Clinical trial NCT02057757: Nitazoxanide Versus Placebo for the Treatment of Hospitalized Subjects With Severe Acute Respiratory Illness
Official title: A Randomized Double-Blind Phase 2 Study Comparing the Efficacy, Safety, and Tolerability of Nitazoxanide Versus Placebo in Addition to Standard Care for the Treatment of Hospitalized Subjects With Severe Acute Respiratory Illness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Acute Respiratory Illness
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Mexican Emerging Infectious Diseases Clinical Research Network
First posted: 2014-02-07
Enrollment: 260
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Respiratory viruses are a significant cause of hospitalization for respiratory tract infections. This study will evaluate the safety, effectiveness, and tolerability of nitazoxanide (NTZ) in treating severe acute respiratory illness (SARI) in people who are hospitalized.

Detailed description: Respiratory viral infections are one of the most common causes of illness in the world. These infections are major causes of SARI and can lead to severe outcomes, including hospitalization and death. NTZ is a medication that is approved in the United States and Mexico to treat gastrointestinal parasitic diseases. This study will evaluate the use of NTZ to treat SARI. The purpose of this study is to evaluate the safety, effectiveness, and tolerability of NTZ, in combination with standard care, in treating SARI in people who are hospitalized.

Participants will be hospitalized and study entry assessments will include medical assessments, blood collection, and a nasopharyngeal swab or wash. Participants will then be randomly assigned to receive NTZ or placebo for 5 days. Participants younger than 12 years will receive an oral suspension formulation of NTZ or placebo; participants 12 years and older will receive NTZ or placebo tablets. All participants will also receive standard of care treatment for acute severe viral respiratory infections, which may include antibiotics and/or treatment for influenza. They will be discharged from the hospital based on their doctors' recommendations. Participants will record their temperature and symptoms in a daily diary, which will be reviewed by study staff during study visits. Follow-up visits will occur on Days 3, 7, 14, and 28, and may occur as inpatient or outpatient visits. These visits may include the same assessments that occurred at baseline, as well as physical examinations, depending on the visit. Participants who are still hospitalized at Day 28 will be followed by study staff until they are discharged from the hospital.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent prior to performance or initiation of any study procedures
* Age greater than or equal to 12 months of age (no upper age limit)
* Influenza-like illness (ILI), defined as (all of the following):

  * Onset of fever greater than or equal to 38°C (or hypothermia less than 36°C)
  * New or worse cough or sore throat
  * New or worse shortness of breath or difficulty breathing
* Onset of illness no more than 5 days before screening defined as when the participant experienced at least 1 respiratory symptom, constitutional symptom, or fever
* Hospitalization for ILI (decision for hospitalization will be up to the individual treating clinician), with anticipated hospitalization for more than 24 hours
* One of the following to avoid pregnancy:

  * Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 1 effective form of contraception from the date of informed consent through Day 28 of study
  * Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms or have a partner use at least 1 effective form of contraception through Day 28 of study

Exclusion Criteria:

* Women who are pregnant or breastfeeding
* Clinical suspicion that etiology of illness is primarily bacterial in origin
* Prior treatment with antivirals (e.g., oseltamivir) for the current illness for more than 24 hours
* Unable to take oral medications (adults must tolerate tablets, children must tolerate suspension)
* Unable to tolerate oral food/fluids (absorption is significantly better with food)
* Prior treatment with any investigational drug therapy within 30 days prior to screening
* Known sensitivity to NTZ or any of the excipients comprising the NTZ tablets
* Prior NTZ use within 1 week
* Self-reported history of chronic kidney disease or impaired renal function (no blood or urine kidney function laboratory testing will be done prior to enrollment, but intent is to exclude disease severe enough to cause estimated creatinine clearance \[CrCl\] less than 30)
* Self-reported history of liver disease (no blood laboratory testing will be done prior to enrollment, but intent is to exclude disease severe enough to cause cirrhosis or total bilirubin greater than 2, aspartate aminotransferase \[AST\]/alanine aminotransferase \[ALT\] greater than 3 times the upper limit of normal \[ULN\])
* Presence of any pre-existing illness that, in the opinion of the investigator, would place the participant at an unreasonably increased risk through participation in this study
* Participants who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol
* The onset of SARI occurs after hospitalization
* Hospitalized for any reason for greater than 48 hours prior to enrollment
* Participants previously enrolled in this study
* Prior hospital discharge within 30 days
* Known chronic respiratory infection (e.g., tuberculosis, atypical mycobacterial infections)

Primary outcomes:
measure: Time to Hospital Discharge
timeFrame: Measured through Day 28
Secondary outcomes:
measure: Number of Participants Hospitalized on Days 3, 7, 14, and 28
timeFrame: Measured at Day 3, Day 7, Day 14, and Day 28
measure: Number of Participants Who Died Within the First 5 Days
timeFrame: Measured within First 5 Days
measure: Number of Participants Who Experienced Clinical Symptoms
timeFrame: Measured through Day 28
measure: Duration of Fever in Study Participants
timeFrame: Measured each day through Day 14 and on Day 28
measure: Number of Participants Who Require Oxygen Use
timeFrame: Measured through Day 28 or participants' last day of hospitalization
measure: Number of Study Participants (e.g., Adult and Children) Admitted to the Intensive Care Unit (ICU) by Time Point (Anytime, Day 0, Day 3, Day 7, Day 14, Day 28)
timeFrame: Measured through Day 28 or participants' last day in the ICU
measure: Study Participants (e.g., Adults, Children) Requiring Mechanical Ventilation at Study Time Points (Any Time, Day 0, Day 3, Day 7, Day 14, Day 28)
timeFrame: Measured through Day 28 or participants' last day of hospitalization
measure: Number of Study Participants With the Presence of Complications (Pneumonia, Respiratory Failure Requiring Mechanical Ventilation, Acute Respiratory Distress Syndrome [ARDS], Sepsis, or Bronchiolitis) During Study
timeFrame: Measured through Day 28 or participants' last day of hospitalization
measure: Duration (Days) Until Affirmative Global Assessment (e.g., Answered Yes) by Study Participants (e.g., Adults, Children)
timeFrame: Measured daily through Day 14 and on Day 28
measure: Number of Participants Using Antibiotics/Antivirals During Hospitalization
timeFrame: Measured through participants' first 5 days of hospitalization
measure: Number of Participants Who Are Re-hospitalized Within 28 Days
timeFrame: Measured through Day 28
measure: Use of Systemic Corticosteroids
timeFrame: Measured within First 5 Days
measure: Presence of Virus on Nasopharyngeal (NP) Swab at Day 3 (Same Virus as Day 0)
timeFrame: Measured through Day 3
measure: Number of Participants Reporting Adverse Events (AEs)
timeFrame: Measured through Day 28 or participants' last day of hospitalization
measure: Number of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Measured through Day 28 or participants' last day of hospitalization
measure: Chemistry Laboratory Assessments (Creatinine, Total Bilirubin) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day, 7 and Day 28
measure: Chemistry Laboratory Assessments (ALT, AST, LDH) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day 7, and Day 28
measure: Chemistry Laboratory Assessment (CRP) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day, 7 and Day 28
measure: Hematologic Laboratory Assessments (Neutrophils, Lymphocytes, Eosinophils, and Hematocrit) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day, 7 and Day 28
measure: Hematologic Laboratory Assessment (Hemoglobin) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day, 7 and Day 28
measure: Hematologic Laboratory Assessments (WBC, Platelets) on Days 3, 7, and 28
timeFrame: Measured on Day 3, Day, 7 and Day 28
Other outcomes:
Locations:
city: Coyoacan
country: Mexico
facility: Instituto Nacional de Pediatria
city: Oaxaca
country: Mexico
facility: Hospital General Dr. Aurelio Valdivieso
city: San Luis Potosi
country: Mexico
facility: Hospital Central Dr. Ignacio Morones Prieto
city: Tamaulipas
country: Mexico
facility: Hospital Infantil de Mexico Federico Gomez
city: Tlalpan
country: Mexico
facility: Instituto Nacional de Ciencias medicas y Nutricion Salvador Zubiran
city: Tlalpan
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias
Study officials:
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Lourdes Guerrero Almeida, M.D.
role: STUDY_CHAIR
affiliation: Hospital Infantil de Mexico Federico Gomez
name: Ana Gamiño, M.D.
role: STUDY_CHAIR
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Arturo Galindo Fraga, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Infantil de Mexico Federico Gomez
name: Sarbelio Moreno, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Central "Dr. Ignacio Morones Prieto"
name: Javier Araujo Melendez, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Enfermedades Respiratorias
name: Alejandra Ramirez Venegas, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Pediatria
name: Beatriz Llamosas Gallardo, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Dr. Aurelio Valdivies
name: Yuri Roldan Aragon, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gamino-Arroyo AE, Guerrero ML, McCarthy S, Ramirez-Venegas A, Llamosas-Gallardo B, Galindo-Fraga A, Moreno-Espinosa S, Roldan-Aragon Y, Araujo-Melendez J, Hunsberger S, Ibarra-Gonzalez V, Martinez-Lopez J, Garcia-Andrade LA, Kapushoc H, Holley HP, Smolskis MC, Ruiz-Palacios GM, Beigel JH; Mexico Emerging Infectious Diseases Clinical Research Network (LaRed). Efficacy and Safety of Nitazoxanide in Addition to Standard of Care for the Treatment of Severe Acute Respiratory Illness. Clin Infect Dis. 2019 Nov 13;69(11):1903-1911. doi: 10.1093/cid/ciz100.