A Randomised, Double-Blind, Placebo Controlled, Multi-Center Study To Investigate The Use Of Mepolizumab (Sb-240563) In Reducing The Need For Surgery In Subjects With Severe Bilateral Nasal Polyposis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 109
- 试验地点
- 1
- 主要终点
- Number of Participants With a Reduced Need for Surgery at Week 25
研究概览
简要总结
A two-part, randomised, double-blind, placebo controlled, multi-centre study to investigate the use of mepolizumab (SB-240563) in reducing the need for surgery in subjects with severe bilateral nasal polyposis.
详细描述
Nasal polyposis has long been known as chronic inflammatory disease of the nasal mucosa. This disease is characterized by the presence of polyps in the upper nasal cavity, originating from within the ostiomeatal complex. The presence of polyps can cause long-term symptoms such as prominent nasal obstruction, post-nasal drip, loss of smell, and discharge. These symptoms can impact greatly upon a patient's quality of life.The etiology of nasal polyposis is currently unknown.
The aim of this present study is to investigate the use of mepolizumab in reducing the potential need for surgery in subjects with severe bilateral nasal polyposis. The study is split into two parts: Part A is the treatment phase and focuses on the reduction of the need for surgery by exploring the efficacy of six doses of mepolizumab (one dose every four weeks) on nasal polyposis. This dosing regime will build upon the previous PoC study by exploring the potential for increased clinical efficacy as assessed by the potential need for surgery, and also and increased duration of action as assessed by time to relapse. Part B is the follow-up phase and will assess post-treatment nasal polyposis dynamics with a focus on time to relapse. All subjects participating in this study will undergo a run-in period on a low dose of intranasal steroids (INS) prior to first dosing. INS will be continued throughout the study up until study exit. This is to reflect the real life circumstances in which mepolizumab is intended to be used as a therapy. The overall aim of the study design is to further assess the impact in the potential need for surgery and explore an appropriate mepolizumab therapeutic regimen strategy for the treatment of nasal polyposis.
In this study, the assessment of nasal polyposis will be performed by means of combining endoscopic polyp score with subject reported symptoms. This approach reflects real-life clinical assessment of nasal polyposis. Also, this study incorporates condition specific and general medical questionnaires in order to obtain a better understanding of the impact of severe nasal polyposis of the subject's quality of life (QOL). This is in line with increasing focus in the medical field on the effects of medical conditions and treatments on the quality of life of patients (Fokkens et al 2007).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Treatment Periods 1-8
Part A comprises eight outpatient visits (Visits 1 - 8). For six of these visits, subjects will receive a dose of either 750 mg mepolizumab or placebo. Dosing occurs in four week intervals. Assessment for entry into Part B will take place at the last visit in Part A (Visit 8). Subjects not eligible for Part B will have study exit procedures performed and be discontinued.
干预措施: Mepolizumab (Drug)
Treatment Periods 1-8
Part A comprises eight outpatient visits (Visits 1 - 8). For six of these visits, subjects will receive a dose of either 750 mg mepolizumab or placebo. Dosing occurs in four week intervals. Assessment for entry into Part B will take place at the last visit in Part A (Visit 8). Subjects not eligible for Part B will have study exit procedures performed and be discontinued.
干预措施: Placebo (Drug)
Run In period
10-14 day run in period to assess the patients suitability for entry into Part A of the trial.
干预措施: Run In Medication (Drug)
结局指标
主要结局
Number of Participants With a Reduced Need for Surgery at Week 25
时间窗: Week 25
Assessment of the nasal polyposis condition was performed after six months of dosing to determine the situation indicative of a reduction in the need for surgery. The components used to determine the need for surgery were endoscopic polyp (ENP) scores and a severity of condition as measured by a visual analogue scale (VAS). Surgery was still deemed required for a participant with an ENP score of \>=3, or an ENP score of 2 and a VAS symptom score of \>7. The number of participants with reduced need for polyp surgery are presented as missing data set to non-responders (NR) and missing data last observation carry forward (LOCF). LOCF is defined as missing responses at Week 25 imputed with the last non-missing post-dose observation for that participant.
次要结局
- Number of Participants Who Required Polyp Surgery at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Weeks 1, 2, 5, 9, 13, 17, 21, and 25)
- Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 2, 5, 9, 13, 17, 21, and 25(Baseline and Weeks 2, 5, 9, 13, 17, 21, and 25)
- Absolute Values of the Hematology Parameter of Mean Corpuscular Volume (MCV) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Value of the Hematology Parameter of Reticulocyte Count/Erythrocyte Uncorrected at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of Clinical Chemistry Parameters Including Blood Urea Nitrogen (BUN), Glucose Fasting, Chloride, Sodium, Potassium, Carbon Dioxide, and Calcium at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of the Clinical Chemistry Parameters of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), and Gamma Glutamyltransferase (GGT) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of the Hematology Parameter of Mean Corpuscular Hemoglobin (MCH) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Weeks 1, 2, 5, 9, 13, 17, 21, and 25)
- Absolute Values of the Clinical Chemistry Parameters of Albumin and Protein at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of the Clinical Chemistry Parameters of Total and Direct Bilirubin, Creatinine (CRT), and Uric Acid (UA) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of the Hematology Parameters of Platelet Count and White Blood Cell (WBC) Count, Basophils, Eosinophils, Lymphocytes, Monocytes, and Neutrophils at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Number of Participants With Any Treatment-emergent Adverse Event (AE) and Serious Adverse Event (SAE)(Up to 11 months)
- Number of Participants With Endoscopic Nasal Polyp (ENP) Score Dynamics at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Weeks 1, 2, 5, 9, 13, 17, 21, and 25)
- Number of Participants With Positive Clinically Relevant Urinalysis Results at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Weeks 1, 2, 5, 9, 13, 17, 21, and 25)
- Mean Change From Baseline in Pulse Rate at Weeks 2, 5, 9, 13, 17, 21, and 25(Baseline and Weeks 2, 5, 9, 13, 17, 21, and 25)
- Absolute Values of the Hematology Parameters of Hemoglobin and Mean Corpuscular Hemoglobin Concentration (MCHC) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Absolute Values of the Hematology Parameter of Red Blood Cell (RBC) Count and Reticulocyte Count (RC) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose))
- Systemic Clearance of Mepolizumab 750 mg(Weeks 1, 2, 5, 9, 13, and 25)
- Volume of Distribution of Mepolizumab 750 mg(Weeks 1, 2, 5, 9, 13, and 25)
- Mean of the Forced Expiratory Volume in 1 Second (FEV1) at Weeks 2, 5, 9, 13, 17, 21, and 25(Weeks 2, 5, 9, 13, 17, 21, and 25)
- Mean of Forced Vital Capacity (FVC) at Weeks 2, 5, 9, 13, 17, 21, and 25(Weeks 2, 5, 9, 13, 17, 21, and 25)
- Mean Peak Expiratory Flow Rate (PEFR) at Indicated Weeks 2, 5, 9, 13, 17, 21, and 25(Weeks 2, 5, 9, 13, 17, 21, and 25)
- Individual Symptoms Visual Analogue Scale (VAS) Scores at Weeks 1, 2, 5, 9, 13, 17, 21, and 25(Weeks 1, 2, 5, 9, 13, 17, 21, and 25)
- Mean Peak Nasal Inspiratory Flow (PNIF) at Weeks 2, 5, 9, 13, 17, 21, and 25(Weeks 2, 5, 9, 13, 17, 21, and 25)
- Olfaction Testing: Worst Nostril Score (WNS) and Mean Nostril Score (MNS) at Weeks 2, 5, 9, 13, 17, 21, and 25(Weeks 2, 5, 9, 13, 17, 21, and 25)
- Sino-Nasal Outcome Test (SNOT)-22 Questionnaire Total Score at Week 25 (Adjusted for Week 1 Baseline)(Week 1 (Baseline) and Week 25)
- Bodyweight-adjusted Clearance(Weeks 1, 2, 5, 9, 13, and 25)
- Steady-State Volume of Distribution(Weeks 1, 2, 5, 9, 13, and 25)
- Index Score of the EuroQoL Quality of Life-5D (EQ-5D) Questionnaire at Week 25 (Adjusting for Week 1 Baseline Scores)(Week 1 (Baseline) and Week 25)
- VAS Score of the EQ-5D Questionnaire at Week 25 (Adjusting for Week 1 Baseline Scores)(Week 1 (Baseline) and Week 25)
- Maximum Observed Plasma Drug Concentration (Cmax), Average Concentration (Cav[0-inf]), and Steady State Maximum Observed Plasma Drug Concentration (Cmax SS)(Weeks 1, 2, 5, 9, 13, and 25)
- Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf])(Weeks 1, 2, 5, 9, 13, and 25)
- Half-life (Alpha) and Half-life (Beta)(Weeks 1, 2, 5, 9, 13, and 25)
- Pharmacokinetic/Pharmacodynamic (PK/PD) Model Derived Baseline(Weeks 1, 2, 5, 9, 13, 17, 21 and 25)
- PK/PD Model Derived Coefficient of Variation of Baseline (CV[Baseline]), Variation of Maximal Effect of Drug (CV[Emax]), and Residual(Weeks 1, 2, 5, 9, 13, 17, 21 and 25)
- PK/PD Model Derived Half Maximal Effective Drug Concentration (EC50)(Weeks 1, 2, 5, 9, 13, 17, 21 and 25)
- PK/PD Model Derived Maximum Inhibition(Weeks 1, 2, 5, 9, 13, 17, 21 and 25)
- Number of Participants With Positive Immunogenicity (Anti-mepolizumab Antibody Testing)(Week 1 pre-dose, Week 5 pre-dose, Week 13 pre-dose and Week 25 (4 weeks post last dose))