Phase 4 Study of Mepolizumab 100 Milligram (mg) Subcutaneous (SC) in Indian Subjects Aged >=18 Years With Severe Eosinophilic Asthma Requiring Maintenance Oral Corticosteroids

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04276233

Collaborator

Tech Observer (Other)

100

Enrollment

Locations

Arm

28.8

Anticipated Duration (Months)

7.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Mepolizumab is a humanized monoclonal antibody (IgG1, kappa) that blocks interleukin-5 (IL-5) thus inhibits production and survival of eosinophils. The aim of this phase 4, open-label, single-arm study is to evaluate the safety and efficacy of Mepolizumab 100 mg SC administered every 4 weeks in Indian subjects aged 18 years or above with severe eosinophilic asthma requiring oral corticosteroid (OCS) treatment to maintain asthma control. The study consists of four phases, OCS Optimization Phase (Week -8 to Week -3), an Induction Phase (Week 0 to Week 4), OCS Reduction Phase (Week 4 to Week 20) followed by Maintenance Phase (Week 20 to Week 24). In the Induction Phase subjects will be administered mepolizumab 100 mg subcutaneously every 4 weeks along with their Baseline asthma medications. This phase will allow sufficient time for subjects to achieve a decrease in the eosinophilic inflammation prior to the reduction in OCS. During the Optimization Phase, the investigator will adjust the OCS (prednisone/prednisolone) dose according to the Optimization titration schedule based on a review of Asthma Control Questionnaire (ACQ)-5 score and exacerbation. During the Reduction Phase, subjects will continue to receive 100 mg mepolizumab every 4 weeks and the OCS dose reduction will be done every 4 weeks using the reduction titration schedule based on a review of eDiary parameters recorded by the subject, the subjects' exacerbation history, and a review of the signs and symptoms of adrenal insufficiency. In the Maintenance Phase, subjects will be maintained during the last 4-weeks of the study without any further OCS dose adjustment.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Prednisone/ Prednisolone Biological: Mepolizumab Drug: Salbutamol	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single arm studySingle arm study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 4, Open-label, Single Arm, 24-week, Phase 4 Study to Evaluate the Safety and Efficacy of Mepolizumab 100 mg SC Administered Every 4 Weeks in Indian Participants Aged >=18 Years With Severe Eosinophilic Asthma Requiring Oral Corticosteroid Treatment to Maintain Asthma Control (PRISM)

Actual Study Start Date :

Jun 29, 2021

Anticipated Primary Completion Date :

Nov 24, 2023

Anticipated Study Completion Date :

Nov 24, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subject severe eosinophilic asthma Subjects with severe eosinophilic asthma will receive Mepolizumab 100 mg subcutaneously into the upper arm or thigh every 4 weeks for a period of 24 weeks (total of 6 doses) along with oral corticosteroid (OCS) as part of their standard of care. Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.	Drug: Prednisone/ Prednisolone Prednisone/prednisolone will be available as 5 mg tablet to be administered via oral route as per prescribed titration regimen. Biological: Mepolizumab Mepolizumab will be available as a lyophilized cake in sterile vials and will be reconstituted with sterile water for injection, just prior to use. Drug: Salbutamol Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.

Arm

Intervention/Treatment

Experimental: Subject severe eosinophilic asthma

Subjects with severe eosinophilic asthma will receive Mepolizumab 100 mg subcutaneously into the upper arm or thigh every 4 weeks for a period of 24 weeks (total of 6 doses) along with oral corticosteroid (OCS) as part of their standard of care. Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.

Drug: Prednisone/ Prednisolone

Prednisone/prednisolone will be available as 5 mg tablet to be administered via oral route as per prescribed titration regimen.

Biological: Mepolizumab

Mepolizumab will be available as a lyophilized cake in sterile vials and will be reconstituted with sterile water for injection, just prior to use.

Drug: Salbutamol

Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.

Outcome Measures

Primary Outcome Measures

Number of subjects with adverse events and serious adverse events [Up to Week 24]
An adverse event is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward medical occurrence resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as serious adverse event.
Number of subjects with abnormal physical examination findings [Up to Week 24]
Physical examination parameter includes measurement of height and weight, assessment of the skin, cardiovascular, respiratory, gastrointestinal, neurological systems and abdomen (liver and spleen) and examination for presence of nasal polyps will be performed.
Number of subjects with abnormal body temperature [Up to Week 24]
Oral/axillary temperature will be assessed.
Number of subjects with abnormal pulse rate [Up to Week 24]
Pulse rate will be assessed in a sitting position after 5 minutes of rest for the subject with an automated device.
Number of subjects with abnormal respiratory rate [Up to Week 24]
Respiratory rate will be assessed.
Number of subjects with abnormal blood pressure [Up to Week 24]
Systolic blood pressure and diastolic blood pressure will be assessed in a sitting position after 5 minutes of rest for the subject with an automated device.
Number of subjects with abnormal 12 lead electrocardiogram (ECG) values [Up to Week 24]
Twelve-lead ECG will be performed with the subject in a supine position after a rest of at least 5 minutes using an automated ECG machine which will calculate heart rate and measure PR, QRS, QT, and corrected QT intervals.
Number of subjects with abnormal hematology parameters [Up to Week 24]
Blood samples will be collected from subjects for the analysis of hematology parameters as a measure of safety, including platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, percent reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils.
Number of subjects with abnormal clinical parameters [Up to Week 24]
Blood samples will be collected from subjects for the analysis of clinical chemistry parameters as a measure of safety, including blood urea nitrogen, potassium, aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase, total bilirubin, direct bilirubin, creatinine, sodium, alanine aminotransferase/ serum glutamic-pyruvic transaminase, total protein, glucose, calcium and alkaline phosphatase.
Number of subjects with abnormal urine analysis [Baseline]
Urine samples will be collected from subjects for the analysis of urinalysis parameters as a measure of safety, including specific gravity and potential of hydrogen (pH) of urine, presence of glucose, protein, blood, ketones, bilirubin, urobilinogen in urine by dipstick test. Microscopic examination will be performed if blood or protein is abnormal.

Secondary Outcome Measures

Percentage of subjects achieving 50% reduction in OCS dose in Weeks 20 to 24 [Baseline and Weeks 20 to 24]
Percentage of subjects achieving 50% reduction in OCS dose during Weeks 20 to 24 will be summarized.
Frequency of clinical significant exacerbations [Up to Week 24]
Clinically significant exacerbations of asthma will be defined as the worsening of asthma which requires use of systemic corticosteroids. Frequency of clinical significant exacerbations including exacerbation requiring hospitalization or emergency department visits will be summarized.
Mean change from Baseline in clinic pre and post-bronchodilator forced expiratory volume in one second (FEV1) at Week 24 [Baseline and Week 24]
FEV1 is defined as the volume of air that can be forced out in one second after taking a deep breath by a person. Change from Baseline in clinic pre and post-bronchodilator FEV1 will be determined.
Mean change from Baseline in Asthma control questionnaire-5 (ACQ-5) score at Week 24 [Baseline and Week 24]
ACQ-5 is a questionnaire includes a five question about the frequency and/or severity of asthma symptoms (nocturnal awakening on waking in the morning, activity limitation, and shortness of breath, wheeze). The response options for all the questions consist of a zero (no impairment/limitation) to six (total impairment/ limitation) scale. Change of ACQ-5 scores from Baseline will be determined.
Mean change from Baseline in morning peak expiratory flow (PEF) in Weeks 20 to 24 [Baseline and Weeks 20 to 24]
PEF is defined as a person's maximum speed of expiration. Change from Baseline in morning PEF during Weeks 20 to 24 will be determined.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
Asthma: Evidence of asthma as documented by either: (a) Airway reversibility (FEV1>=12% and 200 milliliter (ml) demonstrated at Visit 1, Visit 2 or Visit 3 OR documented in the previous 12 months OR (b) Airway hyperresponsiveness (methacholine: PC20 of <8mg/mL or histamine: PD20 of <7.8 μmol; mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 12 months prior to Visit 3 OR (c) Airflow variability in clinic FEV1 >=20% between two consecutive clinic visits documented in the 12 months prior to Visit 3 (FEV1 recorded during an exacerbation should not be considered for this criteria) OR (d) Airflow variability as indicated by

20% diurnal variability in peak flow observed on 3 or more days during the optimization period.

Subjects with Eosinophilic asthma: prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as FEV1: Persistent airflow obstruction as indicated by: (a) For subjects >=18 years of age at Visit 1, Visit 2, or Visit 3, a pre-bronchodilator FEV1 <80% predicted. (b) For subjects 12 to 17 years of age at Visit 1, Visit 2, or Visit 3, a pre-bronchodilator FEV1 <90% predicted OR FEV1:Forced expiratory volume (FVC) ratio < 0.8. For predicted FEV1 values National Health and Nutrition Examination Survey (NHANES) III values will be used and adjustments to these values will be made for race.
Eosinophilic Phenotype: Airway inflammation characterized as eosinophilic in nature as indicated by one of the following characteristics: (a) An elevated peripheral blood eosinophil level of >=300 cells/microliter(μL) that is related to asthma within the previous 12 months prior to Visit 3. OR (b) Peripheral baseline eosinophil level >=150 cells/μL between Visit 1 and Visit 3 that is related to asthma.
Systemic Corticosteroids: Subjects with severe asthma and requirement for regular treatment with maintenance systemic corticosteroids in the 6 months prior to Visit 1 and using a stable oral corticosteroid dose for 4 weeks prior to Visit 1. Subjects must be taking 5.0 to 35 mg/day of prednisone or equivalent at Visit 1 and must agree to switch to study required prednisone/prednisolone as their oral corticosteroid and use it per protocol for the duration of the study.
Inhaled Corticosteroids: requirement for regular treatment with high dose inhaled corticosteroid in the 6 months prior to Visit 1. For 18 years of age and older: Inhaled corticosteroids (ICS) dose must be >=880 microgram (mcg)/day fluticasone propionate (FP) (ex-actuator) or equivalent daily. For ages 12 to 17: ICS dose must be

=440 μg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily.

Controller Medication: Current treatment with an additional controller medication for at least 3 months OR having used and failed an additional controller medication for at least 3 successive months during the prior 12 months [e.g., long-acting beta2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline].
Male or eligible female. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: (a) Is not a woman of childbearing potential (WOCBP) OR (b) Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1% during the intervention period and for at least 16 weeks after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. (c) A WOCBP must have a negative highly sensitive pregnancy test (serum) within 8 weeks before the first dose of study intervention. (d) Additional requirements for pregnancy testing during and after study intervention are located. (e) The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Induction phase inclusion criteria: - Optimized OCS dose: Achieved a stable dose of OCS during the optimisation period, which is defined as 2 weeks on the same dose of oral corticosteroids prior to entering the Induction Phase. The optimised dose must be between 5.0 and 35mg/day of OCS.
Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma.
OCS Compliance: Compliance with use of OCS dose as instructed during the Optimization Phase on at least 10 of the prior 14 days.
eDiary Compliance: Compliance with completion of the eDiary defined as: (a) Completion of symptom scores on 4 or more days out of the last 7 days. (b) Completion of information relating to rescue medication use on 4 or more days out of the last 7 days immediately preceding Visit 3. (c) Completion of PEF measurements on 4 or more days out of the last 7 days immediately preceding Visit 3.

Exclusion Criteria:

Concurrent Respiratory Disease: Presence of a clinically important lung condition other than asthma. This includes but is not limited to current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects who had localized carcinoma (i.e. basal or squamous cell) of the skin which was resected for cure will not be excluded).
Liver Disease: 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).
Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to: (a) known ejection fraction of <30% OR (b) severe heart failure meeting New York Heart Association Class IV OR (c) hospitalized in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III OR (d) angina diagnosed less than 3 months prior to Visit 1 or at Visit 1.
Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic Esophaghitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.
Omalizumab Use: Subjects who have received omalizumab within 130 days of Visit 1.
Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than omalizumab) to treat inflammatory disease within 5 half-lives of Visit 1.
Investigational Medications: Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to Visit 1 (this also includes investigational formulations of marketed products).
Subjects who have previously participated in any study of mepolizumab and received Investigational Product (including placebo).
ECG: ECG assessment QTcF > 450msec or QTcF > 480 msec for subjects with Bundle Branch Block.
Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus - HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.
Smoking history: Current smokers or former smokers with a smoking history of >=10 pack years. A former smoker is defined as a subject who quit smoking at least 6 months prior to Visit 1.
Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic.
Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.
Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
Laboratory abnormality: Evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.
Alanine transferase (ALT) >2 x upper limit of normal (ULN).
Bilirubin > 1.5 x ULN (isolated bilirubin>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice. Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C e.g., presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result) is acceptable if the subject otherwise meets eligibility criteria.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Bangalore	Karnataka	India	560092
2	GSK Investigational Site	Pune	Maharashtra	India	411004
3	GSK Investigational Site	Ahmedabad		India	380013
4	GSK Investigational Site	Bangalore		India	560004
5	GSK Investigational Site	Bengalore		India	560034
6	GSK Investigational Site	Hyderabad		India	500082
7	GSK Investigational Site	Jaipur		India	302039
8	GSK Investigational Site	Kanpur		India	208005
9	GSK Investigational Site	Kolkata		India	700014
10	GSK Investigational Site	Mumbai		India	400008
11	GSK Investigational Site	Mumbai		India	400016
12	GSK Investigational Site	Nagpur		India	440012
13	GSK Investigational Site	Pune		India	411001