Efficacy and Safety of Acetylcysteine for the Treatment of Acute Uncomplicated Rhinosinusitis

Phase 3

Completed

Conditions: Rhinosinusitis

Interventions: Drug: acetylcysteine
Drug: Placebo

Registration Number: NCT04123405

Lead Sponsor: Sandoz

Brief Summary: The trial was conducted as a prospective, randomized, multinational, multicenter, double-blind study in 4 parallel groups of patients.

Detailed Description: The study was the prospective, randomized, multinational, multicenter, double-blind study in 4 parallel groups of patients.

Patients underwent screening examinations at Visit 1. Patients who met all inclusion/ no exclusion criteria were randomized at the baseline visit (Day 1) to the double-blind treatment for a duration of 14 days but in case of delayed final visit (Day 15) the patient could voluntarily take reserve study medication for a maximum of 3 additional days.

After the end of the double-blind treatment phase, the patients underwent an end-of-treatment (EOT) examinations on Day 15 (+3).

A follow-up phone call within 7 days after Day 15 (or earlier in case of premature termination) was performed.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 944

Inclusion Criteria

Male or female subjects aged between 14 and 75 years inclusive on the date of consent
Diagnosis of acute, uncomplicated rhinosinusitis defined at screening visit 1 and at Visit 2 as:
1. major symptom score (MSS) assessed by the patient ≥8 and ≤12 points for the following: rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure, whereupon the nasal congestion is mandatory and no more than 3 of the 5 symptoms are rated as severe
2. individual score for facial pain/pressure ≥1 (mild) and ≤2 (moderate)
3. presence of symptoms ≤3 days prior to screening visit
For adults (≥18 years): Informed consent to participate in the trial provided in written form; For adolescents (≥14 - <18 years): own subject informed consent/ assent to participate in the trial and the informed consent from all parent(s)/ legal guardian(s) provided in written form.

Exclusion Criteria

History of hypersensitivity or intolerance to the active substance or any of the excipients of the trial medication
Patient with history of hereditary fructose intolerance, galactose intolerance, lactase deficiency or glucose-galactose malabsorption
Chronic rhinosinusitis (symptoms lasting longer than 3 months)
Subjects who have undergone sinus or nasal surgery for chronic rhinosinusitis in the 6 months prior to screening visit
Sinus lavage within 7 days prior to screening visit
Odontogenic rhinosinusitis
Allergic (perennial or seasonal) rhinitis
Bronchial asthma or chronic obstructive pulmonary disease
Nasal polyposis or clinically relevant nasal septum deviation
Concomitant otitis
Intranasal or systemic use of corticosteroids within 30 days prior to screening visit
Intranasal or systemic use of antibiotics within 30 days prior to screening visit
Use of nasal decongestants within 2 days prior to screening visit
Concomitant treatment of common cold-like symptoms within 7 days prior to screening visit with any of the following:
1. Analgesics
2. Non-steroidal anti-inflammatory drugs
3. Antihistamines
Concomitant use of intranasal saline irrigation
Use of immunosuppressive agents within 30 days prior to screening visit
Immunocompromised state
Suspicion for acute bacterial rhinosinusitis (defined as presence of purulence for 3 to 4 days with fever ≥ 38.3°C)
Pregnant or breast-feeding female patient
Female patient 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
Any other condition of the patient (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 patient's safety, compliance or adherence to protocol requirements
Participation in ANY research study involving another investigational medicinal product (IMP) within 30 days prior to screening visit, or simultaneous participation in another clinical study or previous participation in present study
Suspected alcohol/ drug dependence or abuse (including heavy smoking: ≥ 20 cigarettes daily)
Use of snuff tobacco
Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the trial
Subjects who are known or suspected:
- not to comply with the trial directives
- not to be reliable or trustworthy
- to be a dependent person, e.g. a relative, family member, or member/employee of the investigator's or sponsor's staff
- subject is in custody or submitted to an institution due to a judicial order.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: 600 mg acetylcysteine	Placebo	one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Group A: 600 mg acetylcysteine	acetylcysteine	one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Group B: 1200 mg acetylcysteine	Placebo	two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Group D: Placebo	Placebo	four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Group B: 1200 mg acetylcysteine	acetylcysteine	two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Group C: 2400 mg acetylcysteine	acetylcysteine	four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Per-Protocol Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Full Analysis Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.

Secondary Outcome Measures

Name	Time	Method
Time to Onset of Action, Per-Protocol Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	Time to onset of action was defined as first day of active treatment on which MSS showed statistically significant (p value\<0.05) improvement from placebo.
Sino-Nasal Outcome Test (SNOT-22) by Visit, Per Protocol Set	Baseline (Day 1), Day 7 and Day 14	SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL.
Number of Responders and Non-responders to Treatment, Per-Protocol Set	Day 4, 7, 10 and 15	Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.
Major Symptom Score (MSS) Development Over the Course of the Study, Per-protocol Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
Time to Onset of Action, Full Analysis Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	Time to onset of action was defined as first day of active treatment on which MSS showed statistically significant (p value\<0.05) improvement from placebo.
Major Symptom Score (MSS) Development Over the Course of the Study, Full Analysis Set	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
Sino-Nasal Outcome Test (SNOT-22) by Visit, Full Analysis Set	Baseline (Day 1), Day 7 and Day 14	SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL.
Sino-Nasal Outcome Test (SNOT-22) by Change to Baseline, Full Analysis Set	Baseline (Day 1), Day 7 and Day 14	SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL. A negative change from baseline in SNOT-22 is considered a favorable outcome.
Sino-Nasal Outcome Test (SNOT-22) by Change to Baseline, Per Protocol Set	Baseline (Day 1), Day 7 and Day 14	SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL. A negative change from baseline in SNOT-22 is considered a favorable outcome.
Number of Responders and Non-responders to Treatment, Full Analysis Set	Day 4, 7, 10 and 15	Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.