This is a randomized, double-blind, parallel-group, placebo-controlled, multi-center study. This study will compare an Investigational new drug (crofelemer) to placebo for the control of HIV-associated diarrhea. The first stage of the study will determine the optimal dose of study drug based on safety and response to therapy and the second stage will evaluate further the effectiveness of the optimal dose.

The purpose of this study is to test the efficacy and safety of crofelemer while treating patients with HIV-associated diarrhea. This study has two stages. The first 200 patients into the study will enroll into Stage 1. In Stage 1, three doses of crofelemer will be compared to placebo. In Stage 1, study participants are randomly assigned to 1 of 4 groups:

• crofelemer 125 mg by mouth twice a day,
• crofelemer 250 mg by mouth twice a day,
• crofelemer 500 mg by mouth twice a day, or
• placebo by mouth twice a day.

After Stage 1 is completed, the dose of crofelemer that appears to work best and /or is better tolerated than the others will be selected to be used exclusively in Stage 2.

The next 150 subjects that enroll will start in Stage 2 and will be randomly assigned to receive either the selected dose of crofelemer or placebo. In Stage 2, participants will have a 50:50 chance of receiving either crofelemer or placebo.

Study Requirements:

Each Stage consists of a 10-day screening period, a 31-day study phase (double-blind, placebo-controlled) and a 5-month extension phase (placebo-free, all participants in this stage will receive crofelemer for up to 5 months).

Daily phone diary describing diarrhea symptoms will be required throughout the 28 weeks of study participation.

Maximum duration of study participation is approximately 28 weeks.

Study Phase: Phase III

Study Type: Interventional, Supportive care

Study Design: Multi-center, Double-blind, Placebo-controlled, Two-stage Adaptive design

Primary Outcome Measures:

The primary objective is to determine the proportion of HIV-positive subjects experiencing relief of diarrhea with crofelemer compared to placebo during the placebo-controlled treatment phase.

Secondary Outcome Measure(s):

To evaluate the effects of crofelemer vs. placebo on:

• Number of bowel movements per day (frequency)
• Number of watery bowel movements per day
• Symptom frequency (urgency, fecal incontinence)
• Symptom severity (abdominal pain or discomfort)
• Daily stool consistency score
• Safety and tolerability of crofelemer therapy, including the need for anti-diarrhea medication

Condition: HIV Associated Diarrhea

Intervention: Antidiarrheal Medication; crofelemer

Inclusion Criteria:

• Written informed consent
• Male or female, age ≥ 18 years
• History of HIV-1 infection confirmed by standard serological tests
• Stable medical regimen for treatment of HIV disease and associated conditions for at least 4 weeks prior to screening
• Patient-reported history of diarrhea, defined as either persistently loose stools despite regular ADM use, or one or more watery bowel movements per day without regular ADM use, of at least 1 month duration
• Negative pregnancy test if female of child-bearing potential
• Agreement to use a method of contraception throughout the study that is deemed acceptable by the investigator
• Colonoscopy within the past 5 years if ≥ 50 years of age.
• Willingness to withdraw all antidiarrheal and certain other medications for the first 6 weeks of the study
• Willingness to comply with the requirements of the study, including regular study visits and daily telephone diary

Exclusion Criteria:

• Pregnancy or breast-feeding
• Current or past gastrointestinal (GI) medical or surgical conditions including but not limited to the following: GI surgery, history of inflammatory gastrointestinal diseases known to be associated with diarrhea, tube feedings, bowel obstruction or stricture, positive gastrointestinal biopsy or stool test result in the past 4 months for certain pathologic organisms
• Bright red blood per rectum judged not to be of an anal (hemorrhoid, fissure) origin.
• Evidence on prior colonoscopy or upper endoscopy of colitis, enteritis, infection (HIV-associated or otherwise), or neoplasm, other than benign polyps.
• Use of certain opiate pain medication within 2 weeks of screening
• Use of an antibiotic within 2 weeks prior to screening, with the exception of stable antibiotic therapy for prophylactic treatment of infection or an HIV-associated condition
• Oral temperature greater than 100.4 oF or unintentional weight loss of 11 lbs. or greater during the prior 2 months
• Any of the following laboratory abnormalities:
• CD4 counts < 100 cells/mm3
• Serum creatinine ≥ 3.0 mg/dL
• Alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin ≥ 3 times the upper limit of normal
• Hemoglobin (Hgb) < 8.0 mg/dL
• Absolute neutrophil count or lymphocyte count ≤ 500 cells/µL
• Presence or history of cancer of any type (except treated basal cell carcinoma), including Kaposi's sarcoma or other HIV-associated neoplasm, within the last 5 years
• Use of any investigational drug, with the exception of a drug administered through an expanded access program that is registered with the U.S. Food and Drug Administration within 4 weeks of receiving study drug
• Active drug or alcohol abuse, or other medical conditions that in the opinion of the investigator may interfere with the subject's ability to comply with this protocol, or places the subject at increased risk.
• Planned in-patient hospitalization during the study
• Previous randomization into this study, or into any other study in which crofelemer (i.e., Provir®, SP-303)