Auranofin for Giardia Protozoa

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Phase IIa Randomized, Single-Blinded, Placebo-Controlled Clinical Trial of the Reprofiled Drug Auranofin for GI Protozoa

Conditions
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Amoebic Dysentery, Giardiasis

Intervention / Treatment
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* Drug: Auranofin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent prior to initiation of any study procedures. Able to understand and comply with planned study procedures and be available for all study visits. Male or non-pregnant non-lactating females 18-65 years of age, inclusive. Females of reproductive potential currently using effective contraceptive methods are eligible. 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. 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. Vital signs (oral temperature, pulse, and blood pressure) are all within normal protocol-defined ranges. 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. Urinalysis with no greater than trace protein. If a high protein is confirmed to be due to menstruation, it should be repeated. 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. 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: Known intolerance of auranofin or gold compounds. 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. Use of metronidazole within the past 7 days. 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. Concurrent participation in other investigational protocols or receipt of an investigational product within the previous 30 days. History of alcohol or drug abuse within the last five years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E. histolytica- Active<br>N=34, 6mg auranofin daily x 7 days | Drug: Auranofin<br>* Auranofin is a gold-containing chemical salt available as 3mg capsules<br>|
| Placebo Comparator: E. histolytica- Placebo<br>N=34, 6mg placebo daily x 7 days | Other: Placebo<br>* Placebo<br>|
| Experimental: Giardia- Active<br>N=34, 6mg auranofin daily x 5 days | Drug: Auranofin<br>* Auranofin is a gold-containing chemical salt available as 3mg capsules<br>|
| Placebo Comparator: Giardia- Placebo<br>N=34, 6mg placebo daily x 5 days | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Positive Rapid Enzyme Immunoassay (EIA) and Positive Antigen Detection EIA for Giardia and Resolution of Diarrhea (Less Than 3 Loose Stools/24 Hours) | Diarrhea was assessed by self-report at each study visit. Resolution of diarrhea occurred when participants reported less than 3 loose stools in 24 hours. | Day 5 | 
| Number of Participants With Positive Rapid Enzyme Immunoassay (EIA) and Positive Antigen Detection EIA for Giardia at Enrollment With Parasitological Response (no Detection of Cysts or Trophozoites on Microscopic Exam or Negative Antigen Test) | Participants provided stool samples on Day 5. Stool samples were assessed for parasitological response by detection of cysts or trophozoites via microscopic exam or a negative antigen test. | Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Negative Giardia Stool Antigens | Participants provided stool samples on Days 3 and 5. Stool samples were tested for Giardia using antigen detection EIA. Proportions are calculated as the number of participants with negative Giardia stool antigen tests divided by the number of participants with results available. | Day 3 through Day 5 | 
| Proportion of Symptomatic Participants With Positive Rapid EIA and Positive Antigen Detection EIA for Giardia and Trophozoites on Smear at Enrollment With Parasitological Response | Participants provided stool samples on Days 3 and 5. Stool samples were assessed for parasitological response by detection of trophozoites via microscopic exam. Proportions are calculated as the number of participants with parasitological response divided by the number of participants with results available. | Day 3 through Day 5 | 
| Proportion of Symptomatic Participants With Sustained Giardia Cure (no Detection of Trophozoites by Microscopic Exam) | Participants provided stool samples on Days 14 and 28. Stool samples were assessed for sustained Giardia cure by detection of trophozoites via microscopic exam. Proportion is calculated as the number of participants with sustained cure divided by the number of participants with results available. | Day 14 through Day 28 | 
| Giardia Trophozoite/Cyst Load by Quantitative Polymerase Chain Reaction (qPCR) in Stools of Symptomatic Participants | Participants provided stool samples on Days 3 and 5. The Giardia trophozoite/cyst load (parasites/uL) for each group was then assessed by Quantitative Polymerase Chain Reaction (qPCR). | Day 3 through Day 5 | 
| Time to Resolution of Diarrhea (Less Than 3 Loose Stools/24 Hours) | Diarrhea was assessed by self-report at each study visit. Resolution of diarrhea occurred when participants reported less than 3 loose stools in 24 hours. | Day 1 through Day 28 | 
| Proportion of Participants With Positive Rapid Enzyme Immunoassay (EIA) and Positive Antigen Detection EIA for Giardia at Enrollment With Parasitological Response (no Detection of Cysts or Trophozoites on Microscopic Exam or Negative Antigen Test) | Participants provided stool samples on Day3. Stool samples were assessed for parasitological response by detection of cysts or trophozoites via microscopic exam or a negative antigen test. Proportions are calculated as the number of participants with parasitological response divided by the number of participants with results available. | Day 3 | 
| Giardia Trophozoite/Cyst Load by Quantitative Polymerase Chain Reaction (qPCR) in Stools | Participants provided stool samples on Days 3 and 5. The Giardia trophozoite/cyst load (parasites/uL) for each group was then assessed by Quantitative Polymerase Chain Reaction (qPCR). | Day 3 through Day 5 | 
| Proportion of Asymptomatic Participants With Sustained Giardia Cure (no Detection of Trophozoites by Microscopic Exam) | Participants provided stool samples on Days 14 and 28. Stool samples were assessed for sustained Giardia cure by detection of cysts or trophozoites via microscopic exam or negative antigen detection. Proportions are calculated as the number of participants with sustained cure divided by the number of participants with results available. | Day 14 through Day 28 | 
| Proportion of Participants With Relapse (Same Strain) or Re-infection (New Strain) With Giardia-positive Stools by Genotyping the Initial vs. Subsequent Strain | Participants provided stool samples on Days 14 and 28. Any stool that was still positive for Giardia or trophozoites at Days 14 and 28 had DNA genotyping of the parasite performed on de-identified specimens of extracted DNA. The genotypes from initial and final isolates were compared to determine relapse and/or re-infection. Proportion is calculated as the number of participants with relapse or re-infection divided by the number of participants with results available. | Day 14 through Day 28 | 
| Proportion of Participants With Relapse (Same Strain) or Re-infection (New Strain) With Giardia-positive Stools by Genotyping the Initial vs. Subsequent Strain | Participants provided stool samples on Days 1, 14 and 28. Participants that were positive for Giardia via antigen detection at Day 1 and had a negative antigen detection test followed by a positive antigen detection test had DNA genotyping of the parasite performed on de-identified specimens of extracted DNA. The genotypes from initial (Day 1) and final isolates (Day 14/28) were compared to determine relapse and/or re-infection. Proportion is calculated as the number of participants with relapse or re-infection divided by the number of participants with results available. | Day 1 through Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amebiasis, Auranofin, GI Protozoa, Giardiasis, Placebo-Controlled, Reprofiled Drug, Single-Blind