Back to resultsEffect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation (MIGLUSTAT-CF)
Primary Purpose
Cystic Fibrosis
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Miglustat ; placebo
Placebo ; Miglustat
Sponsored by
About this trial
This is an interventional treatment trial for Cystic Fibrosis focused on measuring Cystic fibrosis, CFTR, F508del mutation, Miglustat, Total Chloride Secretion, Nasal Potential Difference
Eligibility Criteria
Inclusion Criteria:
Inclusion criteria at screening visit (Visit 1):
- Aged 18 years and older
- Male or female
Women of childbearing potential must:
- have a negative serum pregnancy test at Visit 1
- agree to use from Visit 1 until 3 months after the last study drug intake a reliable method of contraception
- Male patients accepting for the duration of the study and for 3 months thereafter to use a condom
- Homozygous for the F508del mutation as confirmed by genetic testing
- Sweat chloride ≥ 60 mmol/L
- Basal nasal potential difference (NPD) ≤ -30.0 mV (equal to or more electrically negative than -30.0 mV) and total chloride secretion (TCS) ≥ - 5.0 mV for at least one nostril. However, if it is possible to analyze both nostrils, the total chloride secretion (TCS) is to be ≥ - 5.0 mV (equal to or more electrically positive than - 5.0 mV) in both nostrils.
- FEV1 ≥ 25% of predicted
- Able to comply with all protocol requirements
- Signed informed consent prior to any study-mandated procedure
Inclusion criteria at randomization visit (Visit 2):
- Women of child-bearing potential must have a negative urine pregnancy test
- Basal nasal potential difference (NPD) ≤ - 30.0 mV (equal to or more electrically negative than - 30.0 mV) and total chloride secretion (TCS) ≥ - 5.0 mV for at least one nostril. However, if it is possible to analyze both nostrils, the total chloride secretion (TCS) is to be ≥ - 5.0 mV (equal to or more electrically positive than - 5.0 mV) in both nostrils.
Exclusion Criteria:
- Any condition prohibiting the correct measurement of the NPD such as upper respiratory tract infection
- Acute upper or lower respiratory tract infection requiring antibiotic intervention within 2 weeks of screening
- Lung transplant recipient or patient on a lung transplant waiting list
- Any modification in regular treatments (new treatment initiated or discontinued treatment) or modification in dosing within 2 weeks prior to start of Period 1
- Moderate/Severe renal impairment (creatinine clearance < 70 mL/min as per Cockroft and Gault)
- Systemic corticosteroids (> 10 mg/day prednisone or equivalent) within 14 days prior to screening and up to start of study
- Women who are breast-feeding, pregnant, or who plan to become pregnant during the course of the study
- History of significant lactose intolerance
- Presence of clinically significant diarrhoea (> 3 liquid stools per day for > 7 days) without definable cause within one month prior to screening
- Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease
- Active or passive smoking
- Hypersensitivity to Miglustat or any excipients
- Planned treatment or treatment with another investigational drug or therapy (e.g., gene therapy) within one month prior to randomization
- Known concomitant life-threatening disease with a life expectancy < 12 months
- Indication against Isuprel® (Isoproterenol) including heart diseases.
Sites / Locations
- Assistance publique-Hôpitaux de Paris, Hôpital Cochin
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Miglustat then placebo
Placebo then Miglustat
Arm Description
10 patients will received Miglustat then the placebo
10 patients will received Placebo then Miglustat
Outcomes
Primary Outcome Measures
Mean TCS in mV
TCS (Total Chloride Secretion) is the sum of responses in nasal potential difference (NPD) calculated as the mean of the right and left nostril measurements for each patient
Mean TCS in mV
TCS (Total Chloride Secretion) is the sum of responses in nasal potential difference (NPD) calculated as the mean of the right and left nostril measurements for each patient
Secondary Outcome Measures
TCS difference in mV
TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.
TCS difference in mV
TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.
Percentage of patients with a TCS response to treatment ≤ - 5 mV
The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV
Percentage of patients with a TCS response to treatment ≤ - 5 mV
The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV
Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV
The percentage of patients with a TCS response at end-of-treatment ≤ -5mV
Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV
The percentage of patients with a TCS response at end-of-treatment ≤ -5mV
Change of basal NPD in mV
Basal NPD at end-of-treatment minus basal NPD at baseline
Change of basal NPD in mV
Basal NPD at end-of-treatment minus basal NPD at baseline
Change of the response in NPD after superfusion with amiloride
NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline
Change of the response in NPD after superfusion with amiloride
NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline
Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride
NPD after superfusion with a chloride-free buffer in the presence of amiloride at end-of-treatment minus NPD after superfusion with a chloride-free buffer in the presence of amiloride at baseline
Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride
NPD after superfusion with a chloride-free buffer in the presence of amiloride at end-of-treatment minus NPD after superfusion with a chloride-free buffer in the presence of amiloride at baseline
Wilschanski's index change
Wilschanski's index is defined as (exposant(response to Chloride-free and isoproterenol/response amiloride)): Wilschanski's index at end-of-treatment minus Wilschanski's at baseline
Wilschanski's index change
Wilschanski's index is defined as (exposant(response to Chloride-free and isoproterenol/response amiloride)): Wilschanski's index at end-of-treatment minus Wilschanski's at baseline
Sweat chloride concentration in mmol/L
Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline
Sweat chloride concentration in mmol/L
Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline
FEV1 (in % of predicted)
Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline
FEV1 (in % of predicted)
Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline
Change in electrochemical skin conductance
Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline
Change in electrochemical skin conductance
Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline
Number of cells expressing CFTR at the cell membrane (in %percentage)
Percentage of nasal cells expressing CFTR at the cell membrane as assessed by immunochemistry and confocal microscopy
Full Information
NCT ID
NCT02325362
First Posted
December 10, 2014
Last Updated
March 16, 2018
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Actelion, CRCM (Centres de Ressources et de Compétences de la Mucoviscidose)
1. Study Identification
Unique Protocol Identification Number
NCT02325362
Brief Title
Effect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation
Acronym
MIGLUSTAT-CF
Official Title
Single Center, Double-blind, Randomized, Placebo-controlled, Two-period/Two-treatment Crossover, Proof-of-mechanism Study Investigating the Effect of Miglustat on the Nasal Potential Difference in Adult Patients With Cystic Fibrosis Homozygous for the F508del Mutation
Study Type
Interventional
2. Study Status
Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
March 17, 2015 (Actual)
Primary Completion Date
April 3, 2017 (Actual)
Study Completion Date
April 3, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Actelion, CRCM (Centres de Ressources et de Compétences de la Mucoviscidose)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to demonstrate that Miglustat restores the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in adult patients with cystic fibrosis homozygous for the F508del mutation.
Detailed Description
The aims of this study are:
To determine whether Miglustat can restore the function of the CFTR protein in adult patients with cystic fibrosis homozygous for the F508del mutation
To evaluate the safety, tolerability and pharmacokinetics of Miglustat in adult patients with cystic fibrosis homozygous for the F508del mutation.
To investigate pharmacokinetic-pharmacodynamic of Miglustat in adult patients with cystic fibrosis homozygous for the F508del mutation.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis
Keywords
Cystic fibrosis, CFTR, F508del mutation, Miglustat, Total Chloride Secretion, Nasal Potential Difference
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Miglustat then placebo
Arm Type
Experimental
Arm Description
10 patients will received Miglustat then the placebo
Arm Title
Placebo then Miglustat
Arm Type
Experimental
Arm Description
10 patients will received Placebo then Miglustat
Intervention Type
Drug
Intervention Name(s)
Miglustat ; placebo
Intervention Description
For this 2 x 2 (2 periods /2 treatments) crossover design each patient will receive Miglustat during the first period (2 weeks), following by a wash out period(14 days (up to 4 weeks)), then Placebo during the second period (2 weeks). 30 days follow-up will be carried out after end-of-treatment of the second period.
Intervention Type
Drug
Intervention Name(s)
Placebo ; Miglustat
Intervention Description
For this 2 x 2 (2 periods /2 treatments) crossover design each patient will receive Placebo during the first period (2 weeks), following by wash out period (14 days (up to 4 weeks)), then Miglustat during the second period (2 weeks). 30 days follow-up will be carried out after end of treatment of the second period.
Primary Outcome Measure Information:
Title
Mean TCS in mV
Description
TCS (Total Chloride Secretion) is the sum of responses in nasal potential difference (NPD) calculated as the mean of the right and left nostril measurements for each patient
Time Frame
day 1
Title
Mean TCS in mV
Description
TCS (Total Chloride Secretion) is the sum of responses in nasal potential difference (NPD) calculated as the mean of the right and left nostril measurements for each patient
Time Frame
Day 14
Secondary Outcome Measure Information:
Title
TCS difference in mV
Description
TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.
Time Frame
day 1
Title
TCS difference in mV
Description
TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.
Time Frame
Day 14
Title
Percentage of patients with a TCS response to treatment ≤ - 5 mV
Description
The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV
Time Frame
day 1
Title
Percentage of patients with a TCS response to treatment ≤ - 5 mV
Description
The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV
Time Frame
day 14
Title
Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV
Description
The percentage of patients with a TCS response at end-of-treatment ≤ -5mV
Time Frame
day 1
Title
Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV
Description
The percentage of patients with a TCS response at end-of-treatment ≤ -5mV
Time Frame
day 14
Title
Change of basal NPD in mV
Description
Basal NPD at end-of-treatment minus basal NPD at baseline
Time Frame
day 1
Title
Change of basal NPD in mV
Description
Basal NPD at end-of-treatment minus basal NPD at baseline
Time Frame
day 14
Title
Change of the response in NPD after superfusion with amiloride
Description
NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline
Time Frame
day 1
Title
Change of the response in NPD after superfusion with amiloride
Description
NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline
Time Frame
day 14
Title
Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride
Description
NPD after superfusion with a chloride-free buffer in the presence of amiloride at end-of-treatment minus NPD after superfusion with a chloride-free buffer in the presence of amiloride at baseline
Time Frame
day 1
Title
Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride
Description
NPD after superfusion with a chloride-free buffer in the presence of amiloride at end-of-treatment minus NPD after superfusion with a chloride-free buffer in the presence of amiloride at baseline
Time Frame
day 14
Title
Wilschanski's index change
Description
Wilschanski's index is defined as (exposant(response to Chloride-free and isoproterenol/response amiloride)): Wilschanski's index at end-of-treatment minus Wilschanski's at baseline
Time Frame
day 1
Title
Wilschanski's index change
Description
Wilschanski's index is defined as (exposant(response to Chloride-free and isoproterenol/response amiloride)): Wilschanski's index at end-of-treatment minus Wilschanski's at baseline
Time Frame
day 14
Title
Sweat chloride concentration in mmol/L
Description
Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline
Time Frame
day 1
Title
Sweat chloride concentration in mmol/L
Description
Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline
Time Frame
day 14
Title
FEV1 (in % of predicted)
Description
Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline
Time Frame
day 1
Title
FEV1 (in % of predicted)
Description
Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline
Time Frame
day 14
Title
Change in electrochemical skin conductance
Description
Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline
Time Frame
day 1
Title
Change in electrochemical skin conductance
Description
Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline
Time Frame
day 14
Title
Number of cells expressing CFTR at the cell membrane (in %percentage)
Description
Percentage of nasal cells expressing CFTR at the cell membrane as assessed by immunochemistry and confocal microscopy
Time Frame
day 14
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Inclusion criteria at screening visit (Visit 1):
Aged 18 years and older
Male or female
Women of childbearing potential must:
have a negative serum pregnancy test at Visit 1
agree to use from Visit 1 until 3 months after the last study drug intake a reliable method of contraception
Male patients accepting for the duration of the study and for 3 months thereafter to use a condom
Homozygous for the F508del mutation as confirmed by genetic testing
Sweat chloride ≥ 60 mmol/L
Basal nasal potential difference (NPD) ≤ -30.0 mV (equal to or more electrically negative than -30.0 mV) and total chloride secretion (TCS) ≥ - 5.0 mV for at least one nostril. However, if it is possible to analyze both nostrils, the total chloride secretion (TCS) is to be ≥ - 5.0 mV (equal to or more electrically positive than - 5.0 mV) in both nostrils.
FEV1 ≥ 25% of predicted
Able to comply with all protocol requirements
Signed informed consent prior to any study-mandated procedure
Inclusion criteria at randomization visit (Visit 2):
Women of child-bearing potential must have a negative urine pregnancy test
Basal nasal potential difference (NPD) ≤ - 30.0 mV (equal to or more electrically negative than - 30.0 mV) and total chloride secretion (TCS) ≥ - 5.0 mV for at least one nostril. However, if it is possible to analyze both nostrils, the total chloride secretion (TCS) is to be ≥ - 5.0 mV (equal to or more electrically positive than - 5.0 mV) in both nostrils.
Exclusion Criteria:
Any condition prohibiting the correct measurement of the NPD such as upper respiratory tract infection
Acute upper or lower respiratory tract infection requiring antibiotic intervention within 2 weeks of screening
Lung transplant recipient or patient on a lung transplant waiting list
Any modification in regular treatments (new treatment initiated or discontinued treatment) or modification in dosing within 2 weeks prior to start of Period 1
Moderate/Severe renal impairment (creatinine clearance < 70 mL/min as per Cockroft and Gault)
Systemic corticosteroids (> 10 mg/day prednisone or equivalent) within 14 days prior to screening and up to start of study
Women who are breast-feeding, pregnant, or who plan to become pregnant during the course of the study
History of significant lactose intolerance
Presence of clinically significant diarrhoea (> 3 liquid stools per day for > 7 days) without definable cause within one month prior to screening
Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease
Active or passive smoking
Hypersensitivity to Miglustat or any excipients
Planned treatment or treatment with another investigational drug or therapy (e.g., gene therapy) within one month prior to randomization
Known concomitant life-threatening disease with a life expectancy < 12 months
Indication against Isuprel® (Isoproterenol) including heart diseases.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabelle FAJAC, MD, PhD.
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
Facility Information:
Facility Name
Assistance publique-Hôpitaux de Paris, Hôpital Cochin
City
Paris
ZIP/Postal Code
75014
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Effect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation
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