A Study to Evaluate the Efficacy and Safety of IV Peramivir in Addition to Standard of Care Compared to Standard of Care Alone in Adults and Adolescents Who Are Hospitalized Due to Influenza

Headache Clinical Trial

Official title:

A Phase 3, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the Efficacy and Safety of Peramivir Administered Intravenously in Addition to Standard of Care Compared to Standard of Care Alone in Adults and Adolescents Who Are Hospitalized Due to Serious Influenza

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00958776
• Other study ID #: BCX1812-301
• Status: Terminated
• Phase: Phase 3
• First received: August 12, 2009
• Last updated: January 28, 2015
• Start date: November 2009
• Est. completion date: October 2013

Study information

• Verified date: January 2015
• Source: BioCryst Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

A Phase 3, multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of peramivir administered intravenously in addition to standard of care compared to standard of care alone in adults and adolescents who are hospitalized due to serious influenza.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 405
• Est. completion date: October 2013
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Age =12 years of age, male or female.

• Able to provide informed consent, or for whom consent may be provided by guardian, unless informed consent provided by a guardian or a legally authorized representative is not consistent with applicable local or ethical concerns, procedures, directives and/or guidelines.

• Subject must have at least one of the following clinical presentations at Screening:

1. Oral temperature = 38.0 °C (=100.4 °F), =38.6°C (=101.4 °F) tympanic or rectal OR

2. Oxygen saturation <92%, OR

3. Two out of the following three vital signs:

Respiration rate >24/minute, Heart rate >100/minute, Systolic BP <90 mmHg

• Presence of at least one respiratory symptom (cough, sore throat, or nasal congestion) of any severity (mild, moderate, or severe).

• Presence of at least one constitutional symptom (headache, myalgia, feverishness, or fatigue) of any severity (mild, moderate, or severe).

• Onset of illness no more than 72 hours before presentation. Note: Time of onset of illness is defined as the earlier of either (1) the time when the temperature was first measured as elevated, OR (2) the time when the subject experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom.

• Either:

Severity of illness that, in the Investigator's judgment, justifies hospitalization of the subject for supportive care.

OR

Presence of one or more of the following factors:

Age =60 years. Presence of chronic obstructive pulmonary disease (COPD) or other chronic lung disease requiring daily pharmacotherapy.

Current history of congestive heart failure or angina. Presence of diabetes mellitus, clinically stable or unstable. Transcutaneous oxygen saturation <94% without supplemental oxygen for at least 5 minutes, or a medically significant decrease in oxygen saturation from an established baseline value (an investigative site at altitude >2000 ft above sea level will utilize different criteria for oxygen saturation).

History of chronic renal impairment not requiring peritoneal dialysis. Serum creatinine > 2.0 mg/dL or > 177 µmol/L.

• Diagnosis of Influenza by satisfying one of the following:

1. Clinical Influenza with Positive Diagnostic Test. Subjects who have a positive rapid antigen test (RAT) for influenza A and/or influenza B (using a Sponsor-approved test kit), or positive test (using other methodology) for influenza A and/or B virus antigen or RNA performed in a clinical laboratory at the screening/enrollment evaluation are eligible for enrollment.

OR

2. Clinical Influenza with Negative Rapid Antigen Test (RAT). Subjects with a negative RAT test may be enrolled once the site has been approved by the Sponsor to enroll such subjects, based on documentation of an outbreak of influenza in the community. An influenza outbreak may be documented in the catchment area of the hospital via one of the following methods: 1) local confirmation of influenza A or B infection in the current influenza season by a) the institution's local laboratory, or b) the local public health system, or c) the national public health system, or d) a laboratory of a recognized multinational influenza surveillance scheme such as the European Influenza Surveillance Network (EISN); 2) prior enrollment of a RAT positive subject into this study at the same institution in the current influenza season.

Exclusion Criteria:

• Subjects who have been hospitalized for greater than 24 hours (not including time spent in the Emergency Department).

• Treatment with any dose(s) of rimantadine, amantadine, ribavirin, zanamivir, or oseltamivir in the previous 7 days.

• Blood platelet count of < 20 x 109/L at the time of the screening evaluation.

• Serum bilirubin > 6 mg/dL or > 105 µmol/L at time of screening evaluation.

• Serum ALT or AST > 5 times the upper limit of normal at time of screening evaluation.

• Congestive heart failure of NYHA Class III or Class IV functional status.

• Serum creatinine > 5.0 mg/dL or > 500 µmol/L at time of screening evaluation.

• Subjects who require peritoneal dialysis.

• Altered neurologic status as defined by a Glasgow Coma Score of = 9, unless medically induced.

• Females who are pregnant (positive urine or serum pregnancy test at screening evaluation) or breastfeeding.

• Actively undergoing systemic chemotherapy or radiotherapy treatment for a malignancy. Subjects who have completed treatment 30 days prior to enrollment are not excluded. Hormone treatment for cancer is also not excluded.

• Prior hematopoietic stem cell transplantation or solid organ transplant during the previous 4 months.

• HIV infection with a known CD4 count < 200 cells/mm3 unless on a stable highly active antiretroviral therapy (HAART) for at least 6 months.

• Presence of a pre-existing chronic infection that is undergoing or requiring medical therapy (eg, tuberculosis). Subjects with chronic osteomyelitis or Hepatitis B or C not requiring treatment are not excluded.

• Presence of any pre-existing illness that, in the opinion of the investigator, would place the subject at an unreasonably increased risk through participation in this study.

• Previous treatment with intravenous or intramuscular peramivir.

• Participation as a subject in any study of an experimental treatment for any condition within the 30 days prior to the time of the screening evaluation.

• Subjects diagnosed with Cystic Fibrosis.

• Subjects with confirmed clinical evidence of acute non-influenzal infection at the time of screening evaluation.

• Subjects who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cough
• Fever
• Headache
• Influenza, Human
• Nasal Congestion
• Seasonal Influenza
• Sore Throat

Intervention

Drug:
• Peramivir+SOC
Adults (= 18 years): Peramivir (BCX-1812) 600 mg, administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care. Adolescents (12-17 years): Peramivir (BCX-1812) 10 mg/kg (not to exceed a maximum dose of 600 mg), administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.
• Placebo+SOC
Placebo Peramivir (BCX1812) administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.

Locations

Country	Name	City	State
Argentina	Hospital del Torax Dr. Antonio A. Cetrangolo	Buenos Aires
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RS
Bulgaria	DDPPDI - Ruse	Ruse
Bulgaria	Fifth MHAT-Sofia, AD	Sofia
Bulgaria	MHAT - Tokuda Hospital Sofia, AD	Sofia
Bulgaria	Military Medical Academy - MHAT	Sofia
Bulgaria	MHAT - Tokuda Hospital Sofia, AD	Stara Zagora
Bulgaria	MHAT 'Dr. St. Cherkezov', AD	Veliko Tarnovo
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Chile	Hospital Clinico Regional Dr. Guillermo Grant Benavente	Concepcion
Chile	Hosp. de Urgencia Asistencia Publica Dr. Alejandro del Rio	Santiago
Czech Republic	Fakultni nemocnice Brno	Brno
Czech Republic	Krajska zdravotni, a.s. - Masarykova nemocnice v Ustinad La	Usti nad Labem
Germany	Universitaetsklinikum Regensburg	Regensburg
Hungary	Fejer Megyei Szent Gyorgy Korhaz	Szekesfehervar
Hungary	Principal SMO Dr. Bugyi Istvan Korhaz Szentes	Szentes
India	Apollo First Med Hospitals	Chennai	Tamil Nadu
India	Life Line Multispecialty Hospital	Chennai	Tamil Nadu
India	Fortis Escort Hospital	Jaipur	Rajasthan
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill AIDS Clinical Trials Unit	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Remington-Davis, Inc.	Columbus	Ohio
United States	DeKalb Medical Center	Decatur	Georgia
United States	Wayne State University - Hutzel Hospital	Detroit	Michigan
United States	Wayne State University, Department of Emergency Medicine	Detroit	Michigan
United States	Kentucky Lung Clinic	Hazard	Kentucky
United States	Regional Infection Diseases Infusion Center Inc.	Lima	Ohio
United States	Medical Arts Associates, Ltd.	Moline	Illinois
United States	Pulmonary Consultants PC Physicians Medical Group, Inc.	Orange	California
United States	Carilion Infectious Disease	Roanoke	Virginia
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	UC Davis Medical Center	Sacramento	California
United States	VA Medical Center - Salem	Salem	Virginia
United States	Sharp Chula Vista Medical Center	San Diego	California
United States	Washington University School of Medicine	St. Louis	Missouri
United States	ID Clinical Research, LTD	Toledo	Ohio
United States	Medical College Of Ohio	Toledo	Ohio
United States	William Beaumont Hospital	Troy	Michigan
United States	Washington Hospital Center CAR	Washington	District of Columbia
United States	Drogue Medical, LLC	Wheat Ridge	Colorado
United States	Florida Hospital	Winter Park	Florida

Sponsors (2)

Lead Sponsor	Collaborator
BioCryst Pharmaceuticals	Department of Health and Human Services

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Bosnia and Herzegovina,  Brazil,  Bulgaria,  Canada,  Chile,  Czech Republic,  Germany,  Hungary,  India,  Israel,  Latvia,  Lebanon,  Peru,  Poland,  Russian Federation,  Serbia,  Slovakia,  South Africa,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time to Hospital Discharge	Time to hospital discharge, defined as the number of days from initiation of study treatment until the subject was discharged from the hospital, was summarized by treatment group using the method of Kaplan-Meier. Subjects who were not discharged from the hospital were censored at their last study visit.	10 days	No
Other	Incidence of Influenza-Related Complications	Influenza-related complications were defined as the occurrence of sinusitis, otitis, bronchitis, and pneumonia as reported on the influenza-related complications CRF.	10 days	No
Other	Number of Subjects Requiring More Than 5 Days of Study Drug	Subjects who had not met the protocol-defined criteria of clinical resolution on Day 5 or who had detectable virus by RT-PCR from a sample collected on Study Day 4 after dosing continued their assigned treatment for a further 5 days.	10 days	No
Other	Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate)	Survival was calculated as the number of days from initiation of study drug until death or last contact. Estimates and 95% confidence intervals were calculated using the method of Kaplan-Meier and presented by treatment group.	28 days	No
Other	Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM)	Initial viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit.	Initial (baseline or post-baseline) and up to 10 days	No
Other	Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial	Viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented as fold change from initial sensitivity by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit.	Initial (baseline or post-baseline) and up to 10 days	No
Primary	Time to Clinical Resolution (Kaplan-Meier Estimate)	Time to clinical resolution was defined as the time in hours from initiation of study treatment until normalization of at least 4 of the 5 signs within the respective normalization criteria, maintained for at least 24-hours. Time to clinical resolution was summarized by treatment group using the method of Kaplan-Meier. For subjects who did not experience clinical resolution, values were censored at the date of their last non-missing assessment of clinical resolution during the study (whether this assessment occurred as an inpatient or as an outpatient).	10 days	No
Secondary	Change (Reduction) in Influenza Virus Titer	The reduction in viral shedding was assessed as the change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and RT-PCR and was summarized for each treatment group and study visit.	Baseline and 24, 48, 108 hours	No
Secondary	Time to Alleviation of Clinical Symptoms of Influenza	Time to alleviation of clinical symptoms of influenza was measured as the time from the first dose of study drug through the time period in which all 7 symptoms of influenza (cough, sore throat, nasal congestion, myalgia [aches and pains], headache, feverishness, and fatigue) were absent or rated as no greater than mild for at least 24 hours. Time to alleviation of symptoms was estimated using the method of Kaplan-Meier. Subjects who did not have resolution of any individual clinical sign were censored at the time of their last non-missing assessment of that sign.	10 days	No
Secondary	Time to Resolution of Fever (Kaplan-Meier Estimate)	Time to resolution of fever was measured as the time from initiation of study treatment until resolution of fever, maintained for at least 24 hours; temperature measurements taken less than 4 hours after antipyretic use were treated as missing values.	10 days	No
Secondary	Time to Resumption of Usual Activities	Time to resumption of usual activities was determined from the visual analog scale (scale ranged from 0 to 10 where 0 indicated subject was unable to perform usual activities at all and 10 indicated subject was able to perform all usual activities fully). Time to resumption of usual activities was summarized by treatment group using the method of Kaplan-Meier.	10 days	No
Secondary	Number of Subjects With ICU Admission	The number of subjects requiring ICU admission post-randomization was summarized by treatment group.	10 days	No
Secondary	Duration of All ICU Admissions (Kaplan-Meier Estimate)	Duration of postbaseline ICU admission was defined as the total number of days in the ICU for those subjects who had a post-baseline admission to the ICU. Only days starting after the initial postbaseline admission were included. If a subject's stay in the ICU was ongoing, the duration was censored at the last study visit. Subjects who did not have a postbaseline admission had a duration of 0.	10 days	No