Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
This study is intended to evaluate:

 1. 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.

 2. 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.
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.
Inclusion Criteria:

 1. 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.

 2. Body Mass Index (BMI) between 18 and 32 kg/m2 (both inclusive).

 3. 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

 4. No history or evidence of clinically relevant medical disorders as determined by the
 investigator.

 5. 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

 6. Male and female patients receiving a stable CART for ≥ 4 weeks for HIV treatment.

 7. 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

 8. CD4 counts >200/µL at the Screening Visit.

 9. 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

 10. CD4 counts >400/µL inclusive at the Screening Visit.

 11. Plasma levels of HIV RNA < 50 copies/mL at the Screening Visit.

 Exclusion Criteria:

 Applicable to ALL subjects

 1. Any serious systemic disease or infection (other than HIV in PLWHA) that occurred
 within four weeks prior to Screening, as determined by the Investigator.

 2. 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.

 3. Stool cultures that are positive for any pathogenic infection at screening visit.

 4. Clinically significant cardiovascular disease will include:

 1. History of stroke, transient ischemic attack, or myocardial infarction within 6
 months prior to Screening.

 2. History of or currently have New York Heart Association Class III-IV heart
 failure prior to Screening.

 5. Female subject who is pregnant or breast-feeding or intends to become pregnant or is
 of childbearing potential and not using adequate contraceptive methods.

 6. 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.

 7. Use of Mytesi (crofelemer) within 4 weeks of the Screening Visit Applicable to ALL
 HIV-negative subjects

 8. Positive for Human Immunodeficiency Virus (HIV) antibodies, hepatitis B surface
 antigen (HBsAg), hepatitis B core antibody or hepatitis C antibodies (HepCAb).

 9. 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.

 10. 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

 11. HIV Patients with infectious diarrhea identified by either stool culture