Open-Label Extension Of Intravenous Mepolizumab In Patients With Hypereosinophilic Syndrome

Study Overview
=================
Brief Summary
-----------------
This is an open label study of mepolizumab 750 mg intravenous in those subjects who participated in study 100185 to evaluate the long term safety and efficacy of mepolizumab in subjects with hypereosinophilic syndrome. The study will also evaluate the optimal dosing frequency for clinical use, the effects on corticosteroid reduction, and decrease of signs and symptoms of Hypereosinophilic Syndrome.

Official Title
-----------------
An Open Label Extension Study to Evaluate Safety and Efficacy of Mepolizumab in Patients With Hypereosinophilic Syndromes

Conditions
-----------------
Hypereosinophilic Syndrome

Intervention / Treatment
-----------------
* Drug: mepolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Signed informed consent. Subjects who have participated in Study MHE100185 and have been administered at least 2 doses of study medication. Not pregnant or nursing Of non-childbearing potential (i.e., women who had a hysterectomy, are post-menopausal which is defined as 1 year without menses, have both ovaries surgically removed, or have current documented tubule ligation); or Of childbearing potential (i.e., women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea [even severe], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at the Screening Visit, and agree to one of the following:1). Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of investigational product until 3 months after the last dose of investigational product; Or 2). Consistent and correct use of one of the following acceptable methods of birth control for one month prior to the start of the investigation product and three months after the last dose:Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subjects; Implants of levonorgestrel;Injectable progestogen;Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; Oral contraceptives (either combined or progestogen only) Exclusion criteria: Has developed life-threatening or other serious illness or clinical manifestation deemed inappropriate for inclusion in study per the principal investigator Has any of the following abnormal laboratory values at the Week36/EW Visit of Study MHE100185: • Serum creatinine ≥3 times institutional upper limit normal (ULN); • AST or/ALT ≥5 times institutional ULN; • Platelet count < 50,000/uL Has developed abnormal cardiac functions, as the following, within past 3 months:• Left ventricular ejection fraction (LVEF) < 20%; • NYHA class IIIb or IV; • Angina or acute myocardial infarction Has developed allergic reaction to Study MHE100185 investigational product Use of an investigational drug as concurrent medication Does not complete Week36/EW Visit assessments required in Study MHE100185 Has completed or been terminated from Study MHE100185 for more than 1 month Recent history or suspicion of current drug abuse or alcohol abuse within the last 6 months Positive pregnancy test at the Week36/EW Visit of Study MHE100185

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mepolizumab<br>750mg Intravenous, monthly and individual dosing schedule | Drug: mepolizumab<br>* Study Drug<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) During the Treatment Phase | An AE is any untoward medical occurrence in clinical investigation participants temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs are summarized by Treatment phase. Safety and tolerability of the study drug was assessed by number of participants with any AE | From the first dose of study medication up to 7 days after the last dose (up to approximately 6 years) | 
| Number of Participants With Any Adverse Event (AE) During the Follow-up Phase | An AE is any untoward medical occurrence in clinical investigation participants temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs are summarized by Follow-up phase. Safety and tolerability of the study drug was assessed by number of participants with any AE | From end of Treatment Phase up to 97 days after the last dose date (up to approximately 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving a Prednisone Level of =<10 mg (as Sole Background Therapy) at the End of Study | Participants who were receiving a prednisone dose level of =<10 mg as their sole background therapy at the end of the study were included for the analysis. | up to approximately 6 years | 
| Number of Participants Achieving an Eosinophil Level of < 600 Cell/Microliter (uL) (in Addition to the Lowest Background Therapy) at the End of Study | The criteria for eosinophil count was achieved if the participant's eosinophil count remained below <600 cell/uL for the last observation on study i.e. within length of dosing cycle + 7 days of last dose of study drug. For participants who entered in Stage 1, HES medications taking prior to the first infusion date in Stage 2 were considered as the lowest background therapy. For participants who entered in Stage 2, HES medications taken on the date that immediately preceded the first infusion date of study drug and had not been discontinued was regarded as the lowest background therapy. If the dose of the lowest background therapy had increased or the medication had changed or the participant had not reached their lowest background therapy, the participant was regarded as not achieving this endpoint. | up to approximately 6 years | 
| For Those Participants Who Completed 9 Months of Dosing in Study MHE100185 and Achieved a Prednisone Level <=10 mg: Number of Participants Achieving <= 10 mg Prednisone (as Sole Background Therapy) for >= 3months | Participants from study MHE100185 who completed the 9 months treatment period and achieved a level of <=10 mg of prednisone at study end were analyzed. Duration of doses <=10 mg was determined by examining changes in the prednisone dosing or allowable alternative corticosteroid medication (prednisone equivalents). Start and stop dates of other HES medications were checked to ensure that they did not overlap with the steroid dosing dates. If it did, then the number of days <=10 mg during this overlap was considered as zero and the cumulative days reset to zero, as the endpoint was assessing prednisone dose as sole background therapy. The dosing criteria for this endpoint was considered as achieved if the duration of dosing was minimum of 84 days (3months). | up to approximately 6 years | 
| For Those Participants Who Completed 9 Months of Dosing in Study MHE100185 and Achieved a Prednisone Level >10 mg: Number of Participants Achieving <=10 mg Prednisone (as Sole Background Therapy) for >= 8 Weeks | Participants from study MHE100185 who completed the 9 months treatment period and achieved a level of prednisone of >10 mg at the end of the study were analyzed. Duration of doses <= 10 mg were determined by examining changes in the prednisone dosing or allowable alternative corticosteroid medication (prednisone equivalents). Start and stop dates of other HES medications were checked to ensure that they did not overlap with the steroid dosing dates. If overap occurred, then the number of days <=10 mg during this overlap was considered as zero and the cumulative days reset to zero, as the endpoint was assessing prednisone dose as sole background therapy. The dosing criteria for this endpoint was considered as achieved if the duration of dosing was minimum of 53 days (8 weeks). | up to approximately 6 years | 
| For Those Participants Who Entered Stage 2 From Study MHE100185 With a Prednisone Level of <=10 mg Prednisone: Number of Participants Achieving a Prednisone Dose <=10 mg (as Sole Background Therapy) for >=3 Months; | Participants from study MHE100185 who completed the 9 months treatment period and achieved a level of <=10 mg of prednisone at study end and participants who withdrew from the study early who were at a prednisone dose level <=10 mg were analyzed. Duration of doses <= 10 mg were determined by examining changes in the prednisone dosing or allowable alternative corticosteroid medication (prednisone equivalents). Start and stop dates of other HES medications were checked to ensure that they did not overlap with the steroid dosing dates. If overlap occurred, then the number of days <=10 mg during this overlap was considered as zero and the cumulative days reset to zero, as the endpoint was assessing prednisone dose as sole background therapy. The dosing criteria for this endpoint was considered as achieved if the duration of dosing was minimum of 84 days (3months). | up to approximately 6 years | 
| For Those Participants Who Entered Stage 1 From Study MHE100185 With >10 mg Prednisone: Number of Participants Achieving a Prednisone Dose <=10 mg (as Sole Background Therapy) for>=3 Months | Participants from study MHE100185 who completed the 9 months treatment period and achieved a level of >10 mg prednisone at the end of the study and participants who withdrew from the study early who were at a prednisone dose level >10 mg were analyzed. Duration of doses <= 10 mg was determined by examining changes in the prednisone dosing or allowable alternative corticosteroid medication (prednisone equivalents). Start and stop dates of other HES medications were checked to ensure that they do not overlap with the steroid dosing dates. If it did, then the number of days <=10 mg during this overlap was considered as zero and the cumulative days reset to zero, as the endpoint was assessing prednisone dose as sole background therapy. The dosing criteria for this endpoint was considered as achieved if the duration of dosing was minimum of 84 days (3months) | up to approximately 6 years | 
| Blood Eosinophil Count (With Consideration of the HES Background Therapy) During Stages 1-3 | Mean blood eosinophil counts were summarized over time taking into account the effect of HES background therapy. Eosinophil count observations for only those participants taking mepolizumab in conjunction with prednisone or as monotherapy were included. | up to approximately 6 years | 
| Number of Participants by Dosing Frequency Groups (Defined as Two Week Dosing Ranges Greater Than a 4 Week Interval) at the End of Stage 2 | The number of participants at the end of Stage 2 with study medication dosing frequencies of 4 weeks, 5-6 weeks, 7-8 weeks, 9-10 weeks, 11-12 weeks, 13-16 weeks, 17-20 weeks, 21-24 weeks and >24 weeks were summarized. The first infusion date in Stage 3 and the last infusion date in Stage 2 were used to calculate the dosing frequency. | up to approximately 6 years | 
| Change From Baseline in the Pruritus Visual Analogue Scale (pVAS) 3 Months After the Start of Study MHE100901 and Every 6 Months Thereafter | The pruritus visual analogue scale asks participants to rate the status of their Pruritus based on the severity of their itch. Scores range from 0-100 with 0 = No itch and 100 = Worst imaginable itch. Change from Baseline in pVAS score is the difference between the pVAS score at the time point being considered to the MHE100901 Baseline score. | Baseline and up to approximately 6 years | 
| Change From Baseline in Erythema/Edema Score 3 Months After the Start of Study MHE100901 and Every 6 Months Thereafter | The erythema subscale score and edema subscale score are each graded on a 0-3 scale, with 0 = absent , 1 = mild, 2 = moderate, 3 = severe. The total score ranged from 0 to 6, with higher scores indicative of more severe Erythema/Edema. The total score was obtained by summing together the responses for each of the two subscale items. Change from Baseline in erythema/edema total score is the difference between erythema/edema total score at the time point being analyzed to the MHE100901 Baseline score.. | Baseline and up to approximately 6 years | 
| Change From Baseline in Quality of Life (QoL) and Current Health Status: Physical Summary Score of the Study Short Form Health Survey (SF-12) 3 Months After the Start of Study MHE100901 and Every 6 Months Thereafter | The SF-12v2 is the 12 item abbreviated form of SF-36v2 survey . It provides information about how participants feel, and how well they have been able to perform their usual activities, over the past 4 weeks. SF-12v2 questions make up 8 scales: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, Mental Health . Transformed physical component summary score (PCS-12) is derived using all the 12 items and scored onto a 0-100 scale such that a higher score indicates a better health state and better functioning. Change from Baseline in scale or summary measure score is the difference between the score at the time point being analyzed to Baseline. | Baseline and up to approximately 6 years | 
| Change From Baseline in QoL and Current Health Status: Mental Summary Score of the SF12 3 Months After the Start of Study MHE100901 and Every 6 Months Thereafter | The SF-12v2 is the 12 item abbreviated form of SF-36v2 survey developed by the Medical Outcomes Trust and QualityMetric Incorporated. It provides information about how participants feel, and how well they have been able to perform their usual activities, over the past 4 weeks. SF-12v2 scale questions make up 8 scales: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, Mental Health are for mental component summary. Transformed mental component summary score (MCS-12) is derived using all the 12 items and scored onto a 0-100 scale such that a higher score indicates a better health state and better functioning. Change from Baseline in scale or summary measure score is the difference between the score at the time point being analyzed to Baseline. | Baseline and up to approximately 6 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mepolizumab, Open-label, Anti-IL-5, Hypereosinophilic Syndrome, Hypereosinophilia