E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to severe nasal polyposis |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 19.0 |
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 |
|
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 |
The primary objective is to evaluate the effect of each of 2 different dose levels of AK001 separately in combination with an intranasal steroid (INS) versus the INS alone on the reduction in size of nasal polyps as evaluated by the change from Baseline to Week 12 after the start of treatment in Total Polyp Score (TPS) |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of each of 2 different dose levels of AK001 separately in combination with an INS versus the INS alone on changes from Baseline to Week 12 after the start of treatment in:
a) Size of polyps as evaluated by Lund-Mackay score at selected sites by CT scan
b) Nasal airway patency as evaluated by peak nasal inspiratory flow (PNIF)
c) Ability to smell by the UPSIT Test
d) Patient-reported symptoms of sinusitis (Sino-nasal Outcome Test-22 [SNOT-22] and Visual Analogue Scales [VASs])
e) Clinical Symptoms improvement scale
f) Quality of life (Short Form Health Survey [SF-36])
2. To evaluate the time to first response in TPS
3. To evaluate the change in TPS, UPSIT, and patient-reported symptoms of sinusitis over time
4. To evaluate the safety and tolerability of each of 2 different dose levels of AK001 separately in combination with an INS during 7 weeks of study drug in patients with moderate to severe nasal polyps and whose symptoms are resistant to INSs |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker sub-study:
It is hypothesized that AK001 treatment can reduce the number of activated eosinophils and block MC function in nasal polyps and result in suppression of eosinophil and MC dependent biomarkers in the nasal cavity of patients receiving AK001 relative to Baseline and relative to patients receiving placebo. Furthermore, reductions in eosinophilic cationic protein (ECP), histamine, and tryptase in nasal secretions with AK001 may demonstrate a local effect on nasal inflammation. At selected Investigator sites, Baseline and post treatment levels of biomarkers related to the activity of MCs and eosinophils in nasal secretions and blood samples will be evaluated from patients participating in the main study who consent to participate in the sub-study, with the goal of understanding the mechanisms by which AK001 may impact nasal polyps.
|
|
E.3 | Principal inclusion criteria |
Patients are eligible for the study if all of the following criteria are met:
1. Written informed consent
2. Male and female patients aged ≥18 and ≤75 years at the time of Screening
3. SNOT-22 ≥30
4. At Screening, TPS of ≥5 for both nostrils with presence on endoscopy of nasal polyps of grade ≥2 in each nostril according to the polyp grading scale
Polyp grading scale for each nostril:
0=no nasal polyps
1=small polyps in the middle meatus not reaching below the inferior border of the middle turbinate
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 turbinate
4=large polyps causing complete obstruction of the inferior nasal cavity
5. History of at least 2 of the following symptoms for more than 4 weeks prior to Screening:
a) Anterior nasal discharge
b) Posterior nasal discharge
c) Nasal congestion, blockade, or obstruction
d) Decreased sense of smell
e) Facial pain or pressure
6. Received continuous topical nasal steroids and/or leukotriene receptor antagonists for at least 8 weeks prior to Screening unless failure or no effect of prior nasal steroid or leukotriene receptor antagonist therapy is documented
7. At randomization, received ≥80% of doses of NASONEX scheduled during the Run-in period
8. At randomization, TPS of ≥5 for both nostrils with presence on endoscopy of nasal polyps of grade ≥2 in each nostril according to the polyp grading scale (see Inclusion Criterion #4) and despite prior INS treatment during the Run-in period
9. Female patients must be post-menopausal for ≥1 year with documented follicle-stimulating hormone (FSH) >30 IU/L, surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months, or, if of child-bearing potential, willing to use a highly effective method of contraception from Screening until at least 3 months after the last dose of the study drug was administered, which corresponds to approximately 5 half-lives of the study drug
10. Male patients with female partners of childbearing potential must agree to use a highly effective method of contraception from Screening until at least 3 months after the last dose of the study drug was administered, which corresponds to approximately 5 half-lives of the study drug. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant (e.g., missed or late menstrual period) at any time during study participation.
11. Negative Screening ova and parasite test
12. No clinically significant Screening 12-lead ECG, vital sign, hematology, chemistry, or urinalysis findings
13. Able to comply with all study procedures including recording scores of symptoms (i.e., anterior nasal discharge; posterior nasal discharge, nasal congestion, blockade, or obstruction; decreased sense of smell; facial pain or pressure) at clinic visits
Additional Sub-study Inclusion Criteria:
1. Written informed consent to participate in the sub-study
2. Albe to comply with all sub-study requirements (procedures and clinic visits) |
|
E.4 | Principal exclusion criteria |
Patients are ineligible for the study if any of the following criteria are met:
1. Use of systemic corticosteroids within 6 weeks prior to Screening (or 5 half-lives, whichever is longer) or scheduled to receive systemic corticosteroids
2. Chronic use of antibiotic therapy within 3 months prior to Screening
3. Receipt of short-term antibiotic therapy within 14 days prior to Screening or use of antibiotics during the Screening period
4. Nasal surgery (including polypectomy) within 6 months prior to Screening
5. Significant mechanical nasal airway obstruction due to septal deviation based on Investigator assessment
6. Use of investigational drugs or participation in another clinical trial within 30 days prior to Screening or 5 half lives, whichever is longer
7. Use of any medications that may interfere with the study, such as immunosuppressive drugs during the 2 weeks before Screening, or expected to require such medications through Day 112
8. Pregnancy or lactation in women
9. In patients with comorbid asthma, either of the following:
a) A FEV1 ≤60% at Screening
b) An asthma exacerbation requiring systemic (oral and/or parenteral) steroid treatment or hospitalization for >24 hours for treatment of asthma within 30 days prior to Screening
10. History of human immunodeficiency virus infection or other severe immunosuppressive disease
11. Current diagnosis or prior history of allergic fungal sinusitis, cystic fibrosis, ciliary dyskinesia, Wegener’s Granulomatosis, or Churg-Strauss syndrome
12. Current diagnosis or prior history of any other condition likely to present with non eosinophilic nasal polyps |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Total Polyp Score (TPS): Change from Baseline to Week 12 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Day -3, Day 21, Day 49, Day 84, Day 112 |
|
E.5.2 | Secondary end point(s) |
• Size of polyps as evaluated by Lund-Mackay score at selected sites by CT scan
• Nasal airway patency as evaluated by PNIF
• UPSIT
• SNOT-22 (patient-reported symptoms)
• VASs (patient-reported symptoms)
• clinical symptoms improvement scale
• SF-36 (quality of life)
• Blood eosinophil and basophil absolute counts
The following specific additional efficacy endpoints will be evaluated in patients with comorbid asthma:
• TPS by blinded centralized evaluation of endoscopy
• Pulmonary function (FEV1, FVC, and FEF) assessed using spirometry
• ACT
• Use of asthma rescue therapy
Pharmacokinetic endpoints:
Blood samples obtained from the arm that is not used for the study drug infusion will be obtained pre-dose on Days 0, 21, and 49 and on Days 14, 84, and 112 for PK analyses.
Serum concentrations of AK001 will be measured using a validated enzyme-linked immunosorbent assay (ELISA) method.
Safety endpoints:
• TEAEs
• Withdrawals from study due to AEs
• Vital sign findings
• Laboratory test (including anti-drug antibody [ADA]) findings
• Concomitant medication use
• Physical examination (PE) findings |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Size of polyps as evaluated by Lund-Mackay score by CT scan: Days -3, 84, 112
• PNIF: Days 0, 21, 84, 112
• UPSIT: Days 0, 14, 21, 49, 84, 112
• SNOT-22: Screening, Days 0, 14, 21, 49, 84, 112
• VASs: Screening, Run-in, Days -3, 0, 14, 21, 49, 84, 112
• SF-36: Days 0, 21, 49, 84, 112
• Blood eosinophil and basophil absolute counts: Screening, Days -3, 14, 21, 49, 84, 112
• Pulmonary function (FEV1, FVC, and FEF) assessed using spirometry: Screening, Days 21, 49
• ACT: Screening, Days 0, 21, 49, 84, 112
• Use of asthma rescue therapy: Screening, Run-in, Days -3, 0, 14, 21, 49, 84, 112
• Pharmakokinetics: Days 0, 14, 21, 49, 84, 112
• Safety: various timepoints |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 3 |
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 | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Netherlands |
Spain |
Sweden |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |