Effect of Miglustat on the Nasal Potential Difference in Patients With Cystic Fibrosis Homozygous for the F508del Mutation
- Conditions
- Cystic Fibrosis
- Interventions
- Drug: Placebo ; Miglustat
- Registration Number
- NCT02325362
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- 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:
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 16
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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Miglustat then placebo Miglustat ; placebo 10 patients will received Miglustat then the placebo Placebo then Miglustat Placebo ; Miglustat 10 patients will received Placebo then Miglustat
- Primary Outcome Measures
Name Time Method Mean TCS in mV Day 14 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
Name Time Method Change in electrochemical skin conductance day 14 Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline
TCS difference in mV Day 14 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 at end-of-treatment ≤ - 5 mV day 14 The percentage of patients with a TCS response at end-of-treatment ≤ -5mV
Change of basal NPD in mV day 14 Basal NPD at end-of-treatment minus basal NPD at baseline
FEV1 (in % of predicted) day 14 Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline
Number of cells expressing CFTR at the cell membrane (in %percentage) day 14 Percentage of nasal cells expressing CFTR at the cell membrane as assessed by immunochemistry and confocal microscopy
Percentage of patients with a TCS response to treatment ≤ - 5 mV day 14 The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV
Wilschanski's index change day 14 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
Change of the response in NPD after superfusion with amiloride day 14 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 day 14 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
Sweat chloride concentration in mmol/L day 14 Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline
Trial Locations
- Locations (1)
Assistance publique-Hôpitaux de Paris, Hôpital Cochin
🇫🇷Paris, France