| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| 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 |
|
| 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 |
1) To assess the safety and tolerability versus placebo in adult
deltaF508 homozygous Cystic Fibrosis patients not on treatment with
Orkambi
2) To assess early signs of efficacy versus placebo in adult deltaF508
homozygous Cystic Fibrosis patients not on treatment with Orkambias
observed by change from baseline in sweat chloride content |
|
| E.2.2 | Secondary objectives of the trial |
1) To assess early signs of efficacy of BAY63-2521 compared to placebo in homozygous deltaF508 Cystic Fibrosis patients not on treatment with Orkambi based on observed forced expiratory volume in 1 second (FEV1)
2) To assess the safety and tolerability of oral administration of BAY63-2521 in homozygous ΔF508 Cystic Fibrosis patients on stable treatment with Orkambi as background therapy
3) To assess efficacy of BAY63-2521 in homozygous ΔF508 Cystic Fibrosis patients on treatment with Orkambi based on observed sweat chloride content and observed forced expiratory volume in 1 second (FEV1) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent available before any study specific tests or procedures are performed
2. Patients must be at least 18 years of age at time of inclusion (i.e. upon signature of informed consent)
3. Patient diagnosed with Cystic Fibrosis according to standard criteria (i.e. either elevated sweat chloride content above 60 mmol/ L and/ or genetic testing)
4. Patient is homozygous for the deltaF508 mutation
5. Patient has a mild-to-moderate stage of lung disease as determined by FEV1 (FEV1 between 40 and 100% predicted)
6. 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
7. Ability and willingness to understand and follow study procedures for the entire study
8. 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
9. Body mass index (BMI): ≥ 16 kg/ m²
Inclusion criterion valid for study part 1 only: 10. 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 ). 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.
Inclusion criterion valid for study part 2 only: 11. 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). For patients on Orkambi hormonal methods (including hormonal oral contraceptives) cannot be accepted in this study. They need to choose non-hormonal 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.
Inclusion criterion valid for study part 2 only: 12. Patients receiving Orkambi (Lumcaftor + Ivacaftor) as part of their standard care need to be on stable Orkambi treatment for at least 3 months prior to screening |
|
| E.4 | Principal exclusion criteria |
1. Patients with Cystic Fibrosis with any background other than homozygous deltaF508 mutation
Exclusion criterion 2 only valid for study part 1: Patients receiving
treatment with Lumacaftor and/or Ivacaftor
3. 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
4. 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
5. A positive sputum culture for Burkholderia cenocepacia, Burkholderia dolosa, and/ or Mycobacterium absessus either currently or within the previous year.
6. Active allergic broncho-pulmonary aspergillosis
7. Current pulmonary exacerbation
8. Known history of solid organ transplantation
9. Known history of any form of pulmonary hypertension
10. Known or suspected malignant tumors or a history of malignant tumors
11. 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)
12. Patients with severe hepatic impairment (Child Pugh C) should be excluded
13. Recent evidence (within 12 months prior to inclusion) of distal intestinal obstruction syndrome.
14. Patients with creatinine clearance <15 mL/ min or on dialysis need to be excluded.
15. Known history of cardiovascular disease unless stable and without therapy changes in the previous 3 months
16. Known history of clinically relevant arterial hypotension or clinically relevant orthostatic reactions (e.g. as indicated by syncopes, dizziness)
17. Venous/ arterial thromboembolic diseases (particularly deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction)
18. Known current thyroid disorders which require treatment (patients with an euthyroid struma who do not need any treatment can participate)
19. Known hypersensitivity to the study medication (active substances or excipients of the preparations)
20. Documented severe or clinically significant allergic reactions including anaphylaxis or hives
21. Intolerance to lactose requiring strictly lactose-free diet and restriction to lactose-free oral medicines (hereditary galactose intolerance, galactose-glucose malabsorption, lactase deficiency)
22. Recent history (i.e. in the last 12 months prior to screening) of severe hypoglycemic events in patients with severe Cystic Fibrosis diabetes
23. 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
24. Smoking (former smokers who have stopped smoking at least 3 months prior to the first screening visit may be included)
25. Suspicion of drug or alcohol abuse or recent (i.e. within 2 years) history of drug, medicine or alcohol abuse
26. Donation of blood or plasmapheresis after or within 4 weeks of signing the informed consent form
27. 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)
28. Clinically relevant ECG findings in screening ECG
29. Systolic blood pressure below 95 or above 160 mmHg (after at least 10 min in supine position) at screening
30. Diastolic blood pressure below 50 or above 100 mmHg (after at least 10 min in supine position) at screening
31. Heart rate below 45 or above 100 beats/ min (after at least 10 min in supine position) at screening
32. Clinically relevant findings in the physical examination, which in the opinion of the investigator prevents patients from safe participation in the study
33. Positive urine pregnancy test
34. 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.
35. Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, anti- or human immune deficiency virus (HIV 1+2) antibodies
36. 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
37. Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| There is no primary endpoint in this study. All efficacy variables are exploratory. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Sweat chloride content measured at baseline, day 14 and day 28 in study
part 1 and baseline, day 14, 28, 42 and 56 in study part 2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Study part 1: after 28 days of treatment
Study part 2: after 56 days of treatment |
|
| 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 | Information not present in EudraCT |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| part 1: randomized, double-blind and placebo controlled; part 2: open-label sequential study design |
|
| 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 | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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