E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe hypereosinophilic syndrome |
|
E.1.1.1 | Medical condition in easily understood language |
Hypereosinophilic syndrome (HES) |
|
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 | 20.0 |
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 |
|
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 demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control of HES symptoms during the treatment period. |
|
E.2.2 | Secondary objectives of the trial |
To demonstrate supportive evidence of the benefit of mepolizumab compared with placebo based on other measures of efficacy. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
INFORMED CONSENT
1.Capable of giving signed informed consent/assent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
AGE
2. 12 years of age or older, at the time of signing the informed consent/assent
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
3. Subjects who have been diagnosed with HES for at least 6 months at randomization. HES diagnosis is based on signs or symptoms of organ system involvement and/or dysfunction that can be directly related to:
-blood eosinophilia of >1,500 eosinophils/μL on at least two occasions, and/or
-tissue eosinophilia
documented prior to Visit 2 without a discernible secondary cause
Tissue eosinophilia is defined as a history of one or more of the following:
-The percentage of eosinophils exceeds 20% of all nucleated cells in bone marrow sections.
-In the opinion of a pathologist, tissue infiltration by eosinophils is extensive when compared with the normal physiologic range, compared with other inflammatory cells, or both.
-A specific stain directed against an established eosinophil granule protein reveals extensive extracellular deposition of eosinophilderived proteins indicative of local eosinophil activation
4. A history of two or more HES flares within the past 12 months prior to screening. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy. At least one 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. Subjects must have blood eosinophil count ≥1000 cells/μL present in the sample collected during screening (within 4 weeks prior to randomization).
6. Subjects must be on a stable dose of HES therapy for the 4 weeks prior to
randomization. HES therapy includes but is not limited to oralcorticosteroid (OCS), immunosuppressive, and cytotoxic therapy.
SEX
7. Male or female
A female subject is eligible to participate if she is not pregnant, not lactating, and at least one of the following conditions applies:
a. Females of non-reproductive potential (FNRP) defined as:
- Post-menopausal women (including all women over 60 years of age, see below), OR
Pre-menopausal females with one of the following procedures documented and no plans to utilize reproductive techniques (e.g., in vitro fertilization or donor embryo transfer:
- Bilateral tubal ligation or salpingectomy
- Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
- Hysterectomy
- Bilateral Oophorectomy (surgical menopause)
- Post-Menopause
- Females 60 years of age or older
- Menopause is the phase associated with complete cessation of menstrual cycles and implies the loss of reproductive potential by ovarian failure. This typically occurs around 50 years of age, although it may occur earlier or later. A practical definition accepts menopause after 1 year without menses with an appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g., leuprolide treatment).
- In questionable cases for women < 60 years of age, a blood sample with simultaneous follicle stimulating hormone and estradiol falling into the central laboratory’s postmenopausal reference range is confirmatory (these levels need to be adjusted for specific laboratories/assays)
- Females under 60 years of age, who are on HRT and wish to continue, and whose menopausal status is in doubt, are required to use a highly effective method to avoid pregnancy, as outlined in the protocol.
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a highly effective method to avoid pregnancy. If laboratory values for FSH and estradiol are drawn and the results do not confirm menopause on a potential subject that otherwise met the specifications for being post-menopausal defined above without question, the subject may still enrol in the study as a FNRP if approved by the GSK Medical Monitor and the safety
physician.
b. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Section 12.5) from 30 days prior to the first
dose of study medication and until 4 months after the last dose of study treatment.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. |
|
E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
1. Life-threatening HES or life-threatening HES co-morbidities: Imminently lifethreatening
HES disease severity such that the likelihood of death is high unless the course of the disease is interrupted within 12 weeks prior to randomization.
2. Other concurrent medical conditions that may affect the subject’s safety:
Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological, respiratory or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.
3. Eosinophilia of unknown clinical significance
4. 12-lead ECG finding:
QTc > 450 msec or QTc > 480 msec in subjects with bundle branch block
An abnormal ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant and would impact the subject’s participation during the study based on the evaluation of the Investigator.
NOTE: 12-lead ECG results at screening with the over-read by the centralized independent cardiologist must be received prior to assessing eligibility at Visit 2 by the Investigator.
5. Subjects with documented history of any clinically significant cardiac damage prior to screening that, in the opinion of the investigator, would impact the subject’s participation during the study.
6. Liver abnormality/disease:
-ALT >2.5xULN or ALT>5xULN if documented HES with liver manifestations
-Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
-Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
NOTE: Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7. Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)
8. Malignancy:
-Subjects with a history of or current lymphoma
-Subjects with current malignancy or previous history of cancer in remission for less than 12 months prior to randomization. Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded
9. FIP1L1-PDGFR alpha Status: Subjects who test positive for the FIP1L1-PDGFR alpha fusion tyrosine kinase gene translocation
Blood sampling is required for all subjects at screening for this test unless the documented result is available
10. Infection:
-Subjects with chronic or ongoing active infections requiring systemic treatment, as well as subjects who have experienced clinically significant infections due to viruses, bacteria, and fungi within 4 weeks prior to randomization
-Subjects with a pre-existing helminthes infestation within 6 months prior to randomization.
11. Subjects with a known immunodeficiency, other than that explained by the use of OCS or other therapy taken for HES
12. Other laboratory abnormalities: Evidence of clinically significant abnormality in the
hematological, biochemical or urinalysis screen from the sample collected at screening, that could put the subject’s safety at risk by participating in the study, as judged by the investigator
CONCOMITANT MEDICATIONS
13. Subjects who have previously received mepolizumab in the 4 months prior to randomization
14. Subjects receiving any of the following:
-Intravenous or subcutaneous corticosteroids in the 4-week period prior to randomization
-Any other monoclonal antibodies within 30 days or 5 half-lives, whichever is longer, of randomization
15. Other investigational product/clinical study:
-Subjects who have received treatment with an investigational agent within the past 30 days or 5 drug half-lives whichever is longer, prior to randomization. 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
-Subjects who are currently participating in any other interventional clinical study
CONTRAINDICATIONS
16. Subjects who are not responsive to OCS based on clinical response or blood eosinophil counts
17. Subjects with any history of hypersensitivity to any monoclonal antibody (including mepolizumab) or any steroid or steroid-containing product.
RELEVANT HABITS
18. Subjects with a known or suspected history of alcohol or substance abuse at screening which in the opinion of the investigator could interfere with the subject’s proper completion of the protocol requirement.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects who experience an HES flare during the 32-week study treatment period |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During 32 weeks starting randomization |
|
E.5.2 | Secondary end point(s) |
(1) Time to first HES flare;
(2) Proportion of subjects who experience an HES flare during Week 20 through Week 32;
(3) Rate of HES flares;
(4) Change from baseline in fatigue severity based on Brief Fatigue Inventory (BFI) item 3 (worst level of fatigue during past 24 hours) at Week 32
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) & (3) During 32 weeks starting randomization;
(2) During 20-32 weeks after randomization;
(4) At 32 weeks after randomization
|
|
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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Brazil |
France |
Germany |
Italy |
Mexico |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
United Kingdom |
United States |
|
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |