| 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 |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022000 |
| E.1.2 | Term | Influenza |
| 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 of this study is to evaluate the efficacy and safety of inhaled LASAG plus standard of care compared to placebo plus standard of care in patients hospitalized due to acute serious influenza OR an influenza caused worsening of a primary medical condition measured by time to alleviation of influenza symptoms.
Influenza symptoms are defined as:
• nasal congestion
• sore throat
• cough
• aches/myalgia
• fatigue
• headaches
• feverishness/chills/sweats
Time to alleviation is defined as the time in hours from first inhalation of LASAG until at least 5 of 7 clinical influenza symptoms are rated with 0 (not present, i.e. like before the influenza) or 1 (mild) on the influenza symptom questionnaire without any use of symptom relief medication (i.e. acetaminophen) and remained so for at least 24±2 hours. |
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| E.2.2 | Secondary objectives of the trial |
The main secondary objective is to evaluate the clinical efficacy of inhaled LASAG plus standard of care compared to placebo plus standard of care in patients hospitalized due to acute serious influenza OR an influenza caused worsening of a primary medical condition as measured by time to alleviation of the following clinical influenza signs:
1. Body Temperature
• ≤ 37.2 °C (≤ 99 °F) oral
• ≤ 37.8°C (≤ 100°F) rectal or tympanic
2. Oxygen saturation
• ≥ 92% (without oxygen feed)
3. Respiratory rate
• ≤ 24/minute
4. Heart rate
• ≤ 100/minute
5. Systolic BP
• ≥ 90 mm Hg
Time to alleviation is defined as the time in hours from first inhalation of LASAG until resolution of at least 4 of the 5 clinical signs within resolution criteria given above and maintained for at least 24±2 hours without use of symptomatic relief medication (i.e. acetaminophen). 2 of the 4 resolution criteria have to be body temperature and oxygen saturation.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Age ≥ 18 and ≤ 80 years
2) Ability to provide written informed consent prior to performance of any study-related procedure
3) Ability to perform controlled inhalations with the AKITA JET device according to the investigator’s opinion
4) Indication for hospitalization due to suspected acute severe influenza OR patients with another medical condition (e.g. diabetes mellitus, COPD or other chronic lung disease) worsened by influenza and leading to indication for hospitalization
5) Living in a community with documented current influenza transmission, confirmed by viral culture or RT-PCR OR patients with influenza like illness with positive rapid antigen test or RT-PCR at screening
NOTE: 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 (by means of RT-PCR or viral culture), 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) or Pan American Health Organization (PAHO);
2) prior enrollment of a PCR positive subject into this study at the same institution in the current influenza season
6) Presence of at least one respiratory symptom (nasal congestion, sore throat or cough) of any severity (mild, moderate, or severe) and present admission to hospital due to (suspected) influenza
7) Presence of at least one constitutional symptom (aches/myalgia, fatigue headache or feverishness/chills/sweat) of any severity (mild, moderate, or severe) and present admission to hospital due to (suspected) influenza
8) Presence of fever at time of screening of ≥ 38.0 °C taken orally, or ≥ 38.5 °C taken rectally or tympanic OR history of documented fever or patient reported symptom of feverishness at any time during 48 hours prior to screening
NOTE: Axillary temperature measurement is not allowed for
temperature measurement at study site.
9) Patient reported onset of illness less than 120 hours (=5 days) before first study drug application.
NOTE: Time of onset of illness is defined as either (1) the time when the
temperature (either oral or rectal or tympanic) was first measured as
elevated (at least one degree (°C) of elevation in comparison to first
temperature measurement), OR (2) the time when the subject
experienced the presence of at least one moderate respiratory symptom
AND the presence of at least one moderate constitutional symptom.
Axillary temperature measurement is not allowed.
NOTE: Please note time point for onset of illness (<72 hours or ≥72
and <120 hours) in medical records and case report form.
10) Female participants of childbearing (reproductive) potential must have a negative urine pregnancy test at screening and agree to use an acceptable method of contraception throughout their participation in the study. Acceptable methods of contraception (a Pearl Index < 1%) include:
- hormonal methods (oral contraceptives, patches or medroxyprogesterone acetate)
- An intrauterine device (IUD) with a documented failure rate of less than 1% per year
- Abstinence may be considered an acceptable method of contraception at the discretion of the investigator
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral tubal ligation) or who are postmenopausal (total cessation of menses for >1 year) will not be considered as “females of childbearing potential.”
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| E.4 | Principal exclusion criteria |
1) Current clinical evidence or suspicion of an acute non-influenza infectious illness at the time of screening and baseline visit
2) Subjects who have been hospitalized due to a condition other than acute influenza and in whom influenza is diagnosed during hospitalization
3) Known allergy or hypersensitivity against Acetylsalicylic Acid (ASA) or LASAG
4) ASA induced asthma or patients with insufficiently controlled bronchial asthma
5) Presence of any chronic lung condition requiring either continuous or intermittent oxygen therapy
NOTE: Subjects who are determined to require acute supplemental oxygen therapy at the time of hospital admission may be enrolled, if exclusion criteria regarding mechanical ventilation (see below) are not applicable
6) Requirement for acute or chronic mechanical ventilation, either via oral or nasotracheal intubation or via tracheostomy, or chronic or intermittent requirement for BiPAP (bilevel positive airway pressure) at screening
NOTE: Subjects who require overnight Continuous Positive Airway Pressure (CPAP) treatment for sleep apnea (without oxygen supplementation) may be enrolled
7) Respiratory instability requiring ICU admission resulting in inability to breathe from a nebulizer
8) Immunized against influenza with live attenuated virus vaccine in the previous 4 weeks (=4x7 = 28 days)
9) Presence of one of the following uncontrolled or unstable cardiovascular diseases: stroke, ECG confirmed acute ischemia or myocardial infarction and/or clinically significant dysrhythmia
10) Presence of cardiac signs or symptoms compatible with NYHA Class IV functional status for congestive heart failure
11) Known history of gastrointestinal bleeding, uncontrolled peptic or uncontrolled duodenal ulcer
12) Known history of moderate or severe renal impairment and/or previous clinical laboratory data indicating an estimated creatinine clearance <30 mL/min during the last 12 months (=12x28 days = 336 days)
13) Known history of clinically significant proteinuria ( ≥ 1000 mg/24 hrs) during the last 12 months (=12x28 days = 336 days)
14) Presence of currently uncontrolled hyperuricaemia and/or diminished excretion of uric acid without appropriate pharmacotherapy during the last 12 months (=12x28 days = 336 days)
15) Known history of unstable cirrhosis or unstable advanced liver disease (Child-Pugh class B or C)
16) Known history of hemophilia or other bleeding disorders
17) History of organ transplantation, congenital immunodeficiency
18) Use of immunosuppressive therapies with a 10mg or more prednisolone-equivalent dose during the last 6 months (=6x28 days = 168 days). Use of inhaled glucocorticoids is permitted
19) Known history of human immunodeficiency virus (HIV) infection
20) Patients currently on or likely to require anticoagulation with coumarin, heparin, warfarin or similar products
NOTE: 1) chronic oral use of ASA (acetylsalicylic acid) at doses of 100mg/day for the purpose of anticoagulation e.g. in patients with coronary artery disease is allowed 2) Heparin (respectively Low Molecular Weight Heparin (LMWH)) for deep venous thrombosis prophylaxis is allowed 3) new generation of anticoagulation therapy
(e.g. Pradaxa) is not allowed
21) Expected explicit need for NSAIDs (non-steroidal anti-inflammatory drugs) during the study that cannot be covered by symptomatic acetaminophen (i.e. paracetamol) therapy (e.g. patients with chronic rheumatic conditions)
NOTE: For the relief of influenza symptoms, acetaminophen (paracetamol) must be used. Ibuprofen is prohibited. If Ibuprofen is used before screening, medication has to be switched to acetaminophen (paracetamol)
22) Presence of any cancer type (hematologic or solid tumor), that requires chemotherapy or radiation therapy, with the exception of localized non-melanoma skin cancer
23) Known history of alcohol abuse or drug addiction during the last 12 months (=12x28 days = 336 days)
24) Presence of a psychiatric illness or dementia that would preclude ability to use a nebulizer or complete the symptom questionnaire
25) Use of intravenous or intramuscular medications, containing acetylsalicylic acid within 72 hours prior first LASAG inhalation
26) Participation in a clinical study using an experimental medication during the last 4 weeks (=4x7 days = 28 days)
27) Women who are pregnant, breast-feeding or who are willing to become pregnant during the course of the study
28) Vulnerable patients who are not able to give informed consent or who might depend on the clinical study site or investigator
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to alleviation of clinical influenza symptoms which is defined as the time in hours from first inhalation of LASAG until at least 5 of 7 clinical influenza symptoms are rated with 0 (not present, i.e. like before the influenza) or 1 (mild) on the influenza symptom questionnaire without any use of symptom relief medication (i.e. acetaminophen) and remained so for at least 24±2 hours. Influenza symptoms are defined as:
• nasal congestion
• sore throat
• cough
• aches/myalgia
• fatigue
• headaches
• feverishness/chills/sweats |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time to alleviation of clinical influenza symptoms which is defined as the time in hours from first inhalation of LASAG until at least 5 of 7 clinical influenza symptoms are rated with 0 (not present, i.e. like before the influenza) or 1 (mild) on the influenza symptom questionnaire without any use of symptom relief medication (i.e. acetaminophen) and remained so for at least 24±2 hours. Influenza symptoms are defined as:
• nasal congestion
• sore throat
• cough
• aches/myalgia
• fatigue
• headaches
• feverishness/chills/sweats |
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| E.5.2 | Secondary end point(s) |
1) Time from start of treatment to alleviation of at least 4 of 5 clinical influenza signs maintained for at least 24±2 hours and without use of symptomatic relief medicines (i.e. acetaminophen)
2) Percentage of subjects whose influenza symptoms have completely resolved at specific time points (after inhalations 5, 8, 11 and 14)
3) Percentage of subjects whose influenza signs have completely resolved at specific time points (after inhalations 5, 8, 11 and 14)
4) Composite symptom score changes over time (AUC)
5) Change in viral load before inhalation 8
6) Percentage of subjects with >2-log drop in viral load prior to 8th dose
7) Descriptive statistics regarding adverse events and treatment discontinuations
8) Descriptive statistics of influenza related and all-cause mortality at follow-up visit 3
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Time from start of treatment to alleviation of at least 4 of 5 clinical influenza signs maintained for at least 24±2 hours without use of symptomatic relief medicines (i.e. acetaminophen)
2) Percentage of subjects whose influenza symptoms have completely resolved at specific time points (after inhalations 5, 8, 11 and 14)
3) Percentage of subjects whose influenza signs have completely resolved at specific time points (after inhalations 5, 8, 11 and 14)
4) Composite symptom score changes over time (AUC)
5) Change in viral load before inhalation 8
6) Percentage of subjects with >2-log drop in viral load prior to 8th dose
7) Descriptive statistics regarding AEs and treatment discontinuations
8) Descriptive statistics of influenza related and all-cause mortality at follow-up visit 3 |
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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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Bulgaria |
| Chile |
| Czech Republic |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Slovakia |
| Spain |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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