Pemirolast in Allergen Challenge (PEMAG) (PEMAG)

A Placebo-controlled, Cross-over, Study to Assess the Efficacy of the Oral Mast Cell Inhibitor Pemirolast in Allergen-induced Airway Obstruction and Inflammation in Subjects With Allergic Asthma

The purpose of this study is to establish the influence of the non-steroidal candidate-drug pemirolast on allergen-induced airway obstruction and inflammation in allergic subjects with asthma. Pemirolast is an orally available inhibitor of the release of mast cell mediators. The study will therefore test the hypothesis that global inhibition of the mast cell, resulting in decreased production of most of its mediator molecules, will provide a highly significant anti-asthmatic effect.

Study Overview

• Status: Terminated
• Conditions: Allergic Asthma
• Intervention / Treatment: Drug: Pemirolast; Drug: Placebo Oral Tablet

Detailed Description

This is a crossover randomized double blind, placebo-controlled study where the early and late response to allergen inhalation challenge will be compared during two treatment periods, with pemirolast 200 mg bid for 14 (to 16) days and matching placebo, respectively. Non-smoking female and male subjects (n = 12-15) with intermittent atopic asthma, requiring only β2-agonists to treat their asthma, will be recruited. A total of twelve subjects who demonstrate an early and a late asthmatic response to inhaled allergen challenge are required to complete the study for the primary end-point. The sample size is sufficient according to experience from a large number of studies and published power calculations of the model. The effects of pemirolast have never been studied before in an allergen provocation model. Primary variable is the effect of treatment on the mean maximum fall in forced expiratory volume in one second (FEV1) during the early and the late asthmatic reactions induced by allergen. Secondary variables are the effect on mast cell activation and airway inflammation measured as the urinary excretion of metabolites of prostaglandins and other lipid mediators and the percentage of sputum eosinophils, respectively. Tertiary variables are the effect of treatment on airway responsiveness expressed as the provocative dose of methacholine causing 20 per cent decrease in FEV1 (PD20FEV1), as well as biomarkers of airway inflammation in saliva, sputum, exhaled air and blood.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 14186
    • Lung and Allergy Research Unit C2-88 Karolinska University Hospital Huddinge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-65 years inclusive

• Diagnosed asthma as defined by at least one of the following:

  • response to standard asthma treatment
  • episodic wheezing
  • change in lung function over short periods of time
• Non-smoker for the past two years and a total of smoking less than 5 pack-years
• Stable intermittent asthma, only using bronchodilator therapy as needed for the last 4 weeks
• FEV1 ≥ 75 % of predicted
• A positive skin prick test to pollen (grass, birch, mugwort) or animal dander (dog, cat) and a history of associated symptoms on exposure.

Exclusion Criteria:

• Any significant respiratory disease, other than asthma.
• Subjects with seasonal asthma may not be included if they are in their season and subjects allergic to animal dander must not have a pet on their own or similar close exposure.

• Use of:

  • Oral, injectable or inhaled glucocorticosteroid treatment for the last 4 weeks prior to inclusion or during the study
  • Inhaled long-acting β2-agonists, anticholinergic bronchodilators, antihistamines, theofyllines, nasal or inhaled cromones and antileukotrienes within 2 weeks of screening
  • Beta-blocking agents.
  • Immunomodulator drugs
  • NSAIDs.
• Upper or lower respiratory tract infection within 4 weeks of screening
• Females who are pregnant, intend to be or who are lactating. Female subjects of childbearing potential who are not willing to use adequate contraceptive methods (measures as required by local requirements or practice) during participation in the trial until at least three days after last intake of study treatments. Male subjects not surgically sterilized, who or whose partner is not using adequate contraceptive methods (measures as required by local requirements or practice) during participation in the trial until at least three days after last intake of study drug.
• Subjects with BMI >30.
• Evidence (from clinical laboratory tests, physical examination or medical history) of hepatic disease (other than Gilbert´s Syndrome)
• Evidence (from physical examination or medical history) of any diseases that affects gastrointestinal absorption.
• A diagnosis of brittle asthma (rapid fluctuations in disease severity).
• Participation in other study in the four weeks prior to screening.
• Evidence of drug or alcohol abuse.
• History of having taken barbiturates or other drugs affecting the liver drug-metabolising enzymes within one month of the start of the trial.
• Blood donor during the last four months prior to study start and throughout the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pemirolast; Pemirolast 200mg bid 14-16 days	Drug: Pemirolast; Treatment with pemirolast 200 mg bid for 14-16 days; Other Names: CRD 007
Placebo Comparator: Placebo Oral Tablet; Matching placebo bid 14-16 days	Drug: Placebo Oral Tablet; Treatment with placebo bid for 14-16 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bronchoconstriction measured as fall in FEV1 during the early (EAR) and late (LAR) asthmatic reaction induced by allergen	After treatment with pemirolast or matching placebo for 14-16 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mast cell activation measured as urinary excretion of metabolites of lipid mediators (prostaglandins,isoprostanes,leukotrienes,tromboxanes)	Urine samples will be analysed with mass spectrometry (UPLC-MS/MS) and data presented as ng.mmol creatinine-1 for all metabolites	After treatment with pemirolast or matching placebo for 14-16 days
Airway inflammation measured as the percentage of sputum eosinophils	Induced sputum will be collected 7 hours after the last inhaled allergen dose and percentage of eosinophils will be measured	After treatment with pemirolast or matching placebo for 14-16 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Airway responsiveness expressed as methacholine PD20FEV1	Change in methacholine responsiveness after the allergen challenge will be compared during the two treatment periods	After treatment with pemirolast or matching placebo for 14-16 days
Measurement of inflammatory biomarkers in saliva	Saliva is collected before and after challenges to monitor activation of mast cells and other inflammatory pathways	After treatment with pemirolast or matching placebo for 14-16 days
Measurement of biomarkers in blood	Venous blood samples are collected at clinic visits for asthma biomarkers. Biomarkers are taken before and after challenges according to sub-protocols specific for each analyte.	After treatment with pemirolast or matching placebo for 14-16 days
Measurement of biomarkers in sputum	Sputum induction is performed on particular study days to assess inflammatory cell content and to collect sputum supernatant for analysis of biomarkers.	After treatment with pemirolast or matching placebo for 14-16 days
Measurement of biomarkers in exhaled breath samples	Collection of exhaled air using the eNose will be used for exploratory studies of specific volatile and particular components of the exhaled breath	After treatment with pemirolast or matching placebo for 14-16 days

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Experimental Asthma and Allergy Research Unit, Karolinska Institutet; Unit for Chemistry II, Department of Medical Biochemistry, Karolinska Institutet; Occupational and Environmental Medicine, Sahlgrenska UH, Gothenburg; Div Clinical Pharmacology, Karolinska University Hospital; Dept. Respiratory Medicine, University of Amsterdam, Amsterdam; The Centre for Infection Medicine, Karolinska Institutet
• Investigators: Principal Investigator: Barbro Dahlén, MD,PhD, Lung and Allergy Clinic, Karolinska UH

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: November 11, 2016
• First Submitted That Met QC Criteria: April 13, 2017
• First Posted (Actual): April 19, 2017

Study Record Updates

• Last Update Posted (Actual): May 8, 2019
• Last Update Submitted That Met QC Criteria: May 6, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: bronchoprovocation; sputum eosinophils; early-late asthmatic reaction; mast cell stabilizer; mast cell mediators
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Histamine Antagonists; Histamine Agents; Pemirolast
• Other Study ID Numbers: PEMAG-2016-v2.3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not planing to share data