Safety and Efficacy of Lactococcus Lactis Probiotic Bacteria for the Treatment of Chronic Rhinosinusitis
Condition: Chronic Rhinosinusitis
MeSH terms: Sinusitis
Study type: Interventional

Summary: 
      Despite advances in medical treatments and surgery for chronic rhinosinusitis (CRS), there
      remains a large number of patients who continue to suffer from chronic sinusitis despite
      standard therapies. This research project has the goal of evaluating the safety and
      effectiveness of a potentially novel therapy for patients with CRS refractory to medical and
      surgical therapies, consisting of the introduction of a live probiotic bacteria (L lactis
      W136) directly into the nasal and sinus cavities via irrigation.

      In total, 24 patients suffering from refractory CRS will be recruited from ongoing clinical
      activities by the research team of Martin Desrosiers at the CHUM hospital. Study duration is
      six weeks, and will be performed in three phases, with six visits planned in total.

        1. Two-week observation period where only saline irrigation is administered.

        2. Treatment period of 14 days (D0 to D14) during which L lactis W136 will be administered
           twice-daily.

        3. Post treatment observation period of two weeks (D14 to D28) during which the patient
           will cease probiotic but will continue to irrigate his nose with only saline.

      Assessment will use symptom questionnaires, quality of life questionnaires and endoscopic
      examination of the sinus cavities. Sinus culture will be performed at each visit to assess
      development of unusual infections. Exploratory assessments of gene expression and microbiome
      profiling will be performed to explore underlying mechanisms.
    

Detailed description: 
      CONTEXT/JUSTIFICATION:

      Chronic rhinosinusitis (CRS) is one of the most frequent chronic diseases and has a
      significant negative impact on quality of life (QOL) in patients who suffer from it. Despite
      advances in medical treatments and surgery, there remains a large number of patients who
      continue to suffer from chronic sinusitis despite standard therapies. This research project
      has the goal of evaluating the safety and effectiveness of a potentially novel therapy for
      chronic sinusitis, via introduction of a probiotic bacteria (L lactis W136) directly into the
      nasal and sinus cavities via irrigation.

      Probiotics are living micro-organisms (bacteria or fungi), which are added his compliments to
      certain dietary products such as yogurt to cereals with the intended effect of a beneficial
      effect on host health. The World Health Organization (WHO) and the league of the United
      Nations for Foodstuffs and Agriculture have defined probiotics as "living micro-organisms,
      which, when administered in sufficient quantity, exercise a positive effect on health beyond
      those of traditional nutritional benefits".

      GOALS OF THERAPY:

      To study the safety and clinical efficacy of an intranasal treatment with probiotic L lactis
      W136 in a population of patients with rhinosinusitis CRS refractory to medical and surgical
      therapies.

      METHODOLOGY:

      The study was performed in three phases, with six visits planned in total:

        1. An observation period of two weeks (D-14 to D0) during which the patient will irrigate
           his/her sinuses only with saline solution. No other sinus medication will be allowed.

        2. Treatment period of 14 days (D0 to D14) during which L lactis W136 will be administered
           twice daily in the form of 120 ml pf nasal irrigation solution containing dissolved
           probiotics in a buffered saline solution.

        3. Surveillance Period: Post treatment observation period of two weeks (D14 to D28) during
           which the patient will cease probiotic but will continue to irrigate his nose with only
           saline solution and take no other sinus medication.

      In order to assess the tolerance to treatment and the efficacy, selected patients will be
      examined at days D-14, D0, D1, D7, D14 and D28, and assessed according to a standardized
      scale. This assessment will be based on clinical criteria (sinus symptoms, quality-of-life
      assessments) endoscopic aspect of the mucosa and exploratory studies into molecular
      mechanisms of the microbiome and pathogenesis.

      PREPARATION OF THE STUDY PRODUCT L Lactis is furnished by Agropur. Each patient will receive
      the probiotic in frozen individual doses. At time of use, these will be reconstituted into a
      0.9% solution. This will be administered to the nose via nasal irrigation using the NeilMed
      Paediatric Sinus Rinse apparatus which contains 120 cc.

      STUDY TREATMENT Nasal irrigation with 1.2 x 10e9 CFU of L. Lactis dissolved in 120mL of 0.9%
      saline solution administered BID to both nostrils for 14 days.

      Recruitment of study participants

      Patients will be recruited form ongoing clinical activities. Recruitment will be by a staff
      member not associated with clinical care. After explanation of the study and informed
      consent, patients will have a complete ENT history and examination including nasal endoscopy
      to confirm admissibility.

      In addition, the patient will complete questionnaires on sino nasal symptoms and a
      sinus-specific quality of life (SNOT-22)

      Pregnancy tests will be performed on all female participants of reproductive potential.

      CRITERIA FOR EARLY WITHDRAWAL / PREMATURE TERMINATION

        -  Incapable of performing nasal irrigation

        -  Severe irritation of the nose and sinus mucosa

        -  Signs and/or symptoms of acute infection

        -  Development of otitis (ear infection)

      Antidote Oral antibiotic

      Washout period There will be a washout period of fourteen days prior to probiotic
      administration during which the only permitted sinus medication will be continued use sinus
      irrigation.

      Concomitant Medication No rescue medication is planned for in this study.

      Clinical parameters assessed :

        1. Clinical criteria Total nasal and sinus symptoms (0-3 scale) Disease specific Quality of
           life (QOL) SNOT-22 Surveillance of adverse effects

        2. Endoscopic criteria Direct examination of the sinus mucosa using a 0-degree endoscope.
           Grading according to the POSE system.

        3. Markers of inflammation Mucosal brushings will be obtained at the level of the frontal
           recess using a cytology brush. RNA will be extracted and processed for gene expression
           profiling to explore underlying mechanisms.

        4. Composition of the microbiome Conventional sinus cultures will be performed at each
           visit to monitor infection / probiotic overgrowth. Microbiome profiling will be
           performed using 16S sequencing on swabs taken form the sinuses.

      EFFICACY ANALYIS

        -  Sino-nasal symptomatology and quality of life indices

        -  Direct endoscopic assessment of the sinus mucosa

      Safety Analyses

        -  Tolerability of L lactis intranasally will be assessed on Day by questionnaire,
           examination and nasal endoscopy.

        -  Potential impact on adjacent structures :

        -  Olfactive zone of the nose will be assessed by UPSIT smell tests Eustachian tube: Middle
           ear examination with microscopy

      Statistical Analysis At days -14, 0, 7, 14 and 28 after treatment, subjective and endoscopic
      results will be analysed using Brapkar's test for paired qualitative observations.
    

Intervention name(s): Topical probiotic treatment with Lactococcus lactis W136; Saline irrigation
Intervention type(s): Other; Other
Intervention description(s): Nasal and sinus irrigation with reconstituted live probiotic bacteria; Nasal and sinus irrigation with saline solution
Other intervention name(s): Natural health product; Natural health product
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Double (Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Probiotics; Chronic rhinosinusitis; Irrigation; Microbiome