NNITS-Nitazoxanide for Norovirus in Transplant Patients Study

Study Overview
=================
Brief Summary
-----------------
This is a phase 2 multi-center, double-blind, placebo-controlled study of the efficacy and safety of nitazoxanide for the treatment of solid organ and hematopoietic stem cell transplant recipients with symptomatic diarrhea due to Norovirus. The study involves a total of 160 Hematopoietic Stem Cell or Solid Organ transplant recipients, equal to or greater than 12 years of age with diagnosis of Norovirus who will be selected and randomly assigned (1:1) to nitazoxanide or placebo group. The study duration is 60 months and subject participation duration is 6 months. Given the safety of prolonged therapy with nitazoxanide, lack of interactions with common post-transplant medications, putative antiviral activity and prolonged duration of viral shedding we are assessing 56 doses of therapy. The longitudinal monitoring phase will provide useful information on the course of host and viral responses in subjects with chronic Norovirus infection with and without treatment. Randomization will be stratified by age group (pediatric (12 through 17 years) vs. adult (greater than or equal to 18 years)), chronicity of Norovirus-associated symptoms (acute (less than 14 days) vs. chronic (greater than or equal to 14 days)) and transplant type (solid organ (SOT)) vs. hematopoietic stem cell transplant (HSCT)). Enrolled subjects will participate in 2 phases of the study: Treatment Phase, which will include dosing with the assigned study agent for 28 days. Longitudinal Monitoring Phase which will include telephone call on Days 35, 53, 113, 173. Primary objective is 1) to assess the clinical efficacy of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients.

Detailed Description
-----------------
This is a phase 2 multi-center, double-blind, placebo-controlled study of the efficacy and safety of nitazoxanide for the treatment of solid organ and hematopoietic stem cell transplant recipients with symptomatic diarrhea due to Norovirus. The study involves a total of 160 Hematopoietic Stem Cell or Solid Organ transplant recipients, equal to or greater than 12 years of age with diagnosis of Norovirus who will be selected and randomly assigned (1:1) into two treatment groups: nitazoxanide or placebo. The study duration is approximately 60 months and subject participation duration is approximately 6 months. Given the safety of prolonged therapy with nitazoxanide, lack of interactions with common post-transplant medications, putative antiviral activity and prolonged duration of viral shedding we are assessing 56 doses of therapy. The longitudinal monitoring phase will provide useful information on the course of host and viral responses in subjects with chronic Norovirus infection with and without treatment. Randomization will be stratified by age group (pediatric (12 through 17 years) vs. adult (greater than or equal to 18 years)), chronicity of Norovirus-associated symptoms (acute (less than 14 days) vs. chronic (greater than or equal to 14 days)) and transplant type (solid organ (SOT)) vs. hematopoietic stem cell transplant (HSCT)). Enrolled subjects will participate in 2 phases of the study: Treatment Phase, which will include dosing with the assigned study agent for 28 days. Longitudinal Monitoring Phase which will include telephone call on Days 35, 53, 113, 173. Primary objective is 1) to assess the clinical efficacy of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients. Secondary Objectives are 1) to assess the virologic efficacy of nitazoxanide and 2) to assess the safety of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients.

Official Title
-----------------
A Phase 2 Multi-Center, Prospective, Randomized, Double-Blind Study to Assess the Clinical and Antiviral Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem Cell and Solid Organ Transplant Recipients

Conditions
-----------------
Gastroenteritis Norovirus

Intervention / Treatment
-----------------
* Drug: Nitazoxanide
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects should meet all of the following inclusion criteria: Male or female age > / = 12 years. Recipient of a solid organ or hematopoietic stem cell transplant. Positive test result for Norovirus within 14 days of enrollment that is obtained as part of routine clinical care using a Norovirus testing available to the site. Active GI symptoms (diarrhea, or vomiting) that, in the opinion of the PI, are secondary to Norovirus. Patients must have active diarrhea, which is defined as at least 3 days of Bristol 6 or 7 stools in the past 2 weeks prior to enrollment per patient report. Willing and able to provide written informed consent and assent before initiation of any study procedures, consistent with local IRB policy. Subjects must be of non-childbearing potential or if of childbearing potential, must be using an effective method of birth control or must be abstinent. Non-childbearing potential is defined as surgically sterile or postmenopausal for > one year. Effective methods of birth control include the use of hormonal or barrier birth control such as implants, injectable contraceptives, combined oral contraceptives, intrauterine devices (IUDs),or condoms with spermicidal agents during study period. Female subjects must be using an effective method of birth control or practice abstinence and must agree to continue such precautions during the study and for 30 days after the Day 28 study visit. A woman is eligible if she is monogamous with a vasectomized male.This subject is considered low risk and not required to use contraception. Agrees to complete all screening requirements, study visits and procedures. Exclusion Criteria: Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation: Other identified infectious causes of diarrhea at screening. Alternative diagnosis requiring treatment would be considered a co-infection; if the testing is positive for a pathogen that the PI does not feel is causing the symptoms, they may be included but the PI or his/her designee must document that the positive test is not clinically significant, does not require treatment and is not causing the symptoms making the patient eligible for enrollment. Any condition that would, in 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. Subjects receiving oral or intravenous immunoglobulin therapy concurrently or in the 14 days prior to enrollment. Nitazoxanide use for any illness in the previous 30 days prior to randomization. Have received experimental products within 30 days prior to the study entry or plan to receive experimental products at any time during the study Known sensitivity to nitazoxanide or any of the excipients comprising the nitazoxanide tablets. Subjects unable to swallow oral medications. Subjects with ostomy. Women who are pregnant or lactating or have a positive urine pregnancy test at screening/enrollment/Day 1.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitazoxanide Arm<br>500 mg (one tablet) nitazoxanide by mouth twice daily with food for 56 consecutive doses. N=80 | Drug: Nitazoxanide<br>* One 500 mg tablet twice daily with food for 56 consecutive doses<br>|
| Placebo Comparator: Placebo Arm<br>Placebo (one tablet) by mouth twice daily with food for 56 consecutive doses. N=80 | Other: Placebo<br>* One tablet twice daily with food for 56 consecutive doses<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initial Clinical Resolution of Norovirus Symptoms | Time (in days) from randomization until the study day when clinical resolution occurred. Clinical resolution was assessed from participant's daily diaries and was defined as cessation of vomiting and no stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) for at least 48 hours. | 48 hours through Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Laboratory Adverse Events (AEs) | Participants experiencing at least one new laboratory adverse event. Laboratory parameters include White Blood Cell (WBC), Hemoglobin, Platelet Count, Creatinine, Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Blood Urea Nitrogen (BUN), and Bilirubin. Laboratory results were considered AEs using the following thresholds : WBC greater than the upper limit of normal (ULN), hemoglobin less than the lower limit of normal (LLN), platelet count less than the LLN; creatinine greater than the ULN; alkaline phosphatase greater than the ULN; ALT greater than the ULN, AST greater than the ULN, BUN greater than or equal to the ULN, and bilirubin greater than the ULN. ULN and LLN values differed by site, sex, and age category. | Day 1 (baseline) through Day 60 | 
| Change in Viral Titer (Day 1 to Day 180) | Change in viral titer defined as the difference between the Day 180 viral titer and the Day 1 viral titer. Participants were analyzed for the viral load test type (Norovirus GII or Norovirus GI) that they tested positive for at baseline (Day 1). | Day 1 (baseline) and Day 180 | 
| Number of Participants Reporting Hospitalization | Hospitalizations included any admission to a hospital for treatment and were not reported as Serious Adverse Events (SAEs). | Day 1 (baseline) through Day 60 | 
| Number of Participants Reporting Protocol-Specified SAEs | Protocol-specified SAEs included any adverse event or suspected adverse reaction which, in the view of the investigator or sponsor, resulted in any of the following: death, life threatening adverse event, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life function, congenital anomaly or birth defect, or an important medical event that may jeopardize the participant and require medical or surgical intervention. Hospitalizations were collected as a secondary outcome measure and were not reported as SAEs. | Day 1 (baseline) through Day 60 | 
| Number of Participants Experiencing Unsolicited Non-Serious Adverse Events | Unsolicited adverse events were defined as any non-serious clinical adverse events that were not collected as clinical outcome measures and resulted in either modification in the administration of study drug or discontinuation of the study drug. | Day 1 (baseline) through Day 60 | 
| Time to First Negative Viral Load | Time (in days) from randomization until the first study day the participant had either a negative result or a result less than the lower limit of quantitation (LLOQ) for the viral load test type (Norovirus GII or Norovirus GI) that they initially tested positive for at baseline. Participants were analyzed for the viral load test type (Norovirus GII or Norovirus GI) that they tested positive for at baseline (Day 1). | Day 1 (baseline) and Day 180 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Efficacy, Hematopoietic Stem Cell, Nitazoxanide, Norovirus, Prospective, Randomized, Double-Blind Study, Safety, Solid Organ Transplant Recipients, Treatment