Long Term Influenza Prophylaxis With Inhaled Zanamivir or Oral Oseltamivir (SEA 004)

A Phase IV, Multi-center, Randomized, Partially Double Blinded, Placebo Controlled Study, to Evaluate the Safety of Daily Inhaled Zanamivir 10 mg Versus Placebo and Daily Oral Oseltamivir 75 mg Versus Placebo for Influenza Prophylaxis in Healthy Volunteers for 16 Weeks

This is a multicenter, randomised, four arms placebo controlled study to evaluate the safety and tolerability of 10 mg inhaled zanamivir once a day and 75 mg oseltamivir capsule orally once a day relative to placebo over 16 weeks (112 days). Enrolled subjects will be randomly assigned to 2:1:2:1 ratio (active oseltamivir: placebo: active zanamivir: placebo) on one of the four study treatment groups.

It is hypothesized that oseltamivir and zanamivir will protect participants from becoming infected with influenza.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: placebo capsule; Drug: zanamivir for inhalation; Drug: placebo for inhalation; Drug: active oseltamivir

Detailed Description

We plan to recruit 130 non-pregnant subjects including Health Care Workers, which refer to anyone who works in the hospital, into each active arm and 65 healthy, non-pregnant subjects including Health Care Workers into each placebo arm for a total of 390 study subjects from 4 study sites in Bangkok and Nonthaburi province, Thailand: (i) Faculty of Medicine Siriraj Hospital, (ii) Bamrasnaradura Infectious Diseases Institute, (iii) Chest Disease Institute, and (iv) Hospital for Tropical Diseases.

Randomisation Groups:

Zanamivir for inhalation, (5 mg per inhalation), two inhalations, once daily using a ROTADISK/DISKHALER for 112 days. The dose should be administered at approximately the same time each day.

Placebo (lactose powder), two inhalations, once daily using a ROTADISK/ DISKHALER for 112 days. The dose should be administered at approximately the same time each day.

Oseltamivir capsules (75 mg per capsule), one capsule daily by mouth (PO) for 112 days. The dose should be administered at approximately the same time each day.

Placebo capsules, one capsule daily for 112 days. The capsule should be administered at approximately the same time each day.

Study duration

The study is expected to last up to about 12 months. The study will consist of:

• a screening visit
• 10 study visits: Days 0 , 7 (+2), 14 (+2), 28 (+2), 42 (+2), 56 (+2), 70 (+2), 84 (+2), 98 (+2) and 112 (+2) and
• One follow-up visit on Day 120 (+2)

• Study Type: Interventional
• Enrollment (Actual): 390
• Phase: Phase 4

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10400
    • Hospital for Tropical Diseases
  • Bangkoknoi
    • Bangkok, Bangkoknoi, Thailand, 10700
      • Faculty of Medicine Siriraj Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A subject will be eligible for inclusion in this study only if all of the following criteria apply:

  1. Healthy male or female aged 20 - 65 years. Healthy determined by the Investigator based on medical history and screening examinations.
  2. Read and understand study related materials intended for subject.
  3. Signed informed consent prior to study participation.
  4. Willingness and ability to comply with the study protocol for the duration of the trial.
  5. Female subject who is of reproductive potential agrees to use an acceptable method of birth control (e.g., intrauterine device, abstinence or hormonal contraceptive drug) throughout the study (D120+2).

  6. For male subject, he must agree to use an acceptable method of birth control (e.g. abstinence or condom) throughout the study (D120+2).

     Exclusion Criteria:

• A subject will not be eligible for inclusion in this study if any of the following apply:

  1. Females who are pregnant, trying to get pregnant or are lactating.
  2. Current or a history of asthma or chronic obstructive pulmonary disease within the last 5 years.
  3. Abnormal pulmonary function test according to The Thoracic Society of Thailand Guidelines for Pulmonary Function Tests: (i) FVC < 80% of the predicted value for age and sex or (ii) FEV1/FVC <70%. (see Appendix 2)
  4. Any other chronic or acute diseases requiring treatment.
  5. An abnormal ECG indicating disease that requires immediate investigation or treatment
  6. An abnormal chest x-ray indicating an active disease process.
  7. A creatinine clearance < 30 mL/min as determined by Cockcroft-Gault equation (see below)
  8. AST or ALT ≥ 1.5 x ULN
  9. Use of a live attenuated influenza vaccine or any anti-influenza drug within 14 days prior to the first dose of study drugs/placebos.
  10. History of alcohol or substance abuse or dependence which in the opinion of the investigator would interfere with subject compliance or safety
  11. Subjects who have a history of allergy to the study drug or drugs of the same class, or a history of severe drug (e.g. toxic epidermal necrolysis) or other allergy (e.g. previous history of anaphylaxis) that, in the opinion of the investigator, contraindicates participation in the trial.
  12. The subject has participated in a clinical trial and has received investigational drugs within 60 days prior to the first dose of study drug.
  13. Subjects who, in the opinion of the investigator, are unlikely to comply fully with study procedures.
  14. History of any mental illness requiring hospitalisation or outpatient psychiatric treatment within the last 12 months
  15. Any suicidal attempt within the previous 5 years.
  16. Screening HADS anxiety or depression score > 8.
  17. Hemoglobin <11g/dL or neutropenia of < 1000 per microlitre or a platelet count of less than 100,000 cells/mm3 Cockroft formula: CrCl (mL/min) = (140 - age) x Wt / 72 x serum creatinine (females x 0.85), age in years, Wt in kg, serum creatinine in mg/dL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo oseltamivir; Placebo capsules, one capsule daily for 112 days. The capsule should be administered at approximately the same time each day.	Drug: placebo capsule; Placebo capsules, one capsule daily for 112 days. The capsule should be administered at approximately the same time each day.
Active Comparator: zanamivir for inhalation; Zanamivir for inhalation, (5 mg per inhalation), two inhalations, once daily using a ROTADISK/DISKHALER for 112 days. The dose should be administered at approximately the same time each day.	Drug: zanamivir for inhalation; Zanamivir for inhalation, (5 mg per inhalation), two inhalations, once daily using a ROTADISK/DISKHALER for 112 days. The dose should be administered at approximately the same time each day.; Other Names: Rotadisk/Diskhaler
Placebo Comparator: placebo inhalation; Placebo (lactose powder), two inhalations, once daily using a ROTADISK/ DISKHALER for 112 days. The dose should be administered at approximately the same time each day.	Drug: placebo for inhalation; Placebo (lactose powder), two inhalations, once daily using a ROTADISK/ DISKHALER for 112 days. The dose should be administered at approximately the same time each day.
Active Comparator: active oseltamivir; Oseltamivir capsules (75 mg per capsule), one capsule daily by mouth (PO) for 112 days. The dose should be administered at approximately the same time each day.	Drug: active oseltamivir; Oseltamivir capsules (75 mg per capsule), one capsule daily by mouth (PO) for 112 days. The dose should be administered at approximately the same time each day.; Other Names: Tamiflu

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects who withdraw from the study because of serious adverse events (SAEs) that are possibly or probably or definitely related to the study drug	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects who withdraw from the study because of SAEs unlikely or not related to study drug/placebo	1 year

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: September 17, 2009
• First Submitted That Met QC Criteria: September 17, 2009
• First Posted (Estimate): September 18, 2009

Study Record Updates

• Last Update Posted (Estimate): September 22, 2010
• Last Update Submitted That Met QC Criteria: September 21, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Long Term; Influenza Prophylaxis; Oral Oseltamivir; Inhaled Zanamivir
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Zanamivir; Oseltamivir
• Other Study ID Numbers: SEA 004; N01-AO-50042