Safety and tolerability of BAY63-2521 in Cystic Fibrosis patients

• Register: EUCTR
• Last refreshed on: 11 June 2018
• Main ID: EUCTR2013-004595-35-GB
• Date of registration: 16/05/2014
• Prospective Registration: Yes
• Primary sponsor: Bayer AG
• Public title: Safety and tolerability of BAY63-2521 in Cystic Fibrosis patients
• Scientific title: Multi-center phase 2 study to assess the safety, tolerability and early signs of efficacy of tid orally administered BAY63-2521 in adult deltaF508 homozygous Cystic Fibrosis patients - Early signs of efficacy study with BAY63-2521 in adult homozygous deltaF508 Cystic Fibrosis patients
• Date of first enrolment: 11/09/2014
• Target sample size: 63
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004595-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Part 1: randomized, double-blind and placebo controlled; part 2: open-label sequential study design; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Italy, Netherlands, United Kingdom, United States

Contacts

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

Key inclusion & exclusion criteria

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 on contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilisation) 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 61
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
1. Patients with Cystic Fibrosis with any background other than homozygous delta F508 mutation
2. 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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cystic Fibrosis
MedDRA version: 19.1 Level: PT Classification code 10011762 Term: Cystic fibrosis System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Trade Name: Adempas
Product Name: Adempas 0.5 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: Adempas 1.0 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: Adempas 2.0 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Product Name: Adempas 0.125 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet

Primary Outcome(s)

Main Objective: 1) To assess the safety and tolerability versus placebo in adult delta F508 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 Orkambi as observed by change from baseline in sweat chloride content.

Primary end point(s): There is no primary endpoint in this study. All efficacy variables are exploratory.

Secondary Objective: 1) To assess early signs of efficacy of BAY 63-2521 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 deltaF508 Cystic Fibrosis patients on stable treatment with Orkambi as background therapy
3) To assess efficacy of BAY63-2521 in homozygous deltaF508 Cystic Fibrosis patients on treatment with Orkambi based on observed sweat chloride content and observed forced expiratory volume in 1 second (FEV1)

Timepoint(s) of evaluation of this end point: Not applicable

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Study part 1: after 28 days of treatment
Study part 2: after 56 days of treatment

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.

Secondary ID(s)

BAY63-2521/17020

Source(s) of Monetary Support

Bayer AG