Aggravated Airway Inflammation: Research on Genomics and Optimal Medical Care (AirGOs-medical)

Randomization and the treatment arms I-II: The patients are randomized to two treatment arms I) ASA- desensitization po tablet daily for 11 months (n=36) II) Placebo po tablet daily for 11 months (n=18).

ASA challenge and desensitization (Primaspan) /Placebo: is conducted according to modified international protocol. FEV1 should be at least 1.5 L and > 60% of predicted before challenge or desensitization. On the first day every patient will receive 25 mg + 25 mg ASA at a hospital setting. On the second day every patient will receive 50 mg + 25 mg ASA at a hospital setting. On the third day every patient will receive 75 mg + 25 mg ASA at a hospital setting. On the fourth day every patient will receive 100 mg + 25 mg ASA at a hospital setting.

During the ASA challenge, patient who is ASA-challenge positive is then randomized and starts the trial so that he/she uses blinded ½ tablet of 250 mg ASA or ½ tablet of placebo daily at home for the next 1 month. After this period of 1 month, the dosing is increased at hospital setting, so that the patient receives blindly 250 mg ASA 1/2 tablet + 1/2 tablet or placebo 1/2 tablet + 1/2 tablet. Thereafter he/she will continue using blindly 250 mg ASA 1 tablet or placebo 1 tablet daily at home for the next 10 months. If the patient does not tolerate the up-dosing of ASA/placebo, he/she will continue using blindly ½ tablet of 250 mg ASA/placebo daily at home for the next 10 months. The total duration of the ASA/placebo treatment is 11 months. We additionally take nasal, blood and urine samples during the trial.

Follow-ups. The symptom questionnaire and interview of side-effects are performed during each visit. Lung function (eNO, nNO, PEF, spirometry) is monitored and the patient will visit doctor and/or nurse at 1, 5, 11, and 12 months post-starting with the treatment. Samples are taken during recruitment visit, before and after ASA-challenge and at 5, 11 and 12 months post-starting with the treatment. We also monitor side-effects, exacerbations, need of medication (po. cortisocteroids; antibiotics) and satisfaction to treatment.

Primary end point is change in nasal endoscopic nasal polyp score at -4 days vs. +11 months post-randomization. Secondary end point is change in Sinonasal Outcome Test -22 (SNOT-22) score at -4 days vs. +11 months post-randomization, and change in relative Forced expiratory volume in 1 second (FEV1 %) without bronchodilator at -1 month vs. +11 months post-randomization.

Safety (complications, adverse effects), costs and loss of productivity between study arms will be compared.

Trial medication will be discontinued, if surgery is needed before the end of follow-up.

Inclusion criteria

ALL these need to be positive:

• Endoscopic nasal polyp score ≥4
• SNOT-22 ≥30
• Sinus Computed tomography Lund-Mackay score ≥14. The new sinus CT scans are needed if the previous sinus CT scans have been performed over 36 months before recruitment visit or if there is a suspicion of complication of CRS (f.ex. mucocele, invasive fungal rhinosinusitis)
• ≥1 previous partial/total ethmoidectomy surgery.

In addition, patient should have a history of at least one of the following:

>1 oral corticosteroids during the past two years >3 antibiotic courses during the past two years. In patients with contraindication/adverse effects in using oral steroids additional criteria are not required.

Exclusion criteria

• complication of CRS (f.e. mucocele, invasive fungal rhinosinusitis)
• bleeding diathesis
• pregnancy/ breastfeeding
• cystic fibrosis
• primary ciliary dyskinesia (PCD)
• sarcoidosis
• granulomatosis with polyangitis (GPA)
• eosinophilic granulomatosis with polyangitis (EGPA)
• immunosuppression (diagnosed Spesific antibody deficiency (SAD), CVI, HIV
• use of biologicals/immunosuppressive medication
• immunotherapy
• Daily use of systemic corticosteroids (Prednisolon 10mg or equivalent) -communication problems (f.e. neurological/psychiatric disease, language skills) -unlikely to comply
• other severe disease
• uncontrolled asthma
• ASA-challenge negative
• gastric ulcer
• anticoagulant treatment
• SSRI-depression medication
• beta-blocker
• severe chronic urticaria
• ASA anaphylaxis