Randomized, multiCentre, dOuble-blind, double-duMmy, parallel-group clinical study on efficacy and safety of iBuprofen/N-acetylcysteine fixed dose cOmbination vs. its individual components (ibuprofen and N- acetylcysteine monotherapies) in patients with symptomatic uncomplicated upper respiratory tract infections with wet cough COMBO

Overview

Sponsor-declared trial summary

Key facts

Sponsor

E Pharma Trento S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Decision date (initial)

2023-11-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

E-Pharma Trento S.p.A., Via Provina 2 – 38123 Ravina, Italy

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Efficacy: To demonstrate the superiority of a 7-day treatment with IBU/NAC FDC vs. its components administered alone (i.e., IBU monotherapy and NAC monotherapy) in the time to clinically significant improvement of signs and symptoms of uncomplicated URTI with wet cough.
Safety: To assess the safety of the Investigational Medicinal Products (IMPs) throughout the trial.

Secondary objectives 1

1. Efficacy: To further evaluate the efficacy of IBU/NAC FDC in comparison with its individual components, IBU and NAC.

Conditions and MedDRA coding

Upper respiratory tract infections

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female, age ≥18 and ≤ 75 years
2. Clinical diagnosis of symptomatic uncomplicated URTI, as confirmed by the Investigator
3. Signs/symptoms of uncomplicated URTI (e.g., fever [i.e., axillary temperature ≥ 37.5 °C], cold symptoms [i.e., runny nose, plugged nose, sneezing, scratchy throat, hoarseness, head congestion, chest congestion, feeling tired], sore throat, shortness of breath and limitation in daily activities) and wet cough for ≤ 3 days prior to screening
4. Presence of wet cough of at least moderate severity (i.e., a score ≥ 2 on the 5-point Likert scale) and total sum of the 5-point Likert scale (range 0-4) for signs and symptom of uncomplicated URTI (cough, fever, cold symptoms, sore throat, shortness of breath and limitation in daily activities) ≥ 9
5. Signed written informed consent (to be obtained before any trial procedure is performed)
6. Willingness and capability to fulfil all tasks foreseen by the trial protocol
7. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid antigen test at screening
8. Females of childbearing potential must have a negative urine pregnancy test (dipstick) prior to the first Investigational Medicinal Product (IMP) administration, and currently use or agree to use consistently and correctly (i.e., perfect use) a highly effective method of contraception for the individual subject and her partner(s) throughout the trial and for at least one full contraceptive cycle (when applicable). Highly effective methods of contraception include the following: a) implantable progestogen-only hormone contraception associated with inhibition of ovulation; b) intrauterine device (IUD); c) intrauterine hormone-releasing system (IUS); d) combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral; intravaginal; transdermal), provided the patient has been using that hormonal contraceptive for an adequate period of time to ensure effectiveness; e) progestogen-only hormone contraception associated with inhibition of ovulation (oral; injectable), provided the patient has been using that hormonal contraceptive for an adequate period of time to ensure effectiveness; f) vasectomized partner, provided that the partner is the sole patient’s sexual partner and the absence of sperm has been confirmed; g) bilateral tubal occlusion or tubal ligation; h) sexual abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the IMP (i.e., up to 24h after the end of treatment). Barrier contraceptives (i.e., diaphragm or cervical cap with spermicide and/or condoms [male or female] with or without a spermicidal agent) are not considered highly effective methods of contraception, and thus must not be used as sole method of contraception. Of note, females who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal (at least 12 months of amenorrhea following cessation of all exogenous hormonal treatment) are not considered of childbearing potential.

Exclusion criteria 19

1. Patients with asthma or chronic obstructive pulmonary disease (COPD) or other chronic respiratory disorders
2. Patients with suspected lower respiratory tract infection or other infections requiring treatment with antibiotics.
3. Pregnancy or lactation period throughout the whole trial duration.
4. History of allergy or hypersensitivity or intolerance to IBU and/or NAC and/or any of their excipients.
5. Known hypersensitivity to NSAIDs
6. Use within 7 days prior to Visit 1 of oral, rectal, parenteral or inhaled NSAIDs and analgesics with a half-life greater than 5 hours (see Appendix I of the trial protocol for a non-exhaustive list of NSAIDs and analgesics with a half-life lower than 5 hours that are allowed up to the day before Visit 1). The use of other analgesics and modified-release NSAIDs and analgesics within 2 weeks prior to Visit 1 is prohibited. Topical NSAIDs and analgesics are allowed.
7. Use of oral, parenteral or inhaled corticosteroids, and leukotriene antagonists within 4 weeks before Visit 1.
8. Use of antibiotics, antivirals, and bronchodilators in the week before Visit 1. Topical antibiotics and antivirals are allowed.
9. Patients with clinical signs of or known or history of peptic ulcer disease.
10. Patients with clinical signs or history of coagulation disorders, or requiring anticoagulants.
11. Patients with known (as previously documented) severe heart failure (NYHA class IV), severe renal impairment (eGFR <30 mL/min), or severe hepatic impairment (Child-Pugh class C).
12. Patients with uncontrolled arterial hypertension (in unstable pharmacological therapy).
13. History of atrial fibrillation.
14. Clinically significant or unstable concurrent diseases whose sequelae or treatment might contraindicate trial participation or interfere with the trial evaluation parameters, as judged by the Investigator.
15. History of drug abuse or use of illegal drugs.
16. Alcohol abuse, i.e., regular use of more than 2 units of alcohol per day or 10 units per week or a history of alcoholism (one unit of alcohol equals 250 ml beer, 125 ml wine or 25 ml spirits).
17. History of serious psychiatric disorders.
18. Previous participation in this clinical trial.
19. Participation in other clinical trials at the same time or within 90 days prior to Visit 1 (calculated from the date of the final examination of the previous trial).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time from randomization to clinically significant improvement of signs and symptoms of uncomplicated URTI with wet cough, defined as a score ≤ 1 on a 5-point Likert scale (range 0-4; 0 = no symptom, 1 = mild symptom 2 = moderate symptom, 3 = severe symptom, 4 = very severe symptom) for each single URTI sign/symptom (i.e. cough, fever [i.e., axillary temperature ≥ 37.5 °C], cold symptoms and a total sum score for all URTI signs and symptoms ≤ 3.

Secondary endpoints 14

1. Proportion of participants with clinically significant improvement of URTI signs and symptoms at each day up to the end of treatment (EOT) visit (Day 8 ± 1), as defined above
2. Proportion of participants with resolution of URTI signs and symptoms, defined as a total sum score for all URTI signs and symptoms = 0 on the 5-point Likert scale (range 0-4), at each day up to EOT
3. Time to resolution of URTI signs and symptoms
4. Proportion of participants who discontinue early treatment with IMPs due to resolution of URTI signs and symptoms from baseline to EOT
5. Changes from baseline of the total sum score and individual scores for the severity of URTI signs and symptoms, as well as the Area Under the Curve (AUC) of each URTI sign/symptom score over time, as evaluated on the 5-point Likert scale (range 0-4)
6. Changes from baseline of total and single item scores of the Wisconsin Upper Respiratory Symptoms Survey (WURSS-21)
7. Proportion of participants with reduction of symptom severity to ≤1 for each single item related to the cluster of cold symptoms on the WURSS-21 at EOT
8. Investigator’s overall assessment of efficacy at EOT and end of study (EOS) visit (Day 15 ± 2) as cure (complete disappearance of signs and symptoms of inflammation), improvement (non-complete resolution of signs and symptoms of inflammation), or failure (persistency or worsening of signs and symptoms of inflammation)
9. Use of rescue medication during treatment
10. Safety: Incidence of all Adverse Events (AEs), Adverse Drug Reactions (ADRs), Adverse Events of Special Interest (AESIs) (i.e., AEs related to bleeding, such as bleeding diathesis, namely mucosal bleeding [epistaxis, gum bleeding, menorrhagia] and easy bruising, and GI bleeding), Serious Adverse Events (SAEs)
11. Safety:Frequency of discontinuation of treatment due to AEs
12. Safety: Changes from baseline at EOT of vital signs (axillary temperature, blood pressure, heart rate and respiratory rate) (in case of on-site EOT visit only)
13. Safety: Physical examination at baseline and EOT (in case of on-site EOT visit only)
14. Safety: Investigator’s and participant’s opinion on drug tolerability at EOT, using a 5-point Likert scale (range 0-4; 0 = poor, 1 = slight, 2 = moderate, 3 = good, 4 = excellent)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Placebo 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

E Pharma Trento S.p.A.

Sponsor organisation

E Pharma Trento S.p.A.

Address

Via Provina 2

City

Trento

Postcode

38123

Country

Italy

Scientific contact point

Organisation

E Pharma Trento S.p.A.

Contact name

Riccardo Catalano

Public contact point

Organisation

E Pharma Trento S.p.A.

Contact name

Riccardo Catalano

Third parties 5

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications