A Study to Evaluate effectiveness and safety of Tezepelumab in Adults with Oral Corticosteroid Dependent Asthma (SUNRISE)

Phase 3

Recruiting

• Conditions: Severe persistent asthma,

• Registration Number: CTRI/2024/01/061119
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre study to evaluate the efficacy and safety of tezepelumab 210 mg every 4 weeks (Q4W) administered subcutaneously (SC) using an accessorised pre-filled syringe (APFS), compared with placebo in reducing OCS use in OCS-dependent adult asthma participants.

Approximately 207 participants will be randomised in a 2:1 ratio to receive Tezepelumab 210 mg or placebo SC Q4W for a total of 7 doses of study intervention. The randomisation is on Day 1. Study intervention will be administered at weeks: 0 (Day 1), 4, 8, 12, 16, 20, and 24. Treatment allocation will be stratified by region and eosinophil count at Visit 1 (< 150 cells/μL, 150-< 300 cells/μL, ≥ 300 cells/μL), to ensure that treatment assignment across regions and eosinophil subgroups is balanced.

After enrolment at Visit 1, all participants will enter a 2-week run-in period and then an 8-week OCS optimisation phase. The OCS optimisation phase is to establish participant eligibility and to determine the minimum effective dose (the optimised dose) of the participant’s prescribed OCS. The OCS optimisation phase may be shortened if the optimised dose is determined earlier than 8 weeks, or it may be extended to accommodate for treatment of an asthma exacerbation and still allow for the 2-week period of the optimised OCS dose prior to randomisation.

Following the OCS optimisation phase, participants who fulfil the eligibility criteria will be randomised at Visit 6 (Week 0) and will start the 28-week treatment period.

There are 3 phases in the 28-week treatment period:

·       Induction phase – from Visit 6 (Week 0) to Visit 7 (Week 4) during which participants should remain on their optimised OCS dose.

·                   OCS reduction phase – from Visit 7 (Week 4) to Visit 12 (Week 24) during which the  OCS dose reduction should be started at Visit 7, with the possibility of dose reduction every 4 weeks.

·                   Maintenance phase – from one day after Visit 12 (Week 24) to the day of Visit 13 (Week 28), which is the End of Treatment visit. In this phase participants should remain on the stable maintenance OCS dose reached during the reduction phase or continue without OCS if the OCS dose was reduced to 0 mg during the reduction phase. No further OCS dose reduction will take place during this phase.

The End of Treatment visit will be performed at Week 28. A post-treatment safety follow-up visit will be performed at Week 40 (Visit 14).

In this study, tezepelumab is beingcompared to placebo. Both are given in addition to standard of care treatmentin order that their effect can be assessed in an appropriate clinicalcontext.The study will randomise participants treated with documented OCSmaintenance therapy for at least 6 months prior to Visit 1 and who arereceiving a stable dose of OCS in the range ≥ 7.5 mg to ≤ 30 mg (prednisone orprednisolone) daily or daily equivalent for at least 1 month prior to Visit 1.Participants will be required to be on a medium dose (MD) or high dose (HD) ICS(as defined in GINA 2021) for at least 12 months prior to Visit 1 and on LABAwith HD ICS for at least 3 months prior to Visit 1. Additional maintenanceasthma controller medications are allowed according to standard of carepractice

At the end of the study, theparticipant should be given standard of care therapy, at the discretion of theinvestigator, per local practice. Participants permanently discontinuing studyintervention administration should be given locally available standard of caretherapy, at the discretion of the investigator

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2024-04-17
• Study Start: 2024-12-01

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 207

Inclusion Criteria

• 1 Documented physician-diagnosed asthma for at least 12 months prior to Visit 1.
• 2 Participants must have received a physician-prescribed medium- or high-dose ICS (medium dose ICS corresponds to 500 μg and high dose ICS corresponds to > 500 μg fluticasone propionate dry powder formulation or equivalents) as per GINA guideline (GINA 2022) for at least 12 months prior to Visit 1.
• 3Participants must have received physician-prescribed LABA and high dose ICS (total daily dose > 500μg fluticasone propionate dry powder formulation or equivalent) for at least 3 months prior to Visit 1.
• The ICS and LABA can be parts of a combination product or given by separate inhalers.
• a)Equivalent ICS doses as detailed in Appendix G 4 Additional maintenance asthma controller medications are allowed according to standard practice of care ie, leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), and chromones.
• The use of these medications must be documented for at least 3 months prior to Visit 1.
• 5 Participants must have received OCS for the treatment of asthma for at least 6 months prior to Visit 1 and on a stable dose of between ≥ 7.5 to ≤ 30 mg (prednisone or prednisolone) daily or daily equivalent for at least one month prior to Visit 1.
• The OCS dose may be administered every other day (or different doses every other day) Average dose over 2 days equals The daily dose.
• 6 Morning pre-BD FEV1 must be < 80% predicted normal at Visit 1 or Visit 2.
• 7 Evidence of asthma as documented by either: (a)Post-BD (albuterol/salbutamol) responsiveness test result: FEV1 greater than equal to 12% and greater than equal to 200 mL (15-30 min after administration of 4 puffs of albuterol/salbutamol), documented either in the previous 60 months prior to or at Visit 1 or at Visit 2 or at Visit 3.
• or Airway hyperresponsiveness (methacholine: provocative concentration that causes a positive reaction [PC20] of lesser than 8 mg/mL) documented in the 60 months prior to Visit 1.
• 8 Blood eosinophils at Visit 1 ≥150 cells/μL(≥0.15 x109/L or ≥0.15 x103/µl) or documented EOS ≥ 300 cells/μL (≥0.3 x109/L or ≥0.3 x103/µl) within 12 months prior to Visit 1.
• 9 Participants must have a history of at least one asthma exacerbation event within 24 months prior to Visit 1.
• Weight 10 Body weightgreater than equal to 40 kg at Visit 1.
• Sex 11 Male or female.
• 12 All women of childbearing potential must have a negative serum pregnancy test results at Visit 1 and a negative urine pregnancy test at randomisation.
• 13 Female participants of childbearing potential who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, from enrolment throughout the study and until at least 16 weeks after last dose of study intervention.
• Cessation of contraception after this point should be discussed with a responsible physician.
• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception.
• Female condom and male condom should not be used together.
• a A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.
• b Highly effective birth control methods include: sexual abstinence (please note: periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of exposure to Investigational Medicinal Product (IMP), and withdrawal are not acceptable methods of contraception), a vasectomised partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Proveraâ„¢ injections, oral contraceptive, and Evra Patchâ„¢, Xulaneâ„¢, or NuvaRing.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Women not of 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 date of randomisation without an alternative medical cause.
• The following age-specific requirements apply: a Women lesser than 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range.
• b Women greater than equal to 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
• Informed Consent 14 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• 15 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
• Participant must meet the following criteria at the start of optimisation phase (Visit 2): 16 Minimum 10 days compliance with both the morning and evening daily diary completion and morning PEF measurements during the 14 days prior to Visit 2.
• A compliant day requires completion of evening diary assessment and subsequent morning diary assessment such that an ASD daily score can be calculated.
• 17 Minimum 10 days compliance with OCS, ICS, LABA and other asthma controller medications as captured in the daily diary during the 14 days prior to Visit 2.
• Participant must meet the following criteria at the randomisation visit (Visit 6) 18 Participant must have received the optimised OCS dose for at least 2 weeks prior to randomisation.
• 21 Minimum 10 days compliance with the morning and evening daily diary completion and morning PEF measurement during the 14 days prior to randomisation.
• a The period for this criterion is the duration from the evening of the OCS dose adjustment (defining the optimised dose) during the optimisation phase until the morning of the randomisation visit.
• 22 Minimum 10 days compliance with OCS, ICS, LABA and other asthma controller medications as captured in the daily diary during the 14 days prior to randomisation.
• a Days with missing daily diary data treated as non-compliant for this criterion 23 Acceptable inhaler, peak flow meter, and spirometry techniques as judged by the investigator.

Exclusion Criteria

• Medical Conditions 1 Any clinically important pulmonary disease other than asthma (eg, active lung infection, Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
• 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 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 A Affect the safety of the participant throughout the study B Influence the findings of the study or the interpretation C Impede the participants ability to complete the entire duration of study 3 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.
• 4 Asthma exacerbation, requiring use of systemic corticosteroids or increase in the maintenance dose of OCS finalised within 30 days prior to Visit 1.
• 5 Clinically significant infection, including upper or lower respiratory tract infection (URTI and LRTI, respectively) requiring treatment with systemic antibiotics or antiviral medications finalised lesser than 2 weeks before Visit 1 or during the run-in period.
• 6 Participants with evidence of active COVID-19 infection during run-in period and optimisation.
• Evaluation will be based on local standard of care as determined by current local guidelines 7 A helminth 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.
• 8 A participant who is on short-acting beta agonists (SABA) maintenance treatment within 30 days prior to Visit 1.
• 9 Current smokers or participants with smoking history greater than 10 pack years and participants using vaping products, including electronic cigarettes.
• Former smokers with a smoking history of lesser than 10 pack-years and users of vaping or e cigarette products must have stopped for at least 6 months prior to Visit 1 to be eligible.
• 10 Chronic alcohol or drug abuse within 12 months prior to Visit 1.
• 11 Tuberculosis requiring treatment within the 12 months prior to Visit 1.
• 12 A positive human immunodeficiency virus (HIV) test at Visit 1 or participant taking antiretroviral medications or history of any known immunodeficiency disorder, as determined by medical history and or participants verbal report.
• 13 Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures requiring general anaesthesia or hospitalisation for greater than 1 day during the conduct of the study 14 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 longer) prior to Visit 1.
• 15 Treatment with the following medications within the last 12 weeks or 5 half lives (whichever is longer) prior to Visit 1 systemic immunosuppressive or immunomodulating drugs (eg, methotrexate, cyclosporine, oral/parenteral or intra-articular corticosteroids for other use than treatment of asthma) 16 Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
• 17 Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to Visit 1.
• 18 Receipt of live attenuated vaccines 30 days prior to the date of randomisation and during the study including the follow up period.
• 19 COVID 19 vaccination within 28 days prior to randomisation.
• 20 Participants who have been treated with bronchial thermoplasty within 36 months prior to Visit 1.
• Diagnostic Assessments 26 Any clinically meaningful abnormal findings in physical examination, vital signs, electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the run-in period, which in the opinion of the investigator, may put the participant at risk because of his or her participation in the study, or may influence the results of the study, or the participants ability to complete entire duration of the study.
• 27 Evidence of active liver disease, including jaundice or aspartate transaminase, alanine transaminase, or alkaline phosphatase beyond twice the upper limit of normal (ULN), at Visit 1.
• 28 Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at Visit 1, 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.
• Other Exclusions 29 Women who are currently pregnant (confirmed with positive pregnancy test) or breastfeeding or lactating.
• 30 Unwillingness or inability to follow the study procedures, or restrictions, in the opinion of the investigator 31 Previous allogeneic bone marrow transplant.
• Exclusion Criteria at Randomisation: 33 During the optimisation period, asthma control reached at an OCS dose of lesser than 7.5 mg or greater than 30 mg and or 3 consecutive dose reductions after which asthma control was still obtained.
• 35 Despite screening of the participant, enrolment or randomisation is stopped at the study level.
• 5.3 Lifestyle Considerations Participants must abstain from donating blood and plasma from the time of informed consent, and for 16 weeks 5 half lives after last dose of study intervention.
• 5.3.1 Meals and Dietary Restrictions Participants should avoid eating a large meal for at least 2 hours prior to all lung function assessments at the study site.
• Participants should not eat or drink 1 hour prior to having FeNO assessment and should be fasting for at least 12 hours prior to blood collection.
• 5.3.2 Alcohol and Tobacco Chronic alcohol or drug abuse within 12 months prior to Visit 1 and throughout the conduct of the study is not allowed.
• Former smokers with a smoking history of < 10 pack-years must have stopped for at least 6 months to be eligible.
• Smoking is not allowed throughout the course of the study.
• 5.3.3 Activity Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung function assessments at the study site.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To evaluate the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose in participants with asthma requiring chronic treatment with maintenance OCS in addition to high dose ICS plus LABA	Categorised percent reduction from baseline in the daily maintenance OCS dose at Week 28 whilst maintaining asthma control. The categories for percent change from baseline in daily OCS dose are | defined as | 1 90% to lesser than equal to 100% reduction | 2 greater than equal to 75% to less than 90% reduction | 3 greater than equal to 50% to less than 75% reduction | 4 greater than 0% to less than 50% reduction | 5 no change or any increase.

Secondary Outcome Measures

Name	Time	Method
To evaluate the effect of tezepelumab compared with placebo on asthma exacerbations	Annualised asthma exacerbation rate (AAER) over 28 weeks
To evaluate the effect of tezepelumab compared with placebo on pre-BD lung function in participants with asthma requiring chronic treatment with maintenance OCS in addition to high dose ICS plus LABA	Endpoint: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1) at Week 28.Population: Adults with severe asthma who require daily or daily equivalent maintenance OCS therapy in addition to high dose ICS plus LABA, with or without other asthma controllers, who have had at least 1 asthma exacerbation in the previous 2 years & have received at least one dose of study intervention.
To evaluate the effect of tezepelumab compared with placebo on the daily dose of maintenance OCS	Proportion of participants with 100% reduction from baseline in daily maintenance OCS dose at Week 28
To assess the effect of tezepelumab compared with placebo on asthma related quality of life	Change from baseline in
To assess the effect of tezepelumab on biomarkers	Change from baseline in fractional exhaled nitric oxide (FeNO), peripheral blood eosinophils & total serum immunoglobulin E (IgE) at Week 28
To assess the effect of tezepelumab compared with placebo on asthma control & other asthma control metrics	Change from baseline in
To evaluate the safety & tolerability of tezepelumab	Adverse events (AEs), serious adverse events (SAEs)
To evaluate the pharmacokinetics (PK) of tezepelumab	Tezepelumab serum trough concentrations at Week 0, 12, & 28
To evaluate the immunogenicity of tezepelumab	Incidence of anti-drug antibodies (ADAs) at Week 0, 12, 28, & 40
Exploratory	To explore the effect of tezepelumab compared with placebo on other pre-BD lung function measures
To explore the effect of tezepelumab compared with placebo on post-BD lung function	Including, but not limited to, the change from baseline in
To assess the effect of tezepelumab compared with placebo on general health-related quality of life	Change from baseline in European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score at Week 28
To assess the effect of tezepelumab compared with placebo on health status of participants with airway obstruction disease	Change from baseline in weekly mean daily Asthma Symptom Diary (ASD) at Week 28
To evaluate the efficacy of tezepelumab compared with placebo on health resource utilisation	Number of asthma specific resource utilisations (eg, unscheduled physician visits, unscheduled phone calls to physicians, ER/hospitalisations due to asthma, use of other asthma medications)
To evaluate the effect of tezepelumab on circulating pharmacodynamic (PD) biomarkers & relationship of baseline biomarkers with clinical response	Including, but not limited to, serum cytokines (TSLP, IL-5, & IL-13)
To evaluate the effect of tezepelumab on blood transcriptome for PD effect & associate with clinical response	Transcriptomic profiling
To evaluate the relationship of genetic variants from DNA & associate with clinical response	Genomics/genetics profiling
To evaluate the effect of tezepelumab compared with placebo on the exposure of systemic corticosteroids	Mean daily exposure of systemic corticosteroids (mg/day) taken for asthma reasons over 28 weeks

Trial Locations

Locations (13)

Asthma Bhawan; 🇮🇳 Jaipur, RAJASTHAN, India

Dr. Murari Lal Chest Hospital, GSVM Medical College; 🇮🇳 Nagar, UTTAR PRADESH, India

Excelcare Hospital; 🇮🇳 Jaipur, RAJASTHAN, India

Jawaharlal Nehru Medical College; 🇮🇳 Ajmer, RAJASTHAN, India

Jawaharlal Nehru Medical College and Hospital; 🇮🇳 Aligarh, UTTAR PRADESH, India

Jehangir Clinical Development Centre Pvt. Ltd.; 🇮🇳 Pune, MAHARASHTRA, India

Medical College and Hospital -Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

NRS Medical College and Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Rhythm Heart Institute A Unit of Synergy Lifecare Private Limited; 🇮🇳 Vadodara, GUJARAT, India

Siddhi Hospital, C/o Dr.Mutha Hospital; 🇮🇳 Nashik, MAHARASHTRA, India

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Asthma Bhawan

🇮🇳Jaipur, RAJASTHAN, India

Dr Sharad Tikkiwal

Principal investigator

9828027022

Sharadtikkiwal@gmail.com