A Study to Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal Polyposis

Study Overview
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Brief Summary
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The study will evaluate the effect of ACT-774312 on the nasal polyps and will assess the safety and tolerability of ACT-774312 in the patients with bilateral nasal polyposis

Detailed Description
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The clinical trial has 3 periods: Screening and run-in period (4 Weeks). This period starts with the screening visit, and ends on Day 1, just before the first study treatment administration. At Visit 1, all participants will enter a run-in period of 4 weeks on mometasone furoate nasal spray of 2 actuations (50 μg per actuation) in each nostril twice daily (total daily dose of 400 μg), unless they were intolerant to twice daily intranasal corticosteroids, in which case they could use a lower dose regimen, i.e., 200 μg once daily. Treatment period (ACT-774312 or placebo for 12 weeks). This period will start on Day 1 with the first administration of study treatment and consists of 4 visits: Week 2, Week 4, Week 8, and Week 12. Provided that the nasal polyp score (NPS) does not change during the run-in period, participants will be randomized to ACT-774312 (400 mg twice daily) or placebo (twice daily) for 12 weeks. During the double-blind randomized treatment all participants will continue with mometasone furoate nasal spray background therapy. Post-treatment period (4 Weeks). This period will start after the Week 12 Visit and end at Week 16 (End-of-Study).

Official Title
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A Randomized, Double-blind, Placebo-controlled, 12-week Treatment Study to Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal Polyposis

Conditions
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Bilateral Nasal Polyposis

Intervention / Treatment
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* Drug: ACT-774312
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent in the local language prior to any study mandated procedure. A minimum bilateral nasal polyp score (NPS) of 5 out of a maximum of 8 for both nostrils (with at least a score of 2 for each nostril) despite completion of a prior intranasal corticosteroids (INCS) treatment for at least 8 weeks before screening, with at least the 6 last weeks on INCS spray. Presence of at least 2 of the following symptoms at screening: nasal blockade/obstruction nasal discharge (anterior/posterior nasal drip) reduction or loss of smell. Male and female participants aged between 18 and 70 years (inclusive) at screening. Systolic blood pressure 90 to 160 mmHg, diastolic blood pressure 50 to 100 mmHg, pulse rate 45 to 100 bpm (inclusive), measured on the dominant arm, after 5 minutes in the supine position at screening. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test pre-dose on Day 1. Women of childbearing potential must consistently and correctly use (from at least first dosing, during the entire study, and for at least 30 days after last study treatment intake) 1 highly effective method of contraception with a failure rate of less than 1% per year, be sexually abstinent, or have a vasectomized partner. Hormonal contraceptive must have been initiated at least 1 month before first study treatment administration. Exclusion Criteria: CYP2C9 poor metabolizer. Participant with severe renal function impairment (≤ 29 mL/min/1.73 m2) which is defined by estimated glomerular filtration rate at screening using the Modification of Diet in Renal Disease (MDRD) formula. Participant with Sino-Nasal Outcome Test (SNOT-22) less than 20. Participant who has required oral corticosteroids (OCS) within the 2 months before screening or is scheduled to receive OCS during the study period for another condition. Participant who has required INCS drops within the 6 weeks before screening. Participant who was injected with long-lasting activity corticosteroids within the 3 months before screening or is scheduled to receive these during the study period for another condition. Participant who has undergone any nasal surgery within 6 months before screening. Participant with conditions/concomitant diseases making them non-evaluable for the primary efficacy endpoint such as: Antrochoanal polyps Nasal septal deviation that occludes at least one nostril Acute sinusitis, nasal infection or upper respiratory infection at screening or in the 2 weeks before screening Ongoing rhinitis medicamentosa Churg-Strauss syndrome, Young's syndrome, Kartagener's syndrome or dyskinetic ciliary syndromes, Cystic fibrosis Signs or a CT scan suggestive of Allergic fungal rhinosinusitis. Participants with co-morbid asthma are excluded if: Forced expiratory volume in one second (FEV1) ≤ 60% of predicted normal OR An exacerbation requiring systemic (oral and/or parenteral) steroid treatment or hospitalization (>24 h) for treatment of asthma has occurred within 3 months prior screening OR They are on a dose higher than 1000 μg fluticasone or the equivalent of inhaled corticosteroids (ICS). Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol. Participants with active autoimmune disease (e.g., Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis). Participant considered as vulnerable (e.g., sponsor or site employee, investigator subordinate, participant incapable of giving consent, participant committed to an institution by way of official or judicial order). Participant with liver injury related criteria: Underlying hepatobiliary disease OR Alanine aminotransferase greater than 3 x upper limit of normal, OR or Bilirubin greater than 2 x upper limit of normal. Participant with unstable NPS during the run-in period, i.e. altered score at Day 1 when compared to the screening NPS (assessed locally by the investigator).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACT-774312<br>Participants will receive ACT-774312 (400 mg twice daily) in the morning and evening with or without food for 12 weeks together with mometasone furoate nasal spray. | Drug: ACT-774312<br>* ACT-774312 will be available as hard gelatin capsules containing 200 mg of ACT-774312<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo twice daily in the morning and evening with or without food for 12 weeks together with mometasone furoate nasal spray. | Drug: Placebo<br>* Matching placebo hard gelatin capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Nasal Polyp Score as Measured by Nasal Endoscopy (Assessed Centrally) | Independent reviewers, blinded to treatment, reviewed image recordings of nasal endoscopies to determine total endoscopic nasal polyp score based on nasal polyp size. The right and left nostrils were scored from 0 to 4 (0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle concha; 2 = Polyps reaching below the lower border of the middle turbinate; 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha; and 4 = Large polyps causing complete obstruction/congestion of the inferior meatus). The total score is the sum of the right and left nostril scores and ranges from 0 to 8, higher scores indicate greater disease severity. Data up to Week 12 were included in the analyses. The Day 1 value was the baseline. Change from Baseline = (Post-baseline visit value) minus (Baseline visit value). A negative change indicates worsening. | Pre-dose (Baseline on Day 1) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Sinus Opacifications as Assessed by Computed Tomography Scan Using the Modified Lund Mackay Score (Assessed Centrally) | Independent blinded reviewers reviewed image recordings of the computed tomography scan. The modified Lund Mackay Score scores were given for the degree of opacification and their location in the sinus. The right and left sinuses are divided into 6 portions, i.e., maxillary sinus, anterior ethmoid sinuses, posterior ethmoid sinuses, sphenoid sinus, frontal sinus, and ostiomeatal complex (OMC). The OMC is given a score of 0 (no obstruction) or 1 (obstruction) for the frontal recess, middle meatus, infundibulum, and the sphenoethmoidal recess channels. The total score is the sum of the right and left nostril scores and range from 0 to a maximum of 48. A positive change from baseline (Day 1) indicates a worsening. Change in the modified Lund-Mackay score = modified Lund-Mackay score at Week 12 minus the modified Lund-Mackay score at baseline. A positive change from baseline indicated a worsening in the modified Lund-Mackay Score at Week 12 compared to baseline. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline to Week 12 in the Volume of Air in the Left Maxillary Sinus | Independent reviewers, blinded to treatment, reviewed image recordings of the computed tomography scan and performed 3D volumetric measurements of the left maxillary sinus. Absolute changes from baseline were calculated for volume of air (mL). Change in 3D volumetric measurement = (3D volumetric measurement at Week 12) minus (3D volumetric measurement at baseline). A positive change from baseline indicates that more volume for air is in the left maxillary sinus since the baseline visit. More volume of air indicates that the polyposis is improving in the left maxillary sinus. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline to Week 12 in the Volume of Air in the Right Maxillary Sinus | Independent reviewers, blinded to treatment, reviewed image recordings of the computed tomography scan and performed 3D volumetric measurements of the right maxillary sinus. Absolute changes from baseline were calculated for the volume of air (mL) in the right maxillary sinus: Change in 3D volumetric measurement = (3D volumetric measurement at Week 12) minus (3D volumetric measurement at baseline). A positive change from baseline indicates that more volume for air is in the right maxillary sinus since the baseline visit. More volume of air indicates that the polyposis is improving in the right maxillary sinus. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline to Week 12 in the Left Maxillary Sinus Mucosal Volume | Independent reviewers, blinded to treatment, reviewed image recordings of the computed tomography scan and performed 3D volumetric measurements of the left maxillary sinus. Absolute changes from baseline were calculated for the volume of air (mL) in the left maxillary sinus: Change in 3D volumetric measurement = (3D volumetric measurement at Week 12) minus (3D volumetric measurement at baseline). A negative change from baseline indicates that the left maxillary sinus mucosal volume has decreased since the baseline visit. More mucosal volume, a positive change, indicates that the polyposis is worsening in the left maxillary sinus. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline to Week 12 in the Right Maxillary Sinus Mucosal Volume | Independent reviewers, blinded to treatment, reviewed image recordings of the computed tomography scan and performed 3D volumetric measurements of the right maxillary sinus. Absolute changes from baseline were calculated for the volume of air (mL) in the right maxillary sinus: Change in 3D volumetric measurement = (3D volumetric measurement at Week 12) minus (3D volumetric measurement at baseline). A negative change from baseline indicates that the right maxillary sinus mucosal volume has decreased since the baseline visit. More mucosal volume, a positive change, indicates that the polyposis is worsening in the right maxillary sinus. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline to Week 12 in the University of Pennsylvania Smell Identification Test | The UPSIT (University of Pennsylvania Smell Identification Test) is a test that measures an individual's ability to detect odors. It consists of 4 workbooks of 10 pages each. On each page there is a different scratch and sniff strip which is embedded with a micro-encapsulated odorant and a question regarding the smell detected with a four-choice option for the response. The total number of questions in the UPSIT is 40. The number of correct responses regarding the smells being experienced is summed to provide a total score that ranges from 0 to 40, with a higher score indicating a better sense of smell. Absolute changes from baseline to Week 12 was calculated as follows: Change in UPSIT score = (UPSIT score at Week 12) minus (UPSIT score at baseline). A positive change from baseline in the UPSIT score is considered a favorable outcome. | Pre-dose (Baseline on Day 1) and Week 12 | 
| Change From Baseline in the Visual Analog Scale Symptoms Score | The participant was asked to score on a Visual Analog Scale (VAS) the answer to the question: How troublesome are your symptoms? (for the 5 following symptoms: nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain). The VAS ranges from 0 (Not at all troublesome) to 100 (Extremely troublesome). The sum of the score of all symptoms were added to a total VAS score which ranged from 0 to 500. The higher the VAS score the more troublesome the symptoms. Absolute changes from baseline to Weeks 2, 4, 8, 12, and End of Study are calculated as follows: Change in total VAS score = Change in total VAS score = (Total VAS score at visit) minus (Total VAS score at baseline). A negative change from baseline indicates an improvement.. A negative change from baseline indicates an improvement. | Baseline, Week 2, Week 4, Week 8, Week 12 and Week 16 (End-of-Study) | 
| Physician Global Assessment of Change in Disease Severity | The Physician Global Assessment of Disease Severity questionnaire (PGAC-DS) was completed by the physician at Visit 2 and at each subsequent site visit until the End-of-Study (Week 16). The PGAC-DS questionnaire is a self-administered 1-item questionnaire designed to assess the physician's impression of change in disease severity since study treatment start. The physician rated the change since the participant study treatment start. The physician rated the change since the participant started study treatment on a 7-point scale. The rating for the overall score is: 'very much improved' (is scored 1), 'much improved' (is scored 2), 'minimally improved' (is scored 3), 'no change' (is scored 4), 'minimally worse' (is scored 5), 'much worse' (is scored 6), or 'very much worse' (is scored 7). | Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study) | 
| Change From Baseline in the Sino-Nasal Outcome Test | SNOT-22 (Sino-Nasal Outcome Test) is a disease specific quality of life questionnaire measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant was asked to rate how severe each problem had been for them over the past 2 weeks 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. Higher total scores on the SNOT-22 imply greater impact on Quality of Life. Absolute changes from baseline to Weeks 2, 4, 8, 12, and 16 were calculated as follows: Change in SNOT-22 score = (SNOT-22 score at visit) minus (SNOT-22 score at baseline). A negative change from baseline in SNOT-22 is considered a favorable outcome. | Baseline, Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study) | 
| Patient Global Impression of Change in Disease Severity | A patient global impression of change in disease severity questionnaire (PGIC-DS) was completed by the participant at Week 2 and at each subsequent site visit until the End-of-study visit. The PGIC-DS questionnaire was a self-administered 1-item questionnaire designed to assess participant's impression of change in disease severity since study treatment start. Participants rated their change since they started study treatment for the overall severity of the disease symptoms on a 7-point scale (1 to 7) scored as: very much improved (1),much improved, (2), minimally improved,(3) no change, (4) minimally worse, (5) much worse, (6) or very much worse (7). | Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study) |