Sevelamer for Reducing Endotoxemia and Immune Activation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Sevelamer Carbonate for Reducing Endotoxemia and Immune Activation: A Proof of Concept Study

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Sevelamer carbonate
* Device: Sevelamer carbonate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sevelamer carbonate<br>Patients will be administered two 800 mg tablets of Sevelamer carbonate orally three times a day for 8 weeks. | Drug: Sevelamer carbonate<br>* Patients will be administered two 800 mg tablets of Sevelamer carbonate orally three times a day for 8 weeks.<br>* Other names: Renvela;Device: Sevelamer carbonate<br> <br> * Other names: Renvela;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Endotoxin | Change in endotoxin from baseline to week 4, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in Endotoxin | Change in endotoxin from week 8 to week 16 | week 8 and week 16 | 
| Change in sCD14 | Change in sCD14 from baseline to week 4, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in sCD14 | Change in sCD14 from week 8 to week 16 | week 8 and week 16 | 
| Change in CD4+ T-cell Activation | Change from baseline to week 8 in CD4+ T-cell activation, defined as the %CD38+/HLA-DR+, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in CD4+ T-cell Activation | Change from baseline to week 4 in CD4+ T-cell activation, defined as the %CD38+/HLA-DR+, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in CD4+ T-cell Activation | Change from week 8 to week 16 in CD4+ T-cell activation, defined as the %CD38+/HLA-DR+ | week 8 and week 16 | 
| Change in CD8+ T-cell Activation | Change from baseline to week 4 in CD8+ T-cell activation, defined as the %CD38+/HLA-DR+, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in CD8+ T-cell Activation | Change in CD8+ T-cell activation defined as the %CD38+/HLA-DR+ from baseline to week 8, where baseline is the average of pre-entry and entry | Baseline and Week 8 | 
| Change in CD8+ T-cell Activation | Change in CD8+ T-cell activation defined as the %CD38+/HLA-DR+ from week 8 to week 16 | week 8 and week 16 | 
| Change in Proportion of Cycling CD8+ | Change from baseline to week 4 in cycling CD8+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in Proportion of Cycling CD8+ | Change from baseline to week 8 in cycling CD8+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Proportion of Cycling CD8+ | Change from week 8 to week 16 in cycling CD8+ , defined as the %Ki67+ | from week 8 to week 16 | 
| Change in Proportion of Cycling CD4+ | Change from baseline to week 4 in cycling CD4+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in Proportion of Cycling CD4+ | Change from baseline to week 8 in cycling CD4+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Proportion of Cycling CD4+ | Change from week 8 to week 16 in cycling CD4+ , defined as the %Ki67+ | week 8 and week 16 | 
| Change in Blood Phosphate Levels | Change in blood phosphate levels from baseline to week 4, where baseline value is the average of pre-entry and entry | from baseline to week 4 | 
| Change in Blood Phosphate Levels | Change in blood phosphate levels from baseline to week 8 | Baseline to Week 8 | 
| Change in Blood Phosphate Levels | Change in blood phosphate levels from week 8 to week 16 | from week 8 to week 16 | 
| Change in log10 HIV RNA Levels | Change in log10 HIV RNA levels from baseline to week 4, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in log10 HIV RNA Levels | Change in log10 HIV RNA levels from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in log10 HIV RNA Levels | Change in log10 HIV RNA levels from week 8 to week 16 | week 8 and week 16 | 
| Change in CD4+ T-cell Counts | Change in CD4+ T-cell counts from baseline to week 4, where baseline is the average of pre-entry and entry | baseline and week 4 | 
| Change in CD4+ T-cell Counts | Change in CD4+ T-cell counts from baseline to week 8, where baseline is the average of pre-entry and entry | baseline and week 8 | 
| Change in CD4+ T-cell Counts | Change in CD4+ T-cell counts from week 8 to week 16 | week 8 and week 16 | 
| Change in IL-6 | Changes in levels of systemic inflammation marker IL-6 from baseline to week 4, where baseline is the average of pre-entry and entry | baseline and week 4 | 
| Change in IL-6 | Changes in levels of systemic inflammation marker IL-6 from baseline to week 8, where baseline is the average of pre-entry and entry | baseline and week 8 | 
| Change in IL-6 | Changes in levels of systemic inflammation marker IL-6 from week 8 to week 16 | week 8 and week 16 | 
| Change in C-reactive Protein (CRP) | Changes in levels of systemic inflammation marker CRP from baseline to week 4, where baseline is the average of pre-entry and entry | baseline and week 4 | 
| Change in CRP | Changes in levels of systemic inflammation marker CRP from baseline to week 8, where baseline is the average of pre-entry and entry | Baseline and Week 8 | 
| Change in CRP | Changes in levels of systemic inflammation marker CRP from week 8 to week 16, where baseline is the average of pre-entry and entry | week 8 and week 16 | 
| Change in D-dimer | Change in levels of coagulation biomarker d-dimer from baseline to week 4, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in D-dimer | Change in levels of coagulation biomarker d-dimer from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in D-dimer | Change in levels of coagulation biomarker d-dimer from week 8 to week 16 | week 8 and week 16 | 
| Change in Tissue Factor | Change in levels of coagulation biomarker tissue factor from baseline to week 4, where baseline value is the average of pre-entry and entry | baseline and week 4 | 
| Change in Tissue Factor | Change in levels of coagulation biomarker tissue factor from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Tissue Factor | Change in levels of coagulation biomarker tissue factor from week 8 to week 16 | week 8 and week 16 | 
| Change in Total Cholesterol | Change in total cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Total Cholesterol | Change in total cholesterol from week 8 to week 16 | week 8 and week 16 | 
| Change in LDL Cholesterol | Change in fasting LDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in LDL Cholesterol | Change in fasting LDL cholesterol from week 8 to week 16 | week 8 and week 16 | 
| Change in HDL Cholesterol | Change in fasting HDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in HDL Cholesterol | Change in fasting HDL cholesterol from week 8 to week 16 | from week 8 to week 16 | 
| Change in Non-HDL Cholesterol | Change in non-HDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Non-HDL Cholesterol | Change in non-HDL cholesterol from week 8 to week 16 | week 8 and week 16 | 
| Change in Fasting Glucose | Change in fasting glucose from baseline to week 8, where baseline value is the average of pre-entry and entry | baseline and week 8 | 
| Change in Fasting Glucose | Change in fasting glucose from week 8 to week 16 | week 8 and week 16 | 
| Primary Adverse Events | 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) | baseline and week 16 |