Chronic Rhinosinusitis With Nasal Polyps
Conditions
Keywords
Chronic rhinosinusitis, Rhinosinusitis
Brief summary
The main objective of this study is to evaluate treatment outcomes of tezepelumab among participants with physician-determined surgery-eligible CRSwNP, with or without asthma. Study details include: 1. The study duration will be up to 40 weeks. 2. The treatment duration will be up to 24 weeks. 3. The visit frequency will be once every 4 weeks (Q4W).
Detailed description
This is a multicentre, open-label, single-arm, phase IIIb study is to describe changes from baseline in (1) participant-reported nasal congestion as evaluated by the nasal congestion score (NCS) and (2) participant-reported sino-nasal symptoms as evaluated by sino-nasal outcome test, 22 item (SNOT-22) following initiation of tezepelumab treatment. Approximately 60 sites in 10 countries will enrol adult patients with physician determined surgery eligible CRSwNP. The study is divided into 3 periods as described below: * Screening Period (from Week -4 until Week 0, up to 4 Weeks) * Treatment period (Week 0 to Week 24) * Safety Follow-up Period (Week 24 to Week 36)
Interventions
COMBINATION_PRODUCTTezepelumab
IMP. Subcutaneous injection. Unit dose strengths 210 mg.
Sponsors
AstraZeneca
Fortrea
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-Label, single-arm treatment study. Participants will be treated with tezepelumab Q4W from Week 0, with the last dose administered at Week 20
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Participants must be 18 years of age or older, at the time of signing the informed consent. * Participants with physician-diagnosed CRSwNP for at least 12 months prior to Visit 1 who have all of the following: * Severity consistent with the need for surgery as defined by total NPS ≥ 4 (at least 2 for each nostril) at screening, as determined by the central reader * Mean NCS ≥ 2 in the 2 weeks prior to Visit 2 * Ongoing documented NP symptoms for \> 8 weeks prior to screening such as rhinorrhoea, reduction or loss of smell and/or poor quality/loss of sleep * SNOT-22 total score ≥ 30 as assessed at screening. Note: approximately 50 participants with a NPS = 4 at screening will receive treatment with tezepelumab. * Any standard of care for treatment of CRSwNP, which must include treatment with intranasal corticosteroids, provided the participant is stable on that treatment for at least 30 days prior to Visit 1. Investigators should also assure that participants are compliant and on a stable dose of the background INCS during study period. * Either 1) documented treatment of NP exacerbation with SCS for at least 3 consecutive days or one IM depo-injectable dose (or contraindications/intolerance to) within the past 12 months prior to Visit 1 but not within the last 3 months prior to Visit 1 OR 2) any history of NP surgery (or contraindications/intolerance to) * Body weight of ≥ 40 kg at Visit 1 * Female participants: * Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Women of non childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. * Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned start date of the first IMP administration without an alternative medical cause. The following age-specific requirements apply: * Women \< 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range. * Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. * WOCBP must be willing to use one of the methods of contraception described hereafter, from the time of signing the ICF throughout the study and 16 weeks after last tezepelumab administration: * Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal * Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable * Intrauterine device * Intrauterine hormone-releasing system * Bilateral tubal occlusion * Vasectomised partner (vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of the WOCBP participant and that the vasectomised partner has received medical assessment of the surgical success) * Sexual abstinence: it is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. * Cessation of contraception after this point should be discussed with a responsible physician. * Provision of signed and dated written ICF as described in Appendix A 3 prior to any mandatory study-specific procedures, sampling, and analyses. * Participant who is capable of giving signed informed consent as described in Appendix A 3 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
* Participants with documented allergic fungal rhinosinusitis and/or central compartment atopic disease. * Any clinically important pulmonary disease other than asthma (eg, active lung infection, bronchiectasis, pulmonary fibrosis, cystic fibrosis, primary ciliary dyskinesia, allergic bronchopulmonary mycosis, hypereosinophilic syndromes, etc) that could confound interpretation of clinical CRSwNP endpoints results. * Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could: * Affect the safety of the participant throughout the study * Influence the findings of the study or the interpretation * Impede the participant's ability to complete the entire duration of study. * Sinus surgery within 6 months of screening visit OR any sinus surgery in the past which changed the lateral wall of the nose making NPS evaluation impossible. * Participants with conditions or concomitant disease that makes them non-evaluable for the primary CRSwNP endpoints such as: * Antrochoanal polyps * Nasal septal deviation that occludes at least one nostril * Acute sinusitis, nasal infection, asthma exacerbation or upper respiratory infection at screening or in the two weeks before screening, or Churg-Strauss syndrome (also known as eosinophilic granulomatosis with polyangiitis), Young's syndrome or Kartagener's syndrome * History of cancer: 1. Participants who have had basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1. 2. Participants who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1. * Uncontrolled epistaxis within 2 months of Visit 1 * A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy. * For participants with comorbid asthma: Current smokers or participants with a smoking history ≥ 10 packs per year and participants using vaping products, including electronic cigarettes. Former smokers with a smoking history of \< 10 pack per year and users of vaping or e-cigarette products must have stopped for at least 6 months prior to Visit 1 to be eligible. * History of chronic alcohol or drug abuse within 12 months prior to Visit 1. * Tuberculosis requiring treatment within the 12 months prior to Visit 1. * Major surgery within 8 weeks prior to Visit 1 or planned NP surgery or planned surgical procedures requiring general anaesthesia or inpatient status for more than 1 day during the conduct of the study. * History of known immunodeficiency disorder including a positive HIV test at Visit 1, or the participant taking antiretroviral medications as determined by medical history and/or participant's verbal report. * Infection requiring systemic antibiotics within 14 days prior to Visit 1. Note: Participants with respiratory infections requiring antibiotics within 14 days prior to Visit 1 may extend their screening period to allow recovery and return no sooner than 14 days after completion of therapy. * Evidence of COVID-19 within 4 weeks prior to screening or ongoing clinically significant COVID-19 sequelae (eg, participants who have long-term post-COVID-19 anosmia). * Receipt of any marketed or investigational biologic agent within 4 months or 5 half-lives (whichever is longer) prior to Visit 1 or receipt of any investigational non-biologic agent within 30 days or 5 half-lives (whichever is longest) prior to Visit 1. * Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate, cyclosporine, etc.), except for SCS used in the treatment of asthma/asthma exacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) prior to Visit 1. * Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in nasal congestion | Week 24 | Changes from baseline in participant-reported nasal congestion as evaluated by the nasal congestion score (NCS) as part of the nasal polyposis symptom diary (NPSD) following initiation of tezepelumab treatment. |
| Change from baseline in sino-nasal symptoms | Week 24 | changes from baseline in participant reported sino nasal symptoms as evaluated by sino nasal outcome test, 22 item (SNOT 22) total score following initiation of tezepelumab treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first response for SNOT-22 | Screening, Weeks 0, 2, 4, 8, 12, 16, 20, and 24. | Description of time to first response for SNOT-22 by analysing data at all collected timepoints. |
| Change from baseline in SNOT-22 | Screening, Weeks 0, 2, 4, 8, 12, 16, 20, and 24. | Change from baseline in SNOT-22 at each collected timepoint. |
| Change from baseline visit in nasal blockage (NB) | Weeks 0, 4, 12, and 24. | Change from baseline visit in NB measured by PNIF |
| Change from baseline visit in NB | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, 24. | Change from baseline visit in NB measured by VAS-NB |
| Proportion of PNIF responders | Weeks 0, 4, 12, and 24. | Proportion of PNIF responders (MCID from baseline =20 L/min). |
| Proportion of VAS-NB responders | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, 24. | Proportion of VAS-NB responders (MCID from baseline = -3.0) (in participants with VAS-NB ≥ 7 at baseline). |
| Time to first response for PNIF | Weeks 0, 4, 12, and 24 | Description of time to first response for PNIF by analysing data at all collected timepoints. |
| First response for VAS NB | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, 24. | Description of time to first response for VAS NB by analysing data at all collected timepoints (in participants with VAS-NB ≥ 7 at baseline). |
| Change from baseline in loss of smell score evaluated by UPSIT or Sniffin Sticks | Weeks 0, 1, 2, 4, 8, 12, 16, 20, and 24 | Change from baseline in loss of smell score evaluated by UPSIT or Sniffin Sticks |
| Change from baseline in loss of smell score evaluated by VAS-Taste | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Change from baseline in loss of smell score evaluated by VAS-Taste |
| Change from baseline in loss of smell score evaluated by VAS-Smell | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Change from baseline in loss of smell score evaluated by VAS-Smell |
| Proportion of UPSIT responders | Weeks 0, 1, 2, 4, 8, 12, 16, 20, and 24. | Proportion of UPSIT responders (MCID from baseline = 4) |
| Proportion of Sniffin sticks responders | Weeks 0, 1, 2, 4, 8, 12, 16, 20, and 24 | Proportion of Sniffin sticks responders (MCID from baseline = 6) |
| Proportion of VAS-Smell responders | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Proportion of VAS-Smell responders (MCID from baseline = -3.0) (in participants with VAS-Smell ≥ 7 at baseline) |
| Proportion of participants with a reduction in VAS-Taste score from baseline | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Proportion of participants with a reduction in VAS-Taste score from baseline (in participants with VAS-Taste ≥ 7 at baseline) |
| Time to first response for UPSIT/Sniffin sticks | Weeks 0, 1, 2, 4, 8, 12, 16, 20, and 24 | Time to first response for UPSIT/Sniffin sticks by analysing data at all collected timepoints. |
| Time to first response for VAS Smell | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Time to first response for VAS Smell by analysing data at all collected timepoints (in participants with VAS-Smell ≥ 7 at baseline). |
| Time to first improvement in VAS-Taste | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Time to first improvement in VAS-Taste by analysing data at all collected timepoints (in participants with VAS-Taste ≥ 7 at baseline). |
| Change from baseline in sleep as evaluated by PSQI total score | Weeks 0, 12, and 24. | Change from baseline in sleep as evaluated by PSQI total score |
| Change from baseline in sleep as evaluated by SNOT-22 Sleep domain score | Screening, Week 0, Weeks 2, 4, 8, 12, 16, 20, and 24 | Change from baseline in sleep as evaluated by SNOT-22 Sleep domain score |
| Change from baseline in sleep as evaluated by VAS-Sleep | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Change from baseline in sleep as evaluated by VAS-Sleep |
| Proportion of PSQI responders | Weeks 0, 12, and 24 | Proportion of PSQI responders (MCID from baseline = - 4.4) |
| Proportion of SNOT-22 Sleep domain responders | Screening, Week 0, Weeks 2, 4, 8, 12, 16, 20, and 24 | Proportion of SNOT-22 Sleep domain responders (MCID from baseline = -2.9) |
| Proportion of participants with any improvement in VAS Sleep from baseline | Daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Proportion of participants with any improvement in VAS Sleep from baseline (in participants with VAS-Sleep ≥ 7 at baseline) |
| Time to first response for PSQI | Weeks 0, 12, and 24. | Time to first response for PSQI by analysing data at all collected timepoints. |
| Time to first response for SNOT-22 Sleep domain | Screening, Week 0, Weeks 2, 4, 8, 12, 16, 20, and 24. | Time to first response for SNOT-22 Sleep domain by analysing data at all collected timepoints. |
| Time to first improvement for VAS-Sleep | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24 | Time to first improvement for VAS-Sleep by analysing data at all collected timepoints (in participants with VAS-Sleep ≥ 7 at baseline). |
| Change from baseline in total NPS | Screening, Weeks 2 and 24 | Change from baseline in total NPS evaluated by nasal endoscopy. |
| Proportion of NPS responders | Screening, Weeks 2 and 24 | Proportion of NPS responders (MCID from baseline = 1.0) at Weeks 2 and 24. |
| Change from baseline in NPQ score | Weeks 0, 8, 12, and 24. | Change from baseline in NPQ score |
| Proportion of NPQ responders | Weeks 0, 8, 12, and 24 | Proportion of NPQ responders (MCID from baseline = 7.0) |
| Time to first response for NPQ | Weeks 0, 8, 12, and 24. | Time to first response for NPQ by analysing data collected at each specified timepoint. |
| Change from baseline in TSS | daily for the 2 weeks prior to Week 0 and through EOT (Week 24) | Change from baseline in TSS |
| Proportion of TSS responders | daily for the 2 weeks prior to Week 0 and through EOT (Week 24) | Proportion of TSS responders (MCID from baseline = 4.0) |
| Time to first response for TSS | daily for the 2 weeks prior to Week 0 and through EOT (Week 24) | Time to first response for TSS by analysing data at all collected timepoints. |
| Change from baseline in NP severity | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Change from baseline in NP severity as measured by VAS Overall symptoms |
| Proportion of VAS Overall symptom responders | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Proportion of VAS Overall symptom responders (MCID from baseline = 2.5) |
| Time to first response for VAS-Overall symptom | daily for the 2 weeks prior to Week 0 through the first 12 weeks of Treatment Period, and at Weeks 16, 20, and 24. | Time to first response for VAS-Overall symptom by analysing data at all collected timepoints |
| Proportion of participants who respond as 'well controlled' or 'completely controlled' NP symptoms to the NP control question | Weeks 0, 4, 8, 12, 20, and 24. | Proportion of participants who respond as 'well controlled' or 'completely controlled' NP symptoms to the NP control question |
| Time to first response for NP control | Weeks 0, 4, 8, 12, 20, and 24. | Time to first response for NP control by analysing data at all collected timepoints. |
| Proportion of NCS responders | End of treatment - Week 24 | Proportion of NCS responders (minimal clinically important difference \[MCID\] from baseline = 1.0) at each collected timepoint. |
| Change from baseline in NCS | Daily for the 2 weeks prior to Week 0 through end of treatment visit (EOT; Week 24). | Change from baseline in NCS at each collected timepoint. |
| Time to first response for NCS | End of Treatment-week 24 | Description of time to first response for NCS by analysing data at all collected timepoints. |
| Proportion of SNOT-22 responders | Screening, Weeks 0, 2, 4, 8, 12, 16, 20, and 24. | Proportion of SNOT-22 responders (MCID from baseline = -8.9) at each collected timepoint. |
Countries
Bulgaria, Canada, France, Germany, Hungary, Italy, Poland, Spain, United States
Contacts
PRINCIPAL_INVESTIGATORTanya M Laidlaw, MD
Director of Translational Research in Allergy and Director of the Aspirin-Exacerbated Respiratory Disease (AERD) Centre at the Brigham and Women's Hospital.
PRINCIPAL_INVESTIGATOREnrico Heffler, MD, PhD
Associate Professor of Internal Medicine and Consultant at the Personalized Medicine, Asthma and Allergy Unit at IRCCS Humanitas Research Hospital
Outcome results
None listed