Sevelamer for Reducing Endotoxemia and Immune Activation

• ClinicalTrials.gov Identifier: NCT01543958
• Recruitment Status: Completed
• First Posted: March 5, 2012
• Results First Posted: November 25, 2013
• Last Update Posted: October 11, 2018
• Sponsor: AIDS Clinical Trials Group
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): AIDS Clinical Trials Group

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: Sevelamer carbonate; Device: Sevelamer carbonate	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sevelamer Carbonate for Reducing Endotoxemia and Immune Activation: A Proof of Concept Study
• Study Start Date: November 2011
• Actual Primary Completion Date: September 2012
• Actual Study Completion Date: November 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sevelamer carbonate; Patients will be administered two 800 mg tablets of Sevelamer carbonate orally three times a day for 8 weeks.	Drug: Sevelamer carbonate; Patients will be administered two 800 mg tablets of Sevelamer carbonate orally three times a day for 8 weeks.; Other Name: Renvela; Device: Sevelamer carbonate; Other Name: Renvela

Outcome Measures

Primary Outcome Measures :

1. Change in Endotoxin [ Time Frame: baseline and Week 8 ]
   Change in LPS from baseline to week 8, where baseline value is the average of pre-entry and entry values.
2. Change in Soluble CD14 (sCD14) [ Time Frame: 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

Secondary Outcome Measures :

1. Change in Endotoxin [ Time Frame: baseline and week 4 ]
   Change in endotoxin from baseline to week 4, where baseline value is the average of pre-entry and entry
2. Change in Endotoxin [ Time Frame: week 8 and week 16 ]
   Change in endotoxin from week 8 to week 16
3. Change in sCD14 [ Time Frame: baseline and week 4 ]
   Change in sCD14 from baseline to week 4, where baseline value is the average of pre-entry and entry
4. Change in sCD14 [ Time Frame: week 8 and week 16 ]
   Change in sCD14 from week 8 to week 16
5. Change in CD4+ T-cell Activation [ Time Frame: baseline and week 8 ]
   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
6. Change in CD4+ T-cell Activation [ Time Frame: baseline and week 4 ]
   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
7. Change in CD4+ T-cell Activation [ Time Frame: week 8 and week 16 ]
   Change from week 8 to week 16 in CD4+ T-cell activation, defined as the %CD38+/HLA-DR+
8. Change in CD8+ T-cell Activation [ Time Frame: baseline and week 4 ]
   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
9. Change in CD8+ T-cell Activation [ Time Frame: Baseline and Week 8 ]
   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
10. Change in CD8+ T-cell Activation [ Time Frame: week 8 and week 16 ]
    Change in CD8+ T-cell activation defined as the %CD38+/HLA-DR+ from week 8 to week 16
11. Change in Proportion of Cycling CD8+ [ Time Frame: baseline and week 4 ]
    Change from baseline to week 4 in cycling CD8+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry
12. Change in Proportion of Cycling CD8+ [ Time Frame: baseline and week 8 ]
    Change from baseline to week 8 in cycling CD8+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry
13. Change in Proportion of Cycling CD8+ [ Time Frame: from week 8 to week 16 ]
    Change from week 8 to week 16 in cycling CD8+ , defined as the %Ki67+
14. Change in Proportion of Cycling CD4+ [ Time Frame: baseline and week 4 ]
    Change from baseline to week 4 in cycling CD4+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry
15. Change in Proportion of Cycling CD4+ [ Time Frame: baseline and week 8 ]
    Change from baseline to week 8 in cycling CD4+ , defined as the %Ki67+, where baseline value is the average of pre-entry and entry
16. Change in Proportion of Cycling CD4+ [ Time Frame: week 8 and week 16 ]
    Change from week 8 to week 16 in cycling CD4+ , defined as the %Ki67+
17. Change in Blood Phosphate Levels [ Time Frame: from baseline to week 4 ]
    Change in blood phosphate levels from baseline to week 4, where baseline value is the average of pre-entry and entry
18. Change in Blood Phosphate Levels [ Time Frame: Baseline to Week 8 ]
    Change in blood phosphate levels from baseline to week 8
19. Change in Blood Phosphate Levels [ Time Frame: from week 8 to week 16 ]
    Change in blood phosphate levels from week 8 to week 16
20. Change in log10 HIV RNA Levels [ Time Frame: baseline and week 4 ]
    Change in log10 HIV RNA levels from baseline to week 4, where baseline value is the average of pre-entry and entry
21. Change in log10 HIV RNA Levels [ Time Frame: baseline and week 8 ]
    Change in log10 HIV RNA levels from baseline to week 8, where baseline value is the average of pre-entry and entry
22. Change in log10 HIV RNA Levels [ Time Frame: week 8 and week 16 ]
    Change in log10 HIV RNA levels from week 8 to week 16
23. Change in CD4+ T-cell Counts [ Time Frame: baseline and week 4 ]
    Change in CD4+ T-cell counts from baseline to week 4, where baseline is the average of pre-entry and entry
24. Change in CD4+ T-cell Counts [ Time Frame: baseline and week 8 ]
    Change in CD4+ T-cell counts from baseline to week 8, where baseline is the average of pre-entry and entry
25. Change in CD4+ T-cell Counts [ Time Frame: week 8 and week 16 ]
    Change in CD4+ T-cell counts from week 8 to week 16
26. Change in IL-6 [ Time Frame: baseline and week 4 ]
    Changes in levels of systemic inflammation marker IL-6 from baseline to week 4, where baseline is the average of pre-entry and entry
27. Change in IL-6 [ Time Frame: baseline and week 8 ]
    Changes in levels of systemic inflammation marker IL-6 from baseline to week 8, where baseline is the average of pre-entry and entry
28. Change in IL-6 [ Time Frame: week 8 and week 16 ]
    Changes in levels of systemic inflammation marker IL-6 from week 8 to week 16
29. Change in C-reactive Protein (CRP) [ Time Frame: 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
30. Change in CRP [ Time Frame: Baseline and Week 8 ]
    Changes in levels of systemic inflammation marker CRP from baseline to week 8, where baseline is the average of pre-entry and entry
31. Change in CRP [ Time Frame: 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
32. Change in D-dimer [ Time Frame: baseline and week 4 ]
    Change in levels of coagulation biomarker d-dimer from baseline to week 4, where baseline value is the average of pre-entry and entry
33. Change in D-dimer [ Time Frame: baseline and week 8 ]
    Change in levels of coagulation biomarker d-dimer from baseline to week 8, where baseline value is the average of pre-entry and entry
34. Change in D-dimer [ Time Frame: week 8 and week 16 ]
    Change in levels of coagulation biomarker d-dimer from week 8 to week 16
35. Change in Tissue Factor [ Time Frame: baseline and week 4 ]
    Change in levels of coagulation biomarker tissue factor from baseline to week 4, where baseline value is the average of pre-entry and entry
36. Change in Tissue Factor [ Time Frame: baseline and week 8 ]
    Change in levels of coagulation biomarker tissue factor from baseline to week 8, where baseline value is the average of pre-entry and entry
37. Change in Tissue Factor [ Time Frame: week 8 and week 16 ]
    Change in levels of coagulation biomarker tissue factor from week 8 to week 16
38. Change in Total Cholesterol [ Time Frame: baseline and week 8 ]
    Change in total cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry
39. Change in Total Cholesterol [ Time Frame: week 8 and week 16 ]
    Change in total cholesterol from week 8 to week 16
40. Change in LDL Cholesterol [ Time Frame: baseline and week 8 ]
    Change in fasting LDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry
41. Change in LDL Cholesterol [ Time Frame: week 8 and week 16 ]
    Change in fasting LDL cholesterol from week 8 to week 16
42. Change in HDL Cholesterol [ Time Frame: baseline and week 8 ]
    Change in fasting HDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry
43. Change in HDL Cholesterol [ Time Frame: from week 8 to week 16 ]
    Change in fasting HDL cholesterol from week 8 to week 16
44. Change in Non-HDL Cholesterol [ Time Frame: baseline and week 8 ]
    Change in non-HDL cholesterol from baseline to week 8, where baseline value is the average of pre-entry and entry
45. Change in Non-HDL Cholesterol [ Time Frame: week 8 and week 16 ]
    Change in non-HDL cholesterol from week 8 to week 16
46. Change in Fasting Glucose [ Time Frame: baseline and week 8 ]
    Change in fasting glucose from baseline to week 8, where baseline value is the average of pre-entry and entry
47. Change in Fasting Glucose [ Time Frame: week 8 and week 16 ]
    Change in fasting glucose from week 8 to week 16
48. Primary Adverse Events [ Time Frame: 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)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

Alabama Therapeutics CRS (5801)

Birmingham, Alabama, United States, 35294

United States, California

UCLA CARE Center CRS (601)

Los Angeles, California, United States, 90095

Ucsf Aids Crs (801)

San Francisco, California, United States, 94110

Harbor-UCLA Med. Ctr. CRS (603)

Torrance, California, United States, 90502

United States, Colorado

University of Colorado Hospital CRS (6101)

Aurora, Colorado, United States, 80045

United States, Florida

Univ. of Miami AIDS CRS (901)

Miami, Florida, United States, 33136

United States, Illinois

Northwestern University CRS (2701)

Chicago, Illinois, United States, 60611

United States, Massachusetts

Massachusetts General Hospital ACTG CRS (101)

Boston, Massachusetts, United States, 02114

United States, Missouri

Washington University CRS (2101)

Saint Louis, Missouri, United States, 63110

United States, New York

AIDS Care CRS (1108)

Rochester, New York, United States, 14642

Univ. of Rochester ACTG CRS (1101)

Rochester, New York, United States, 14642

United States, Ohio

Univ. of Cincinnati CRS (2401)

Cincinnati, Ohio, United States, 45267

Case CRS (2501)

Cleveland, Ohio, United States, 44106

Metro Health CRS (2503)

Cleveland, Ohio, United States, 44109

United States, Pennsylvania

Hosp. of the Univ. of Pennsylvania CRS (6201)

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

AIDS Clinical Trials Group

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Rajesh Gandhi, MD; Massachusetts General Hospital ACTG CRS
• Study Chair: Netanya Sandler, MD; National Institutes of Health (NIH)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01543958
• Other Study ID Numbers: ACTG A5296; 1U01AI068636 ( U.S. NIH Grant/Contract )
• First Posted: March 5, 2012
• Results First Posted: November 25, 2013
• Last Update Posted: October 11, 2018
• Last Verified: September 2018

Additional relevant MeSH terms:

Endotoxemia; Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Sevelamer; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action