E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that miglustat restores the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis homozygous for the ∆F508 mutation as reflected in nasal potential difference (NPD). |
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E.2.2 | Secondary objectives of the trial |
. To investigate the effect of miglustat on the concentration of sodium and chloride in sweat in this patient population.
· To investigate the safety and tolerability of miglustat in this patient population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
· Aged 12 years and older
· Male or female
· Non-pregnant women who are to remain non-pregnant for 3 months after the end of the study: only women who are surgically sterile, who are in the menopause (no menstruation for at least one year) or those of childbearing potential who are using a reliable method of contraception. Reliable methods of contraception for female patients include the following: Ø barrier type devices (e.g., female condom, diaphragm and contraceptive sponge) used ONLY in combination with a spermicide Ø intrauterine devices Ø oral contraceptive agent Ø Depo-Provera TM (medroxyprogesterone acetate) Ø levonorgestrel implants Abstention, the rhythm method or contraception by the partner alone are NOT reliable methods of contraception. For children, a reliable method of contraception must be considered, if appropriate.
· Accepting for the duration of the study and for 3 months thereafter to use a condom and not to procreate a child (males only)
· Cystic fibrosis patients homozygous for the ∆F508 mutation as confirmed by genetic test
· Signed informed consent prior to any study-mandated procedure. |
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E.4 | Principal exclusion criteria |
· Any condition prohibiting the correct measurement of the NPD such as upper respiratory tract infection
· Acute upper respiratory tract or pulmonary exacerbation requiring antibiotic intervention within 2 weeks of screening
· Severe renal impairment (creatinine clearance < 30 ml/min as per Cockroft and Gault)
· Female patients who will not undergo a pregnancy test prior to enrollment into the study
· History of significant lactose intolerance
· History of neuropathy
· History of cataracts or known increased risk of cataract formation
· Presence of clinically significant diarrhea (>3 liquid stools per day for >7 days) without definable cause within 1 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
· FEV1 < 25% of predicted normal
· Oxygen saturation at rest < 88%
· Active or passive smoking as measured using the Smokelyzer®
· Hypersensitivity to miglustat or any excipients
· Planned treatment or treatment with another investigational drug or therapy (e.g., gene therapy) within 1 month prior to randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint:
Change from baseline (pre-dose on day 1) to end-of-treatment (day 8) in nasal potential difference (NPD) in response to isoproterenol in chloride-free buffer in the presence of amiloride Assumptions: · A difference of 3.2 mV to the isoproterenol challenge between placebo and miglustat treatment (as measured after the morning dose on day 8 of each period) represents about 20% of the response seen in non cystic fibrosis subjects, which is considered clinically significant. · No carry-over effect is expected with a washout of 2 weeks. · No period effect is expected · It is assumed that the NPD is normally distributed and that the standard deviation of the difference of 2 repeat measurements is 4.4 mV.
Secondary endpoints: · Change from baseline to end-of-treatment in baseline NPD response · Change from baseline to end-of-treatment in amiloride-sensitive NP · Change from baseline to end-of-treatment in low-chloride sensitive NPD in the presence of amiloride · Change from baseline to end-of-treatment in ATP-sensitive NPD in the presence of chloride-free buffer, amiloride, and isoproterenol · Change from baseline to end-of-treatment in sweat sodium and chloride concentration
Baseline and end-of-treatment are defined as predose on day 1 and 8, respectively, of both treatment periods |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
2-period/2-treatment crossover, proof-of-concept |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |