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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02325362
Recruitment Status : Completed
First Posted : December 25, 2014
Last Update Posted : March 19, 2018
Sponsor:
Collaborators:
Actelion
CRCM (Centres de Ressources et de Compétences de la Mucoviscidose)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Miglustat ; placebo Drug: Placebo ; Miglustat Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : March 17, 2015
Actual Primary Completion Date : April 3, 2017
Actual Study Completion Date : April 3, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis
Drug Information available for: Miglustat

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.




Primary Outcome Measures :
  1. Mean TCS in mV [ Time Frame: day 1 ]
    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

  2. Mean TCS in mV [ Time Frame: 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 :
  1. TCS difference in mV [ Time Frame: day 1 ]
    TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.

  2. TCS difference in mV [ Time Frame: Day 14 ]
    TCS difference is calculated as the change in measurements of TCS for the right and left nostrils independently for each patient.

  3. Percentage of patients with a TCS response to treatment ≤ - 5 mV [ Time Frame: day 1 ]
    The percentage of patients with a TCS response to treatment defined as a difference in TCS from baseline to end-of-treatment ≤ -5mV

  4. Percentage of patients with a TCS response to treatment ≤ - 5 mV [ Time Frame: 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

  5. Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV [ Time Frame: day 1 ]
    The percentage of patients with a TCS response at end-of-treatment ≤ -5mV

  6. Percentage of patients with a TCS at end-of-treatment ≤ - 5 mV [ Time Frame: day 14 ]
    The percentage of patients with a TCS response at end-of-treatment ≤ -5mV

  7. Change of basal NPD in mV [ Time Frame: day 1 ]
    Basal NPD at end-of-treatment minus basal NPD at baseline

  8. Change of basal NPD in mV [ Time Frame: day 14 ]
    Basal NPD at end-of-treatment minus basal NPD at baseline

  9. Change of the response in NPD after superfusion with amiloride [ Time Frame: day 1 ]
    NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline

  10. Change of the response in NPD after superfusion with amiloride [ Time Frame: day 14 ]
    NPD after superfusion with amiloride at end-of-treatment minus NPD after superfusion with amiloride at baseline

  11. Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride [ Time Frame: day 1 ]
    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

  12. Change of the response in NPD after superfusion with a chloride-free buffer in the presence of amiloride [ Time Frame: 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

  13. Wilschanski's index change [ Time Frame: day 1 ]
    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

  14. Wilschanski's index change [ Time Frame: 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

  15. Sweat chloride concentration in mmol/L [ Time Frame: day 1 ]
    Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline

  16. Sweat chloride concentration in mmol/L [ Time Frame: day 14 ]
    Sweat chloride concentration at end-of-treatment minus sweat chloride concentration at baseline

  17. FEV1 (in % of predicted) [ Time Frame: day 1 ]
    Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline

  18. FEV1 (in % of predicted) [ Time Frame: day 14 ]
    Pulmonary function FEV1: mean Forced expiry volume in 1 second. FEV1 at end-of-treatment minus FEV1 at baseline

  19. Change in electrochemical skin conductance [ Time Frame: day 1 ]
    Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline

  20. Change in electrochemical skin conductance [ Time Frame: day 14 ]
    Electrochemical skin conductance at end-of-treatment minus electrochemical skin conductance at baseline

  21. Number of cells expressing CFTR at the cell membrane (in %percentage) [ Time Frame: day 14 ]
    Percentage of nasal cells expressing CFTR at the cell membrane as assessed by immunochemistry and confocal microscopy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02325362


Locations
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France
Assistance publique-Hôpitaux de Paris, Hôpital Cochin
Paris, France, 75014
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Actelion
CRCM (Centres de Ressources et de Compétences de la Mucoviscidose)
Investigators
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Study Director: Isabelle FAJAC, MD, PhD. Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02325362    
Other Study ID Numbers: P120703
2013-000497-29 ( EudraCT Number )
First Posted: December 25, 2014    Key Record Dates
Last Update Posted: March 19, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Cystic fibrosis
CFTR
F508del mutation
Miglustat
Total Chloride Secretion
Nasal Potential Difference
Additional relevant MeSH terms:
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Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Miglustat
1-Deoxynojirimycin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Glycoside Hydrolase Inhibitors
Hypoglycemic Agents
Physiological Effects of Drugs