| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| (Uncomplicated) Influenza A |
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| E.1.1.1 | Medical condition in easily understood language |
| Influenza, commonly referred to as the flu, is an infectious disease |
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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 | 13.1 |
| 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 |
| To assess the efficacy of an 8-day treatment with carbabenzpyride in adult subjects with influenza A in three different dosages compared to placebo on the basis of the duration of illness in terms of alleviation of symptoms. |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety of three different doses of carbabenzpyride compared to placebo in subjects with influenza A.
To determine the dose with the best benefit / risk ratio for the treatment of influenza A. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject who has given his / her signed declaration of consent and data protection declaration after having been informed about benefits and potential risks of the trial, as well as details of the insurance taken out to cover the subjects participating in the study.
2. Male or female outpatient subject at the age between 18 and 65 years
3. Diagnosis of influenza A·
- characterized by the presence of at least one respiratory symptom (cough, sore throat or nasal symptoms) of at least moderate severity
- characterized by the presence of at least one constitutional symptom (headache, myalgia sweats and / or chills, or fatigue) of at least moderate severity· characterized by fever ≥ 37.5°C / ≥ 99.5°F (sublingual) measured at the investigator’s office·
- onset of symptoms no longer than 36 hours prior to randomization; onset of symptoms is defined as appearance of at least one respiratory and one constitutional symptom of any severity
- positive influenza A rapid antigen test performed with a commercially available test kit on an adequate nasopharyngeal swab |
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| E.4 | Principal exclusion criteria |
Medical conditions
1. Influenza with concurrent clinical evidence of otitis media, bronchitis, rhinosinusitis and / or pneumonia or any other bacterial infection requiring therapy with oral or systemic antibiotics
2. Influenza - except the current infection - within the past 3 months prior to study enrollment
3. Presence or history of hypothyroidism, hyperthyroidism or thyroiditis (e.g., Hashimoto’s or Basedow’s disease, subacute thyroiditis) or history of hemithyroidectomy; presence of goiter
4. Subject with BMI > 35 kg/m2
5. Presence of relevant pulmonary disease (e.g., asthma, treatment requiring chronic obstructive pulmonary disease (COPD), cystic fibrosis, alpha-1-antitrypsin deficiency, sarcoidosis, bronchiectasis, allergic alveolitis, tuberculosis)
6. Existing cardiac, hematological, hepatic, renal, gastrointestinal and / or pathological findings, which might interfere with the drug’s safety, tolerability and / or absorption
7. Major surgery of the gastrointestinal tract, mal-absorption and / or mal-digestion
8. History or presence of malignant growth
9. Subject with impaired hematopoesis or coagulation disorder including medically induced inhibition of coagulation
10. Subject with active peptic ulcer or history of recurrent ulceration
11. Subject with gastrointestinal, cerebrovascular or other active bleeding
12. History or presence of relevant CNS and psychiatric disorders and currently treated CNS and psychiatric disorders
13. Presence of immuno-compromised status due to chronic illness, previous organ transplant or use of immunomodulatory or -suppressive therapy including oral or systemic corticosteroids within the past 4 weeks prior to study enrollment
14. Subject with known positive HIV test result
15. History or presence of drug allergy or hypersensitivity (e.g., anaphylaxis, urticaria, angiooedema, exanthema, erythema multiforme majus)
16. Subject with current signs of an allergy (e.g., skin or respiratory tract manifestations)
17. History or presence of hypersensitivity to iodine containing drugs and / or to the active ingredient or any excipient of the study medication
18. History or presence of drug or alcohol abuse (alcohol consumption > 40 g and > 20 g / day for male and female subjects, respectively)
19. Abnormal 12-lead ECG which might interfere with drug safety (e.g., but not limited to PR > 250 ms or higher degree av-block, QTc-prolongation, rhythm disorders, ectopic rhythm, complete right or left bundle branch block, hemi- and bifascicular blocks)
20. Positive TSH rapid test performed with a commercially available test kit / TSH value outside normal range in local laboratory in countries without licensed TSH rapid test
21. TSH value at Visit 1 outside normal range according to central laboratory
22. Laboratory value(s) out of normal range, unless the deviation from normal is judged as clinically not relevant by the investigator (e.g., but not limited to ASAT and / or ALAT > 2xULN, creatinine > 2.0 mg/dL)
23. Systemic use of iodine containing medications (e.g., amiodarone) or large-area use of iodine-containing antiseptics for local treatment of wounds or use of lithium within the last 6 months prior to study enrollment
24. Influenza vaccination or application of a live vaccine within the past 4 weeks prior to study enrollment
25. Treatment with antiviral drugs (e.g., neuraminidase inhibitors) within the past 2 weeks prior to study enrollment
26. Treatment with anticoagulants or with CYP2D6-substrates / -inhibitors or / -inducers within 1 week prior to study enrollment
27. Subject with concomitant medication not stable for at least 1 month prior to study enrollment
28. Blood donation or other blood loss of more than 400 ml within the past 2 months prior to study enrollment
29. Receipt of blood or blood products within the last 6 months prior to study enrollment
30. Participation in another clinical trial with an investigational product within the past 2 months prior to enrollment in the study or previous participation in the same study
31. Pregnant or breast-feeding woman
32. Woman of childbearing potential without highly effective contraception (failure rate less than 1%)
General conditions
33. Known to be, or suspected of being unable to comply with the study protocol (e.g., no permanent address, history of drug abuse, known to be non-compliant or presenting an unstable psychiatric history)
34. Legal incapacity and / or other circumstances rendering the subject unable to understand the nature, scope and possible impact of the study
35. Subject in custody by juridical or official order
36. Subject who has difficulties in understanding the language in which the subject information is given
37. Subject who does not agree to the transmission of their pseudonymous data within the liability of documentation and notification
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is defined as:
Time to alleviation [days] of influenza symptoms from Day 1 (Visit 1) to Day 22 comparing different dosages of carbabenzpyride with placebo in the Full Analysis Set (FAS) population.
The time to alleviation [days] of symptoms (cough, sore throat, nasal symptoms, headache, fatigue, myalgia, sweat and / or chill) will be calculated for a (maximum) observation period of 21 days (Day 1 to Day 22). Alleviation is defined as the start of a 24 ± 3 hour period, in which a symptom is less or equal to mild intensity (i.e. score = 1) and does not increase during that period. The analysis of the primary endpoint will be based on the subjects’ daily diary assessments.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuously up to Day 22. |
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| E.5.2 | Secondary end point(s) |
1. The AUC of all symptoms (sum of scores of all influenza symptoms) will be calculated from Day 1 to Day 22 as assessed by the subject in the diary and analyzed by the ANOVA with the factors “treatment” and “geographical regions“, and baseline as covariate using Dunnett’s test approach and tested for each active treatment group vs. placebo. In addition with the nonparametric Wilcoxon-Mann-Whitney test adjusted for “geographical regions” (van Elteren’s test) will be calculated. In order to show a dose-response relationship, also the Jonkheere-Terpstra test will be performed.
2. The duration of each individual symptom of influenza from Day 1 to Day 22 as assessed by the subject in the diary will be analyzed analogously to the primary endpoint.
3. The AUC of each individual symptom of influenza from Day 1 to Day 22 as assessed by the subject in the diary will be analyzed by the Wilcoxon test adjusted for “geographical regions” (van Elteren’s test) for each treatment group vs. placebo.
4. The AUC of all symptoms (sum of scores of all influenza symptoms) calculated from Day 1 to Day 22 for two subgroups, either with or without intake of paracetamol / acetaminophen during the course of the study will be analyzed by the ANCOVA with the factors “treatment” and “geographical regions“, and baseline as covariate using Dunnett’s test approach will be tested pairwise for each active treatment group vs. placebo. In addition, the nonparametric Wilcoxon test adjusted for “geographical regions” (Van Elteren’s test) will be calculated.
5. The AUC of virus titer per dose group from Visit 1 to Visit 5 will be log-transferred and analyzed by the ANCOVA with the factors “treatment” and “geographical regions“, and baseline as covariate using Dunnett’s test approach for each active treatment group vs. placebo.
6. The AUC of antibody response (HAI) from Visit 1 to Visit 6 will be log-transferred and tested by the ANCOVA with the factors “treatment” and “geographical regions“, and baseline as covariate using Dunnett’s test approach for each active treatment group vs. placebo.
7. The efficacy in patients with flu-like illness (i.e. subgroup of subjects with false positive rapid test for influenza A) will be analyzed analogously to the patients with influenza A, provided there is sufficient number of subjects in this specific patient subgroup.
8. The duration of the illness will be analyzed analogously to the primary endpoint as subgroups of subjects that received the influenza vaccine for the current season and those who did not receive the influenza vaccine.
9. The incidence of complications of influenza A such as otitis media, bronchitis, rhinosinusitis and / or pneumonia will be analyzed by the Fisher’s exact test and the Cochran-Mantel-Haenszel test controlling for “geographical regions” for each active treatment group compared to placebo.
10. The response to treatment as judged by the investigator and the subject (each separately) from Visit 2 to Visit 5 will be analyzed by the Cochran-Armitage trend test for each active treatment group compared to placebo (pairwise comparisons).
11. The percentage of subjects who used rescue medication will be analyzed Cochran-Mantel-Haenszel test controlling for “geographical regions” for each active treatment group compared to placebo.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See E.5.2, described for each endpoint. |
|
| 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 | Yes |
| 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 | 4 |
| 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 | 30 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Australia |
| Austria |
| Canada |
| New Zealand |
| South Africa |
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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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| End of study: last subject, last visit (i.e. 2nd follow-up visit of the last randomized subject) |
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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 | 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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