Phase 3b Multicenter Study on Tezepelumab for Symptom Modulation in Chronic Rhinosinusitis with Nasal Polyposis

Trial ID: 2024-513862-20-00
Protocol: D5242C00002
Sponsor: AstraZeneca AB

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Diseases & Conditions

Chronic rhinosinusitis with nasal polyps

Objectives

The primary objective of this study is to evaluate changes from baseline in participant-reported **nasal congestion** and sino-nasal symptoms in individuals with **Chronic Rhinosinusitis with Nasal Polyposis** following the initiation of treatment with tezepelumab. This is assessed using the nasal congestion score (NCS) and the sino-nasal outcome test, 22 item (SNOT-22) total score. Understanding these changes is clinically relevant as it provides insights into the efficacy of tezepelumab in alleviating symptoms associated with this chronic condition, potentially improving patient quality of life.

Secondary objectives include: - Describing the responder proportion and time to response in participant-reported nasal congestion and sino-nasal symptoms. - Evaluating changes in nasal blockage using peak nasal inspiratory flow (PNIF) and a visual analogue scale (VAS-NB). - Assessing changes in the sense of smell/taste using the University of Pennsylvania Smell Identification Test (UPSIT) or Sniffin Stick, VAS-Smell, and VAS-Taste. - Monitoring changes in sleep quality using the Pittsburgh sleep quality index (PSQI), SNOT-22 Sleep domain, and VAS-Sleep. - Observing changes in nasal polyp score (NPS) and nasal polyposis quality of life (NPQ). - Evaluating changes in overall symptoms using the NPSD Total Nasal Symptom Score (TSS). - Assessing changes in nasal polyposis severity and control.

Participants

The clinical trial involves a total of **160 participants** diagnosed with **Chronic Rhinosinusitis with Nasal Polyposis** (CRSwNP). The study population includes both male and female subjects, aged 18 years and older, who have been diagnosed with CRSwNP for at least 12 months prior to the study. Participants were selected based on specific criteria, including a severity of symptoms consistent with the need for surgery and a history of treatment with intranasal corticosteroids. The trial also considers lifestyle factors such as the stability of the participants' current treatment regimen. Participants must have a body weight of at least 40 kg and meet certain health criteria, including the ability to provide informed consent. The study does not exclude based on gender, and it includes individuals from vulnerable populations. The trial aims to evaluate changes in nasal congestion and sino-nasal symptoms following treatment with tezepelumab.

Plans and Procedures

The clinical trial is a multicenter, single-arm, Phase 3b study designed to assess changes in symptoms in participants with **Chronic Rhinosinusitis with Nasal Polyposis** (CRSwNP) initiating treatment with **tezepelumab**. The trial aims to evaluate changes from baseline in participant-reported nasal congestion and sino-nasal symptoms using the Nasal Congestion Score (NCS) and the Sino-Nasal Outcome Test (SNOT-22) following the initiation of treatment. The study is expected to last until January 2027, with recruitment starting in March 2025. Participants will be involved for a maximum treatment period of 24 weeks.

Participants eligible for the study must be 18 years or older, with a physician-diagnosed CRSwNP for at least 12 months prior to the screening visit. They must exhibit symptoms consistent with the need for surgery and have been on a stable dose of intranasal corticosteroids for at least 30 days before the first visit. The study will exclude individuals who do not meet these criteria. The primary endpoints include changes from baseline in nasal congestion and sino-nasal symptoms at Week 24. Secondary endpoints involve various measures of symptom response and time to first response across multiple collected timepoints.

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility. Participants will then attend follow-up visits at specified intervals to monitor changes in symptoms and treatment response. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment. Participants may be terminated early from the study if they experience adverse effects or fail to comply with study protocols. The study will utilize a solution for injection in a pre-filled syringe, administered subcutaneously, with a maximum daily dose of 210 mg and a total dose not exceeding 1260 mg over the treatment period.

Treatment

The clinical trial involves the administration of **Tezepelumab**, marketed under the name Tezspire, which is a **solution for injection** provided in a pre-filled syringe. The pharmaceutical form is specifically designed for subcutaneous administration. Each syringe contains a dosage of 210 mg of the active substance, **tezepelumab**, which is a protein-based therapeutic agent. The maximum daily dose is set at 210 mg, with a total maximum dose of 1260 mg over the course of the treatment period. The treatment is administered every four weeks for a maximum duration of 24 weeks. The manufacturing, packaging, labeling, testing, and release sites for the clinical product differ from the commercial product, as detailed in the simplified IMPD (sIMPD).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the effects of Tezepelumab in participants with chronic rhinosinusitis with nasal polyposis. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to assess changes in symptoms, specifically nasal congestion and sino-nasal symptoms, as reported by participants using validated scoring systems.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating changes in symptoms associated with Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) following treatment with **tezepelumab**. The primary endpoints include the change from baseline in nasal congestion measured by the Nasal Congestion Score (NCS) and the change from baseline in sino-nasal symptoms measured by the Sino-Nasal Outcome Test, 22 item (SNOT-22) total score, both evaluated at Week 24.

Secondary endpoints will further explore the efficacy of the treatment by assessing various parameters at multiple timepoints. These include the proportion of NCS and SNOT-22 responders, defined by a minimal clinically important difference (MCID) from baseline, and the time to first response for these scores. Additional assessments will include changes from baseline in nasal blockage (NB) using Peak Nasal Inspiratory Flow (PNIF) and Visual Analog Scale for Nasal Blockage (VAS-NB), as well as changes in loss of smell score using tools such as the University of Pennsylvania Smell Identification Test (UPSIT) or Sniffin Sticks, and VAS for Taste and Smell.

Further efficacy evaluations will involve changes in sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) total score, SNOT-22 Sleep domain score, and VAS for Sleep. The trial will also assess changes in total Nasal Polyp Score (NPS) through nasal endoscopy, and changes in Nasal Polyposis Quality of Life Questionnaire (NPQ) score, Total Symptom Score (TSS), and Visual Analog Scale for Overall symptoms. The proportion of participants achieving 'well controlled' or 'completely controlled' NP symptoms will also be analyzed. Data will be collected and analyzed at specified timepoints throughout the trial to provide a comprehensive evaluation of the treatment's efficacy.

Inclusion and Exclusion Criteria

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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.

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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: (a) 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. (b) 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.
Receipt of live attenuated vaccines 30 days prior to the date of Visit 1 and during the study including the follow-up period.
Receipt of COVID-19 vaccine (regardless of vaccine delivery platform) within 28 days prior to date of first tezepelumab administration at Visit 2.
Known history of sensitivity to any component of the tezepelumab formulation or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
History of anaphylaxis or documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
Regular use of decongestants (topical or systemic) from Visit 1 onward is not allowed unless used for endoscopic procedure.
Use of corticosteroid-eluting intranasal stents within 6 months prior to Visit 1 and during the study period.
Recent aspirin desensitization within 6 months of enrolment.
Concurrent enrolment in another clinical study involving an IMP.
Any clinically meaningful abnormal finding in physical examination, haematology, or clinical chemistry at Visit 1 which, in the opinion of the investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
Evidence of active liver disease, including jaundice or AST, ALT, or ALP > 2 times ULN at Visit 1.
Positive hepatitis B surface antigen, or hepatitis C antibody serology at screening, or a positive medical history for hepatitis B or C. Participants with a history of hepatitis B vaccination without a history of hepatitis B are allowed to participate.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or participants employed by or relatives of the employees of the site or sponsor.
Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
For women only: Pregnant, breastfeeding, or lactating women. A serum β-HCG pregnancy test must be drawn for WOCBP at the screening visit. If the results of the serum β-HCG cannot be obtained prior to dosing of the IMP, a participant may be enrolled on the basis of a negative urine pregnancy test, though serum β-HCG must still be obtained. If either test is positive, the participant should be excluded. Since urine and serum tests may miss a pregnancy in the first days after conception, relevant menstrual history and sexual history, including methods of contraception, should be considered. Any participant whose menstrual and/or sexual history suggests the possibility of early pregnancy should be excluded.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	30 Mar 2025	50
France	Not Recruiting	30 Mar 2025	50
Germany	Not Recruiting	30 Mar 2025	50
Hungary	Not Recruiting	30 Mar 2025	50
Italy	Not Recruiting	30 Mar 2025	70
Poland	Not Recruiting	30 Mar 2025	26
Spain	Not Recruiting	30 Mar 2025	60