NNITS-Nitazoxanide for Norovirus in Transplant Patients Study

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT03395405

Collaborator

(none)

Enrollment

Locations

Arms

35.5

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Gastroenteritis Norovirus	Drug: Nitazoxanide Other: Placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 15, 2018

Anticipated Primary Completion Date :

Oct 1, 2021

Anticipated Study Completion Date :

Oct 1, 2021

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Nitazoxanide Arm

500 mg (one tablet) nitazoxanide by mouth twice daily with food for 56 consecutive doses. N=80

Drug: Nitazoxanide

One 500 mg tablet twice daily with food for 56 consecutive doses

Placebo Comparator: Placebo Arm

Placebo (one tablet) by mouth twice daily with food for 56 consecutive doses. N=80

Other: Placebo

One tablet twice daily with food for 56 consecutive doses

Outcome Measures

Primary Outcome Measures

The time from randomization until initial clinical resolution of Norovirus symptoms [48 hours through 180 days]
Clinical resolution is defined as cessation of vomiting and diarrhea.

Secondary Outcome Measures

Incidence of laboratory adverse events (AEs) [Day 1 through day 60]
Laboratory AEs including White Blood Cell (WBC), Hemoglobin, Platelet Count, Creatinine, Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Blood Urea Nitrogen (BUN) and Bilirubin
The change in viral titer [Day 1 through day 180]
The incidence of Hospitalization [Day 1 through day 60]
The incidence of protocol-specified serious adverse events [Day 1 through day 60]
The incidence of unsolicited non-serious adverse events [Day 1 through day 60]
The Time from randomization to first negative viral load [Day 1 through day 180]

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University - Comprehensive Transplant Center	Chicago	Illinois	United States	60611-2927
2	University of Kansas Medical Center - Infectious Diseases	Kansas City	Kansas	United States	66160-8500
3	Johns Hopkins Hospital - Medicine - Infectious Diseases	Baltimore	Maryland	United States	21287-0005
4	University of Michigan School of Public Health - Epidemiology	Ann Arbor	Michigan	United States	48109-2029
5	University of Michigan - Infectious Disease Clinic at Taubman Center	Ann Arbor	Michigan	United States	48109
6	University of Nebraska Medical Center - Infectious Diseases	Omaha	Nebraska	United States	68198-5400
7	Cincinnati Children's Hospital Medical Center - Infectious Diseases	Cincinnati	Ohio	United States	45229-3039
8	University of Pittsburgh - Medicine - Infectious Diseases	Pittsburgh	Pennsylvania	United States	15213-3403
9	Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases	Pittsburgh	Pennsylvania	United States	15224-1529
10	University of Texas Southwestern Medical Center - Internal Medicine Subspecialties Clinic	Dallas	Texas	United States	75390-8884
11	Fred Hutchinson Cancer Research Center - Vaccine and Infectious Diseases	Seattle	Washington	United States	98109-4433
12	University of Washington - Medicine	Seattle	Washington	United States	98195-7110