Dexpramipexole Dose-Ranging Biomarker Study in Subjects With Eosinophilic Asthma (EXHALE-1)

A Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Biomarker Study of the Effects of Dexpramipexole on Eosinophils in Subjects With Eosinophilic Asthma

This is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, multi-center study to evaluate the clinical effects of oral administration of dexpramipexole for 12 weeks on peripheral blood eosinophil count in subjects with eosinophilic asthma.

Study Overview

• Status: Completed
• Conditions: Asthma; Eosinophilic Asthma
• Intervention / Treatment: Drug: Placebo; Drug: Dexpramipexole

Detailed Description

One hundred subjects will receive study drug or matching placebo over 12 weeks of consecutive dosing. Following a short Run-in Period, eligible subjects will enter the Primary Assessment Period and receive twice-daily dosing of study drug or placebo for 12 weeks. Following 12 weeks of treatment, subjects will enter a 12-week Eosinophil Recovery Period. The primary endpoint for the study is the change in blood absolute eosinophil count from Baseline to Week 12.

• Study Type: Interventional
• Enrollment (Actual): 534
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Research Site
    • Mission Viejo, California, United States, 92691
      • Research Site
    • Westminster, California, United States, 92683
      • Research Site
  • Colorado
    • Denver, Colorado, United States, 80230
      • Research Site
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Research Site
    • Miami, Florida, United States, 33186
      • Research Site
    • Orlando, Florida, United States, 32803
      • Research Site
    • Tampa, Florida, United States, 33612
      • Research Site
    • Tampa, Florida, United States, 33634
      • Research Site
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Research Site
    • Winder, Georgia, United States, 30680
      • Research Site
  • Idaho
    • Boise, Idaho, United States, 83706
      • Research Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48336
      • Research Site
  • Minnesota
    • Plymouth, Minnesota, United States, 55441
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
    • Saint Louis, Missouri, United States, 63141
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Research Site
  • New York
    • Corning, New York, United States, 14830
      • Research Site
    • New Hyde Park, New York, United States, 11042
      • Research Site
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Research Site
    • Cincinnati, Ohio, United States, 45242
      • Research Site
    • Columbus, Ohio, United States, 43235
      • Research Site
    • Dublin, Ohio, United States, 43016
      • Research Site
  • Oklahoma
    • Edmond, Oklahoma, United States, 73034
      • Research Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Research Site
    • Portland, Oregon, United States, 97202
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15205
      • Research Site
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Research Site
    • North Charleston, South Carolina, United States, 29406
      • Research Site
  • Texas
    • Allen, Texas, United States, 75013
      • Research Site
    • Boerne, Texas, United States, 78006
      • Research Site
    • Dallas, Texas, United States, 75240
      • Research Site
    • El Paso, Texas, United States, 79902
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female ≥18 and <75 years of age at the time of consent
• Physician diagnosis of asthma for ≥12 months (relative to Baseline) based on Global Initiative for Asthma (GINA) 2018 Guidelines
• Asthma requiring treatment with, at a minimum, low dose inhaled corticosteroids in combination with a long-acting β2 agonist, on a stable dose for at least 1 month before Screening
• Bronchodilator reversibility, as evidenced by ≥12% and ≥200 mL improvement in FEV1 15 to 25 minutes following inhalation of albuterol at Screening
• Pre-bronchodilator FEV1 ≥40% and <80% of predicted at Screening and Baseline
• AEC ≥0.30 x10^9/L at the Screening visit
• ACQ-7 ≥1.5 at Screening
• Negative pregnancy test at Baseline
• Adherence ≥85% with twice-daily placebo taken during the Run-in Period

Exclusion Criteria:

• Treatment for an asthma exacerbation within 8 weeks prior to Baseline visit
• Treatment with systemic corticosteroids in the 8 weeks prior to Screening
• Treatment with monoclonal antibody therapy, within 5-half-lives prior to Baseline
• Treatment with selected drugs known to have a substantial risk of neutropenia
• Absolute neutrophil count <2.0x10^9/L at Screening, or any documented history of absolute neutrophil count <2.0x10^9/L.
• Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m^2 at Screening
• Clinically significant abnormal laboratory or ECG values
• Other medically significant illness
• Use of any smoke or inhaled nicotine delivery device within 1 year prior to Screening
• Pregnant women or women breastfeeding
• Currently taking pramipexole or other dopamine agonists

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo BID; Following a 2-4 week placebo run-in, randomized subjects received 1 tablet placebo twice daily for 12 weeks.	Drug: Placebo; placebo twice daily oral dosing for up to 12 weeks; Other Names: PBO
Active Comparator: 37.5 mg BID dexpramipexole; Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 37.5 mg dexpramipexole twice daily for 12 weeks.	Drug: Dexpramipexole; dexpramipexole twice daily oral dosing for up to 12 weeks; Other Names: KNS-760704; BIIB050
Active Comparator: 75 mg BID dexpramipexole; Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 75 mg dexpramipexole twice daily for 12 weeks.	Drug: Dexpramipexole; dexpramipexole twice daily oral dosing for up to 12 weeks; Other Names: KNS-760704; BIIB050
Active Comparator: 150 mg BID dexpramipexole; Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 150 mg dexpramipexole twice daily for 12 weeks.	Drug: Dexpramipexole; dexpramipexole twice daily oral dosing for up to 12 weeks; Other Names: KNS-760704; BIIB050

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Blood Absolute Eosinophil Count From Baseline to Week 12	The primary endpoint of this study was the change in AEC from Baseline to Week 12 on a ratio scale. The analysis used a mixed effects model repeated-measures (MMRM) with terms for log10 transformed baseline, GINA treatment step, treatment, visit, treatment by visit interaction, and log10 transformed baseline by visit interaction as fixed effects, and subject as a random effect. An unstructured covariance matrix was used. The response variable was the log10 transformed post-baseline value minus the log10 transformed baseline value. The estimates of Geometric LS Means and their ratios were obtained by back transforming the corresponding estimates of LS means and their differences to the original scale.	Baseline, 12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pre-bronchodilator FEV1 (Liters) From Baseline to Week 12	FEV1 is defined as the amount of air that can be forcibly exhaled from the lungs in the first second of a forced exhalation.	Baseline, 12 Weeks
Change in Asthma Control Questionnaire (ACQ-6) Score From Baseline to Week 12	ACQ-6 is simple questionnaire to measure the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment. The 6-point self-administered scale has items measuring asthma symptoms and rescue inhaler use. The ACQ score is the mean of the questions and therefore between 0 (totally controlled) and 6 (severely uncontrolled). The original protocol planned to analyze the ACQ-7 score. As a result of FEV1 testing restrictions imposed on the study during the COVID-19 pandemic, the analysis was prospectively modified to the ACQ-6 score prior to database lock. The ACQ-6 is a validated questionnaire and is identical to the ACQ-7, with the exception of FEV1 data that is also utilized in the ACQ-7 questionnaire total score calculation.	Baseline, 12 Weeks
Change in Post-bronchodilator FEV1 From Baseline to Week 12	Post-bronchodilator FEV1 is defined as the amount of air that can be forcibly exhaled from the lungs in the first second of a forced exhalation, after treatment with inhaled albuterol.	Baseline, 12 Weeks
Change in Quality of Life, as Measured by the Asthma Quality of Life Questionnaire (AQLQ) From Baseline to Week 12	The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma. The 32 questions in the AQLQ are divided into four domains; activity limitations, symptoms, emotional function, and environmental stimuli. Individual questions are equally weighted. The overall AQLQ score is the mean of the responses to each of the 32 questions and ranges from 1 to 7. A score 7.0 indicates that the patient has no impairments due to asthma and score 1.0 indicates severe impairment.	Baseline, 12 Weeks
Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group Post Randomization Through Week 12	Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.	Immediately post-baseline up to Week 12
Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group Post Randomization Through Week 12	Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.	Immediately post-baseline up to Week 12
Number of Participants With Potentially Clinically Significant Urinalysis Results by Treatment Group Post Randomization Through Week 12	Number of Participants with Potentially Clinically Significant Urinalysis Results (glycosuria, ketonuria, or proteinuria) by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline urinalysis value in each treatment group. Patients are only counted once per criterion per laboratory test. The number of participants with potential clinical important urinalysis findings at any post-baseline visit were reported.	Immediately post-baseline up to Week 12
Number of Participants With Potentially Clinically Significant Vital Signs Results by Treatment Group Post Randomization Through Week 12	Number of Participants with Potentially Clinically Significant Vital Signs Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.	Immediately post-baseline up to Week 12
Number of Participants With Potentially Clinically Significant ECG Results by Treatment Group Post Randomization Through Week 12	Number of Participants with Potentially Clinically Significant ECG Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.	Immediately post-baseline up to Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Nasal Eosinophil Peroxidase (Presented as Ratio to Protein) From Baseline to Week 12	The EPX:protein ratio was used to normalize the EPX for the quantity of sample, yielding the values in ng EPX per mg protein. The ratio of nasal Eosinophil Peroxidase to Protein is a biomarker for airway eosinophils. A lower ratio to Baseline represents a lowering in airway eosinophilia, which is a marker of successful drug therapy.	Baseline, Week 12
Change in Blood Absolute Blood Basophil Count From Baseline to Week 12	The analysis used a mixed effects model repeated-measures MMRM with terms for baseline, GINA treatment step, treatment, visit, treatment by visit interaction, and baseline by visit interaction as fixed effects, and subject as a random effect. An unstructured covariance matrix was used. The response variable was the post-baseline value minus the baseline value. Basophils were enumerated as part of the WBC automated differential performed by the Central Laboratory.	Baseline, Week 12
Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 12	FeNO is non-invasive biomarker of airway inflammation in asthma participants.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: Knopp Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2019
• Primary Completion (Actual): December 3, 2020
• Study Completion (Actual): March 2, 2021

Study Registration Dates

• First Submitted: July 30, 2019
• First Submitted That Met QC Criteria: August 2, 2019
• First Posted (Actual): August 6, 2019

Study Record Updates

• Last Update Posted (Estimate): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Asthma; Eosinophilic Asthma; dexpramipexole
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Asthma; Pulmonary Eosinophilia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Dopamine Agonists; Dopamine Agents; Antioxidants; Antiparkinson Agents; Anti-Dyskinesia Agents; Pramipexole
• Other Study ID Numbers: KNS-760704-AS201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No