E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of severe influenza A virus disease. |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of severe influenza (flu). |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070215 |
E.1.2 | Term | Influenza A virus test positive |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
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 | 10021881 - Infections and infestations |
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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 objective is to evaluate the effect of TCN-032 compared to placebo in the development of influenza symptoms Grade 2 or higher, or pyrexia, from Day 1 to Day 7, after viral challenge. |
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E.2.2 | Secondary objectives of the trial |
Evaluate effect of TCN-032 vs. placebo in nasal virus AUC (viral culture, D1-7).
Additional objectives- evaluation of:
• Duration, time to peak, daily incidence of influenza symptoms ≥Grade 2, or pyrexia
• Proportion (D1-7), duration, time to peak, daily incidence of components of primary objective: Upper & Lower respiratory & systemic influenza symptoms and pyrexia
• Proportion (D1-7), duration, time to peak, daily incidence of any grade influenza symptoms, or pyrexia
• Mucus weight (D1-7)
• Peak value, time to peak, duration &daily incidence of virus shedding from nasal mucosa (viral culture)
• AUC (D2-7), peak value, time to peak, duration & daily incidence of virus shedding from nasal mucosa (qPCR)
• PK & immunogenicity of TCN-032
• Seroconversion and seroprotection to viral challenge strain
• Change in HAI titre pre-challenge to D28
• Viral resistance to TCN-032
Evaluate safety of subjects who undergo viral challenge, with or without TCN-032 treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects will be considered eligible if they satisfy all of the following inclusion criteria:
1. Age 18 to 45 years, inclusive.
2. In good health with no history of major medical conditions from medical history, physical examination, and routine laboratory tests as determined by the Investigator by a screening evaluation no greater than 45 days prior to inoculum.
3. Body weight between 50 and 100 kg, inclusive (body mass index [BMI] >18 kg/m2 to <33 kg/m2).
4. Female subjects must not be pregnant or nursing and must either be of non-childbearing potential (e.g. surgically sterile) or agree to use reliable contraceptive practices as in Table 2 (2 methods must be used) should they be heterosexually active. The provision of this history does NOT replace the requirement to perform, and obtain negative results in pregnancy tests and subjects must refrain from becoming pregnant until 4 months after IMP dosing. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female condoms and male condoms should not be used together as friction between the two can result in either product failing. Postmenopausal: Female subjects who have been amenorrheic for at least 2 years and have a serum follicle-stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females.
5. For non-sterilised male subjects who are heterosexually active, agreement to use 2 effective forms of birth control from admission into quarantine, and refrain from fathering a child at least until 4 months after the IMP dosing. Female condoms and male condoms should not be used together as friction between the two can result in either product failing. If a male subject has had a vasectomy (with a negative sperm post-vasectomy semen analysis) 6 months or greater before the Screening Visit, one additional contraception method is required until 4 months after dose of IMP.
6. Willingness to provide written consent for participation after reading the Subject Information Sheet and Consent Form and after having adequate opportunity to discuss the study with an Investigator. Comprehension of the study requirements; availability for the required study period, ability to attend scheduled study visits, and willingness to participate in the quarantine stay.
7. Serosusceptible (HAI titre <10) to the challenge virus at all visits prior to admission into quarantine.
8. Have not been vaccinated for influenza virus since 2006 (as determined in the medical history) or had a known influenza-like illness in the current season, defined as in the last 12 months prior to screening.
9. Should have a negative cotinine test on Day –2. However if a subject has a positive test on Day –2, then a repeat test on Day –1 or Day 0 must be negative.
10. Non smoker or current smoker willing/able to desist for the quarantine phase of the study or anyone who has a cumulative smoking history of ≤ 5 pack years. |
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E.4 | Principal exclusion criteria |
1. Presence of significant acute or chronic, uncontrolled medical or psychiatric illness
2. History of autoimmune disease
3. History of adulthood asthma/chronic lung condition
4. History of recurrent lower respiratory tract infection or lower respiratory tract infection within 3 months of study
5. Positive for HIV, HBV or HCV
6. Subject is diabetic
7. Anatomic or neurologic abnormality impairing gag reflex
8. History of frequent epistaxis
9. Known IgA deficiency, immotile cilia syndrome or Kartageners syndrome
10. Nasal or sinus surgery within 6 months of study
11. Recent and/or recurrent history of autonomic dysfunction
12. Abnormal laboratory test deemed clinically significant
13. Abnormal ECG or abnormal spirometry deemed clinically relevant
14. Acute medical condition or significant past medical history of hepatic, renal, cardiovascular, pulmonary, gastrointestinal, hematological, locomotor, immunologic, ophthalmologic, metabolic, endocrine, or other diseases
15. Major surgery within 3 months of study
16. Evidence of drug abuse or positive urine Class A drug or alcohol screen
17. Venous access deemed inadequate
18. Subjects symptomatic with hay fever on admission into the unit for quarantine session or prior to viral inoculation will be excluded.
19. History of significant adverse reactions or allergies
20. History of allergy or intolerance to oseltamivir or zanamivir.
21. Health care workers
22. Presence of household member or close contact (for 2 weeks after discharge) who is at risk of contracting influenza
23. Intending to travel within the next 3 months
24. Employed or immediate relatives of those employed at RVL or Sponsor.
25. Receipt of blood or blood products or loss of >450 mL of blood within 3 months of study
26. Acute use of medication for rhinitis or nasal congestion within 1 week of study
27. Use of prescription drugs, herbal supplements, within 4 weeks of study at the discretion of the Investigator in conjunction with TCN
28. Chronic use of any medication for rhinitis/nasal congestion or chronic nasopharyngeal complaint
29. Receipt of any investigational drug within 3 months of study or prior participation in a clinical trial of influenza vaccine, experimental influenza viral challenge or other respiratory virus challenge within 1year prior study
30. Receipt of antiviral drugs within 1 month of study
31. Receipt of systemic glucocorticoids, immunoglobulins (Igs), other cytotoxic/immunosuppressive drugs, or systemic chemotherapy agent
32. Previous treatment with monoclonal antibodies
33. Presence of febrile illness/symptoms of viral respiratory infection within 2 weeks prior study
34. Physical examination or screening investigations which lead the Investigator(s) to consider the subject unfit for the study
35. Subjects, who in the opinion of their General Practitioner or the Chief Investigator or designee, should not participate in the study
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects who develop influenza symptoms Grade 2 or higher, or pyrexia, from Day 1 to Day 7, after influenza A viral challenge. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The main secondary endpoint is the total virus shedding (AUC) from the nasal mucosa, measured by viral culture, from Day 1 to Day 7, after influenza A viral challenge.
Additional secondary endpoints include:
• The duration, time to peak, and daily incidence of influenza symptoms Grade 2 or higher, or pyrexia
• The proportion (from Day 1 to Day 7), duration, time to peak, and daily incidence of the components of the primary endpoint:
o Upper respiratory symptoms
o Lower respiratory symptoms
o Systemic influenza symptoms
o Pyrexia
• The proportion (from Day 1 to Day 7), duration, time to peak, and daily incidence of any grade influenza symptoms, or pyrexia
• Mucus weight (from Day 1 to Day 7) assessed by paper tissue weights
• The peak value, time to peak, duration, and daily incidence of virus shedding from the nasal mucosa measured by viral culture
• The AUC (Day 2 to Day 7), peak value, time to peak, duration, and daily incidence of virus shedding from the nasal mucosa measured by qPCR
• PK and immunogenicity of TCN-032
• Incidence of seroconversion and seroprotection to viral challenge strain
• Change in HAI titre pre-challenge to Day 28
• Proportion of subjects who develop viral resistance to TCN-032 (based on changes in TCN-032 binding, sequence changes in M2, ADCC susceptibility of infected cells)
Safety endpoints:
Incidence and severity of adverse events, incidence and severity of laboratory changes, changes in vital signs and clinical tests (ECG, spirometry) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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.8.5 | The trial involves multiple Member States | No |
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 | No |
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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LVLS. However, the duration could, on the rare occasion, extend out to 190 days if the subject should require follow-up ADA samples. |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |