E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypereosinophilic Syndrome (HES) |
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E.1.1.1 | Medical condition in easily understood language |
Hypereosinophilic Syndrome (HES) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10048643 |
E.1.2 | Term | Hypereosinophilic syndrome |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of depemokimab 200mg subcutaneous (SC) given every 6 months versus placebo in participants with uncontrolled HES receiving standard of care (SoC) |
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E.2.2 | Secondary objectives of the trial |
To assess supportive evidence of the efficacy of depemokimab 200mg SC given every 6 months versus placebo on multiple clinical outcomes in participants with uncontrolled HES receiving SoC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participant must be ≥18 years of age, at the time of signing the informed consent.
2. Participants who are ≥40 kg at Screening Visit 1.
3. Participants who have a documented diagnosis of HES prior to Visit 2. HES diagnosis is based on:
• blood eosinophilia of >1,500 eosinophils/μL on at least 2 occasions at ≥1 month interval, without a discernible non haematological secondary cause, and
• signs or symptoms of organ involvement and/or dysfunction that can be directly related to eosinophilia
4. Flare history: A history of 2 or more HES flares within the past 12 months prior to Visit 1. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an addition or escalation in OCS or cytotoxic/immunosuppressive therapy. At least 1 HES flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
5. Male or female participants
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
• Is a woman of non-childbearing potential (WONCBP) as defined in protocol Section 10.4, Appendix 4
OR
• 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, Appendix 4, from at least 14 days prior to the first dose of study intervention until at least 30 weeks after the last administered dose of study intervention. The Investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
6. Capable of giving signed informed consent as described in protocol Section 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. |
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E.4 | Principal exclusion criteria |
1. HES disease manifestations which in the opinion of the Investigator may put the participant at unacceptable risk from study participation or confound interpretation of efficacy or safety data. Specific consideration should be given to the participant’s ability to comply with protocol requirements, including the list of prohibited therapies; exclusion criteria no. 13 - 16.
2. Infection:
• Participants with chronic or ongoing active infections requiring systemic treatment.
• Participants with a pre-existing parasitic infestation within 6 months prior to Visit 1.
3. Immunodeficiency: Participants with a known immunodeficiency (e.g., HIV), other than that explained by the use of oral corticosteroid (OCS) or other therapy taken for HES.
4. Malignancy:
• Participants with a history of or current lymphoma.
• Participants with current malignancy or previous history of cancer in remission for less than 5 years prior to Visit 1. Participants that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded.
• Participants with a haematologic malignancy with hypereosinophilia in which HES is not the primary diagnosis, e.g., chronic myeloid leukaemia, myelodysplastic syndrome, chronic eosinophilic leukaemia-not otherwise specified.
5. 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) is acceptable if participant otherwise meets entry criteria.
6. Cardiovascular: Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment.
7. Vasculitis: Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at Screening will be evaluated and current vasculitis must be excluded prior to randomization.
8. Eosinophilia of unknown significance: Hypereosinophila with no clinical symptoms and/or proof of organ dysfunction.
9. Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA).
10. COVID-19: Participants that, according to the Investigator's medical judgment, are likely to have active COVID-19 infection should be excluded. Participants with known COVID-19 positive contacts within the past 14 days must be excluded for at least 14 days following the exposure during which the participant must remain symptom-free.
11. Other concurrent medical conditions that may affect the participant’s safety: Participants who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, cardiac or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.
12. Hypersensitivity: Participants with an allergy/ intolerance to a monoclonal antibody or biologic, or any of the excipients of the investigational product in protocol Section 6.1.
13. Monoclonal antibodies (mAb) targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy, based on
investigator's discretion.
14. mAbs: Participants who have received mAb within 30 days or 5 half-lives, whichever is longer, prior to Visit 1 (other than approved mAbs for
the treatment of COVID-19). If a participant has been treated with and responsive to biologics for HES, the participant should not stop the treatment for study eligibility purpose.
15. Non oral systemic corticosteroids: Participants who have received intravenous, intramuscular, or subcutaneous corticosteroids within 4-weeks prior to Visit 2.
16. Investigational medications/clinical study:
• Participants who have received treatment with an investigational agent within 30 days or 5 drug half-lives whichever is longer, prior to Visit 1. The term “investigational” applies to any drug not approved for sale in the country in which it is being used or investigational formulations of marketed products.
• Participants who are currently participating in any other interventional clinical study.
17. FIP1L1-PDGFRα Status: Participants who test positive for the FIP1L1-PDGFRα fusion gene (i.e., participants with the myeloid-variant
HES are excluded).
Blood sampling is required for all participants at Screening (Visit 1) for this test unless the documented result is available.
18. ECG Assessment: QTcF ≥450 msec or QTcF ≥480 msec for participants with Bundle Branch Block at Screening Visit 1.
19. OCS responsiveness: Participants who are not responsive to OCS based on clinical response or blood eosinophil counts in the opinion of the Investigator.
20. Alcohol/Substance Abuse
21. Pregnancy
22. Adherence: Please see protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Frequency of HES flares during the 52-week study intervention period |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Defined within the primary endpoint description |
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E.5.2 | Secondary end point(s) |
• Time to first HES flare (days)
• At least one HES flare during the 52-week study intervention period
• Change from Baseline to Week 52 in weekly average score of Brief Fatigue Inventory (BFI) item 3 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Defined within the secondary endpoints description |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
United Kingdom |
United States |
Belgium |
Czechia |
Denmark |
Germany |
Italy |
Poland |
Portugal |
Romania |
Spain |
Türkiye |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |