Study of mepolizumab vs. placebo in patients with HES who receive standard therapy

Phase 1

• Conditions: severe hypereosinophilic syndrome; MedDRA version: 20.0 Level: PT Classification code 10048643 Term: Hypereosinophilic syndrome System Organ Class: 10005329 - Blood and lymphatic system disorders; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2014-001232-11-GB
• Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-09-05
• Last Update Posted: 16 December 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 120

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 m

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control of HES symptoms during the treatment period.;Secondary Objective: To demonstrate supportive evidence of the benefit of mepolizumab compared with placebo based on other measures of efficacy.;Primary end point(s): Proportion of subjects who experience an HES flare during the 32-week study treatment period;Timepoint(s) of evaluation of this end point: During 32 weeks starting randomization

Secondary Outcome Measures

Name	Time	Method
<br> Secondary end point(s): (1) Time to first HES flare;<br> (2) Proportion of subjects who experience an HES flare during Week 20 through Week 32;<br> (3) Rate of HES flares;<br> (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<br> ;<br> Timepoint(s) of evaluation of this end point: (1) & (3) During 32 weeks starting randomization;<br> (2) During 20-32 weeks after randomization;<br> (4) At 32 weeks after randomization<br>