Non-Inferiority Trial of Depemokimab Versus Mepolizumab or Benralizumab in Severe Eosinophilic Asthma Patients
- Trial ID
- 2023-510230-84-00
- Protocol
- 206785
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of GSK3511294 (depemokimab) 100 mg administered subcutaneously every 26 weeks compared to maintaining existing treatment with either mepolizumab or benralizumab in participants with severe asthma with an eosinophilic phenotype who have previously benefited from anti-IL-5/5R therapy. This is clinically relevant as it aims to determine whether GSK3511294 can provide a comparable or superior therapeutic benefit in managing severe asthma, potentially offering an alternative treatment option for patients.
Secondary objectives include evaluating GSK3511294 100 mg (SC) every 26 weeks versus maintaining existing treatment with either mepolizumab or benralizumab on health-related quality of life (HRQoL) and additional efficacy assessments. These objectives are important for understanding the broader impact of the treatment on patient well-being and its overall effectiveness beyond primary efficacy measures.
Participants
The clinical trial involves a total of **950 participants** diagnosed with **severe asthma with an eosinophilic phenotype**. The study population includes both male and female subjects, with an age range starting from 12 years, although in certain countries such as Germany, the UK, and Norway, only adults aged 18 years and older are included. Participants are required to have a documented history of asthma for at least two years and must have been receiving anti-IL-5/5R therapy, such as mepolizumab or benralizumab, for a minimum of 12 months prior to screening. The trial population was selected based on their previous benefit from such therapies, evidenced by a significant reduction in exacerbation frequency or maintenance oral corticosteroid use, or the absence of exacerbations in the past six months. All participants are required to be on regular treatment with medium to high-dose inhaled corticosteroids, with or without maintenance oral corticosteroids, and must be using at least one additional controller medication. The study includes individuals who are capable of providing informed consent and are compliant with the study's requirements. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data. The trial also includes a vulnerable population, although specific details regarding this aspect are not provided.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, double-dummy, parallel group, multi-center, non-inferiority study. It aims to assess the exacerbation rate, additional measures of asthma control, and safety in adult and adolescent participants with **severe asthma with an eosinophilic phenotype**. The trial will compare the efficacy of GSK3511294 (depemokimab) with mepolizumab or benralizumab over a period of 52 weeks. Participants will be randomly assigned to receive either the investigational product or a comparator, with both groups receiving a placebo to maintain blinding.
The trial will consist of several key visits, starting with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age, documented diagnosis of asthma, and previous benefit from anti-IL-5/5R therapy. Following the screening, eligible participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will involve assessments such as the St. George's Respiratory Questionnaire (SGRQ) and the Asthma Control Questionnaire-5 (ACQ-5), as well as measurements of pre-bronchodilator forced expiratory volume in one second (FEV1). The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the primary and secondary endpoints.
Participant involvement is expected to last for the entire 52-week duration of the trial. However, conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events that compromise participant safety, or withdrawal of consent. The trial's primary endpoint is the annualized rate of clinically significant exacerbations over the 52-week period, while secondary endpoints include changes in SGRQ and ACQ-5 scores, and FEV1 measurements. The trial is not classified as a low-intervention study and is categorized as a Phase III clinical trial.
Treatment
The clinical trial involves the administration of **Depemokimab**, an experimental medication developed by GlaxoSmithKline. Depemokimab is provided as a **solution for injection** and is administered subcutaneously. The dosage is set at 100 mg every 26 weeks, with a maximum total dose of 200 mg over a 52-week treatment period. The medication is delivered using a pre-filled syringe, ensuring precise dosing and ease of administration. Participant compliance is monitored through regular follow-ups and documentation of dosing schedules.
In addition to the experimental treatment, the study includes a comparator treatment with **Mepolizumab**. Mepolizumab is also a solution for injection, provided in a pre-filled syringe, and administered subcutaneously. The dosage for Mepolizumab is 100 mg, with a maximum total dose of 1300 mg over the 52-week period. This medication is repackaged and labeled specifically for the trial to ensure consistency and accuracy in administration.
Another comparator treatment in the study is **Benralizumab**, marketed as Fasenra. Benralizumab is provided as a 30 mg solution for injection in a pre-filled syringe, administered subcutaneously. The maximum total dose for Benralizumab is 210 mg over the 52-week treatment period. Similar to Mepolizumab, Benralizumab is repackaged and labeled for the trial to maintain standardization across study sites.
The trial also includes placebo treatments to match the active medications. A placebo matching Mepolizumab is used, as well as a placebo for Benralizumab, both presented as sterile liquid solutions in accessorized prefilled syringes for subcutaneous injection. Additionally, a placebo matching Depemokimab is included in the study. These placebos are utilized to maintain the double-blind nature of the trial, ensuring unbiased assessment of the experimental medication's efficacy and safety.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the annualized rate of clinically significant exacerbations over a 52-week period. This will provide a direct measure of the treatment's impact on the frequency of exacerbations in participants with severe asthma and an eosinophilic phenotype.
Secondary endpoints include the weighted mean change from baseline in the St. George's Respiratory Questionnaire (SGRQ) total score, the Asthma Control Questionnaire-5 (ACQ-5) score, and pre-bronchodilator forced expiratory volume in one second (FEV1), all calculated over 52 weeks. These secondary endpoints will offer additional insights into the treatment's effect on overall asthma control and lung function.
The efficacy parameters will be measured and collected at specified intervals throughout the trial, ensuring a comprehensive evaluation of the treatment's impact over the study duration. The use of validated scales such as the SGRQ and ACQ-5 will ensure the reliability and accuracy of the patient-reported outcomes. The trial is designed to compare the efficacy of GSK3511294 (depemokimab) administered subcutaneously every 26 weeks against the existing treatments with mepolizumab or benralizumab, providing a robust framework for assessing the non-inferiority of the investigational product.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age: Adults and adolescents ≥12 years of age, at the time of signing the informed consent/assent.[For countries where local regulations or the regulatory status of study medication permit enrolment of adults only, participants recruited will be ≥18 years of age] Note for Germany, UK and Norway Participants: In Germany, UK and Norway, only adult participants (≥18 years) are to be included in this clinical trial. Note for Austrian Participants: In Austria, participants who are ≥16 years are to be included in this clinical trial.
- Asthma: Participants who have a documented physician diagnosis of asthma for ≥2 years that meets the National Heart, Lung, and Blood Institute guidelines [NHLBI, 2007] or GINA guidelines [GINA, 2020].
- Anti-IL-5/5R Therapy: Receiving either mepolizumab 100 mg SC or benralizumab 30 mg SC for ≥12 months prior to Screening and have a documented benefit to therapy assessed by either: • ≥50% reduction in exacerbation frequency since initiating treatment, OR • ≥50% reduction in maintenance OCS use since initiating treatment, OR • no exacerbations in the past 6 months whilst receiving anti-IL-5/5R therapy and an ACQ-5 score of ≤1.5 at Screening.
- Inhaled Corticosteroid: A well-documented requirement for regular treatment with medium to high dose ICS in the 12 months prior to Visit 1 with or without maintenance OCS. The maintenance ICS dose must be ≥ 440 mcg fluticasone propionate [FP] hydrofluoroalkane product [HFA] daily, or clinically comparable [GINA, 2020; see Appendix 10 of the protocol]. Participants who are treated with medium dose ICS will also need to be treated with a Long-acting beta-agonist (LABA) to qualify for inclusion.
- Additional Controller Medication: Current treatment with at least one additional controller medication, besides ICS [e.g., LABA, LAMA, leukotriene receptor antagonist (LTRA), or theophylline].
- Male or eligible female. • A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: o Is a woman of non-childbearing potential (WONCBP) as defined in Section 10.4.1 of the protocol OR o Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4.2 of the protocol from at least 14 days prior to the first dose of study intervention until at least 30 weeks after either: the first dose (if study intervention was permanently discontinued prior to Week 26), or the dose at Week 26. • A WOCBP must have a negative highly sensitive serum pregnancy test at screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5 of the protocol. • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention). • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Informed Consent: Capable of giving signed informed consent/assent as described in Section 10.1 of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. French participants: In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
Exclusion Criteria
- Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes (but is not limited to) current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
- Eosinophilic Diseases: Participants with other conditions that could lead to elevated eosinophils such as hyper-eosinophilic syndromes including (but not limited to) Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly known as Churg-Strauss Syndrome) or Eosinophilic Esophagitis.
- Parasitic Infection: Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are to be excluded.
- Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus – HIV), other than that explained by the use of CSs taken as therapy for asthma.
- Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (Participants that had localised carcinoma of the skin which was resected for cure will not be excluded).
- Liver Disease: Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if participant otherwise meets entry criteria.
- Other Concurrent Medical Conditions: Participants who have known, preexisting, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
- Vasculitis: Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at screening will be evaluated and current vasculitis excluded prior to enrolment.
- COVID-19: Participants that, according to the investigator's medical judgment, are likely to have active COVID-19 infection should be excluded.
- Other mAbs used in the treatment of asthma: Participants who have received omalizumab (Xolair), dupilumab (Dupixent), reslizumab (Cinqair/Cinqaero) or Tezepelumab (Tezspire) within 130 days prior to Visit 1.
- Other mAbs not used for the treatment of asthma: Participants who have received any mAb within 5 half-lives of Visit 1. Authorised treatments for COVID-19 are permitted and should be used in line with local regulatory guidance.
- Investigational Medications: Participants who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to visit 1.
- ECG Assessment: QTcF ≥450msec or QTcF ≥480 msec for participants with Bundle Branch Block in the central over-read 12-lead ECG at screening Visit 1.
- Smoking history: Current smokers or former smokers with a smoking history of ≥20 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). Pipes and/or cigars and/or electronic cigarettes/vaping use cannot be used to calculate pack-year history. Current and former use of these is exclusionary.
- Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
- Hypersensitivity: Participants with allergy/intolerance to a mAb or biologic or any of the excipients of the investigational products listed in section 6.1 of the protocol.
- Pregnancy: Participants who are pregnant or breastfeeding.
- Adherence: Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 26 Jan 2021 | 15 |
 Finland | Not Recruiting | 26 Jan 2021 | 9 |
 France | Not Recruiting | 26 Jan 2021 | 124 |
 Germany | Not Recruiting | 26 Jan 2021 | 198 |
 Ireland | Not Recruiting | 26 Jan 2021 | 12 |
 Italy | Not Recruiting | 26 Jan 2021 | 138 |
 The Netherlands | Not Recruiting | 26 Jan 2021 | — |
 Norway | Not Recruiting | 26 Jan 2021 | 9 |
 Portugal | Not Recruiting | 26 Jan 2021 | 10 |
 Slovenia | Not Recruiting | 26 Jan 2021 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
A placebo matching Mepolizumab | Placebo | N/A | — | — | — | N/A |
Nucala 100 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 100 | 52 | PRD7486574 |
A placebo matching Depemokimab, GSK3511294 | Placebo | N/A | — | — | — | N/A |
Placebo for benralizumab for clinical trials is a sterile liquid solution presented in an accessorized prefilled syringe (apfs) for subcutaneous injection | Placebo | N/A | — | — | — | N/A |
Nucala 100 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 100 | 52 | PRD7486576 |
Fasenra 30 mg solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 30 | 52 | PRD5759004 |