| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Influenza A virus infection also known as the flu is a viral infection. Symptoms usually include, fever, muscle and body pain, sore throat, stuffy nose, headache and sneezing. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022002 |
| E.1.2 | Term | Influenza A virus infection |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives are:
1.To determine the effect of FF-3 in the prevention of infection by the influenza virus, in comparison to placebo (dummy medication), in subjects who are experimentally given the "flu".
2.To evaluate how safe and well tolerated FF-3 is when administered through the nose to volunteers who have been infected with a strain of influenza A virus.
The study will also assess the safety and performance of the EPIC drug delivery device. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives include an assessment of the effect of FF-3 in comparison to placebo on symptom scores (reported by investigators and by subjects), the level of certain chemicals produced in the nose in response to infection and on the quantity of virus shed over time in the nose of subjects who are experimentally exposed to a flu virus. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Healthy male and non-pregnant, non-lactating female subjects of 18 to 50 years of age inclusive. Subjects must not be over 50 years of age at the 30-Day follow up.
2. Body Mass Index (BMI) of 18 to 32 kg/m2 inclusive and body weight of 50 to 110 kg inclusive.
3. Normal spirometry values at Screening and Baseline defined as forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) greater than or equal to 80% predicted or above the LLN and the FEV1/FVC ratio greater than or equal to 70%.
4. Post-menopausal women with amenorrhea for at least 2 years will be eligible (confirmed by follicle stimulating hormone [FSH] test).
5. Females of childbearing potential must use two of the following acceptable birth control methods throughout the study and for 30 days after the last dose of the IMP:
(a) Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) 6 months minimum prior to the first dose of the IMP.
(b) Intrauterine device (IUD) in place for at least 90 days prior to the first dose of the IMP.
(c) Barrier methods (diaphragm plus spermicide or condom) starting at least 14 days prior to the first dose of the IMP.
(d) Abstinence (the subject must be willing to remain abstinent from screening to 30 days after the last dose of IMP).
(e) Surgical sterilization of partner(s) (vasectomy) for ≥180 days prior to the first dose of the IMP.
(f) Hormonal contraceptives starting ≥90 days prior to the first dose of the IMP. If hormonal contraceptives are started <90 days prior to the first dose of IMP, subjects must agree to use a barrier method (diaphragm plus spermicide or condom) from screening through 90 days after initiation of hormonal contraceptives.
6. Male subjects:
(a) Must agree to use a condom (or diaphragm plus spermicide in female partner) from the time of the first dose of IMP through 90 days after the last dose.
(b) Must agree to not donate sperm for 90 days after the last dose of IMP.
(c) Documented evidence of vasectomies in males for 180 days minimum prior to the first dose of the IMP is an acceptable form of contraception.
(d) Males who claim abstinence as their method of contraception are allowed provided they agree to use a double barrier method (diaphragm plus spermicide in female partner or condom) should they become sexually active from screening to 90 days after the last dose of IMP.
7. Willing and able to provide written informed consent.
8. Willing and able to adhere to the lifestyle guideline restrictions outlined in the protocol.
9. Willing and able to be confined to the Clinical Research Unit (CRU) as required by the protocol.
10. Evidence of HAI antibody titer (i.e., less than 1:10) at Panel Screening (to be conducted under protocol number QLON-2011-SCR-01; DMID protocol number 15-0030) that indicates that the subject will be susceptible to infection with the challenge strain. The HAI titer will be assessed at Study Specific Screening only if the subject exhibits signs of respiratory infection at the Study Specific Screening visit.
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| E.4 | Principal exclusion criteria |
1. Evidence of or history of clinically significant oncologic, pulmonary (e.g., chronic bronchitis, chronic obstructive pulmonary disease), hepatic (e.g., hepatitis, cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease), gastrointestinal, cardiovascular (e.g., congestive heart failure, congenital heart disease, coronary artery disease), hematologic (e.g., sickle cell anemia), metabolic (e.g., Gaucher’s Disease, glucose malabsorption, phenylketonuria), neurological (e.g., cerebral palsy, epilepsy, stroke, seizures), immunologic (e.g., HIV infection, chronic immunosuppressive medication), nephrologic (e.g., bacterial infection, kidney stones), endocrine (e.g., diabetes mellitus), or psychiatric disease
2. Current infection of any nature unless agreed as insignificant to the study by the Investigator and Medical Monitor. Evidence of concurrent respiratory infection as determined by a rapid diagnostic test with the FilmArray™ Respiratory Panel from BioFire Diagnostics, Inc.
3. Nasal abnormalities, including nasal septum deviation, septum perforations, or polyps; history of recurrent epistaxis; history of sinus surgery and/or persistent hypertrophic inferior turbinates.
4. Significant abnormalities at screening in safety laboratory tests, ECGs, or spirometry as defined by Quintiles SOPs.
5. Inability to perform spirometry according to the 2005 American Thoracic Society (ATS) acceptability and repeatability standards.
6. Broncho-reactive airway disease (asthma, chronic obstructive pulmonary disease, current allergic rhinitis, cystic fibrosis, chronic bronchitis, emphysema). Individuals with a history of childhood asthma are acceptable for screening.
7. History of significant nasal irritation from use of nasal sprays or drops.
8. History of drug or alcohol abuse within the past 2 years; current excessive user of alcohol defined as regular weekly intake of greater than 21 units for male subjects and 14 units for female subjects. One unit equals 25 mL spirits, 125 mL wine or 250 mL beer.
9. Nicotine product users (includes users who stopped smoking 90 days prior to the screening evaluation and 30 days prior to the first dose of IMP). [Note: “Nicotine use” includes smoking and the use of snuff, e-cigarettes, and chewing tobacco, and other nicotine or nicotine containing products.]
10. Received an investigational drug or participated in another research study within 90 days of the first dose of IMP.
11. Participated in a previous investigational study of FF-3.
12. History of influenza vaccination with a live or attenuated vaccine within the previous year prior to experimental inoculation on Study Day 1.
13. Use of prescription drugs within 14 days prior to the first dose of IMP, excepting oral contraceptives.
14. Received any non-prescription medications, vitamins, or dietary supplements within 14 days of administration of the first dose of IMP, unless both the Principal Investigator and the Medical Monitor grant prior approval. Herbal supplements must be discontinued 7 days prior to the first dose of IMP.
15. Use of antihistamines and/or decongestants within 30 days, nasal corticosteroids within 90 days, or systemic corticosteroids within 90 days prior to the first dose of IMP
16. Tested positive for alcohol at screening or admission to the CRU.
17. Positive urine pregnancy test at the Screening Visit or positive serum pregnancy test on admission to the CRU (females only).
18. Positive test for HIV, hepatitis B surface antigen (HBsAg) or anti hepatitis C virus (anti-HCV) at the Screening Visit.
19. Positive urine drug test at the Screening Visit or at admission to the CRU.
20. Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol.
21. Subjects who have donated blood or experienced other significant blood loss within 56 days of screening for the study.
22. Subjects who care for or co-habit with the elderly (greater than or equal to 65 years of age), children (less than or equal to 5 years of age), employed in care facilities (e.g., nursing homes), or close contacts with individuals of any age who have significant chronic medical conditions such as chronic pulmonary disease (e.g., asthma, chronic obstructive pulmonary disease), chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects), neurological and neuro-developmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures), immunosuppression or cancer, children or teens on long term aspirin therapy, or women who are pregnant, breast feeding or attempting to become pregnant.
23. Known allergy to any of the following: eggs or egg products, oseltamivir, relenza, non-steroidal anti-inflammatory agents, or antibiotics in at least two of the following categories: beta lactams, cephalosporins, fluoroquinolones, glycopeptides.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Three co-primary endpoints will be evaluated:
• Evidence of viral shedding will be defined as a positive RT PCR result for the challenge virus obtained on at least one post inoculation day in the time interval beginning on Study Day 2 and ending on the completion of the inpatient observation period on Study Day 10.
• Evidence of infectivity will be defined as a positive tissue culture result for the challenge virus obtained on at least one post inoculation day in the time interval beginning on Study Day 2 and ending on the completion of the inpatient observation period on Study Day 10.
• Evidence of sero-conversion against the challenge virus will be defined as a four-fold or greater rise in serum HAI antibody titer between patient serum samples obtained at Check-in on Study Day -2 and at the post-treatment Follow-up on Study Day 30.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Viral shedding and infection will be evaluated through analysis of the nasal wash samples that will be collected on admission, Day 2 to Day 10 and on Day 30.
Sero-conversion will be assessed with measuring the hemagglutination inhibition antibody, which will take place on screening, admission and Day 30. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints will include the following:
• All safety data including laboratory assessments (i.e., hematology, clinical chemistry, and urinalysis), 12-lead electrocardiograms, vital signs, physical examinations, concomitant medications, and spontaneously occurring adverse events occurring from Check-in through the Day 30 Follow-up visit.
• The magnitude and duration of symptoms over time (as recorded by physician’s assessments and by patient self-assessment questionnaires) obtained during the 10-day period beginning immediately prior to inoculation on Study Day 1 and ending on the completion of the inpatient observation period on Study Day 10. Investigators will evaluate subjects two times daily for signs and symptoms of clinical respiratory illness. Investigators will evaluate signs of illness including fever, nasal discharge, pharyngitis, and new wheezes, rales, or rhonchi on lung auscultation and percussion. Symptoms will be graded on a 4-point scale: 0 Absent, 1 Mild, 2 Moderate, 3 Severe. Subjects will provide self-evaluations two times daily for signs and symptoms of clinical respiratory illness. Subjects will evaluate 16 signs and symptoms of illness including nasal stuffiness/congestion, runny nose, sore throat, sneezing, hoarseness, earache, facial or eye pain/tenderness, cough, wheezy chest, breathing difficulty, musculoskeletal ache, nausea/vomiting, feeling hot/feverishness/chills/rigor, headache, fatigue, diarrhea. Symptoms will be graded on a 4-point scale: 0 Absent, 1 Mild, 2 Moderate, 3 Severe.
• The quantity of virus shed over time in nasal washings calculated as an Area Under the Curve (AUC) /time for viral titers obtained during the 10-day period beginning immediately prior to inoculation on Study Day 1 and ending on the completion of the inpatient observation period on Study Day 10. Two separate calculations will be performed. Viral titers will be determined using quantitative RT PCR and quantitative TCID50 methods.
• Levels of pro-inflammatory and antiviral cytokines (including interleukin 6 (IL-6), tumor necrosis factor α, interferon α, and interferon γ produced over time in nasal washings calculated as an Area Under the Curve (AUC/time) for quantitative concentration data obtained during the 10-day period beginning immediately prior to inoculation on Study Day 1 and ending on the completion of the inpatient observation period on Study Day 10.
• The safety (as assessed by monitoring spontaneously occurring adverse events) and performance (as assessed by monitoring for device malfunctions) of the EPIC Inhaler starting from Day 1 through Day 6. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Symptom scores will be collected by physicians and by the volunteers separately, twice daily at screening, admission, from Day 1 to Day 10 and on Day 30.
Levels of pro-inflammatory and antiviral cytokines will be assessed in the nasal wash samples will be collected on admission, Day 2 to Day 10 and on Day 30. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as ‘the last visit of the last healthy volunteer undergoing the study’ |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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