E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bilateral nasal polyposis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028756 |
E.1.2 | Term | Nasal polyps |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of ACT-774312 on bilateral nasal polyposis (NP). |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of ACT-774312 during 12 weeks of treatment; - To evaluate the pharmacokinetics (PK) of ACT-774312 in subjects with NP; - To evaluate the pharmacodynamic (PD) responses to ACT-774312 based on Th-2 biomarkers
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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: o nasal blockade/obstruction o nasal discharge (anterior/posterior nasal drip) o reduction or loss of smell
• Male and female subjects aged between 18 and 70 years (inclusive) at screening.
• Subjects with a body mass index (BMI) ≥ 18 kg/m2.
• 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 min 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 < 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 |
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E.4 | Principal exclusion criteria |
• CYP2C9 poor metabolizer subject.
• Subject with severe renal function impairment (≤ 29 mL/min/1.73 m2) which is defined by eGFR estimated at screening using the Modification of Diet in Renal Disease (MDRD) formula.
• Subject with Sino-Nasal Outcome Test (SNOT-22) <20.
• Subject 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.
• Subject who has required intranasal corticosteroids (INCS) drops within the 6 weeks before screening.
• Subject 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.
• Subject who has undergone any nasal surgery within 6 months before screening.
• Subjects with conditions/concomitant diseases making them non-evaluable for the primary efficacy endpoint such as: o Antrochoanal polyps o Nasal septal deviation that occludes at least one nostril o Acute sinusitis, nasal infection or upper respiratory infection at screening or in the 2 weeks before screening o Ongoing rhinitis medicamentosa o Churg-Strauss syndrome, Young’s syndrome, Kartagener’s syndrome or dyskinetic ciliary syndromes, Cystic fibrosis o Signs or a CT scan suggestive of Allergic fungal rhinosinusitis
• Subjects with co-morbid asthma are excluded if: o Forced expiratory volume in one second (FEV1) ≤ 60% of predicted normal OR o 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 o 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.
• Subject 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).
• Subject with evidence of acute or chronic infection.
• Subject considered as vulnerable (e.g., sponsor or site employee, investigator subordinate, subject incapable of giving consent, subject committed to an institution by way of official or judicial order).
• Subject with liver injury related criteria: o Underlying hepatobiliary disease OR o ALT>3 (Upper Limit of Normal) ULN OR o or Bilirubin>2 ULN
• Subject with any contraindications or warning/precautions of use related to mometasone furoate nasal spray. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Week 12 in NPS as measured by nasal endoscopy assessed centrally |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Change from baseline to Week 12 in sinus opacifications as assessed by CT scan using the Zinreich-modified Lund Mackay Score assessed centrally. 2) Change from baseline to Week 12 in 3D volumetric computerized values. 3) Change from baseline to Week 2, 4, 8, 12, and EOS in University of Pennsylvania Smell Identification Test (UPSIT). 4) Change from baseline to Week 2, 4, 8, 12, and EOS in the sum of Visual Analog Scale (VAS) symptoms score for nasal obstruction, nasal discharge, mucus in the throat, loss of smell, and facial pain. 5) Change from baseline to Week 2, 4, 8, 12, and EOS in Physician Global Assessment (PGA) score. 6) Change from baseline to Week 2, 4, 8, 12, and EOS in SNOT-22. 7) Patient global impression of change in disease severity at Week 2, 4, 8, 12, and EOS.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1), 2): from baseline to week 12 3) to 7): from baseline to week 2, 4, 8, 12 and End of study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as the last subject last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |