Study to Assess Efficacy and Safety of Tozorakimab in Adults with Uncontrolled Asthma on Medium-to-High Dose Inhaled Corticosteroids
Scientific Title of Study
A Phase IIb, Multicentre, Double-blind, Placebo-controlled Dose Range Finding Study to Assess Efficacy and Safety of Tozorakimab in Adult Participants With Uncontrolled Asthma on Medium-to-High Dose Inhaled Corticosteroids (UMBRIEL)
Trial Acronym
UMBRIEL
Secondary IDs if Any
Secondary ID
Identifier
D9181C00002 CSP V1.0, dated 26 Nov 2024
Protocol Number
NCT00766415
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Randeep Guleria
Designation
Chairman, Internal Medicine Respiratory & Sleep Medicin
Affiliation
Medanta- The Medicity
Address
CH Baktawar Singh Road,
Sector 38
Gurgaon HARYANA 121001 India
Phone
9810184738
Fax
Email
randeepguleria2002@yahoo.com
Details of Contact Person Scientific Query
Name
Tapankumar Shah
Designation
Senior Director – Site Management and Monitoring, Biopharmaceuticals R&D
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road.
Bangalore KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Tapankumar Shah
Designation
Senior Director – Site Management and Monitoring, Biopharmaceuticals R&D
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road.
KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045,
Karnataka, India
Countries of Recruitment
Argentina Brazil Chile China France Greece Hungary India Israel Italy Japan Peru Philippines Republic of Korea South Africa Spain Taiwan Thailand Turkey United States of America Viet Nam
Sites of Study
No of Sites = 12
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Anant Mohan
All India Institute of Medical Sciences, Delhi
Professor and Head, Department of Pulmonary Medicine, Ansari Nagar, PIN - 110029
New Delhi DELHI
9810048204
anantmohan@yahoo.com
Dr Praveen Valsalan
Aster Medcity, Kochi
Lead Consultant Pulmonologist, Department of Pulmonary Medicine,South Chittoor P.O, Cheranelloor, PIN - 682027
Ernakulam KERALA
9496072264
drpraveen.valsalan@asterhospital.in
Dr Sandeep Nayar
BLK-Max Super Speciality Hospital
Principal Director & HOD, Department of Pulmonology, Pusa Road, PIN - 110005
New Delhi DELHI
9810006781
sandeep.nayar@blkhospital.com
Dr Rahul Kumar Rathore
Charak Hospital and Research Centre
Consultant Pulmonologist, Department of Pulmonary Medicine, Hardoi Road, Dubagga, PIN - 226003
Lucknow UTTAR PRADESH
7408441522
drrahulkgmu85@gmail.com
Dr Arti Dhawal Shah
Dhiraj Hospital
Smt. B.K Shah Medical Institute & Research Centre, affiliated to Sumandeep Vidyapeeth - Deemed to be University.
Professor & Head, Department of Pulmonary Medicine, At & PO. Piparia, Ta. Waghodia, PIN - 391760
Vadodara GUJARAT
9925047880
hod_pul_medicine@sumandeepvidyapeethdu.edu.in
Dr Kamran Choudhary
ESIC Medical College and Hospital, Faridabad
Assistant Professor, Department of Pulmonary Medicine, Clinical Trial Unit, MRU (Multidisciplinary Research Unit), Basement, NH-3, NIT, Fariabad, PIN-121001
Faridabad HARYANA
9871022476
kamran851@hotmail.com
Dr Anand Patel
GMERS Medical College and General Hospital
Consultant Pulmonologist, Department of Pulmonary Medicine, Old TB Hospital Campus, Gotri Road, PIN - 390021
Vadodara GUJARAT
9879771079
anand.trials@gmail.com
Dr Srikanth Krishnamurthy
Hindusthan Hospital
Consultant Pulmonologist, Department of Pulmonary Medicine, 522/3, 523/3 Nava India Road, Udaiyampalayam, Coimbatore,PIN - 641028
Coimbatore TAMIL NADU
9894257706
drsrikanthcbe@gmail.com
Dr Jyothi Hattiholi
KLES Dr Prabhakar Kore Hospital & Medical Research Centre
Cosultant Pulmonologist, Department of Pulmonary Medicine, Nehrunagar, PIN- 590010
Belgaum KARNATAKA
Institutional Human Ethics Committee GMERS Medical College and Hospita
Submittted/Under Review
Institutional Human Ethics Committee, Hindusthan Hospital
Submittted/Under Review
Medanta Institutional Ethics Committee, Gurugram
Submittted/Under Review
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: J459||Other and unspecified asthma,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Placebo
Formulation: Injection
Dose strength: NA
Route: Subcutaneous
Frequency: once every 2 weeks
Intervention
Tozorakimab 300 mg Q2W
Formulation: Injection
Dose strength: 150 mg/mL
Route: Subcutaneous
Frequency: once every 2 weeks
Intervention
Tozorakimab 300 mg Q4W
Formulation: Injection
Dose strength: 150 mg/mL
Route: Subcutaneous
Frequency: once every 4 weeks
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
Provision of signed and dated written informed consent prior to any study-specific procedures.
Optional: Provision of signed and dated written Optional Genetic Research Information informed consent before the sample collection for optional genetic research that supports the Genomic Initiative.
Age
Adults aged 18 to 75, inclusive when signing the informed consent at V1.
For Republic of Korea only, participants must be greater than or equal to 19 to 75 years old, inclusive.
Type of Participant and Disease Characteristics
Documented physician-diagnosis of asthma for at least 12 months prior to V1, according to GINA guidelines (GINA 2024), and as evidenced by any of the following:
Post-BD reversibility of FEV1 greater than or equal to 12percentage and greater than or equal to 200mL within 5 years prior to V1 or at V1
Treated with medium- or high-dose ICS (as per GINA 2024 report) in combination with LABA (GINA step 4 or 5 therapy); the dose of ICS must be stable for at least 30 days prior to V1.
The ICS can be contained within an ICS-LABA or ICS-LABA-LAMA fixed- dose combination product.
Treatment with additional asthma controller therapies (eg, LAMA, OCS) at a stable dose greater than or equal to 3 months prior to V1, with the intent to continue with the controller on a stable dose throughout the study, is allowed.
Individual component changes or switches between devices are allowed as long as the participant remains on the same class therapies in equivalent doses.
Demonstration of uncontrolled asthma through ACQ-6 score greater than or equal to 1.5 at screening and randomisation.
Pre-bronchodilator FEV1 greater than or equal to 40percentage to less than or equal to 90percentage of predicted normal at both screening and randomisation.
Documented exacerbation history in the last 12 months before screening and biomarker requirements of:
2 severe exacerbations
OR
1 severe exacerbation and:
Eosinophils greater than or equal to 150 cells per microliter at screening
or
FeNO greater than or equal to 25 ppb at screening and randomisation (Visits 1 and 2)
A severe exacerbation is defined as an episode of symptoms of asthma worsening that results in at least one of the following: OCS use for 3 consecutive days, inpatient
(greater than or equal to 24 hours) hospitalisation for asthma or emergency room or equivalent visit for asthma that results in systemic CS use. Refer to Section 8.2.1 for the complete definition of severe exacerbation and acceptable documentation.
Participants need to demonstrate greater than or equal to 70percentage compliance for Asthma Daily Diary completion and background medication during screening period, defined as completing the Asthma Daily Diary for any 10 mornings, and any 10 evenings of the last 14 days prior to randomisation, and answering “Yes” to taking regularly scheduled asthma medication for at least 10 out of the 14 last days prior to randomisation.
Sex and Contraceptive/Barrier Requirements
WOCBP must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test prior to randomisation.
Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants
Non-sterile 1 male participants who are sexually active with a female partner of childbearing potential must agree to use a male condom while engaging in sexual activity from enrolment throughout the study duration and until 14 weeks after last dose of study intervention. In countries where spermicide is available, it is strongly recommended.
It is strongly recommended for the female partner of a male participant to use a highly effective method of contraception throughout this period.
Non-sterilised male participants should also refrain from biologically fathering a child or donating sperm during the same period.
Female participants
Women of Child Bearing Potential (WOCBP): A woman is considered of childbearing potential if she is capable of conceiving. While this is typically the case following menarche and up until she becomes post-menopausal, adolescents can ovulate prior to first menarche, and women with irregular menses may also be fertile. Women Not of Child Bearing Potential (WNOCBP): Females not of childbearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Females will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. A high follicle stimulating hormone (FSH) level in postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. A postmenopausal state is confirmed by 2 consecutive high FSH values (at least 4 weeks apart) in the post-menopausal range.
Contraception methods:
Female participants should be stable on the chosen method of contraception for a minimum of one month before randomization
Female participants of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1percentage per year when used consistently and correctly. Females 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, throughout the study and until at least at least 14 weeks after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician.
Highly effective birth control methods include:
Non-hormonal
Total sexual abstinence provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments)
A vasectomised partner (confirmed absence of sperm in semen)
Bilateral tubal occlusion (caveat: failure rate greater than 1percentage)
Intrauterine device (copper)
Hormonal contraceptives associated with inhibition of ovulation.
levonorgestrel intrauterine system
medroxyprogesterone injections
combined oral or transdermal contraceptives (ethinyl estradiol plus progestin)
Intravaginal device (eg, ethinyl estradiol and etonogestrel)
The following are not acceptable methods of contraception: periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea. Female condom and male condom should not be used together.
ExclusionCriteria
Details
Participants are excluded from the study if any of the following criteria apply:
1 BMI greater than 40 kg m2 at V1
2 Participants who are unable to demonstrate ability to perform acceptable inhaler and spirometry techniques.
Medical Conditions
3 Major surgery within 8 weeks prior to V1, or planned major inpatient surgery, major procedure or hospitalisation during the screening, intervention, or follow-up periods.
4 Any other clinically relevant abnormal findings on vital signs, physical examination or laboratory testing, including haematology, coagulation, serum chemistry, urinalysis or
ECG during the screening period that, in the opinion of the investigator or medical monitor might compromise the safety of the participant in the study or interfere with evaluation of the study intervention. Abnormal findings include, but are not limited to:
(a) ALT or AST greater than 2 × ULN
(b) TBL greater than 1.5 × ULN (unless due to Gilbert s disease)
5 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.
6 Unstable cardiovascular disorders, including but not limited to ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure (NYHA class IV), uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator; or any ECG abnormality obtained during the screening/run-in period that in Investigator s judgement may put the participant at risk or negatively affect the outcome of the study.
7 Completed treatment for respiratory infection and/or asthma exacerbation with systemic corticosteroids and/or antibiotics/antivirals in the 4 weeks prior to V1.
8 Clinically significant pulmonary disease other than asthma, including but not limited to those with co-existent COPD.
9 History of severe episodes of colitis within one year before enrolment, active inflammatory bowel disease, high risk of having severe flare-ups during the study, or unexplained diarrhoea within the 4 weeks before randomisation.
10 History of clinically significant aortic stenosis or pulmonary arterial hypertension
11 Participants who, in the opinion of the Investigator, have evidence of active tuberculosis (TB) or are currently on treatment for active or latent TB. Investigation for active or latent TB, with interferon-gamma release assay (IGRA) and/or chest X-ray, should only be considered if deemed clinically indicated by the Principal Investigator.
12 Medical history of or treatment for hepatitis B or hepatitis C, except for cured hepatitis C, as defined by:
(a) Positive test for HBsAg
(b) Positive test for anti-HBc: Participants who test positive for anti-HBc antibody but negative for HBsAg may be enrolled if their hepatitis virus DNA test result is negative.
(c) Positive test for anti-hepatitis C antibody: Participants who test positive for anti- hepatitis C antibody may be enrolled if their hepatitis C viral RNA test result is negative in the absence of cirrhosis.
13 History of known immunodeficiency disorder, including a positive test for HIV-1 or HIV-2.
14 Current smokers, former smokers with greater than 10 pack-years history, or former smokers who stopped smoking less than 6 months before V1 (including all forms of tobacco, e-cigarettes (vaping), and other recreational drugs, including marijuana).
15 History of current or previous alcohol or drug misuse in the last 12 months prior to V1.
16 Malignancy, current or within the past 5 years, except for adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than one year prior to enrolment. Suspected malignancy or undefined neoplasms.
17 Known history of anaphylaxis that required the use of epinephrine/adrenaline or hospitalisation.
18 Known history of immune complex disease (Type III hypersensitivity reactions) to monoclonal or polyclonal antibody administration.
19 A helminth parasitic infection diagnosed within 24 weeks of V1 that has not been treated or has not responded to standard of care therapy
20 Use of as-required anti-inflammatory ICS therapy for asthma (including anti- inflammatory reliever/maintenance and reliever therapy) within 30 days of V1.
Note: Participants can be converted to an equivalent twice daily dose of ICS/LABA and considered for screening after greater than or equal to 30 days.
21 Treatment with marketed or investigational systemic biologics within 4 months, or inhaled biologics for asthma within 4 weeks, or a minimum of 5 half-lives, whichever is longer, prior to V1.
Exceptions include:
- Participants on stable therapy for at least 3 months before randomisation, who intend to stay on treatment throughout the study with marketed biologics that are not likely to interfere with the safety assessment and/or efficacy of tozorakimab for the treatment of osteoporosis, migraine pain, T2DM, obesity, ocular, cardiovascular, or metabolic diseases are allowed to participate in the study.
Examples of approved marketed biologics include: denosumab, romosozumab, CGRP-antagonists, GLP-1 agonists, GIP/GLP-1 agonists, PCSK9 inhibitors, recombinant botulinum neurotoxin, mAbs targeting SARS-COV-2 viral components (marketed or authorised), recombinant erythropoietin, VEGF inhibitors for ocular diseases.
- Medications not listed here should be discussed with the study team.
22 Use of the following therapeutic interventions within the specified time before screening:
(a) Participants who have previously received tozorakimab.
(b) Increased or new systemic steroid use within 4 weeks prior to the Screening Visit.
(c) Live, attenuated vaccine in the 4 weeks prior to randomisation (Note: Vaccines with adenoviral vectors that are unable to replicate, eg, ChAdOx1, are not considered live or attenuated).
(d) Any systemic immunosuppressive therapy within 3 months of randomisation.
(e) Allergen immunotherapy within 3 months of randomisation, except for stable maintenance dose allergen-specific immunotherapy started 4 weeks prior to V1.
(f) Bronchial thermoplasty in the last 12 months prior to V1.
N.B. Intranasal / topical steroid use is permitted, provided that there has been a stable treatment regimen for at least 4 weeks.
Other exclusions
23 Donation of blood (greater than or equal to 450 mL) within 3 months or donation of plasma within 14 days before V1
24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and/or vendor and/or site staff).
25 Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to randomisation, whichever is longer.
Lifestyle Considerations
Meals and Dietary Restrictions
- Participants should avoid eating a large meal for at least 2 hours prior to all spirometry and FeNO assessments at the site.
- Participants should not eat or drink one hour prior to having FeNO assessment.
Caffeine, Alcohol, and Tobacco
- Participants will abstain from ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 4 hours prior to in-clinic spirometry.
- Tobacco and tobacco products, including vaping and e-cigarettes, will be prohibited for at least 6 months prior to V1 and during the study up until final follow-up.
Activity
Participants should avoid engaging in strenuous exercise for 2 hours prior to all spirometry, and FeNO assessments, both in clinic and at home.
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To evaluate the effect of two dose levels of tozorakimab compared with placebo on annualised rate of severe asthma exacerbations
Population: Participants with uncontrolled moderate to severe asthma and greater than or equal to 1 severe exacerbation a within 12 months prior to screening.
Endpoint: Annualised rate of severe asthma exacerbations Summary measure: Rate ratio tozorakimab versus placeb Intercurrent event strategy - Treatment policy Supportive analysis: While-on-treatment
Secondary Outcome
Outcome
TimePoints
To evaluate the effect of two dose levels of tozorakimab as compared to placebo on annualised rate of severe asthma exacerbations in participants with uncontrolled moderate to severe asthma and baseline eosinophils less than 300 cells per microliter and history of greater than or equal to 2 severe exacerbations within 12 months prior to screening.
Population: Participants with uncontrolled moderate to severe asthma and baseline eosinophils less than 300 cells per microliter and history of greater than or equal 2 severe exacerbations within 12 months prior to screening.
Endpoint: Annualised rate of severe asthma exacerbations Summary measure: Rate ratio (tozorakimab versus placebo) Intercurrent event strategy: Treatment policy
To evaluate the effect of two dose levels of tozorakimab compared to placebo on time to first severe asthma exacerbations.
Population: Participants with uncontrolled moderate-to-severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening Endpoint: Time-to-first severe asthma exacerbation
Summary measure: Hazard ratio (tozorakimab versus placebo)
Intercurrent event strategy: Treatment policy
To evaluate the effect of two dose levels of tozorakimab as compared to placebo on lung function.
Population: Participants with uncontrolled moderate to severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening Endpoints:
- change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) over weeks 20 to 26
- change from baseline in post-bronchodilator FEV1 at Week 26 Summary measure: Difference in mean change from baseline between tozorakimab and placebo
Intercurrent event strategy: Treatment policy
To evaluate the effect of two dose levels of tozorakimab as compared to placebo on asthma symptoms and control.
Population: Participants with uncontrolled moderate-to-severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening.
Endpoints:
- change from baseline in ACQ-6 at Week 26
- change from baseline in AQLQ(S) PLUS 2 at Week 26
Summary measure: Difference in mean change from baseline between tozorakimab and placebo
Intercurrent event strategy: Treatment policy
To evaluate the PK and immunogenicity of tozorakimab.
Population: Participants with uncontrolled moderate-to-severe asthma
Endpoints:
- Trough serum concentrations of tozorakimab over 52 weeks treatment period
Anti-drug antibody (ADA) prevalence, incidence, and titre
Target Sample Size
Total Sample Size="540" Sample Size from India="70" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This Phase IIb study is designed to demonstrate the efficacy and safety and determine the dose of tozorakimab in adult participants with uncontrolled moderate-to-severe asthma (receiving medium-to-high dose inhaled corticosteroid / long-acting beta-2 agonist). The study population was identified based on tozorakimab mechanism of action and unmet need in adult asthma patients who remain uncontrolled on standard of care. Based on the findings of the asthma Phase II study (Study D181C00001), participants are included from across the spectrum of baseline eosinophil levels. Asthma is a chronic inflammatory disease of the airways characterised by bronchial hyperreactivity and reversible airflow limitation. India has a high and growing burden of asthma: according to the Global Burden of Disease Report 2019, India ranks number one in the world in terms of burden, disability-adjusted life years and deaths related to asthma. Over 34 million people in India have asthma, and although this reflects only 13 percent of the world’s population with asthma, 42 percent of global asthma deaths occur in India. People with asthma in India also suffer a disproportionately high burden of day-to-day symptoms, effects on quality of life, and absence from school and work. In low-income households, even minor levels of healthcare utilization can be financially catastrophic. For patients who are symptomatic on inhaled corticosteroid monotherapy, the addition of long-acting beta-2 agonist is the recommended treatment. However, there are many patients with asthma who are still symptomatic despite treatment with inhaled corticosteroid and long-acting beta-2 agonist combinations (Rabe et al 2004). Biologic therapies that inhibit specific molecular targets, including Immunoglobulin E and T-helper 2 cytokines and their respective receptors are increasingly available, but are currently mainly indicated for subsets of patients with uncontrolled, moderate-to-severe asthma, despite medium to high dose inhaled corticosteroid. Omalizumab is indicated for patients with moderate-to-severe persistent asthma with proven reactivity to an aeroallergen. Benralizumab and Mepolizumab are indicated for add-on maintenance treatment of patients with severe or moderate-to-severe asthma with an eosinophilic phenotype. There remains significant unmet need in asthma patients with blood eosinophil counts less than 300 cells per microliter at baseline and on improving aspects of asthma other than exacerbations including lung function and patient related outcomes (Doroudchi et al 2020). There are several recommended step-up therapy options available. However, despite the introduction of approved biologics, a proportion of patients continue to experience exacerbations, indicating that there remains an unmet medical need in the severe asthma space. Various asthma phenotypes have been described to have an increased and modifiable risk of exacerbations, identified by key prognostic and theragnostic biomarker, such as blood eosinophils and Fractional exhaled Nitric Oxide (FeNO), as well as clinical risk factors (Couillard et al 2022). In recent years, treatment goals in asthma have also shifted towards achieving clinical remission, though a universally accepted definition has yet to be established. Hence, substantial unmet need remains