Effect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation

Study Overview
=================
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.

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

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: Miglustat ; placebo
* Drug: Placebo ; Miglustat


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Miglustat then placebo<br>10 patients will received Miglustat then the placebo | Drug: Miglustat ; placebo<br>* 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.<br>|
| Experimental: Placebo then Miglustat<br>10 patients will received Placebo then Miglustat | Drug: Placebo ; Miglustat<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cystic fibrosis, CFTR, F508del mutation, Miglustat, Total Chloride Secretion, Nasal Potential Difference