| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Temporary relief of cold and flu symptoms, i.e. mild to moderate pain, sore
throat, fever and nasal congestion |
|
| E.1.1.1 | Medical condition in easily understood language |
Temporary relief of cold and flu symptoms, i.e. mild to moderate pain, sore
throat, fever and nasal congestion |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009851 |
| E.1.2 | Term | Cold |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022009 |
| E.1.2 | Term | Influenza-like symptoms |
| E.1.2 | System Organ Class | 100000004867 |
|
| 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 demonstrate the superiority of the FDC product containing 200 mg
ibuprofen, 500 mg paracetamol, and 10 mg phenylephrine hydrochloride
per film-coated tablet administered as 2 tablets PO TID compared to two
reference products: Doregrippin® (containing 500 mg paracetamol and 10
mg phenylephrine hydrochloride per coated tablet) administered as 2
tablets PO TID and Nurofen® (containing 200 mg ibuprofen per coated
tablet) administered as 2 tablets PO TID for a duration of 7 days, for the
temporary relief of cold and flu symptoms, i.e. mild to moderate pain, sore
throat, fever and nasal congestion. |
|
| E.2.2 | Secondary objectives of the trial |
1. To demonstrate the superiority of the FDC product containing 500 mg paracetamol,
200 mg ibuprofen, and 10 mg phenylephrine per tablet versus placebo for the temporary
relief of cold and flu symptoms, i.e. mild to moderate pain, sore throat, fever and nasal
congestion.
2. To demonstrate the superiority of each of the reference products Doregrippin®
(containing 500 mg paracetamol and 10 mg phenylephrine per tablet) and Nurofen®
(containing 200 mg ibuprofen per tablet) versus placebo for the temporary relief of cold
and flu symptoms, i.e. mild to moderate pain, sore throat, fever and nasal congestion.
3. To assess the safety and tolerability of the investigational product (i.e. the FDC) as
compared to the two reference products.
4. To assess the safety and tolerability of the investigational product (i.e. the FDC) as
compared to the placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Subjects willing and able to provide voluntary written informed consent.
[2] Male or female subjects aged between 18 and 60 years inclusive on the date of
consent.
[3] Diagnosis of common cold/flu-like syndrome defined as presence of at least two of
the following symptoms of at least moderate severity on 4-point symptom severity
scale (1=no; 2=mild; 3=moderate; 4=severe): cough, throat discomfort, nasal
obstruction, myalgia, fever and head congestion.
[4] Subjects with presence of the following at inclusion:
a. Mild to moderate pain defined as overall pain NRS score in between ≥ 4 to ≤
6 (at a 0 to 10 Likert scale) by the subject.
b. At least ≥ 38°C axillary armpit body temperature.
c. Nasal obstruction with a total nasal airflow resistance (NAR) of >0.25 Pa/cm3
second as determined by posterior rhinomanometry.
[5] Onset of symptoms ≤48 hours prior to screening visit.
[6] Subjects who are tested negative for rapid antigen test for COVID-19 within 15
days prior to screening or who are vaccinated (at least one dose) against COVID-
19 at least 15 days prior to screening.
[7] Male subjects who agree to use effective contraception during treatment and for 4
weeks after the last investigational product dose.
[8] Female subject of childbearing potential (not surgically sterilized/ hysterectomized
or postmenopausal for at least 1 year) who agree to use reliable methods of
contraception for the entire trial duration and for 4 weeks after the last
investigational product dose.
[9] Willing to avoid alcohol, smoking, coffee and chewing tobacco products during the
study period. |
|
| E.4 | Principal exclusion criteria |
[1] History of hypersensitivity or intolerance to the active substances or any of the
excipients of the trial medications.
[2] Known previous hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or
urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.
[3] Diagnosis / history of any other infectious disease that produces also symptoms of
common cold but needs specific treatment with antibacterial or antiviral drugs (e.g.
bronchitis, pneumonia etc.).
[4] Subject with any of the following conditions
a. Hyperthyreosis
b. Pheochromocytoma
c. Narrow angle glaucoma
d. Severe liver failure (Child- Pugh score > 9)
e. Severe renal failure
f. Congenital elevated bilirubin level in the blood (Gilbert’s syndrome or
Meulengracht’s disease)
g. Severe cardiovascular disease, severe cardiac arrhythmia, and uncontrolled
hypertension
h. Asthma bronchiale, chronic obstructive pulmonary disease, respiratory
depression or insufficiency
i. Allergic rhinitis
j. Glucose-6-phosphate and dehydrogenase deficiency
k. Narrowing of the upper urinary tract or prostate hyperplasia with residual urine
l. Porphyria
m. Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct
episodes of proven ulceration or bleeding).
n. History of gastrointestinal bleeding or perforation related to previous nonsteroidal
anti-inflammatory drug therapy
o. Active corona virus disease (COVID-19) according to PCR or rapid Antigen
test
p. Clinical evidence of immunosuppression.
[5] Concomitant or recent (within last 14 days before screening) use of tricyclic
antidepressants and MAO-inhibitors, MAO-inhibitors, SSRIs, SNRIs or Lithium.
[6] Subjects under treatment with anticoagulants including warfarin etc.
[7] Changes in existing concomitant therapy with corticosteroids, or other drugs with
influence on the immune system (e.g. immunosuppressive or cytostatic agents).
[8] Any other continuous drug treatment of symptoms of common cold and flu (except
analgesic rescue medication intake e.g. 500 mg of metamizole for pain relief).
[9] Pregnant or breast-feeding female subject.
[10] Female subject of childbearing potential (not surgically sterilized/ hysterectomized
or postmenopausal for at least 1 year) who is not currently using (documented at
screening visit) and not willing to use medically reliable methods of contraception
for the entire trial duration such as oral, injectable or implantable contraceptives,
intrauterine contraceptive devices (IUD), sexual abstinence or vasectomized
partner.
[11] Any other condition of the subject (e.g. serious or unstable medical or
psychological condition, acute psychosis) that in the opinion of the investigator may
compromise evaluation of the trial treatment or may jeopardize subject’s safety,
compliance or adherence to protocol requirements.
[12] Participation in any research study involving another investigational medicinalproduct (IMP) within 30 days prior to screening visit, or simultaneous participation
in another clinical study or previous participation in present study.
[13] Suspected alcohol/ drug dependence or abuse (including heavy smoking: ≥ 20
cigarettes daily).
[14] Subjects with known positive serology for Hepatitis B Virus (HBV), Hepatitis C Virus
(HCV), or Human Immunodeficiency Virus (HIV).
[15] Subjects with eating disorders, cystic fibrosis, or on a controlled sodium diet.
[16] Subjects with rare hereditary problems of fructose intolerance, glucose-galactose
malabsorption or sucrase-isomaltase insufficiency.
[17] Legal incapacity and/or other circumstances rendering the subject unable to
understand the nature, scope and possible consequences of the trial.
[18] Subjects who are known or suspected:
a. not to comply with the trial directives
b. not to be reliable or trustworthy
c. to be a dependent person, e.g. a relative, family member, or member/
employee of the investigator’s or sponsor’s staff
d. subject is in custody or submitted to an institution due to a judicial order. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Mean change of nasal airflow resistance as determined by posterior
rhinomanometry from baseline to 4.0 hours after first dose on day 1 of treatment.
2. Mean change of subjective intensity of nasal congestion using a 4-point scale (1=no,
2=mild, 3=moderate, 4=severe) from baseline to 4.0 hours after first dose on day 1
of treatment.
3. Mean change in overall pain score from baseline to end of study (day 8+1)
4. Mean change in axillary armpit temperature from baseline to end of study (day 8+1).
5. Mean change in Wisconsin Upper Respiratory Symptoms Survey-21 (WURSS-21)
from baseline to end of study (day 8+1).
6. Time to resolution of cold symptoms according to Wisconsin Upper Respiratory
Symptoms Survey-21 (WURSS-21). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Mean change of nasal airflow resistance from baseline to 4.0 hours after first dose on day 1 of treatment.
2. Mean change of subjective intensity of nasal congestion from baseline to 4.0 hours after first dose on day 1 of treatment.
3. Mean change in overall pain score from baseline to end of study (day 8+1)
4. Mean change in axillary armpit temperature from baseline to end of study (day 8+1).
5. Mean change in Wisconsin Upper Respiratory Symptoms Survey-21 (WURSS-21)
from baseline to end of study (day 8+1).
6. Time to resolution of cold symptoms according to Wisconsin Upper Respiratory
Symptoms Survey-21 (WURSS-21). |
|
| E.5.2 | Secondary end point(s) |
1. Mean change of nasal airflow resistance as determined by posterior
Rhinomanometry from baseline to 0.5, 1.0, 2.0 and 3.0 h after first dose on day 1.
2. Mean change of subjective intensity of nasal congestion using a 4-point scale (1=no,
2=mild, 3=moderate, 4=severe) from baseline to 0.5, 1.0, 2.0 and 3.0 h after first
dose.
3. Mean change in overall pain score from baseline to day 1 (0.5, 1.0, 2.0, 3.0, 4.0 and
6.0 h), day 2, 3, 4, 5, 6 and 7.
4. Mean change in Headache pain score from baseline to day 1 (0.5, 1.0, 2.0, 3.0, 4.0
and 6.0 h), day 2, 3, 4, 5, 6 and 7.
5. Mean change in Throat pain score from baseline to day 1 (0.5, 1.0, 2.0, 3.0, 4.0 and
6.0 h), day 2, 3, 4, 5, 6 and 7.
6. Mean change in Muscle pain score from baseline to day 1 (0.5, 1.0, 2.0, 3.0, 4.0 and
6.0 h), day 2, 3, 4, 5, 6 and 7.
7. Mean change in axillary armpit temperature from baseline to day 1 (1.0, 3.0, 4.0 and
6.0 h) day 2, 3, 4, 5, 6 and 7.
8. Mean change in Wisconsin Upper Respiratory Symptoms Survey-21 (WURSS-21)
from baseline to day 2, 3, 4, 5, 6 and 7.
9. Mean reduction in axillary armpit temperature at 1.0, 3.0, 4.0, and 6.0 h after first
dosing on day 1.
10. Wisconsin Upper Respiratory Symptoms Survey-21 (WURSS-21) sub group
analysis on Day 1, 2, 3, 4, 5, 6, and 7
11. Axillary armpit temperature sub group analysis on Day 1, 2, 3, 4, 5, 6, and 7.
12. Overall pain score sub group analysis on Day 1, 2, 3, 4, 5, 6, and 7.
13. Number and proportion of patients requiring rescue analgesic treatment during 6.0
h after first drug administration on day 1.
14. Duration of pain relief defined as the time to reach a main intensity score < 3 on a 0
to 10 pain intensity scale or the time to rescue analgesic intake.
15. Number and proportion of patients requiring rescue analgesic treatment during the
study.
16. Time before rescue analgesic treatment intake.
17. Time to reduce the axillary armpit temperature below 38.0˚C. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Mean change of nasal airflow resistance from baseline to 0.5, 1.0, 2.0 and 3.0 h after first dose on day 1.
2. Mean change of subjective intensity of nasal congestion from baseline to 0.5, 1.0, 2.0 and 3.0 h after first dose.
3. Mean change in overall pain score, headache, throat pain, muscle pain, axillary armpit temperature from baseline to day 1 (0.5, 1.0, 2.0, 3.0, 4.0 and
6.0 h), day 2, 3, 4, 5, 6 and 7.
8. Mean change in WURSS-21 from baseline to day 2, 3, 4, 5, 6 and 7.
9. Mean reduction in axillary armpit temperature at 1.0, 3.0, 4.0, and 6.0 h after first
dosing on day 1.
10. WURSS-21 sub group analysis on Day 1-7
11. Axillary armpit temperature sub group analysis on Day 1-7.
12. Overall pain score sub group analysis on Day 1-7.
|
|
| 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 | 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 | 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) | Yes |
| 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 | 10 |
| 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
|
|
| 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 | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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