Clinical trial NCT01362244: Mepolizumab in Nasal Polyposis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nasal Polyps
Keywords: Quality of Life
Intranasal Steroids
Severe Nasal Polyposis
Polyp Relapse
Endoscopic Polyp Score
Surgery
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-05-30
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: Inclusion:

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Subjects have a diagnosis of severe bilateral nasal polyposis at the screening visit and Visit 1 (i.e. at end of run-in period) which meets the definition of the situation indicative of the need for surgery as described in Decision Table 1 in Appendix 3.
2. Subjects must have had at least one previous surgery for the removal of nasal polyps.
3. Subjects must have an history of refractory response to steroid therapy as shown by being deemed potentially eligible for surgery despite having been on a regular/continuous course of nasal corticosteroids for the treatment of nasal polyposis for at least 3 months and/or have received a short course of oral steroids in the past for nasal polyp treatment.
4. Male or female between 18 and 70 years of age, inclusive at time of signing informed consent.
5. BMI within the range 19.0 to 31.0 kg/m2 (inclusive).
6. Subjects must be free of any clinically significant disease that would interfere with the study schedule or procedures or compromise his/her safety.
7. Subjects with concurrent asthma must be maintained on no more than 10mg/day of Prednisolone or the equivalent.
8. Female subjects of childbearing potential must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from 1 month prior to first dose of study medication until four months after last dose of study medication.

   Females of non -childbearing potential are defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study (from 1 month prior to first dose of study medication until four months after last dose of study medication). Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2- 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
9. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until four months after last dose of study medication.
10. Subjects are capable of giving written informed consent, which includes agreeing to be compliant with the study requirements and restrictions listed in the consent form.
11. Subjects are willing and available to complete the study and all measurements.
12. Subjects are capable of reading, comprehending, and writing the local language at a sufficient level to complete study related materials.

Exclusion:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. As a result of medical interview, physical examination, or screening investigation the physician responsible considers the subject unfit for the study.
2. Subjects requiring oral corticosteroids at a dose greater than 10mg Prednisolone or equivalent during the study will be terminated from the study.
3. Subjects who have had an asthma exacerbation requiring admission to hospital within 4 weeks of Screening.
4. Subjects who have received immunotherapy within the previous 12 months.
5. Subjects with a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
6. Subjects with a known medical history of Hepatitis B, Hepatitis C, or HIV infection.
7. Subjects with a history or suspicion of drug abuse or alcohol abuse within the last 6 months.
8. Subjects who are currently receiving, or have received within 3 months prior to first mepolizumab dose, chemotherapy, radiotherapy or investigational medications/therapies.
9. Subjects with one or more of the following abnormal laboratory values:

   * Serum creatinine ≥ 3 times institutional ULN
   * AST or/ALT ≥ 5 times institutional ULN
   * Platelet count \< 50,000/μL
10. Subjects with a history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Aspirin-sensitive subjects are acceptable.
11. Subjects with a history of allergic reaction to anti-IL-5 or other antibody therapy.
12. Pregnant females as determined by positive serum pregnancy test at screening or positive urine pregnancy test prior to each dosing occasion.
13. Breastfeeding/Lactating females.
14. Subjects who currently smoke or have smoked in the last 6 months.
15. Subjects who are unwilling or unable to follow the procedures outlined in the protocol.

Primary outcomes:
measure: Number of Participants With a Reduced Need for Surgery at Week 25
timeFrame: Week 25
Secondary outcomes:
measure: Number of Participants With Endoscopic Nasal Polyp (ENP) Score Dynamics at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21, and 25
measure: Number of Participants Who Required Polyp Surgery at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21, and 25
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Baseline and Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Mean Change From Baseline in Pulse Rate at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Baseline and Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21, and 25
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Absolute Values of the Clinical Chemistry Parameters of Albumin and Protein at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Absolute Values of the Hematology Parameter of Mean Corpuscular Hemoglobin (MCH) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: 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)
measure: Absolute Values of the Hematology Parameter of Mean Corpuscular Volume (MCV) at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: 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)
measure: Absolute Value of the Hematology Parameter of Reticulocyte Count/Erythrocyte Uncorrected at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: 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)
measure: Number of Participants With Positive Clinically Relevant Urinalysis Results at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21, and 25
measure: Number of Participants With Any Treatment-emergent Adverse Event (AE) and Serious Adverse Event (SAE)
timeFrame: Up to 11 months
measure: Mean of the Forced Expiratory Volume in 1 Second (FEV1) at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Mean of Forced Vital Capacity (FVC) at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Mean Peak Expiratory Flow Rate (PEFR) at Indicated Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Individual Symptoms Visual Analogue Scale (VAS) Scores at Weeks 1, 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21, and 25
measure: Mean Peak Nasal Inspiratory Flow (PNIF) at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Olfaction Testing: Worst Nostril Score (WNS) and Mean Nostril Score (MNS) at Weeks 2, 5, 9, 13, 17, 21, and 25
timeFrame: Weeks 2, 5, 9, 13, 17, 21, and 25
measure: Sino-Nasal Outcome Test (SNOT)-22 Questionnaire Total Score at Week 25 (Adjusted for Week 1 Baseline)
timeFrame: Week 1 (Baseline) and Week 25
measure: Index Score of the EuroQoL Quality of Life-5D (EQ-5D) Questionnaire at Week 25 (Adjusting for Week 1 Baseline Scores)
timeFrame: Week 1 (Baseline) and Week 25
measure: VAS Score of the EQ-5D Questionnaire at Week 25 (Adjusting for Week 1 Baseline Scores)
timeFrame: Week 1 (Baseline) and Week 25
measure: Systemic Clearance of Mepolizumab 750 mg
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Volume of Distribution of Mepolizumab 750 mg
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Bodyweight-adjusted Clearance
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Steady-State Volume of Distribution
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Maximum Observed Plasma Drug Concentration (Cmax), Average Concentration (Cav[0-inf]), and Steady State Maximum Observed Plasma Drug Concentration (Cmax SS)
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Half-life (Alpha) and Half-life (Beta)
timeFrame: Weeks 1, 2, 5, 9, 13, and 25
measure: Pharmacokinetic/Pharmacodynamic (PK/PD) Model Derived Baseline
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21 and 25
measure: PK/PD Model Derived Coefficient of Variation of Baseline (CV[Baseline]), Variation of Maximal Effect of Drug (CV[Emax]), and Residual
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21 and 25
measure: PK/PD Model Derived Half Maximal Effective Drug Concentration (EC50)
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21 and 25
measure: PK/PD Model Derived Maximum Inhibition
timeFrame: Weeks 1, 2, 5, 9, 13, 17, 21 and 25
measure: Number of Participants With Positive Immunogenicity (Anti-mepolizumab Antibody Testing)
timeFrame: Week 1 pre-dose, Week 5 pre-dose, Week 13 pre-dose and Week 25 (4 weeks post last dose)
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Bachert C, Sousa AR, Lund VJ, Scadding GK, Gevaert P, Nasser S, Durham SR, Cornet ME, Kariyawasam HH, Gilbert J, Austin D, Maxwell AC, Marshall RP, Fokkens WJ. Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin Immunol. 2017 Oct;140(4):1024-1031.e14. doi: 10.1016/j.jaci.2017.05.044. Epub 2017 Jul 4.
citation: Chong LY, Piromchai P, Sharp S, Snidvongs K, Webster KE, Philpott C, Hopkins C, Burton MJ. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2021 Mar 12;3(3):CD013513. doi: 10.1002/14651858.CD013513.pub3.