| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Acute otitis media (AOM) is an acute inflammatory disease involving the mucosa of the middle ear. AOM is one of the most frequent complications of upper respiratory tract infections in children.
Treatment of AOM requires use of drugs with antipiretic, analgesic and antinflammatory action, as well as antibiotics. |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute otitis with pain and fever requires administration of drugs to treat increased temperature and to reduce pain as well as antibiotics and topical agents (e.g. nasal drops). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| 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 |
1. To investigate the analgesic effect of the study drugs Ibuprofen oral suspension 20 mg/ml and Ibuprofen oral suspension 40 mg/ml (ear pain relief assessed by Pain rating scale) in children with AOM.
2. To investigate the antipyretic effect of the study drugs Ibuprofen oral suspension 20 mg/ml and Ibuprofen oral suspension 40 mg/ml (reduction of axillary temperature) in children with AOM.
3. To investigate the anti-inflammatory effect of the study drugs Ibuprofen oral suspension 20 mg/ml and Ibuprofen oral suspension 40 mg/ml (reduction of laboratory markers of inflammation) in children with AOM.
4. To examine the effect of the study drugs Ibuprofen oral suspension 20 mg/ml and Ibuprofen oral suspension 40 mg/ml on appetite, sleep, and playing activity in children with AOM.
5. To evaluate the safety of the study drugs Ibuprofen oral suspension 20 mg/ml and Ibuprofen oral suspension 40 mg/ml based on frequency and severity of treatment-related adverse events. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Child’s parents’ written informed consent for the child’s participation in the study.
2) Boys and girls 3 to 9 years old inclusive.
3) Body weight 10 – 29 kg inclusive.
4) Established diagnosis of AOM, either unilateral or bilateral, following diagnosis criteria:
a) Presence of uni- or bilateral otalgia (pain rating scale score ≥ 4);
b) Recent onset of signs and symptoms including ear pain (within 48 hours);
c) Presence of erythema or fullness or bugling of the tympanic membrane (assessed by otoscopy).
5) Fever ≥ 37.5 ºะก at screening.
6) Indications for oral antibiotics administration.
7) Parent(s) is(are) able to complete the study protocol (e.g. filling the Diary, assessing ear pain by pain scales) and has(-ve) access to telephone contacts. |
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| E.4 | Principal exclusion criteria |
1) Known or suspected hypersensitivity to the ibuprofen or to any of the excipients of study drugs, including fructose intolerance.
2) Known or suspected hypersensitivity to antibiotics (penicillines, cephalosporines, carbapenems).
3) History of bronchospasm, asthma, rhinitis, angioedema or urticaria associated with the intake of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs).
4) Previous treatment of the current AOM:
a) any systemic antibiotic treatment at screening and at least 3 days before screening.
b) any systemic and/or topical analgesics for AOM at screening and within previous 24 hours.
c) previous invasive treatment of current AOM.
5) Severe fever at screening (> 40 °C)
6) Patients requiring non-oral administration of antibiotics.
7) Recurrent AOM (clinical recurrence of AOM within 30 days or history of more than 4 episodes of AOM over the course of 12 months).
8) Presence of otogenic complications of AOM (such as mastoiditis, labyrintitis etc.) or spontaneous perforation of the tympanic membrane.
9) Known presence of complications of the upper respiratory tract infections such as sinusitis (including catarrhal sinusitis) or pneumonia.
10) Known presence of AOM underlying chronic otitis media.
11) Presence of cochlear implants or prior middle ear surgery (e.g., tympanostomy tube[s] in place or a history of tympanostomy tubes).
12) Patients who underwent ear surgery such as canal wall down, mastoidectomy or tympanoplasty less than a year ago.
13) Any form of coagulation disturbances (e.g. hemophilia) or any active bleeding.
14) History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
15) Underlying systemic problems that might obscure response to infection, e.g., serious underlying disease (cystic fibrosis, neoplasm, juvenile diabetes, HIV-infection).
16) Presence of immunodeficiency or receipt of immunosuppressive therapy.
17) Concomitant active infection other than AOM or acute respiratory illness.
18) Known presence of severe hepatic failure (AST, ALT more than 3 times the upper value of the reference range).
19) Known presence of severe renal failure (creatinine clearance < 30 ml/min).
20) Chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease).
21) Severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake).
22) Congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)
23) Otologic or craniofacial abnormalities (e.g. unrepaired or repaired overt or submucous cleft palate, high-arched palate), or Down's syndrome.
24) Children, who cannot cooperate, comprehend or use the Pain rating scale.
25) The patient requires or may require medications prohibited by the protocol (e.g. ear drops, other NSAIDs and analgesics, systemic corticosteroids, anti-coagulants, CYP2C9 inhibitors, phenylbutazone, oxyphenbutazone, methotrexate and other medications that may interact with study drugs).
26) Participation in another clinical study within previous 30 days. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with pain relief defined as a reduction of pain score by ≥2 on the 6-item Wong-Baker FACES Pain rating scale on the basis of Parent’s diary. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at 48 h (Day 3) of therapy, |
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| E.5.2 | Secondary end point(s) |
1) Proportion of patients with pain relief defined as a reduction of pain score by ≥2 on the Pain rating scale on the basis of Parent’s diary.
2) Proportion of patients with pain relief defined as a reduction of pain score by ≥2 on the Pain rating scale on the basis of Parent’s diary.
3) Time (hours) to onset of pain relief on the basis of Parents’s diary.
4) Mean change in pain rating scale.
5) Proportion of patients with normal axillary temperature (< 37°C) on the basis of Parent’s diary.
6) Mean axillary temperature change on the basis of Parent’s diary.
7) Proportion of patients with a drop of at least 1°C in axillary temperature on the basis of Parent’s diary.
8) Time to normalization of axillary temperature (< 37°C)
9) Mean change in laboratory markers of inflammation (C-reactive protein, white blood cells, neutrophills).
10) Change of quality of life on three items: appetite, sleep, and playing activity assessed by a 3-item scale (0 – severe impairment, 1 – mild impairment, 2 – normal).
11) Treatment safety based on frequency and severity of adverse events.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) at 24 h (Day 2)
2) at 4 h after 1st dose of study treatment
3) after 1st dose of study treatment
4) at Day 2, Day 3, and Day 5 compared to baseline on Day 1
5) at 4 h after 1st dose of study treatment
6) from baseline to 4 h
7) at 4h
8) ad-hoc
9) at the end of analgesic therapy (Day5) from baseline (Day 1)
10) at 48 h (Day 3) of therapy and at the end of analgesic therapy (Day 5) as compared to baseline
11) ad-hoc
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Russian Federation |
| Ukraine |
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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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The duration of each patient’s participation in the trial was no more than 8 days (screening – day 1, study treatment – days 1-7, final visit – day 8).
The whole trial duration was no more than 2.5 months (8 weeks of enrollment and no more than 8 days of therapy).
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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