Sinupret Extract Coated Tablets in Chronic Rhinosinusitis

Study Overview
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Brief Summary
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To assess the efficacy of the herbal medicinal product Sinupret extract versus placebo in the treatment of chronic rhinosinusitis (CRS) in adults.

Detailed Description
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The aim of the present double-blind, placebo-controlled, parallel-group, randomized, phase III clinical trial is to assess the efficacy, safety, and tolerability of Sinupret extract (3 x 160 mg = 480 mg daily) taken for up to 16-weeks compared with placebo in the treatment of chronic rhinosinusitis (CRS) in adults. In addition, in an exploratory approach to identify potential pharmacological modes of action underlying the expected treatment benefit, the anti-inflammatory activity of Sinupret extract will be assessed in a subset of CRS patients.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Clinical Trial to Assess Efficacy and Safety of the Herbal Medicinal Product Sinupret Extract Coated Tablets in Patients With Chronic Rhinosinusitis

Conditions
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Chronic Rhinosinusitis

Intervention / Treatment
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* Drug: Sinupret extract coated tablets
* Drug: Placebo coated tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent (IC) including data protection declaration Male and female outpatients aged ≥18 and ≤75 years Women will be considered for inclusion if they are not pregnant (as confirmed by urine pregnancy test at V1 and V2), not breastfeeding, or if they are surgically sterile (have had a documented bilateral oophorectomy and/or hysterectomy) or if menopause is ensured (at least 12 months without menstrual bleeding). Women of childbearing potential must use a highly effective (failure rate less than 1% per year, i.e. Pearl Index <1) method of contraception 2 weeks prior to trial inclusion and during the screening/treatment period of the clinical trial (e.g. vasectomized partner, sexual abstinence - the lifestyle of the female has to be such that there is complete abstinence from intercourse from 2 weeks prior to the first dose of trial medication until at least 72 hours after treatment - implants, injectables, combined oral contraceptives, or hormonal intrauterine devices). Diagnosis of bilateral CRS without nasal polyps confirmed by: Nasal endoscopy during the screening phase to confirm inflammation, mucopurulent discharge, and/or edema/mucosal obstruction primarily in middle meatus without nasal polyps being present At the discretion of the investigator, results from a historic imaging diagnostic, i.e. computer tomography (CT), digital volume tomography (DVT), or magnetic resonance tomography (MRT) (before screening and not older than 24 months, not taken during acute exacerbation), which will be considered additionally for confirmation of bilateral involvement of middle meatus and paranasal sinuses without resolution of symptoms (mucosal changes within the ostiomeatal complex and/or sinuses) Bilateral CRS characterized by: Presence of CRS symptoms for >52 weeks prior to enrolment (V1) as documented in the medical file of the patient Major Symptom Score (MSS) ≥10 at V1 and V2 as assessed by the investigator (MSS INV), and rhinorrhea (anterior or posterior) and pain (facial pain or headache) each of at least moderate intensity (score ≥2) Exclusion Criteria: Sinus surgery within the last 2 years (solitary sinus puncture is allowed) Inferior turbinate reduction (by surgery or other methods) within the last 3 months Presence or history of uni- or bilateral nasal polyps Moderate to severe co-morbid asthma, including allergic asthma Cystic fibrosis Perennial (e.g. patients with clinical symptoms of allergic rhinitis against house dust/mite antigen) or seasonal allergic rhinitis Rhinitis medicamentosa (drug induced rhinitis) Aspirin-exacerbated respiratory disease (aspirin sensitivity) Dentogenic sinusitis or otherwise unilateral sinusitis Presence of anatomical deviations of the nasal septum that significantly impair nasal and paranasal ventilation/airflow Known hypersensitivity to trial medication or excipients Rare hereditary problems of fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption, or sucrase- isomaltase insufficiency Signs or symptoms of acute bacterial sinusitis (e.g. fever >38.5°C, orbital complications, severe unilateral frontal headache, or toothache) Treatment with antihistamines within 4 weeks prior to V1 Treatment with 2-3.5% hypertonic saline solution within 2 weeks prior to V1 Treatment with systemic or nasal antibiotics or corticosteroids within 4 weeks prior to V1 Treatment with decongestant preparations (α-sympathomimetics), analgesics (including systemic non-steroidal inflammatory drugs [NSAIDs], including paracetamol), mucolytics/secretolytics, or alternative medicine preparations for treatment of common cold-like symptoms or with immunomodulating properties within 7 days prior to V1 Peptic ulcer Gastritis Other diseases within 5 years prior to V1 that, in the opinion of the investigator, disqualifies the patient for trial enrolment (e.g. liver or kidney disease, severe somatopathic, neurological and/or psychiatric diseases, history of malignancy, alcohol or drug abuse, or immunodeficiency) Parallel participation in another clinical trial, participation in a different trial within less than 6 weeks prior to trial entry, or previous randomization into this clinical trial Known to be, or suspected of being unable to comply with the clinical trial protocol (CTP) that in the opinion of the investigator disqualifies the patient for trial enrolment (e.g. no permanent address, known to be non-compliant, or presenting an unstable psychiatric history) Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope, and possible impact of the clinical trial Patients in custody by juridical or official order Patients who have difficulties in understanding the local language in which the patient information (PI) is given Patients who are members of the staff of the investigational site, staff of the sponsor or involved CRO, the investigator him/herself or close relatives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sinupret extract coated tablets<br>Sinupret extract coated tablets: one tablet three times a day orally during the 16-week treatment phase. There will be no dose change during the trial. | Drug: Sinupret extract coated tablets<br>* 1 coated tablet 3 times a day for 16-weeks (1-1-1)<br>* Other names: Sinupret extract;|
| Placebo Comparator: Placebo coated tablets<br>Placebo coated tablets: One tablet three times a day orally during the 16-week treatment Phase. | Drug: Placebo coated tablets<br>* 1 coated tablet 3 times a day for 16-weeks (1-1-1)<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MSS-INV at V7 | Major Symptom Score (MSS) assessed by the investigator at Visit 7 with Baseline as Covariate; The MSS considers: rhinorrhea [anterior], rhinorrhea [posterior], nasal congestion, headache, and facial pain/pressure | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MSS-INV at V4-6 | Major Symptom Score (MSS) assessed by the investigator at Visits 4, 5, and 6 with Baseline as Covariate | 12 weeks | 
| MSS-PAT at V4-7 | Major Symptom Score (MSS) assessed by the Patient at Visits 4, 5, 6, and 7 with Baseline as Covariate | 16 weeks | 
| Minimal MSS-INV at V4-7 | Minimal Major Symptom Score (MSS) assessed by the Investigator of all visits from Visits 4, 5, 6, and 7 | 16 weeks | 
| Minimal MSS-PAT at V4-7 | Minimal Major Symptom Score (MSS) assessed by the Patient of all visits from Visits 4, 5, 6, and 7 | 16 weeks | 
| Investigator's Ratings of CRS symptom | Investigator's ratings of each individual CRS symptom (i.e. rhinorrhea [anterior], rhinorrhea [posterior], nasal congestion, headache, and facial pain/pressure) at V4, V5, V6, and V7 | 16 weeks | 
| Patient's Ratings of CRS symptom | Patient's ratings of each individual CRS symptom (i.e. rhinorrhea [anterior], rhinorrhea [posterior], nasal congestion, headache, and facial pain/pressure) at V4, V5, V6, and V7 | 16 weeks | 
| SNOT-22 | 22-Item Sino-Nasal Outcome Test (SNOT-22)Total Score as well as SNOT-22 primary nasal score (SNOT-22 PNS) and SNOT-22 general quality of life score (SNOT-22 ALQ) at V4, V5, V6, and V7 | 16 weeks | 
| VAS | Total symptom severity assessed by the patient on a visual analogue scale (VAS) at V4, V5, V6, and V7 | 16 weeks | 
| Responder Rate | Proportion of patients whose MSS-INV and MSS-PAT improved by ≥30%, ≥40%, ≥50%, ≥60% and ≥70% at V4, V5, V6, and V7. Responders are defined as patients who show at least an MSS improvement of ≥30% | 16 weeks | 
| Concomitant drug and non-drug therapy | Patients with permitted concomitant drug and non-drug therapy (i.e. isotonic saline solution as nasal spray, nasal irrigation [nasal lavage], or ultrasonic nebulizer) for CRS | 22 weeks | 
| Premature Terminations | Number of patients with premature termination due to exacerbation of CRS symptoms | 20 weeks | 
| Investigator's and patient's overall assessment of efficacy (questionnaire) | At each on-site visit during the treatment phase (V4 to V7), both the investigator and the patient have to provide an overall assessment of treatment efficacy using 5 categories (very good, good, moderate, poor, and very poor; ranges from 0 to 4). | 16 weeks | 
| WPAI:GH questionnaire | Pharmacoeconomic evaluation (utilization of health care resources) based on Work Productivity and Activity Impairment, Global Health (WPAI:GH) questionnaire completed by the patient at V4, V5, V6, and V7 | 22 weeks | 
| Inflammatory Parameter IL-1beta (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interleukin-1β (IL-1beta) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter IL-2 (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interleukin-2 (IL-2) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter IL-4 (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interleukin-4 (IL-4) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter IL-6 (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interleukin-6 (IL-6) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter IL-8 (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interleukin-8 (IL-8) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter IFN-gamma (nasal secretions: substudy) | Absolute concentrations and total amount per sample of interferon gamma (IFN-gamma) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter TNF-alpha (nasal secretions: substudy) | Absolute concentrations and total amount per sample of tumor necrosis factor alpha (TNF-alpha) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter MPO (nasal secretions: substudy) | Absolute concentrations and total amount per sample of myeloperoxidase (MPO) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter ECP (nasal secretions: substudy) | Absolute concentrations and total amount per sample of eosinophil cationic protein (ECP) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter alpha-2-macroglobulin (nasal secretions: substudy) | Absolute concentrations and total amount per sample of α2-macroglobulin (alpha-2-macroglobulin) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter HMGB-1 (nasal secretions: substudy) | Absolute concentrations and total amount per sample of high-mobility group box protein 1 (HMGB-1) in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 
| Inflammatory Parameter albumin (nasal secretions: substudy) | Absolute concentrations and total amount per sample of albumin in nasal secretions collected at V2, V5, and V7 for a subset of approximately 60 patients in selected investigational sites in Germany | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic rhinosinusitis, Sinupret extract, herbal medicinal product