Study of Efficacy and Safety of ABO809 in Healthy Participants

An Open Label Cryptosporidium Controlled Human Infection Model (CHIM) to Assess the Efficacy and Safety of ABO809 in Healthy Participants

The purpose of this Phase I controlled human infection model (CHIM) study was to determine if oral administration of a good manufacturing practice (GMP) supply of Cryptosporidium parvum oocysts (ABO809) to healthy volunteers resulted in a Cryptosporidium infection and diarrheal illness. The study measured fecal oocysts (parasitological endpoint) as well as diarrhea and associated signs and symptoms (clinical endpoint).

This study was funded by the Wellcome Trust. This Phase 1 Cryptosporidium controlled human infection model (CHIM) study employed a single-center, open-label design to characterize the incidence of infection and associated symptoms following the administration of single doses of Cryptosporidium parvum oocysts (CE). Healthy volunteers were enrolled in cohorts of approximately 10 participants who received ABO809 on the same day (Day 1). The study consisted of three (to a maximum of six) sequential cohorts which were dosed one after the other for a total of 30 (to a maximum of approximately 60) participants. A dose level group received the same ABO809 dose and could be comprised of multiple cohorts. The first dose level group started with a cohort of 10 participants who received ABO809 at a dose of 1x10^4 oocysts. The study continued to enroll participants in the same dose level group if the desired incidences of infection and diarrheal illness were observed, up to a total of approximately 30 participants. If the desired incidences of infection and diarrheal illness were not observed, a new dose level group, receiving ABO809 at a dose of 1x10^6 oocysts, could be initiated. If needed to optimize the model, intermediate ABO809 doses could be evaluated.

Controlled Human Infection Model, CHIM, infection, diarrhea, safety, tolerability, healthy volunteers, Phase I, cryptosporidiosis, Cryptosporidium, oral, ABO809

Participants will receive ABO809 at a single oral dose of 1x10^4 oocysts. Other doses such as 1x10^6 oocysts may be considered to optimize the model

Percentage of participants with cryptosporidium infection from 72 hours to 10 Days post ABO809 oral administration

Percentage of participants with cryptosporidium infection following an oral administration of ABO809. Cryptosporidium infection will be measured by examining the presence of a Cryptosporidium antigen in stool using a commercially available diagnostic Enzyme Immunoassay (EIA) test.

From 72 hours post-administration (or sooner if associated with symptoms suggestive of diarrheal illness) up to Day 10

Percentage of participants showing clinical diarrheal illness from Day 1 to Day 28 post ABO809 oral administration

A participant will be considered as showing clinical diarrheal illness if diarrhea is observed on at least two days during the observation period from Day 1 to Day 28. Resolution of diarrheal illness from Crypotosporidium infection requires ≥2 consecutive days with no diarrheal stools (stool sample grades 1 or 2).

Diarrhea is defined as at least one stool sample grading 3-5 on the Stool Grading system in one day. Grades 1 and 2 are considered normal stool and Grades 3-5 are considered diarrheal stool. Grades 3-5 stools are defined as thick liquid diarrhea taking the shape of the container, opaque watery, rice water or clear watery stools.

Stool weight in grams of each stool from each participant will be measured during inpatient period from Day 1 up to Day 10. Stool weight in grams of stool collected 24 hours prior to outpatient visit from each participant will be measured during outpatient period from Day 14 to Day 28.

All collected stool samples will be graded according to the Stool Grading system. Grades 1 and 2 are considered normal stool and Grades 3-5 are considered diarrheal stool. Grades 3-5 stools are defined as thick liquid diarrhea taking the shape of the container, opaque watery, rice water or clear watery stools.

Number of days until the start diarrheal illness, which is defined as at least 2 diarrheal bowel movements within 24 hours on at least 2 days.

Number of days until the resolution of diarrheal illness, which is defined as 2 or more consecutive days with no diarrheal stools (stool grades 1 or 2).

Percentage of participants with characteristics of clinical signs and symptoms associated with clinical diarrheal illness

Clinical signs and symptoms associated with clinical diarrheal illness such as: abdominal pain, abdominal cramping, nausea, vomiting, fever, electrolyte disbalance, dehydration.

Percentage of participants with Cryptosporidium infection from 72 hours to Day 28 post ABO809 oral administration

Percentage of participants with Cryptosporidium infection following an oral administration of ABO809. Cryptosporidium infection will be measured by examining the presence of a Cryptosporidium antigen in stool using a commercially available diagnostic Enzyme Immunoassay (EIA) test.

From 72 hours post-administration (or sooner if associated with symptoms suggestive of diarrheal illness) up to Day 28

Percentage of participants with fecal shedding of Cryptosporidium parvum oocysts following an oral administration of ABO809. Fecal shedding will be measured by examining the presence of a Cryptosporidium antigen in stool using a commercially available diagnostic Enzyme Immunoassay (EIA) test.

Number of days until the start of Cryptosporidium infection which will be measured by examining the presence of a Cryptosporidium antigen in stool using a commercially available diagnostic Enzyme Immunoassay (EIA) test.

Number of days until the resolution of Cryptosporidium infection in participants who developed an infection following an oral administration of ABO809. Resolution of Cryptosporidium infection is defined as no evidence of Cryptosporidium in stool samples collected over ≥2 consecutive days.

Number of adverse events of special interest (AESIs) by telephone follow-up after Day 28 visit through 12 months post ABO809 oral administration

The following adverse events associated with Cryptosporidium infection are considered AESIs in this trial: Gastroenteritis in the absence of Cryptosporidium infection, extraintestinal cryptosporidiosis, persistent or recurrent cryptosporidosis, persistent cryptosporidium shedding, moderate or severe dehydration and non-intestinal sequelae including eye pain or joint pain.

Inclusion Criteria: Demonstrated understanding of Cryptosporidium disease, safety measures and transmission risks Good health Ability to communicate well with the Investigator Exclusion Criteria: - History of Cryptosporidium infection, gastrointestinal conditions (including diarrheal syndromes, gastroenteritis and gastrointestinal tract surgery), immunodeficiency, infections, significant medical concerns, hypersensitivity to nitazoxanide or other specified antibiotics. Other protocol-defined inclusion/exclusion criteria may apply.