Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea

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

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

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

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

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

• CD4 counts >400/µL inclusive at the Screening Visit.
• Plasma levels of HIV RNA < 50 copies/mL at the Screening Visit.

Exclusion criteria

Applicable to ALL subjects

• Any serious systemic disease or infection (other than HIV in PLWHA) that occurred within four weeks prior to Screening, as determined by the Investigator.
• 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.
• Stool cultures that are positive for any pathogenic infection at screening visit.
• Clinically significant cardiovascular disease will include:

• History of stroke, transient ischemic attack, or myocardial infarction within 6 months prior to Screening.
• History of or currently have New York Heart Association Class III-IV heart failure prior to Screening.
• Female subject who is pregnant or breast-feeding or intends to become pregnant or is of childbearing potential and not using adequate contraceptive methods.
• 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.
• Use of Mytesi (crofelemer) within 4 weeks of the Screening Visit Applicable to ALL HIV-negative subjects
• Positive for Human Immunodeficiency Virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody or hepatitis C antibodies (HepCAb).
• 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.
• 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