Auranofin for Giardia Protozoa
Auranofin for Giardia Protozoa
This is a phase IIa, randomized, placebo-controlled, single-blinded superiority treatment
 study in males and non-pregnant females, 18 to 65 years of age who are in good health. This
 study is designed to compare placebo to once daily doses of 6mg auranofin for adults with
 amebiasis or giardiasis. A sample size of 68 subjects enrolled with amebiasis (34 per arm)
 and 68 with giardiasis (34 per arm); Power based on 60 subjects with amebiasis and 60 with
 giardiasis completing the study.Eligible subjects will be randomly assigned to a treatment
 group with auranofin (6 mg orally once daily for 5 days for giardiasis or 7 days for
 amebiasis) compared to a placebo group receiving similar but not identical placebo capsules.
 Projected duration of subject participation will be approximately 30 days of face to face
 visits, including the pre-enrollment screening period of up to 4 days. It is anticipated that
 it will take approximately 3.5 years to finish the study. Primary objectives are: 1) to
 compare the proportion of subjects with stools positive by rapid Enzyme Immunoassay (EIA) and
 positive antigen detection EIA for E. histolytica at enrollment with resolution of diarrhea
 (less than 3 loose stools/24 hrs) by Day 7 for E. histolytica infections. 2) to compare the
 proportion of subjects with stools positive by rapid EIA and positive antigen detection EIA
 for Giardia at enrollment with resolution of diarrhea (less than 3 loose stools/24 hrs) by
 Day 5 for Giardia infections.
This is a phase IIa, randomized, placebo-controlled, single-blinded superiority treatment
 study in males and non-pregnant females, 18 to 65 years of age who are in good health. This
 study is designed to compare placebo to once daily doses of 6mg auranofin for adults with
 amebiasis or giardiasis. A sample size of 68 subjects enrolled with amebiasis (34 per arm)
 and 68 with giardiasis (34 per arm); Power based on 60 subjects with amebiasis and 60 with
 giardiasis completing the study. Eligible subjects will be randomly assigned to a treatment
 group with auranofin (6 mg orally once daily for 5 days for giardiasis or 7 days for
 amebiasis) compared to a placebo group receiving similar but not identical placebo capsules.
 Projected duration of subject participation will be approximately 30 days of face to face
 visits, including the pre-enrollment screening period of up to 4 days. It is anticipated that
 it will take approximately 3.5 years to finish the study. Primary objectives are: 1) to
 compare the proportion of subjects with stools positive by rapid Enzyme Immunoassay (EIA) and
 positive antigen detection EIA for E. histolytica at enrollment with resolution of diarrhea
 (less than 3 loose stools/24 hrs) by Day 7 for E. histolytica infections. 2) to compare the
 proportion of subjects with stools positive by rapid EIA and positive antigen detection EIA
 for Giardia at enrollment with resolution of diarrhea (less than 3 loose stools/24 hrs) by
 Day 5 for Giardia infections. Secondary objectives for E. histolytica infections are: 1) to
 compare the proportion of subjects with stools positive by rapid EIA and positive antigen
 detection EIA for E. histolytica and trophozoites on smear at enrollment with parasitological
 response (no detection of trophozoites of E. histolytica on microscopic exam) by Day 7; 2) to
 compare the proportion of subjects with stools positive rapid EIA and positive antigen
 detection EIA for E. histolytica and trophozoites on smear at enrollment with parasitological
 response (no detection of trophozoites on microscopic exam or negative antigen detection) by
 Days 3 and 5; 3) to compare the rate of decrease of trophozoites/cyst load by Quantitative
 Polymerase Chain Reaction (qPCR) in stools by Days 3, 5, and 7; 4) to compare the proportion
 of subjects with negative stool antigen tests by days 3, 5, 7, and 14; 5) to compare the
 proportion of subjects with sustained cure (no detection of trophozoites by microscopic exam)
 at 14 and 28 days; 6) to compare the proportion of subjects with relapse (same strain) or
 re-infection (new strain) with positive stools at 14 and 28 days by genotyping the initial
 vs. subsequent strain; 7) to compare the time to resolution of diarrhea (less than 3 loose
 stools/24 hours). Secondary objectives for Giardia infections are: 1) to compare the
 proportion of subjects with parasitological response (no detection of trophozoites on
 microscopic exam ) on Day 3, and 5; 2) to compare the rate of decrease of trophozoites/cyst
 load by qPCR in stools by Days 3 and 5; 3) to compare the proportion of subjects with
 negative stool antigens by days 3 and 5; 4) to compare the proportion of subjects with
 sustained cure (no detection of trophozoites by microscopic exam) at 14 and 28 days; 5) to
 compare the proportion of subjects with relapse (same strain) or re-infection (new strain)
 with positive stools at 14 and 28 days by genotyping the initial vs. subsequent strain; 6) to
 compare the time to resolution of diarrhea (less than 3 loose stools/24 hours).
Inclusion Criteria:

 1. Provide written informed consent prior to initiation of any study procedures.

 2. Able to understand and comply with planned study procedures and be available for all
 study visits.

 3. Male or non-pregnant non-lactating females 18-65 years of age, inclusive. Females of
 reproductive potential currently using effective contraceptive methods are eligible.

 4. Amebiasis or giardiasis identified by rapid Enzyme Immunoassay (EIA) and positive
 antigen detection EIA of stool

 - if a subject is infected with both E. histolytica and Giardia, they will be enrolled
 in the E. histolytica study arm. Once the Entamoeba study arm is fully enrolled, any
 subsequent dual infected subjects will be enrolled in the Giardia arm. If a subject is
 infected with both Giardia and Cryptosporidium, they will not be enrolled.

 5. Has diarrhea (defined as three or more loose stools) in the past 24 hrs, but is
 assessed to be clinically stable and in otherwise good health

 - as determined by medical history and targeted physical examination, if indicated
 based on medical history, to evaluate acute or currently ongoing chronic medical
 diagnoses or conditions that would affect the assessment of eligibility and safety of
 subjects. Existing medical diagnoses or conditions (except those in the Subject
 Exclusion Criteria) must be deemed as stable chronic medical conditions. A stable
 chronic medical condition is defined as no change in prescription medication, dose, or
 frequency of medication in the last 3 months (90 days) and health outcomes of the
 specific disease are considered to be within acceptable limits in the last 6 months
 (180 days). Any change due to change of health care provider, insurance company, or
 that is done for financial reasons, as long as in the same class of medication, will
 not be considered a violation of this inclusion criterion. Any change in prescription
 medication due to improvement of a disease outcome, as determined by the site
 principal investigator or appropriate sub-investigator, will not be considered a
 violation of this inclusion criterion. Subjects may be on chronic or as needed (prn)
 medications if, in the opinion of the site principal investigator or appropriate
 sub-investigator, they pose no additional risk to subject safety. Topical, nasal, and
 inhaled medications, vitamins, and contraceptives are permitted.

 6. Vital signs (oral temperature, pulse, and blood pressure) are all within normal
 protocol-defined ranges.

 7. Laboratory tests (blood urea nitrogen, creatinine, aspartate transaminase (AST),
 alanine transaminase (ALT), white blood cells, platelets, and hemoglobin) are all
 within protocol-defined ranges. Subjects will be eligible for enrollment with the
 following laboratory values: blood urea nitrogen less than or equal to 30 mg/dL,
 creatinine less than or equal to 133 umol/L, AST or ALT less than or equal to 70.0
 U/L, white cell count between 3.5 and 13.0 inclusive (10^9/L), platelets between 131
 and 550 (10^9/L), hemoglobin between 11.0 and 18.0 gm/dL inclusive.

 8. Urinalysis with no greater than trace protein. If a high protein is confirmed to be
 due to menstruation, it should be repeated.

 9. Women of reproductive potential must have a negative urine pregnancy test within 72
 hours of starting study medications.

 - Female subjects who are surgically sterile via tubal sterilization, bilateral
 oophorectomy or hysterectomy who have been postmenopausal for greater than 1 year are
 not considered to be of reproductive potential.

 10. Female subjects participating in sexual activity that could lead to pregnancy must be
 using and continue to use highly effective contraception for a total of 4 months after
 enrollment.

 -  Highly effective methods of contraception are defined as having low failure rates
 (i.e. less than 1 percent per year) when used consistently and correctly and may
 include, but are not limited to, abstinence from intercourse, monogamous
 relationship with a vasectomized partner, male condoms with spermicide, diaphragm
 with spermicide, intrauterine devices, and licensed hormonal methods. Females on
 effective forms of birth control will continue while on the study and for the
 follow-up period of 4 months total. The method and compliance of birth control
 used will be confirmed and documented at all study visits.

 Exclusion Criteria:

 1. Known intolerance of auranofin or gold compounds.

 2. Pregnant or breastfeeding women or women of reproductive potential not using effective
 contraception or who plan to become pregnant or breastfeed at any given time during
 the study or within 3 months of study completion.

 3. Use of metronidazole within the past 7 days.

 4. Has any condition that would, in the opinion of the site investigator, place the
 subject at an unacceptable risk of injury or render the subject unable to meet the
 requirements of the protocol.

 5. Concurrent participation in other investigational protocols or receipt of an
 investigational product within the previous 30 days.

 6. History of alcohol or drug abuse within the last five years.