Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus

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 duration is 60
months and subject participation duration is 6 months. A total of 160 subjects greater than
or equal to 12 years of age will be selected. Upon enrollment in the study, subjects will be
randomized into two treatment groups: active nitazoxanide and placebo. 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 and study visits on study Day 1, 7, 14, 21, and 28; Longitudinal Monitoring Phase which
will include telephone call on Day 35 study visits on study Day 60, 120 and 180 days. 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.

Inclusion Criteria:

Subjects should meet all of the following inclusion criteria:

1. Male or female age > / = 12 years.

2. Recipient of a solid organ or hematopoietic stem cell transplant.

3. Positive test for Norovirus within 7 days of enrollment that is obtained as part of
routine clinical care using the local Norovirus testing available at the site.

4. Active GI symptoms (diarrhea, or vomiting) that, in the opinion of the PI, are
secondary to Norovirus.

5. Willing and able to provide written informed consent and assent before initiation of
any study procedures, consistent with local IRB policy.

6. 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.

7. 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:

1. Other identified infectious causes of diarrhea at screening.

2. 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.

3. Subjects receiving oral or intravenous immunoglobulin therapy concurrently or in the
14 days prior to enrollment.

4. Nitazoxanide use for any illness in the previous 30 days prior to randomization.

5. Have received experimental products within 30 days prior to the study entry or plan to
receive experimental products at any time during the study

6. Known sensitivity to nitazoxanide or any of the excipients comprising the nitazoxanide
tablets.

7. Subjects unable to swallow oral medications.

8. Subjects with ostomy.

9. Women who are pregnant or lactating or have a positive urine pregnancy test at
screening/enrollment/Day 1.