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A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 52-Week, Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Non-Cystic Fibrosis Bronchiectasis (MAHALE)

PHRR210504-003526

D325BC00001

2021-CT0594

A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 52-Week, Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Non-Cystic Fibrosis Bronchiectasis 

This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 52-week Phase III study to test the hypothesis that benralizumab will reduce exacerbation rates compared with placebo on top of standard-of-care therapy in adult patients with NCFB+EI. The study will be conducted at approximately 105 sites in 17 countries

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2021-06-01 57 2026-03-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca AB Private Business Sweden LTO-3000002234602
Institution Region
AstraZeneca Pharmaceuticals (Philippines) Inc. NCR
Name E-Mail Institution and Institution Address
Vanessa May Mendoza vanessamay.mendoza@astrazeneca.com 16th Floor, Inoza Tower, 40th St., Bonifacio Global City, Taguig 1634 Philippines
Name E-Mail Institution and Institution Address
Vanessa May Mendoza vanessamay.mendoza@astrazeneca.com 16th Floor, Inoza Tower, 40th St., Bonifacio Global City, Taguig 1634 Philippines
Name Expertise Affiliation
Ronnie Z. Samoro, MD Pulmonologist Healthlink Medical-Surgical-Dental Clinics & Diagnostics Center
Project Location Institutional Ethics Review Board
Healthlink Medical-Surgical-Dental Clinics & Diagnostics Center N/A

Patients With Non-Cystic Fibrosis Bronchiectasis

To evaluate the effect of benralizumab 30 mg Q4W on bronchiectasis exacerbations

  • Annualised exacerbation rate at Week 52 EstimandPopulation a: PFASIntercurrent event strategy a: Included in analysis regardless of treatment discontinuation (treatment policy)Population-level summary: Rate ratio for interventions (negative binomial model)
  • Time to first bronchiectasis exacerbation
  • Change from baseline in QoL-B-RSS over 52-week treatment period
  • Change from baseline in pre-dose FEV1 over 52-week treatment period

Recruiting

  • Argentina
  • Australia
  • Canada
  • China
  • Denmark
  • Germany
  • India
  • Italy
  • Japan
  • Philippines
  • Poland
  • Russia
  • South Korea
  • Spain
  • United Kingdom
  • United States
  • Vietnam

Clinical Trial

D325BC00001

20201210085827

2021-04-19

0000-00-00

20

Unspecified

Unspecified

01 Jun 2021

Inclusion Criteria

Age

  • Must be at least 18 years of age inclusive at the time of signing the ICF.

Type of Patient and Disease Characteristics

  • Must have NCFB diagnosed by a physician and confirmed by CT (measured at screening; if a new CT is not possible, a CT performed within 12 months of the screening visit is acceptable). CT must demonstrate > 1 segment affected within a single lobe. On CT, small bronchiectasis features only visible in a single pulmonary segment and judged
  • Documented history of 2 or more bronchiectasis exacerbations within a year of the screening visit. NOTE: Examples of documentation include but not limited to: hospital records, medical records, prescription records, copies or transcriptions certified as being accurate copies (eg, X-rays, records kept at the pharmacy).
  • At least 70% compliance on the daily BED ePRO assessment during the entire screening period.
  • Greater than 50% compliance on the daily BED ePRO assessment in the 14-day period prior to the randomisation visit.
  • If receiving prophylactic systemic or inhaled antibiotics to prevent bronchiectasis exacerbations, the dose/regimen must be stable for at least 3 months prior to the screening visit and remain stable throughout the DB period of the study. If prophylactic macrolides have been recently discontinued, patients must have been off treatment for at least 3 months prior to randomisation. In all other cases of prophylactic antibiotic use, ≥ 4 weeks wash-out period should be in place after the last dose of antibiotic and prior to randomisation.
  • Patients must be on airway clearance therapy, physiotherapy, or mucus clearance therapy. Examples including active cycle of breathing techniques, postural drainage, positive expiratory pressure (eg, Acapella™), and other clearance devices. The dose and regimen of these therapies and any drugs used to aid expectoration (eg, hypertonic saline, isotonic saline, carbocysteine, N-acetylcysteine) should be stable for at least 3 months prior to the screening visit and remain stable throughout the DB period of the study.
  • If receiving inhaled corticosteroid or bronchodilator (long-acting β-agonists and/or long-acting muscarinic antagonist) therapy, the dose and regimen should be stable with no alteration to dose or formulation for at least 3 months prior to the screening visit and this should remain stable throughout the DB period of the study.

Sex

  • Male or female.

Reproduction

  • Negative pregnancy test (serum) for WOCBP at the screening visit
  • WOCBP must:
    (a) Have a negative urine pregnancy test prior to randomisation, and
    (b) Must agree to use a highly effective method of birth control from enrolment, throughout the study duration, and for 12 weeks after the last dose of IP. Highly effective birth control methods (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include:
    • Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation - oral, intravaginal, or transdermal
    • Progestogen-only hormonal contraception associated with inhibition of ovulation – oral, injectable, or implantable
    • Intrauterine device
    • Intrauterine hormone-releasing system
    • Bilateral tubal occlusion
    • Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.)
    • Vasectomised sexual partner, provided that the partner is the sole sexual partner of the WOCBP and that the vasectomised partner has received medical assessment of the surgical success
    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 < 50 years of age will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with follicle-stimulating hormone levels in the postmenopausal range.Until follicle-stimulating hormone is documented to be within menopausal range, the patient will be considered as a WOCBP.
    (b) Women ≥ 50 years of age would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments.
    (c) If the criteria are not met, the patient should be regarded as having childbearing potential.

Informed Consent and Other

  • Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
  • Provision of signed and dated Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
  • Capable of complying with all study procedures and of completing the study.

Exclusion Criteria

Medical Conditions

  • Pulmonary disease other than bronchiectasis (eg, COPD, asthma, active lung infection including tuberculosis or NTM, pulmonary fibrosis, cystic fibrosis, primary ciliary dyskinesia, pulmonary hypertension, lung cancer, a1 anti-trypsin deficiency). Patients with a history of NTM disease may be enrolled if they have completed treatment prior to the screening visit, if at least 3 months have elapsed since the last day of antibiotic treatment for NTM at the screening visit, and if they have had a negative sputum culture prior to the screening visit.
  • Another diagnosed or suspected pulmonary or systemic disease associated with elevated peripheral eosinophil counts (eg, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis).
  • Respiratory infection or bronchiectasis exacerbation during the screening period. In the event of a respiratory infection or bronchiectasis exacerbation during the screening period, the screening period may be extended once only after the last dose of antibiotics is given to ensure the patient has recovered from the infection or exacerbation.
  • A helminth parasitic infection diagnosed within 24 weeks of the screening visit that has not been treated with or has failed to respond to standard-of-care therapy.
  • Any other clinical condition (ie, 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 patient during the study.
    (b) Influence the findings of the study or their interpretation.
    (c) Impede the patient’s ability to complete the entire duration of the study.
  • Radiological findings suggestive of a clinically important respiratory disease other than bronchiectasis, suggestive of acute infection, or of solitary pulmonary nodules without appropriate follow-up and demonstration of stability as per standard of care. Pulmonary nodules > 6 mm in size should have at least 2 years of follow-up with no change on CT imaging.
  • Current active liver disease:
    (a) Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen [HBsAg] or hepatitis C antibody) or other stable chronic liver disease is acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis.
    (b) Patients with alanine aminotransferase or aspartate aminotransferase level ≥ 3 times the upper limit of normal confirmed by repeated testing during screening period should not be randomised. Transient increase of aspartate aminotransferase/alanine aminotransferase level that resolves by the time of randomisation is acceptable if, in the Investigator’s opinion, the patient does not have an active liver disease and meets other eligibility criteria.
  • Current malignancy, or history of malignancy, except for:
    (a) Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to Visit 1.
    (b) Patients who have had other malignancies are eligible provided that the participant is in remission and curative therapy was completed at least 5 years prior to Visit 1.
  • History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2.
  • Current smokers with a tobacco history of ≥ 10 pack-years or ex-smoker with a tobacco history of ≥ 10 pack-years. Current smoking is not in itself an exclusion criterion, provided that the patient has smoked for less than 10 pack-years.
  • History of alcohol or drug abuse within the past year, which may compromise the study data interpretation as judged by Investigator or AstraZeneca study physician.
  • Patients receiving long-term oxygen treatment.
  • Patients participating in, or scheduled for, an intensive (active) pulmonary rehabilitation programme. Patients who are in the maintenance phase of a rehabilitation programme are eligible.
  • Use of non-invasive positive-pressure ventilation for conditions other than obstructive sleep apnoea.
  • Use of immunosuppressive medication (including but not limited to: methotrexate, cyclosporine, azathioprine, systemic corticosteroids, or any experimental anti-inflammatory therapy) within 3 months of the screening visit or expected need for chronic use (≥ 4 weeks) during study.
  • Receipt of any marketed or investigational biologic products (monoclonal or polyclonal antibody) within one year of the screening visit.
  • Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to randomisation.
  • Receipt of immunoglobulin and blood products within 30 days of the date of the screening visit.
  • Receipt of live attenuated vaccines within 30 days of the date of randomisation.

Other Exclusions

  • Concurrent enrolment in another clinical drug interventional trial.
  • History of anaphylaxis to any biologic therapy or vaccine.
  • Known history of allergy or reaction to any component of the IP formulation.
  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
  • Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
  • Previous randomisation in the present study.
  • Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Observational

Unspecified

None

Randomized

Double Blind

Parallel

This is a multicentre, randomised, DB, parallel-group, placebo-controlled, 52-week Phase III study to test the hypothesis that benralizumab will reduce exacerbation rates compared with placebo on top of standard-of-care therapy in adult patients with NCFB+EI. The study will be conducted at approximately 105 sites in 17 countries. To be eligible, patients must have a primary diagnosis of NCFB confirmed by CT and a documented history of ≥ 2 exacerbations within the past year. Patients will be excluded if they have pulmonary disease other than bronchiectasis (see Sections 5.1 and 5.2 for detailed inclusion and exclusion criteria).
Potentially eligible patients will enter a screening period of approximately 2 to 6 weeks. After the screening period, approximately 420 eligible patients will be randomised in a 1:1 ratio to receive either benralizumab 30 mg administered by SC injection Q4W or matching placebo. The DB treatment period will last 52 weeks. Patients will be stratified at randomisation by screening blood eosinophil count (≥ 300/μL and < 300/μL strata in a 2:1 ratio), country, and current chronic macrolide use (yes, no). Patients will be assigned to the ≥ 300/μL eosinophil stratum if 1 test shows eosinophils ≥ 300/μL and 1 test shows eosinophils ≥ 150/μL. All other patients will be assigned to the < 300 cells/μL eosinophil stratum.
All patients who complete the 52-week DB treatment period on IP may be eligible to continue into an OLE period, during which all patients will receive benralizumab 30 mg Q4W. The OLE treatment period is intended to allow patients at least one year of treatment with open-label benralizumab. The Sponsor may choose to extend the OLE period beyond one year and reserves the right of terminating the OLE early (eg, if development in this indication is terminated or marketing authorisation is obtained).
The primary database lock will occur after all randomised patients have been followed up for the 52-week DB treatment period. The study will remain blinded until the primary database lock. The final database lock will occur after the last patient completes the OLE. The primary analysis of efficacy endpoints will include all data captured during the DB treatment period (intention-to-treat approach). Data from the OLE treatment period of the study will be presented in an addendum to the primary analysis CSR, and/or a separate OLE treatment period CSR.
An independent Data Monitoring Committee may be established for this study in the event of futility analysis being performed

Phase III

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