Effect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation (MIGLUSTAT-CF)

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Miglustat ; placebo; Drug: Placebo ; Miglustat

Detailed Description

The aims of this study are:

1. To determine whether Miglustat can restore the function of the CFTR protein in adult patients with cystic fibrosis homozygous for the F508del mutation
2. To evaluate the safety, tolerability and pharmacokinetics of Miglustat in adult patients with cystic fibrosis homozygous for the F508del mutation.
3. To investigate pharmacokinetic-pharmacodynamic of Miglustat in adult patients with cystic fibrosis homozygous for the F508del mutation.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • Assistance publique-Hôpitaux de Paris, Hôpital Cochin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Miglustat then placebo; 10 patients will received Miglustat then the placebo	Drug: Miglustat ; placebo; 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.
Experimental: Placebo then Miglustat; 10 patients will received Placebo then Miglustat	Drug: Placebo ; Miglustat; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	day 1
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	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	day 1
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.	Day 14
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	day 1
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	day 14
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	day 1
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	day 14
Change of basal NPD in mV	Basal NPD at end-of-treatment minus basal NPD at baseline	day 1
Change of basal NPD in mV	Basal NPD at end-of-treatment minus basal NPD at baseline	day 14
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	day 1
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	day 14
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	day 1
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	day 14
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	day 1
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	day 14
Sweat chloride concentration in mmol/L	Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline	day 1
Sweat chloride concentration in mmol/L	Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline	day 14
FEV1 (in % of predicted)	Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline	day 1
FEV1 (in % of predicted)	Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline	day 14
Change in electrochemical skin conductance	Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline	day 1
Change in electrochemical skin conductance	Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline	day 14
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	day 14

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Actelion; CRCM (Centres de Ressources et de Compétences de la Mucoviscidose)
• Investigators: Study Director: Isabelle FAJAC, MD, PhD., Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2015
• Primary Completion (Actual): April 3, 2017
• Study Completion (Actual): April 3, 2017

Study Registration Dates

• First Submitted: December 10, 2014
• First Submitted That Met QC Criteria: December 19, 2014
• First Posted (Estimate): December 25, 2014

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 16, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Cystic fibrosis; CFTR; Nasal Potential Difference; Miglustat; F508del mutation; Total Chloride Secretion
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Glycoside Hydrolase Inhibitors; Miglustat; 1-Deoxynojirimycin
• Other Study ID Numbers: P120703; 2013-000497-29 (EudraCT Number)

Plan for Individual participant data (IPD)

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