A Study of the Gut Barrier and Blood Vessel Inflammation in Individuals With and Without HIV

• ClinicalTrials.gov Identifier: NCT02431325
• Recruitment Status: Completed
• First Posted: May 1, 2015
• Last Update Posted: May 28, 2021
• Sponsor: Massachusetts General Hospital
• Collaborators: Ragon Institute of MGH, MIT and Harvard; National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)
• Information provided by (Responsible Party): Janet Lo, MD, Massachusetts General Hospital

Study Description

Brief Summary:

The purpose of this research study is to determine whether teduglutide can repair a "leaky" gut, decrease inflammation, and prevent or treat plaque, a build-up of fat and other materials in the blood vessels of the heart, in people with HIV. HIV disease is linked to inflammatory changes and leakiness of the gut. These changes or conditions may increase the risk of developing heart and blood vessel disease. The investigators believe teduglutide can help repair the gut barrier in people with HIV, leading to a decrease in inflammation and plaque in the blood vessels of the heart.

Condition or disease	Intervention/treatment	Phase
HIV	Drug: Teduglutide; Drug: Placebo	Phase 2

Detailed Description:

As more people with HIV gain access to combination antiretroviral therapy (cART), cardiovascular disease has become increasingly prevalent and a significant cause of mortality. Activation of the innate immune system may stimulate inflammatory mechanisms of atherosclerosis development. Loss of gastrointestinal (GI) mucosal epithelial integrity and loss of CD4+ T-lymphocytes in the intestinal lamina propria occur in HIV-infected patients and are not fully restored by cART. Translocation of microbial products from the intestinal lumen into the systemic circulation has been demonstrated to be increased in HIV-infected patients and the investigators hypothesize that it is a key driver of monocyte and macrophage activation. In turn, these pro-inflammatory monocytes and macrophages can induce atherosclerotic disease development. The purpose of the research study is to determine the effects of a glucagon-like peptide-2 analog, teduglutide, on intestinal epithelial integrity, microbial translocation across the gut lumen, markers of innate immune system activation including the monocyte transcriptome, bone, arterial inflammation, and atherosclerosis in a 6-month randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Study to Investigate Gastrointestinal Epithelial Integrity and Arterial Inflammation in Individuals With and Without HIV
• Study Start Date: December 2015
• Actual Primary Completion Date: January 21, 2020
• Actual Study Completion Date: January 21, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Teduglutide; Teduglutide, subcutaneous injection, 0.05 mg/kg/day, 6 months duration	Drug: Teduglutide; Other Name: Gattex
Placebo Comparator: Placebo; Placebo, subcutaneous injection, 6 months duration	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in soluble CD14 concentration [ Time Frame: Change from baseline at 6 months ]
2. Change in intestinal epithelial integrity [ Time Frame: Change from baseline at 6 months ]
3. Change in arterial target to background ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) uptake [ Time Frame: Change from baseline at 6 months ]

Secondary Outcome Measures :

1. Change in intestinal CD4+ T-cells [ Time Frame: Change from baseline at 6 months ]
2. Change in plaque volume on cardiac computed tomography angiography [ Time Frame: Change from baseline at 6 months ]
3. Change in hemoglobin A1c percentage [ Time Frame: Change from baseline at 6 months ]
4. Change in Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) [ Time Frame: Change from baseline at 6 months ]
5. Change in visceral adipose tissue (VAT) area [ Time Frame: Change from baseline at 6 months ]
6. Change in subcutaneous adipose tissue (SAT) area [ Time Frame: Change from baseline at 6 months ]
7. Change in body mass index (BMI) [ Time Frame: Change from baseline at 6 months ]
8. Change in soluble CD163 concentration [ Time Frame: Change from baseline at 6 months ]
9. Change in intestinal fatty acid binding protein concentration [ Time Frame: Change from baseline at 6 months ]
10. Change in bone mineral density [ Time Frame: Change from baseline at 6 months ]
11. Change in depressive symptoms [ Time Frame: Change from baseline at week 12 and at week 24 ]
12. Change in cognitive performance, defined as a global neurocognitive z-score [ Time Frame: Change from baseline at week 24 ]
13. Change in domain-specific cognitive performance, defined as a domain-specific neurocognitive z-score [ Time Frame: Change from baseline at week 24 ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Men and women age 21-65 with previously diagnosed HIV disease
2. Stable anti-retroviral therapy (ART) as defined by no changes in ART regimen for >6 months
3. HIV viral load < 200 copies/mL

4. To be eligible for colonoscopy procedure, laboratory values that meet the following criteria:

   1. Hemoglobin > 9.0 g/dL
   2. Absolute neutrophil count ≥ 1000/mm3
   3. Platelet count ≥ 100,000/mm3
   4. Prothrombin time (PT) < 1.2 x upper limit of normal (ULN)
   5. Partial thromboplastin time (PTT) < 1.5 x ULN

4. Ability and willingness to give written informed consent and to comply with study requirements

Exclusion Criteria:

1. History of clinically significant gastrointestinal disease including but not limited to: colon cancer, intestinal obstruction, ulcerative colitis, Crohn's disease, or history of C. difficile within the past 3 months
2. First-degree relative with history of colon cancer
3. Active gall bladder, biliary or pancreatic disease
4. Female subject who is pregnant, nursing or less than 8 weeks post partum.
5. Use of any immunomodulatory agents within 30 days prior to study enrollment
6. History of intolerance, sensitivity, allergy or anaphylaxis to benzodiazepines or other narcotics to be used during the colonoscopy or upper endoscopy procedure
7. Contraindication to beta-blocker (including moderate to severe asthma or heart block) or nitroglycerin use as these drugs are given as part of the standard cardiac CT protocol. Previous allergic reaction to beta blocker or nitroglycerin.
8. Patients with previous allergic reactions to iodine-containing contrast media
9. Renal disease or creatinine >1.5 mg/dL (contrast will be administered during CT angiography of the heart)
10. History of requiring antibiotic prophylaxis for invasive procedures
11. History of myocardial infarction, decompensated cirrhosis, or any other condition that in the opinion of the investigator will compromise ability to participate in the study
12. Currently taking anticoagulants including but not limited to: heparin (Hep-Lock, Hep-Pak), Hep-Pak CVC, Heparin Lock Flush), warfarin (Coumadin), tinzaparin (Innohep), enoxaparin (Lovenox), danaparoid (Orgaran), dalteparin (Fragmin), clopidogrel (Plavix), prophylactic aspirin, and regular NSAID use
13. Subject taking any of the following medications: statins, systemic steroids (inhaled or nasal steroid therapy is permitted), interleukins, systemic interferons (e.g. local injection of interferon alpha for treatment of HPV is permitted), systemic chemotherapy including oral chemotherapeutic agents, methotrexate, octreotide, growth hormone, antiarrhythmics including digoxin, antiepileptics, immunosuppressants, vancomycin, rifampin, aminoglycosides, clonidine, prazosin, lithium and ritonavir-boosted lopinavir (Kaletra).
14. Subject has had two or more endoscopy procedures (sigmoidoscopy, upper endoscopy or colonoscopy) within the past 12 months for clinical purposes or other research studies.
15. Body weight greater than 300 lbs due to CT scanner table limitations
16. Active illicit drug use

17. Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as:

    1. More than 2 percutaneous coronary interventions (PCI) within 12 months of randomization
    2. More than 2 myocardial perfusion studies within the past 12 months
    3. More than 2 CT angiograms within the past 12 months
    4. Any subjects with history of radiation therapy

18. Patients already scheduled or being considered for a procedure or treatment

    1. requiring significant radiation exposure (e.g., radiation therapy, PCI, or catheter
    2. ablation of arrhythmia) within 12 months of randomization
19. History of malignancy
20. Prior recipient of a HIV vaccine

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

Ragon Institute of MGH, MIT and Harvard

National Heart, Lung, and Blood Institute (NHLBI)

National Institutes of Health (NIH)

Investigators

• Principal Investigator: Janet Lo, MD, MMSc; Massachusetts General Hospital

More Information

• Responsible Party: Janet Lo, MD, Assistant Professor in Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02431325
• Other Study ID Numbers: 2013P002669; 1R01HL123351-01 ( U.S. NIH Grant/Contract )
• First Posted: May 1, 2015
• Last Update Posted: May 28, 2021
• Last Verified: May 2021

Keywords provided by Janet Lo, MD, Massachusetts General Hospital:

HIV; Atherosclerosis; Microbial Translocation; Teduglutide; Gastrointestinal Permeability; Inflammation

Additional relevant MeSH terms:

Inflammation; Pathologic Processes; Teduglutide; Gastrointestinal Agents; Radiation-Protective Agents; Protective Agents; Physiological Effects of Drugs