
* Screening serum phosphate \> 2.6 mg/dL within 60 days prior to entry.
* Certain laboratory values, as detailed in section 4.1.6 of the protocol, obtained within 30 days prior to entry
* Female subjects of reproductive potential must have a negative serum or urine pregnancy test performed within 30 days prior to entry.
* Female subjects participating in sexual activity that could lead to pregnancy must agree to use at least one of the following forms of birth control for at least 30 days prior to study entry until the final study visit:

  * Condoms (male or female) with or without a spermicidal agent
  * Diaphragm or cervical cap with spermicide
  * Intrauterine device (IUD)
  * Hormone-based contraceptive
* Female subjects who are not of reproductive potential are eligible without requiring the use of a contraceptive.
* Confirmation of the availability of the stored pre-entry plasma and peripheral blood mononuclear cell (PBMC) samples for endotoxin, sCD14, and immune activation determinations, obtained from a fasting sample.
* Ability and willingness of subject to provide informed consent.
* No plans to use probiotics (defined as products that contain significant amounts of live microorganisms and are ingested for specific health benefits, e.g., yogurt with live and active cultures, Lactobacillus GG, Saccharomyces boulardii) during the study.

Exclusion Criteria:

* Known diagnosis of acute HIV infection within 180 days prior to study entry.
* Pregnant or breastfeeding.
* Use of any antiretroviral agent within 24 weeks prior to study entry.
* Use of systemic cancer chemotherapy or radiation therapy, immunosuppressive or immunomodulatory therapy (e.g., interferons, tumor necrosis factor antagonists, interleukins, systemic corticosteroids) within 24 weeks prior to study entry.

NOTE A: Use of inhaled steroids, nasal steroids, topical steroids, or the equivalent of 10 mg of prednisone or less per day or a less than 2-week course of oral steroids is not exclusionary.

NOTE B: A single course of 1% hydrocortisone cream applied up to 3 times a day to \<10 square inches area for \<2 weeks is permitted while on study. Use of all other topical steroids is excluded.

* Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation.
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* Serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry.
* Known cirrhosis or severe liver disease (e.g., ascites, encephalopathy, history of variceal bleeding).

NOTE: Potential subjects with chronic hepatitis B or C virus infection who do not have known cirrhosis or severe liver disease may participate in the study.

* Severe kidney disease (defined as estimated glomerular filtration rate \[GFR\] \<30 mL/min/1.73m2) at screening.
* History of bowel obstruction or severe GI motility disorders including severe constipation.
* Severe dysphagia or swallowing disorders.
* Major GI tract surgery within 60 days prior to study entry.
* Intent to initiate or change the dose of lipid-lowering drugs during study. NOTE: Potential subjects on stable doses of lipid-lowering agents (defined as no change in preparation or dose within 90 days prior to study entry) are permitted and may be enrolled.
* Use of investigational therapies within 90 days prior to study entry unless permission was granted by the A5296 protocol chairs (see Study Management page).
* Currently receiving hepatitis C therapy or anticipation that such therapy will be started during the study.
* Use of probiotics, for more than 3 consecutive days within the 60 days prior to study entry.

Primary outcomes:
measure: Change in Endotoxin
timeFrame: baseline and Week 8
measure: Change in Soluble CD14 (sCD14)
timeFrame: baseline and week 8
Secondary outcomes:
measure: Change in Endotoxin
timeFrame: baseline and week 4
measure: Change in Endotoxin
timeFrame: week 8 and week 16
measure: Change in sCD14
timeFrame: baseline and week 4
measure: Change in sCD14
timeFrame: week 8 and week 16
measure: Change in CD4+ T-cell Activation
timeFrame: baseline and week 8
measure: Change in CD4+ T-cell Activation
timeFrame: baseline and week 4
measure: Change in CD4+ T-cell Activation
timeFrame: week 8 and week 16
measure: Change in CD8+ T-cell Activation
timeFrame: baseline and week 4
measure: Change in CD8+ T-cell Activation
timeFrame: Baseline and Week 8
measure: Change in CD8+ T-cell Activation
timeFrame: week 8 and week 16
measure: Change in Proportion of Cycling CD8+
timeFrame: baseline and week 4
measure: Change in Proportion of Cycling CD8+
timeFrame: baseline and week 8
measure: Change in Proportion of Cycling CD8+
timeFrame: from week 8 to week 16
measure: Change in Proportion of Cycling CD4+
timeFrame: baseline and week 4
measure: Change in Proportion of Cycling CD4+
timeFrame: baseline and week 8
measure: Change in Proportion of Cycling CD4+
timeFrame: week 8 and week 16
measure: Change in Blood Phosphate Levels
timeFrame: from baseline to week 4
measure: Change in Blood Phosphate Levels
timeFrame: Baseline to Week 8
measure: Change in Blood Phosphate Levels
timeFrame: from week 8 to week 16
measure: Change in log10 HIV RNA Levels
timeFrame: baseline and week 4
measure: Change in log10 HIV RNA Levels
timeFrame: baseline and week 8
measure: Change in log10 HIV RNA Levels
timeFrame: week 8 and week 16
measure: Change in CD4+ T-cell Counts
timeFrame: baseline and week 4
measure: Change in CD4+ T-cell Counts
timeFrame: baseline and week 8
measure: Change in CD4+ T-cell Counts
timeFrame: week 8 and week 16
measure: Change in IL-6
timeFrame: baseline and week 4
measure: Change in IL-6
timeFrame: baseline and week 8
measure: Change in IL-6
timeFrame: week 8 and week 16
measure: Change in C-reactive Protein (CRP)
timeFrame: baseline and week 4
measure: Change in CRP
timeFrame: Baseline and Week 8
measure: Change in CRP
timeFrame: week 8 and week 16
measure: Change in D-dimer
timeFrame: baseline and week 4
measure: Change in D-dimer
timeFrame: baseline and week 8
measure: Change in D-dimer
timeFrame: week 8 and week 16
measure: Change in Tissue Factor
timeFrame: baseline and week 4
measure: Change in Tissue Factor
timeFrame: baseline and week 8
measure: Change in Tissue Factor
timeFrame: week 8 and week 16
measure: Change in Total Cholesterol
timeFrame: baseline and week 8
measure: Change in Total Cholesterol
timeFrame: week 8 and week 16
measure: Change in LDL Cholesterol
timeFrame: baseline and week 8
measure: Change in LDL Cholesterol
timeFrame: week 8 and week 16
measure: Change in HDL Cholesterol
timeFrame: baseline and week 8
measure: Change in HDL Cholesterol
timeFrame: from week 8 to week 16
measure: Change in Non-HDL Cholesterol
timeFrame: baseline and week 8
measure: Change in Non-HDL Cholesterol
timeFrame: week 8 and week 16
measure: Change in Fasting Glucose
timeFrame: baseline and week 8
measure: Change in Fasting Glucose
timeFrame: week 8 and week 16
measure: Primary Adverse Events
timeFrame: baseline and week 16
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS (5801)
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs (801)
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS (603)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: Rochester
country: United States
facility: AIDS Care CRS (1108)
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS (1101)
state: New York
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
Study officials:
affiliation: Massachusetts General Hospital ACTG CRS
name: Rajesh Gandhi, MD
role: STUDY_CHAIR
affiliation: National Institutes of Health (NIH)
name: Netanya Sandler, MD
role: STUDY_CHAIR
References:
citation: Sandler NG, Zhang X, Bosch RJ, Funderburg NT, Choi AI, Robinson JK, Fine DM, Coombs RW, Jacobson JM, Landay AL, Douek DC, Tressler R, Read SW, Wilson CC, Deeks SG, Lederman MM, Gandhi RT; AIDS Clinical Trials Group A5296 Team. Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection. J Infect Dis. 2014 Nov 15;210(10):1549-54. doi: 10.1093/infdis/jiu305. Epub 2014 May 26.