Clinical trial NCT03688555: A Study to Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal Polyposis
Official title: A Randomized, Double-blind, Placebo-controlled, 12-week Treatment Study to Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal Polyposis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bilateral Nasal Polyposis
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2018-09-28
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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).

Primary outcomes:
measure: Change From Baseline to Week 12 in Nasal Polyp Score as Measured by Nasal Endoscopy (Assessed Centrally)
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
Secondary outcomes:
measure: Change From Baseline to Week 12 in Sinus Opacifications as Assessed by Computed Tomography Scan Using the Modified Lund Mackay Score (Assessed Centrally)
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline to Week 12 in the Volume of Air in the Left Maxillary Sinus
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline to Week 12 in the Volume of Air in the Right Maxillary Sinus
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline to Week 12 in the Left Maxillary Sinus Mucosal Volume
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline to Week 12 in the Right Maxillary Sinus Mucosal Volume
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline to Week 12 in the University of Pennsylvania Smell Identification Test
timeFrame: Pre-dose (Baseline on Day 1) and Week 12
measure: Change From Baseline in the Visual Analog Scale Symptoms Score
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 and Week 16 (End-of-Study)
measure: Physician Global Assessment of Change in Disease Severity
timeFrame: Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study)
measure: Change From Baseline in the Sino-Nasal Outcome Test
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study)
measure: Patient Global Impression of Change in Disease Severity
timeFrame: Week 2, Week 4, Week 8, Week 12, and Week 16 (End-of-Study)
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: University Hospital Ghent
city: Berlin
country: Germany
facility: Charité Research Organisation GmbH
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Clinical Trials
role: STUDY_DIRECTOR
References: