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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01227967




Registration number
NCT01227967
Ethics application status
Date submitted
22/10/2010
Date registered
25/10/2010
Date last updated
4/02/2019

Titles & IDs
Public title
Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir) Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications
Scientific title
A Randomized Double-Blind Phase 2 Study Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir) Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications
Secondary ID [1] 0 0
10-I-0210
Secondary ID [2] 0 0
10-I-0210
Universal Trial Number (UTN)
Trial acronym
IRC003
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Amantadine, Ribavirin, Oseltamivir
Treatment: Drugs - Oseltamivir

Experimental: Combination Therapy - Amantadine, Ribavirin, Oseltamivir

Active comparator: Oseltamivir monotherapy - Oseltamivir


Treatment: Drugs: Amantadine, Ribavirin, Oseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.

Treatment: Drugs: Oseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
Assessment method [1] 0 0
The central laboratory performed a qualitative PCR test on the NP sample from Day 0 in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.
Timepoint [1] 0 0
At Day 3
Secondary outcome [1] 0 0
Number of Participants by Virus Detection Status
Assessment method [1] 0 0
Number of participants who had undetectable values (less than the limit of detection \[LOD\]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values =LLOQ
Timepoint [1] 0 0
At Day 0, 3 and 7.
Secondary outcome [2] 0 0
qPCR Viral Shedding
Assessment method [2] 0 0
Median, 25% and 75% percentile of the value of viral shedding (Results \= LOD, \
Timepoint [2] 0 0
At Day 0, 3 and 7
Secondary outcome [3] 0 0
Number of Participants Shedding Virus
Assessment method [3] 0 0
Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).
Timepoint [3] 0 0
At day 3 and 7.
Secondary outcome [4] 0 0
Time to Alleviation of Influenza Clinical Symptoms.
Assessment method [4] 0 0
The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1 (mild). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.
Timepoint [4] 0 0
From treatment initiation to Day 28
Secondary outcome [5] 0 0
Time to Absence of Fever
Assessment method [5] 0 0
Fever was considered present based on the diary cards if a subject reported a maximal temperature =38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.
Timepoint [5] 0 0
From treatment initiation to Day 28
Secondary outcome [6] 0 0
Time to Resolution of All Symptoms AND Fever
Assessment method [6] 0 0
The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature =38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever \>=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.
Timepoint [6] 0 0
From treatment initiation to Day 28
Secondary outcome [7] 0 0
Time to Feeling as Good as Before the Onset of the Influenza Illness
Assessment method [7] 0 0
Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Timepoint [7] 0 0
From treatment initiation to Day 28
Secondary outcome [8] 0 0
Time to Return to Pre-influenza Function
Assessment method [8] 0 0
Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Timepoint [8] 0 0
From treatment initiation to Day 28
Secondary outcome [9] 0 0
Time to Return of Physical Function to Pre-illness Leve
Assessment method [9] 0 0
Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment).For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.
Timepoint [9] 0 0
From treatment initiation to Day 28
Secondary outcome [10] 0 0
Percentage of Participants With Clinical Failure at Day 5
Assessment method [10] 0 0
Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.
Timepoint [10] 0 0
From treatment initiation to Day 28
Secondary outcome [11] 0 0
Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.
Assessment method [11] 0 0
Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.
Timepoint [11] 0 0
From treatment initiation to Day 28
Secondary outcome [12] 0 0
Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen
Assessment method [12] 0 0
Percentage of participants who required new or increased use of supplemental oxygen
Timepoint [12] 0 0
From treatment initiation to Day 28
Secondary outcome [13] 0 0
Percentage of Participants Who Required Hospitalization.
Assessment method [13] 0 0
The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.
Timepoint [13] 0 0
From treatment initiation to Day 28
Secondary outcome [14] 0 0
28-day Mortality
Assessment method [14] 0 0
Number of deaths
Timepoint [14] 0 0
From treatment initiation to Day 28

Eligibility
Key inclusion criteria
* INCLUSION CRITERIA:

Enrollment (Screening)

1. Signed informed consent prior to initiation of any study procedures
2. Presence of an underlying medical condition(s) that might increase risk of complications from influenza
3. History of an influenza-like illness defined as:

* One or more respiratory symptom (cough, sore throat, or nasal symptoms) AND
* Either
* Fever (subjective or documented >38 degrees C) OR
* 1 or more constitutional symptom (headache, malaise, myalgia, sweats/chills or fatigue)
4. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever
5. Willingness to have samples stored

Randomization

1. Signed informed consent
2. Presence of a medical condition(s) that had been associated with increased risk of complications from influenza

* Age 65 years of age or older
* Asthma
* Neurological and neuro-developmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) [though still able to provide informed consent per inclusion criteria #1]
* Chronic lung disease (such as COPD and cystic fibrosis)
* Heart disease (such as congenital heart disease, congestive heart failure, and coronary artery disease)
* Blood disorders (excluding genetic causes of anemia, as noted in the exclusion criteria)
* Endocrine disorders (such as diabetes mellitus)
* Kidney disorders
* Liver disorders
* Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)
* Weakened immune system due to disease or medication (such as people with HIV/AIDS, or cancer, chronic steroids or other medications causing immune suppression)
* BMI = 40(kg/m²)
3. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever
4. Positive test for influenza (either rapid antigen or PCR)

- Results from influenza testing obtained for clinical indications within 12 hours before screening/enrollment may be used if available. Randomization may proceed in cases of discrepant results (one positive and one negative)
5. One of the following to avoid pregnancy:

* Females who were 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 2 effective forms of contraception from the date of informed consent through 6 months after the last dose of study drug. At least one of the methods of contraception should be a barrier method
* Males who had not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of informed consent through 6 months after the last dose of study drug
6. Willingness to have samples stored

EXCLUSION CRITERIA:

(for Enrollment or Randomization)

1. Women who were pregnant or breast-feeding, and men whose female partner(s) was pregnant
2. Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication.
3. Hemoglobin < 10 g/dL
4. WBC < 1.5 times 10(9)/L
5. Neutrophils < 0.75 x 10(9)/L
6. Platelets < 50 x 10(9)/L
7. History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia
8. Received more than 2 doses of any antiviral influenza medications since onset of influenza symptoms
9. Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within 30 days prior to study entry
10. Creatinine clearance less than 60 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine)
11. History of autoimmune hepatitis
12. Uncompensated liver disease (defined as AST > 3 times site upper limit of normal (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN)
13. Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal bleeding, or encephalopathy
14. Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15)
15. Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir, or zanamivir
16. Received live attenuated virus vaccine (influenza or other) within 3 weeks prior to study entry
17. Use of any investigational drug within 30 days or 5 half-lives (whichever was longer) prior to study entry
18. Participation in other research protocols that would require more than 100 mL of blood to be drawn in any 4-week period that overlaps with this study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/09/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
30/03/2017
Sample size
Target
Accrual to date
Final
881
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Holdsworth House Med Practice - Darlinghurst
Recruitment hospital [2] 0 0
Taylor Square Private Clinic - Darlinghurst
Recruitment hospital [3] 0 0
Westmead Hospital - Westmead
Recruitment hospital [4] 0 0
Royal Brisbane - Herston
Recruitment hospital [5] 0 0
Northside Clinic - Fitzroy North
Recruitment hospital [6] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [7] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
- Westmead
Recruitment postcode(s) [3] 0 0
4029 - Herston
Recruitment postcode(s) [4] 0 0
3068 - Fitzroy North
Recruitment postcode(s) [5] 0 0
3004 - Melbourne
Recruitment postcode(s) [6] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Iowa
Country [8] 0 0
United States of America
State/province [8] 0 0
Kentucky
Country [9] 0 0
United States of America
State/province [9] 0 0
Louisiana
Country [10] 0 0
United States of America
State/province [10] 0 0
Maryland
Country [11] 0 0
United States of America
State/province [11] 0 0
Massachusetts
Country [12] 0 0
United States of America
State/province [12] 0 0
Michigan
Country [13] 0 0
United States of America
State/province [13] 0 0
Missouri
Country [14] 0 0
United States of America
State/province [14] 0 0
Nebraska
Country [15] 0 0
United States of America
State/province [15] 0 0
New Jersey
Country [16] 0 0
United States of America
State/province [16] 0 0
New York
Country [17] 0 0
United States of America
State/province [17] 0 0
North Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Ohio
Country [19] 0 0
United States of America
State/province [19] 0 0
Pennsylvania
Country [20] 0 0
United States of America
State/province [20] 0 0
South Dakota
Country [21] 0 0
United States of America
State/province [21] 0 0
Tennessee
Country [22] 0 0
United States of America
State/province [22] 0 0
Texas
Country [23] 0 0
United States of America
State/province [23] 0 0
Virginia
Country [24] 0 0
Argentina
State/province [24] 0 0
Buenos Aires
Country [25] 0 0
Argentina
State/province [25] 0 0
Provincia De Buenos Aires
Country [26] 0 0
Argentina
State/province [26] 0 0
Cordoba
Country [27] 0 0
Argentina
State/province [27] 0 0
Santa Fe
Country [28] 0 0
Mexico
State/province [28] 0 0
México City
Country [29] 0 0
Mexico
State/province [29] 0 0
Tlalpan
Country [30] 0 0
Thailand
State/province [30] 0 0
Bangkok
Country [31] 0 0
Thailand
State/province [31] 0 0
Khon Kaen
Country [32] 0 0
Thailand
State/province [32] 0 0
Nonthaburi

Funding & Sponsors
Primary sponsor type
Government body
Name
National Institute of Allergy and Infectious Diseases (NIAID)
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
John Beigel, MD
Address 0 0
Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT01227967