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

Efficacy and Safety of Acetylcysteine for the Treatment of Acute Uncomplicated Rhinosinusitis: a Prospective, Randomized, Double-blind, Placebo-controlled Trial

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

Study Overview

• Status: Completed
• Conditions: Rhinosinusitis
• Intervention / Treatment: Drug: acetylcysteine; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 944
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Burgas, Bulgaria, 8000
    • Sandoz Investigative Site
  • Gabrovo, Bulgaria, 5300
    • Sandoz Investigative Site
  • Plovdiv, Bulgaria, 4000
    • Sandoz Investigative Site
  • Sliven, Bulgaria, 8800
    • Sandoz Investigative Site
  • Sofia, Bulgaria, 1000
    • Sandoz Investigative Site
  • Sofia, Bulgaria, 1408
    • Sandoz Investigative Site
  • Sofia, Bulgaria, 1527
    • Sandoz Investigative Site
  • Sofia, Bulgaria, 1606
    • Sandoz Investigative Site
  • Yambol, Bulgaria, 8600
    • Sandoz Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Sandoz Investigative Site
  • Dresden, Germany, 01139
    • Sandoz Investigative Site
  • Duisburg, Germany, 47051
    • Sandoz Investigative Site
• Moldova, Republic of
  • Chișinău, Moldova, Republic of, 2012
    • Sandoz Investigative Site
  • Chișinău, Moldova, Republic of, 2025
    • Sandoz Investigative Site
  • Chișinău, Moldova, Republic of, 2032
    • Sandoz Investigative Site
  • Chișinău, Moldova, Republic of, 2044
    • Sandoz Investigative Site
  • Chișinău, Moldova, Republic of, 2051
    • Sandoz Investigative Site
  • Chișinău, Moldova, Republic of, 37
    • Sandoz Investigative Site
  • Orhei, Moldova, Republic of, 3005
    • Sandoz Investigative Site
• Russian Federation
  • Kazan, Russian Federation, 420029
    • Sandoz Investigative Site
  • Kemerovo, Russian Federation, 650066
    • Sandoz Investigative Site
  • Moscow, Russian Federation, 117552
    • Sandoz Investigative Site
  • Moscow, Russian Federation, 119571
    • Sandoz Investigative Site
  • Moscow, Russian Federation, 123184
    • Sandoz Investigative Site
  • Moscow, Russian Federation, 142190
    • Sandoz Investigative Site
  • Novosibirsk, Russian Federation, 630051
    • Sandoz Investigative Site
  • Ryazan, Russian Federation, 390026
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 191025
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 191186
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 192283
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 194291
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 195197
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 196084
    • Sandoz Investigative Site
  • Saint Petersburg, Russian Federation, 196158
    • Sandoz Investigative Site
  • Smolensk, Russian Federation, 214031
    • Sandoz Investigative Site
  • St. Petersburg, Russian Federation, 197376
    • Sandoz Investigative Site
  • Yaroslavl, Russian Federation, 150000
    • Sandoz Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female subjects aged between 14 and 75 years inclusive on the date of consent

2. 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
3. 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:

1. History of hypersensitivity or intolerance to the active substance or any of the excipients of the trial medication
2. Patient with history of hereditary fructose intolerance, galactose intolerance, lactase deficiency or glucose-galactose malabsorption
3. Chronic rhinosinusitis (symptoms lasting longer than 3 months)
4. Subjects who have undergone sinus or nasal surgery for chronic rhinosinusitis in the 6 months prior to screening visit
5. Sinus lavage within 7 days prior to screening visit
6. Odontogenic rhinosinusitis
7. Allergic (perennial or seasonal) rhinitis
8. Bronchial asthma or chronic obstructive pulmonary disease
9. Nasal polyposis or clinically relevant nasal septum deviation
10. Concomitant otitis
11. Intranasal or systemic use of corticosteroids within 30 days prior to screening visit
12. Intranasal or systemic use of antibiotics within 30 days prior to screening visit
13. Use of nasal decongestants within 2 days prior to screening visit

14. 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
15. Concomitant use of intranasal saline irrigation
16. Use of immunosuppressive agents within 30 days prior to screening visit
17. Immunocompromised state
18. Suspicion for acute bacterial rhinosinusitis (defined as presence of purulence for 3 to 4 days with fever ≥ 38.3°C)
19. Pregnant or breast-feeding female patient
20. 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
21. 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
22. 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
23. Suspected alcohol/ drug dependence or abuse (including heavy smoking: ≥ 20 cigarettes daily)
24. Use of snuff tobacco
25. Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the trial

26. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: 600 mg acetylcysteine; one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)	Drug: acetylcysteine; 600 mg tablet; Drug: Placebo; Placebo to acetylcysteine
Experimental: Group B: 1200 mg acetylcysteine; two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)	Drug: acetylcysteine; 600 mg tablet; Drug: Placebo; Placebo to acetylcysteine
Experimental: Group C: 2400 mg acetylcysteine; four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)	Drug: acetylcysteine; 600 mg tablet
Placebo Comparator: Group D: Placebo; four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)	Drug: Placebo; Placebo to acetylcysteine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Full Analysis Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Per-Protocol Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Action, Full Analysis Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
Time to Onset of Action, Per-Protocol Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
Major Symptom Score (MSS) Development Over the Course of the Study, Full Analysis Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
Major Symptom Score (MSS) Development Over the Course of the Study, Per-protocol Set	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.	Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
Sino-Nasal Outcome Test (SNOT-22) by Visit, Full Analysis Set	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.	Baseline (Day 1), Day 7 and Day 14
Sino-Nasal Outcome Test (SNOT-22) by Visit, Per Protocol Set	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.	Baseline (Day 1), Day 7 and Day 14
Sino-Nasal Outcome Test (SNOT-22) by Change to Baseline, Full Analysis Set	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.	Baseline (Day 1), Day 7 and Day 14
Sino-Nasal Outcome Test (SNOT-22) by Change to Baseline, Per Protocol Set	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.	Baseline (Day 1), Day 7 and Day 14
Number of Responders and Non-responders to Treatment, Full Analysis Set	Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.	Day 4, 7, 10 and 15
Number of Responders and Non-responders to Treatment, Per-Protocol Set	Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.	Day 4, 7, 10 and 15

Collaborators and Investigators

• Sponsor: Sandoz

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2020
• Primary Completion (Actual): April 20, 2021
• Study Completion (Actual): April 20, 2021

Study Registration Dates

• First Submitted: October 9, 2019
• First Submitted That Met QC Criteria: October 9, 2019
• First Posted (Actual): October 10, 2019

Study Record Updates

• Last Update Posted (Actual): November 19, 2021
• Last Update Submitted That Met QC Criteria: October 20, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: acute uncomplicated rhinosinusitis, acetylcysteine
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Paranasal Sinus Diseases; Nose Diseases; Sinusitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 2018-08-EFT-1; 2019-000060-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No