Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
Study Details
Study Description
Brief Summary
This study is intended to evaluate:
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Any changes in the gut microbiome from baseline compared to end of study in both healthy (HIV-negative) subjects and HIV+ patients with or without chronic diarrhea, following one month of treatment with crofelemer (Mytesi), delayed release 125 mg tablets twice daily (BID) following one month of treatment.
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The safety and tolerability of crofelemer, (Mytesi) delayed release 125 mg tablets BID in healthy (HIV-negative) volunteers and HIV+ patients following one month of treatment.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Detailed Description
Mytesi ®(crofelemer) is an FDA-approved anti-diarrheal drug indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on combination anti-retroviral therapy (CART). Crofelemer, a first-in-class intraluminally active, use-dependent chloride (Cl-) ion channel modulator that produces an antidiarrheal effect by reducing Cl- secretion and the accompanying high-volume fluid secretion into the GI lumen.
This Phase 4 trial will explore the induced gut microbiome changes in comparison to a group of normal healthy volunteers also receiving crofelemer delayed release 125 mg tablets twice daily for 30 days.
This is a non-randomized study. The study will enroll approximately 24 male or female subjects aged at least 18 years in three cohorts of approximately 8 subjects each.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Healthy Volunteers (HIV-negative) Drug: crofelemer delayed-release tablets, 125 mg BID x 30 days |
Drug: Crofelemer delayed-release tablets 125mg
1 crofelemer delayed-release tablet twice daily at least 8 hours apart for 30 days with or without meals.
Other Names:
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Experimental: HIV+ Patients (Fully Suppressed, Viral Load < 50c/mL) Drug: crofelemer delayed-release tablets, 125mg BID x 30 Days |
Drug: Crofelemer delayed-release tablets 125mg
1 crofelemer delayed-release tablet twice daily at least 8 hours apart for 30 days with or without meals.
Other Names:
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Experimental: HIV+ Patients (Not fully suppressed viral load > 1000c/mL Drug: crofelemer delayed-release tablets, 125mg BID x 30 Days |
Drug: Crofelemer delayed-release tablets 125mg
1 crofelemer delayed-release tablet twice daily at least 8 hours apart for 30 days with or without meals.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Changes in gut microbiome [Screening (Visit 1/Day -21) to end of Study Visit 4 (Day 60)]
Stool microbiomes will be evaluated to compare the differences in the stool microbiome at Visits 2, (Day 1) Visit 3 (Day 30) and Visit 4 (Day 60) using a proprietary microbiome statistical tool (μScope) and R statistical computing and graphics software.
Secondary Outcome Measures
- Evaluation of reduction in the number of watery BMs [From baseline (Day -7) to end of study (Day 60)]
Defined as a score of 6 or 7 on the Bristol Stool Scale
- Assessment of changes in Daily GI symptom Scale (DGIS) [From baseline (Day -7) to end of study (Day 60)]
Daily presence or absence of abdominal pain, bloating, gurgling, flatulence, and bowel incontinence
Eligibility Criteria
Criteria
Inclusion Criteria:
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Voluntary informed consent from the subject to be obtained in accordance with requirements of the Institutional Review Board (IRB) before any study-related activities are performed.
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Body Mass Index (BMI) between 18 and 32 kg/m2 (both inclusive).
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Females of child-bearing potential must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test at Visit 2.
Inclusion Criteria for Healthy, HIV-negative Volunteers
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No history or evidence of clinically relevant medical disorders as determined by the investigator.
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No history of chronic diarrhea or loose stools and/or non-specific incidence of acute diarrhea or loose stools between the Screening Visit and Baseline Visit 2 (Day 1).
Inclusion Criteria applicable to all PLWHA subjects
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Male and female patients receiving a stable CART for ≥ 4 weeks for HIV treatment.
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Have a history of diarrhea (persistently loose stools despite periodic or regular use of antimotility medications) or ≥1 watery bowel movement per day (without periodic or regular use of antimotility drugs); i.e. - diarrhea for a continuous period of ≥1 month.
Inclusion Criteria for PLWHA males and females receiving CART WITHOUT fully suppressed HIV RNA counts
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CD4 counts >200/µL at the Screening Visit.
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Plasma levels of HIV RNA greater than 1,000 copies/mL at the Screening Visit.
Inclusion Criteria for PLWHA males and females receiving CART WITH fully suppressed HIV RNA counts
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CD4 counts >400/µL inclusive at the Screening Visit.
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Plasma levels of HIV RNA < 50 copies/mL at the Screening Visit.
Exclusion Criteria:
Applicable to ALL subjects
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Any serious systemic disease or infection (other than HIV in PLWHA) that occurred within four weeks prior to Screening, as determined by the Investigator.
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Patients with active bacterial or parasitic infections requiring antibiotics or antiparasitic agents will be excluded. Antibiotic or antiparasitic agents used for prophylaxis are acceptable until 7 days prior to treatment initiation.
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Stool cultures that are positive for any pathogenic infection at screening visit.
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Clinically significant cardiovascular disease will include:
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History of stroke, transient ischemic attack, or myocardial infarction within 6 months prior to Screening.
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History of or currently have New York Heart Association Class III-IV heart failure prior to Screening.
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Female subject who is pregnant or breast-feeding or intends to become pregnant or is of childbearing potential and not using adequate contraceptive methods.
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Subject has participated in another clinical study, involving an Investigational Product or an Investigational Device use in the past 1 month prior to commencement of this study.
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Use of Mytesi (crofelemer) within 4 weeks of the Screening Visit Applicable to ALL HIV-negative subjects
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Positive for Human Immunodeficiency Virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody or hepatitis C antibodies (HepCAb).
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Presence or history of cancer within the past five years except for adequately treated localized basal cell skin cancer or in situ uterine cervical cancer.
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Chronic diarrhea or loose stools requiring antimotility medications including, but not limited to loperamide, diphenoxylate/atropine, tincture opium and/or octreotide within 2 weeks of the Screening Visit.
Applicable to ALL PLWHA subjects
- HIV Patients with infectious diarrhea identified by either stool culture
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Orange County Research Center | Tustin | California | United States | 92780 |
2 | Healthcare Advocates International | Stratford | Connecticut | United States | 06615 |
3 | The Research Institute | Springfield | Massachusetts | United States | 01105 |
Sponsors and Collaborators
- Napo Pharmaceuticals, Inc.
Investigators
- Principal Investigator: David Smith, MD, Integrium Clinical Research
Study Documents (Full-Text)
None provided.More Information
Publications
- Cello JP, Day LW. Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens. Gastroenterology. 2009 May;136(6):1952-65. doi: 10.1053/j.gastro.2008.12.073. Epub 2009 May 7. Review. Erratum in: Gastroenterology. 2009 Jul;137(1):393.
- MacArthur RD, DuPont HL. Etiology and pharmacologic management of noninfectious diarrhea in HIV-infected individuals in the highly active antiretroviral therapy era. Clin Infect Dis. 2012 Sep;55(6):860-7. doi: 10.1093/cid/cis544. Epub 2012 Jun 14. Review.
- Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013 Nov-Dec;14(6):261-73. doi: 10.1310/hct1406-261.
- Siddiqui U, Bini EJ, Chandarana K, Leong J, Ramsetty S, Schiliro D, Poles M. Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of highly active antiretroviral therapy. J Clin Gastroenterol. 2007 May-Jun;41(5):484-90.
- Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6.
- NP 303-103