Dose Ranging Pharmacokinetics and Pharmacodynamics Study With Mepolizumab in Asthma Patients With Elevated Eosinophils

NCT01366521 | Completed Phase 2 Results

• 1 other identifier: 114092
• Study Type: interventional
• Target: 70
• Locations: 4 countries
• Sites: 11

Brief Summary

A multi-center, randomized, open-label, parallel-group, repeat dose study in asthma patients with elevated eosinophils. Eligible subjects will receive 3 doses (28 days apart) of mepolizumab given intravenous (IV) or subcutaneously (SC). Blood samples for safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity analysis, as well as safety/tolerability assessments will be collected throughout the study

Conditions

Asthma

Outcome Measures

Primary Outcomes (9)

• Change From Baseline in Blood Eosinophil Levels at Week 12 (Day 84)

  Change from Baseline in blood eosinophils was calculated as the post-Baseline value minus the Baseline value. The change from Baseline in log-transformed blood eosinophil levels at Week 12 was analyzed using both a linear and non-linear (Imax) dose response models. The dose response was found to be non-linear and hence only the results of the non-linear model are presented. Mepolizumab 75mg IV assumed to equate to 100 mg SC within model. Prior to log10-transformation, zero values were imputed with half the minimum value across all dose groups and time points. An adjustment for Baseline eosinophil count was also incorporated into the model.

  Baseline (Day 1 pre-dose) and Week 12

• Area Under the Blood Eosinophil Time Curve (AUEC) up to Day 84

  Area under the absolute blood eosinophil time curve to Day 84 (AUECeos\[0-day 84\]) determined using the linear trapezoidal rule for subset of participants with blood eosinophil data to Day 84. Blood samples for the analyses of AUEC(eos) (0-day 84) were collected at Days 1, 3, 7, 28, 56, 70 and 84.

  Days 1, 3, 7, 28, 56, 70 and 84

• Maximum Change From Baseline in Blood Eosinophils (Emax)

  Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 to assess the maximum reduction from Baseline in blood eosinophils between Day 1 pre-dose and last quantifiable study measurement. Change from Baseline was calculated as the ratio of the post-Baseline value divided by the Baseline value. The maximum reduction from Baseline in eosinophils is represented by the minimum ratio to Baseline.

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Time to Maximum Change in Blood Eosinophils Levels (Tmaxeos)

  Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 to assess the time to first occurrence of maximum reduction from baseline in blood eosinophil levels between Day 1 pre-dose and last quantifiable study measurement.

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Number of Participants Who Achieved >=50% Eosinophil Repletion by Day 140

  This summarizes the number of participants who returned to at least 50% of their Baseline blood eosinophil levels after maximum inhibition had been achieved and without any subsequent decrease in blood eosinophil levels. Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140.

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Mean Area Under the Plasma-concentration Time Curve (AUC) Following SC and IV Administration of Mepolizumab

  AUC of mepolizumab was estimated by population modeling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Individual cumulative plasma of mepolizumab AUC to Day 84 (cumAUC(0-day 84)), is the sum of the AUCs over each dosing interval after each of the three doses administered, for those participants with data up to Day 84. Individual cumulative plasma of mepolizumab AUC to Day 140 (cumAUC(0-day 140) is the sum of the AUCs over each dosing interval after each of the three doses administered plus the AUC post the last dose interval up to Day 140 (i.e. from Day 84 to Day 140). Blood samples for PK analyses were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 hour (h), 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit).

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Maximum Plasma Concentration (Cmax) From Pre-dose (Day 1) to Day 140 for Mepolizumab

  Maximum plasma concentration was estimated by population modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit).

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Time to Maximum Plasma Concentration (Tmax) From Pre-dose (Day 1) to Day 140 for Mepolizumab

  Time to maximum plasma concentration was estimated by population modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit).

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

• Terminal Half-life (t½) From Pre-dose (Day 1) to Day 140 for Mepolizumab

  Terminal half-life (t1/2) was estimated by modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters for mepolizumab from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit).

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140

Secondary Outcomes (8)

• Number of Participants With Clinical Chemistry Parameters Outside the Normal Range Following Treatment

  Baseline (Day 1 pre-dose), Weeks 4, 8, 12 and 20

• Number of Participants With Hematology Laboratory Parameters Outside the Normal Range at Following Treatment

  Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 (follow-up visit)

• Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Assessed at Baseline, Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140

  Baseline (Day 1 pre-dose) and at Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140

• Change From Baseline in Heart Rate Assessed at Baseline, Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140

  Baseline (Day 1 pre-dose) and at Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140

• Number of Participants With Levels of Anti-mepolizumab Antibodies at Indicated Time Points

  Day 1, Day 112 and Day 140

Study Arms (4)

Mepolizumab 250 mg subcutaneous (SC)

EXPERIMENTAL

250 mg subcutaneous (SC)

Biological: Mepolizumab

Mepolizumab 125 mg subcutaneous (SC)

EXPERIMENTAL

125 mg subcutaneous (SC)

Biological: Mepolizumab

Mepolizumab 12.5 mg subcutaneous (SC)

EXPERIMENTAL

12.5 mg subcutaneous (SC)

Biological: Mepolizumab

Mepolizimab 75 mg intravenously (I.V.)

EXPERIMENTAL

75 mg intravenously (I.V.)

Biological: Mepolizumab

Interventions

Mepolizumab BIOLOGICAL

Monoclonal antibody

Mepolizimab 75 mg intravenously (I.V.); Mepolizumab 12.5 mg subcutaneous (SC); Mepolizumab 125 mg subcutaneous (SC); Mepolizumab 250 mg subcutaneous (SC)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or eligible females between 18 and 65 years of age inclusive, at the time of signing the informed consent; Non-childbearing potential is defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<147 pmol/L) is confirmatory\]. To be eligible for entry into the study, females of child-bearing potential and females whose menopausal status is in question must commit to consistent and correct use of an acceptable method of birth control as defined in Section 7.1.1 from one month prior to the first dose of investigational product until 4 months after the last dose of investigational product.
• History of asthma for at least one year.
• Subjects must be on a stable dose of an inhaled corticosteroid or combination (ICS+LABA) therapy for at least 12 weeks prior to screening.
• FEV1≥45% and \<90 % of predicted normal value during screening (obtained between 6:00 AM and 1:00 PM).
• Evidence of airway reversibility (FEV1≥12%) within 30 minutes of inhalation of albuterol OR airway hyperresponsiveness (PC20 of \<8mg/mL or PD20 of \<7.8 µ mol methacholine/histamine) documented in the 12 months prior to randomization.
• Subjects with documented evidence of elevated blood eosinophilia levels (\>0.3 cells 109/L) within 12 months of screening and evidence of elevated blood eosinophilia levels (\>0.3 cells 109/L) at screening.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

You may not qualify if:

• QTcF ≥450 msec; or QTcF ≥ 480 msec in subjects with Bundle Branch Block.
• AST, ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin \<1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin ≥35%).
• Subjects with elevated blood eosinophil levels which is not related to asthma
• Current smokers (any subject who has smoked within the six months prior to screening or has a positive urine cotinine at screening) or subjects with a smoking history of \>10 pack years calculated as follows:
• Number of cigarettes per day X number of years smoked 20
• Presence of a clinically important lung condition other than asthma including current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, Churg-Strauss syndrome, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
• An asthma exacerbation or respiratory tract infection within six weeks prior to screening (an exacerbation is defined as worsening asthma requiring the use of systemic corticosteroids and/or emergency department visit, hospitalisation).
• Subjects with a parasitic infestation within six months of screening.
• A current malignancy or previous history of cancer in remission for less than five years prior screening (except for localized carcinoma of the skin that has been resected for cure).
• Subjects who have clinically significant cardiovascular, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Subjects with a known immunodeficiency (e.g. human immunodeficiency virus - HIV).
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within three months of screening.
• Subjects who have received omalizumab \[Xolair\] within 130 days of administration of the first dose of study medication.
• Subjects with recent history (within two years prior to screening) of alcohol misuse or substance abuse prior screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (11)

GSK Investigational Site

Winston-Salem, North Carolina, 27103, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15213, United States

Location

GSK Investigational Site

Tallinn, 13619, Estonia

Location

GSK Investigational Site

Tartu, 51014, Estonia

Location

GSK Investigational Site

Marseille, 13915, France

Location

GSK Investigational Site

Montpellier, 34295, France

Location

GSK Investigational Site

Pessac, 33604, France

Location

GSK Investigational Site

Gauting, Bavaria, 82131, Germany

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60596, Germany

Location

GSK Investigational Site

Magdeburg, Saxony-Anhalt, 39112, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 14050, Germany

Location

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Asthma

Interventions

mepolizumab

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2011
• First Posted: June 6, 2011
• Study Start: February 1, 2011
• Primary Completion: March 1, 2012
• Study Completion: March 1, 2012
• Last Updated: January 11, 2017
• Results First Posted: December 10, 2015

Record last verified: 2016-11

Data Sharing

• IPD Sharing: Will share

Locations

ES (2); FR (3); DE (4); US (2)