Sevelamer for Reducing Endotoxemia and Immune Activation

Phase 2

Completed

Conditions: HIV-1 Infection

Interventions: Device: Sevelamer carbonate

Registration Number: NCT01543958

Lead Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sevelamer carbonate	Sevelamer carbonate	Patients will be administered two 800 mg tablets of Sevelamer carbonate orally three times a day for 8 weeks.

Primary Outcome Measures

Name	Time	Method
Change in Soluble CD14 (sCD14)	baseline and week 8	Change in soluble CD14 (sCD14) from baseline to week 8, where baseline value is the average of pre-entry and entry
Change in Endotoxin	baseline and Week 8	Change in LPS from baseline to week 8, where baseline value is the average of pre-entry and entry values.

Secondary Outcome Measures

Name	Time	Method
Change in sCD14	week 8 and week 16	Change in sCD14 from week 8 to week 16
Change in Endotoxin	week 8 and week 16	Change in endotoxin from week 8 to week 16
Change in Proportion of Cycling CD4+	week 8 and week 16	Change from week 8 to week 16 in cycling CD4+ , defined as the %Ki67+
Change in CD8+ T-cell Activation	week 8 and week 16	Change in CD8+ T-cell activation defined as the %CD38+/HLA-DR+ from week 8 to week 16
Change in Blood Phosphate Levels	from week 8 to week 16	Change in blood phosphate levels from week 8 to week 16
Change in Proportion of Cycling CD8+	from week 8 to week 16	Change from week 8 to week 16 in cycling CD8+ , defined as the %Ki67+
Change in CD4+ T-cell Counts	week 8 and week 16	Change in CD4+ T-cell counts from week 8 to week 16
Change in IL-6	week 8 and week 16	Changes in levels of systemic inflammation marker IL-6 from week 8 to week 16
Change in C-reactive Protein (CRP)	baseline and week 4	Changes in levels of systemic inflammation marker CRP from baseline to week 4, where baseline is the average of pre-entry and entry
Change in D-dimer	week 8 and week 16	Change in levels of coagulation biomarker d-dimer from week 8 to week 16
Primary Adverse Events	baseline and week 16	Number of subjects experiencing primary adverse events, defined as all reported Grade ≥ 2 signs and symptoms, Grade ≥ 2 laboratory abnormalities and other serious adverse events (SAEs)
Change in CD4+ T-cell Activation	week 8 and week 16	Change from week 8 to week 16 in CD4+ T-cell activation, defined as the %CD38+/HLA-DR+
Change in log10 HIV RNA Levels	week 8 and week 16	Change in log10 HIV RNA levels from week 8 to week 16
Change in Tissue Factor	week 8 and week 16	Change in levels of coagulation biomarker tissue factor from week 8 to week 16
Change in HDL Cholesterol	from week 8 to week 16	Change in fasting HDL cholesterol from week 8 to week 16
Change in Fasting Glucose	week 8 and week 16	Change in fasting glucose from week 8 to week 16
Change in CRP	week 8 and week 16	Changes in levels of systemic inflammation marker CRP from week 8 to week 16, where baseline is the average of pre-entry and entry
Change in LDL Cholesterol	week 8 and week 16	Change in fasting LDL cholesterol from week 8 to week 16
Change in Non-HDL Cholesterol	week 8 and week 16	Change in non-HDL cholesterol from week 8 to week 16
Change in Total Cholesterol	week 8 and week 16	Change in total cholesterol from week 8 to week 16

Trial Locations

Locations (15): Harbor-UCLA Med. Ctr. CRS (603)
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Torrance, California, United States
Univ. of Miami AIDS CRS (901)
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Miami, Florida, United States
Massachusetts General Hospital ACTG CRS (101)
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Boston, Massachusetts, United States
Metro Health CRS (2503)
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Cleveland, Ohio, United States
Univ. of Cincinnati CRS (2401)
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Cincinnati, Ohio, United States
Alabama Therapeutics CRS (5801)
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Birmingham, Alabama, United States
UCLA CARE Center CRS (601)
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Los Angeles, California, United States
University of Colorado Hospital CRS (6101)
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Aurora, Colorado, United States
Northwestern University CRS (2701)
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Chicago, Illinois, United States
Univ. of Rochester ACTG CRS (1101)
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Rochester, New York, United States
AIDS Care CRS (1108)
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Rochester, New York, United States
Washington University CRS (2101)
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Saint Louis, Missouri, United States
Case CRS (2501)
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Cleveland, Ohio, United States
Hosp. of the Univ. of Pennsylvania CRS (6201)
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Philadelphia, Pennsylvania, United States
Ucsf Aids Crs (801)
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San Francisco, California, United States