| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety, tolerability and early signs of efficacy when BAY63-25121 is orally administered three times a day in adult deltaF508 homozygous Cystic Fibrosis patients |
|
| E.2.2 | Secondary objectives of the trial |
- To assess early signs of efficacy of BAY63-2521 versus placebo in homozygous deltaF508 Cystic Fibrosis patients as observed by change from baseline in nasal potential difference (NPD), lung clearance index (LCI) and forced expiratory volume in 1 second (FEV1)
- To assess the pharmacokinetics (PK) of BAY63-2521 and its main metabolite M1 (BAY60 4552) in homozygous deltaF508 Cystic Fibrosis patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Signed informed consent available before any study specific tests or procedures are performed
- Patients must be at least 18 years of age at time of inclusion (i.e. upon signature of informed consent)
- Patient diagnosed with Cystic Fibrosis according to standard criteria (i.e. either elevated sweat chloride content above 60 mmol/ L and/ or genetic testing)
- Patient is homozygous for the deltaF508 mutation
- Patient has a mild-to-moderate stage of lung disease as determined by FEV1 (FEV1 between 60 and 90% predicted)
- Patient has a stable condition of lung disease (no ongoing or recent pulmonary exacerbation and no change in current treatment) within the last 4 weeks prior to screening
- Ability and willingness to understand and follow study procedures for the entire study
- Patients do not smoke. Patients with a history of smoking can be included, if they have refrained from smoking for the last 3 months. If a patients starts smoking during the study participation, he/ she needs to be excluded and considered to be a drop out
- Body mass index (BMI): ≥ 16 and ≤ 32 kg/ m²
- Women of childbearing potential must agree to use adequate contraception when sexually active. ‘Adequate contraception’ is defined as one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception or if a partner has documented azoospermia, a hormone or barrier method must be used in combination. Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration. |
|
| E.4 | Principal exclusion criteria |
- Patients with Cystic Fibrosis with any background other than homozygous deltaF508 mutation
- Patients receiving treatment with Ivacaftor
- Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization. Also any history of moderate hemoptysis within the 3 months prior to inclusion
- Any history of pneumothorax, bronchial artery embolization or massive hemoptysis. Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour period or recurrent bleeding >100 mL/ d over several days
- A positive sputum culture for Burkholderia cenocepacia, Burkholderia dolosa, and/ or Mycobacterium absessus either currently or within the previous year.
- Active allergic broncho-pulmonary aspergillosis
- Current pulmonary exacerbation
- Known history of solid organ transplantation
- Known history of any form of pulmonary arterial hypertension
- Nasal conditions that would interfere with conducting NPD. Well controlled seasonal allergic rhinitis is not an exclusion criterion.
- Known or suspected malignant tumors or a history of malignant tumors
- Unstable liver disease as indicated by
a.bilirubin >2 times upper limit normal (ULN) and/ or hepatic transaminases >5 times ULN
b.signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin < 32g/ L, hepatic encephalopathy > Grade 1a)
- Patients with severe hepatic impairment (Child Pugh C) should be excluded
- Recent evidence (within 12 months prior to inclusion) of distal intestinal obstruction syndrome.
- Patients with creatinine clearance <15 mL/ min or on dialysis need to be excluded.
- Known history of cardiovascular disease unless stable and without therapy changes in the previous 3 months
- Known history of clinically relevant arterial hypotension or clinically relevant orthostatic reactions (e.g. as indicated by syncopes, dizziness)
- Venous/ arterial thromboembolic diseases (particularly deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction)
- Known current thyroid disorders which require treatment (patients with an euthyroid struma who do not need any treatment can participate)
- Known hypersensitivity to the study medication (active substances or excipients of the preparations)
- Documented severe or clinically significant allergic reactions including anaphylaxis or hives
- Intolerance to lactose requiring strictly lactose-free diet and restriction to lactose-free oral medicines (hereditary galactose intolerance, galactose-glucose malabsorption, lactase deficiency)
- Recent history (i.e. in the last 12 months prior to screening) of severe hypoglycemic events in patients with severe Cystic Fibrosis diabetes
- Any medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator
- Smoking (former smokers who have stopped smoking at least 3 months prior to the first screening visit may be included)
- Suspicion of drug or alcohol abuse or recent (i.e. within 2 years) history of drug, medicine or alcohol abuse
- Donation of blood or plasmapheresis after or within 4 weeks of signing the informed consent form
- Concomitant use of the following medication: nitrates or nitric oxide donors (such as amyl nitrite) in any form, PDE 5 inhibitors (such as sildenafil, tadalafil, vardenafil), strong multi pathway CYP and p-gp/ BCRP inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir)
- Clinically relevant ECG findings in screening ECG
- Systolic blood pressure below 95 or above 140 mmHg (after at least 10 min in supine position) at screening
- Diastolic blood pressure below 50 or above 90 mmHg (after at least 10 min in supine position) at screening
- Heart rate below 45 or above 100 beats/ min (after at least 10 min in supine position) at screening
- Clinically relevant findings in the physical examination, which in the opinion of the investigator prevents patients from safe participation in the study
- Positive urine pregnancy test
- Positive cotinine test in conjunction with current tobacco smoking. In case cotinine positivity refers to oral/nasal nicotine consumption only and current smoking is excluded, the patient may be enrolled.
- Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, anti- or human immune deficiency virus (HIV 1+2) antibodies
- Clinically relevant deviations of the screened laboratory parameters from reference ranges outside of expected changes for Cystic Fibrosis patients, especially a hemoglobin value below 110 g/L or a creatinine clearance based on the Cockcroft-Gault formula < 15 ml/ min
- Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| There is no primary endpoint in this study. All eficacy variables are exploratory. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Change from baseline in sweat chloride
- Change from baseline in nasal potential difference
- Change from baseline in lung clearance index
- Change from baseline in forced expiratory volume in 1 second |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Netherlands |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| As for this study, the primary outcome will be analyzed after last patient last visit (LPLV), the end of the study as a whole will be the date when the data base is closed. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
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