Gastroenteritis Norovirus
Conditions
Keywords
Efficacy, Hematopoietic Stem Cell, Nitazoxanide, Norovirus, Prospective, Randomized, Double-Blind Study, Safety, Solid Organ Transplant Recipients, Treatment
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.
Interventions
DRUGNitazoxanide
One 500 mg tablet twice daily with food for 56 consecutive doses
OTHERPlacebo
One tablet twice daily with food for 56 consecutive doses
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 99 Years
Healthy volunteers
No
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 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. 4. 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. 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.This subject is considered low risk and not required to use contraception. 7. Agrees to complete all screening requirements, study visits and procedures.
Exclusion criteria
Subjects meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Initial Clinical Resolution of Norovirus Symptoms | 48 hours through Day 180 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Viral Titer (Day 1 to Day 180) | Day 1 (baseline) and 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). |
| Number of Participants Reporting Hospitalization | Day 1 (baseline) through Day 60 | Hospitalizations included any admission to a hospital for treatment and were not reported as Serious Adverse Events (SAEs). |
| Number of Participants Experiencing Laboratory Adverse Events (AEs) | Day 1 (baseline) through Day 60 | 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. |
| Number of Participants Experiencing Unsolicited Non-Serious Adverse Events | Day 1 (baseline) through Day 60 | 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. |
| Time to First Negative Viral Load | Day 1 (baseline) and Day 180 | 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). |
| Number of Participants Reporting Protocol-Specified SAEs | Day 1 (baseline) through Day 60 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nitazoxanide (500 mg) A single 500 mg tablet of nitazoxanide administered orally twice daily with food for 56 consecutive doses over 28 days. | 16 |
| Placebo A single matching placebo tablet administered orally twice daily with food for 56 consecutive doses over 28 days. | 15 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | COVID-19 Pandemic | 1 | 0 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Nitazoxanide (500 mg) |
|---|---|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 14 | 57.4 years STANDARD_DEVIATION 12.3 | 58.9 years STANDARD_DEVIATION 10.7 |
| Duration of symptoms Acute | 3 Participants | 7 Participants | 4 Participants |
| Duration of symptoms Chronic | 12 Participants | 24 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 25 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 24 Participants | 11 Participants |
| Sex: Female, Male Female | 8 Participants | 15 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 16 Participants | 9 Participants |
| Transplant type Hematopoietic Stem Cell Transplant | 0 Participants | 1 Participants | 1 Participants |
| Transplant type Solid organ | 15 Participants | 30 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 2 / 15 |
| other Total, other adverse events | 12 / 16 | 13 / 15 |
| serious Total, serious adverse events | 0 / 16 | 2 / 15 |
Outcome results
Primary
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.
Time frame: 48 hours through Day 180
Population: Modified Intention-to-Treat (mITT) Population: The mITT population included all randomized participants who received at least one dose of assigned study drug. Analyses were performed according to randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide (500 mg) | Time to Initial Clinical Resolution of Norovirus Symptoms | 19 days |
| Placebo | Time to Initial Clinical Resolution of Norovirus Symptoms | 11 days |
Comparison: The null hypothesis is that there is no difference in time until clinical resolution between study arms, with a two-sided alternative.p-value: 0.45995% CI: [0.33, 1.64]Likelihood Ratio Test
Secondary
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).
Time frame: Day 1 (baseline) and Day 180
Population: Modified Intention-to-Treat (mITT) Population: The mITT population included all randomized participants who received at least one dose of assigned study drug. Only participants with results at Days 1 and 180 were included. No participants in Placebo GI subgroup had results at both days. Analyses were performed based on randomized treatment assignment. Fewer than 5 participants per treatment arm tested positive for Norovirus GI at baseline thus no GI specific statistical analyses were conducted.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nitazoxanide (500 mg) | Change in Viral Titer (Day 1 to Day 180) | Norovirus GII | -3.9 titer | Standard Deviation 9.8 |
| Nitazoxanide (500 mg) | Change in Viral Titer (Day 1 to Day 180) | Norovirus GI | -11.4 titer | Standard Deviation 3.5 |
| Placebo | Change in Viral Titer (Day 1 to Day 180) | Norovirus GII | -4.2 titer | Standard Deviation 6.8 |
Comparison: Includes participants in the Norovirus GII subgroup. The null hypothesis is that there is no difference in time until clinical resolution between study arms, with a two-sided alternative.p-value: 0.735ANCOVA
Secondary
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.
Time frame: Day 1 (baseline) through Day 60
Population: Safety Population: The safety population includes all participants who were randomized and received at least one dose of study treatment. Analyses are performed according to treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide (500 mg) | Number of Participants Experiencing Laboratory Adverse Events (AEs) | 11 Participants |
| Placebo | Number of Participants Experiencing Laboratory Adverse Events (AEs) | 13 Participants |
Secondary
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.
Time frame: Day 1 (baseline) through Day 60
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide (500 mg) | Number of Participants Experiencing Unsolicited Non-Serious Adverse Events | 2 Participants |
| Placebo | Number of Participants Experiencing Unsolicited Non-Serious Adverse Events | 0 Participants |
Secondary
Number of Participants Reporting Hospitalization
Hospitalizations included any admission to a hospital for treatment and were not reported as Serious Adverse Events (SAEs).
Time frame: Day 1 (baseline) through Day 60
Population: Safety Population: The safety population includes all participants who were randomized and received at least one dose of study treatment. Analyses are performed according to treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide (500 mg) | Number of Participants Reporting Hospitalization | 4 Participants |
| Placebo | Number of Participants Reporting Hospitalization | 7 Participants |
Secondary
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.
Time frame: Day 1 (baseline) through Day 60
Population: Safety Population: The safety population includes all participants who were randomized and received at least one dose of study treatment. Analyses are performed according to treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide (500 mg) | Number of Participants Reporting Protocol-Specified SAEs | 0 Participants |
| Placebo | Number of Participants Reporting Protocol-Specified SAEs | 2 Participants |
Secondary
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).
Time frame: Day 1 (baseline) and Day 180
Population: Modified Intention-to-Treat (mITT) Population: The mITT population included all randomized participants who received at least one dose of assigned study drug. Only participants who tested positive at Day 1 were included. Analyses were performed based on randomized treatment assignment. Fewer than 5 participants per treatment arm tested positive for Norovirus GI at baseline thus no GI specific statistical analyses were conducted.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nitazoxanide (500 mg) | Time to First Negative Viral Load | Norovirus GII | NA days |
| Nitazoxanide (500 mg) | Time to First Negative Viral Load | Norovirus GI | NA days |
| Placebo | Time to First Negative Viral Load | Norovirus GII | NA days |
| Placebo | Time to First Negative Viral Load | Norovirus GI | 22 days |
Comparison: Includes participants in the Norovirus GII subgroup. The null hypothesis is that there is no difference in time until first negative viral load between study arms, with a two-sided alternative.p-value: 0.87395% CI: [0.19, 4.06]Likelihood Ratio Test