Early Signs of Efficacy Study With Riociguat in Adult Homozygous Delta F508 Cystic Fibrosis Patients

• ClinicalTrials.gov Identifier: NCT02170025
• Recruitment Status: Terminated
• Results First Posted: March 29, 2018
• Last Update Posted: September 13, 2018
• Sponsor: Bayer
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Bayer

Study Description

Brief Summary:

Assessment of the safety, tolerability and early signs of efficacy of three times a day orally administered BAY63-2521 in adult delta F508 homozygous Cystic Fibrosis patients not on treatment with Orkambi

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Riociguat (Adempas, BAY63-2521); Drug: Placebo	Phase 2

Detailed Description:

The study consists of two parts. The first part is double-blind, randomized and placebo-controlled. The second part has an open-label study design. In part 1 patients on Orkambi or other CFTR-modulators are excluded. In part 2 patients on Orkambi are allowed to be included under certain conditions.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multi-center Phase 2 Study to Assess the Safety, Tolerability and Early Signs of Efficacy of Tid Orally Administered BAY63-2521 in Adult Delta F508 Homozygous Cystic Fibrosis Patients
• Actual Study Start Date: September 30, 2014
• Actual Primary Completion Date: January 17, 2017
• Actual Study Completion Date: September 22, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Riociguat (Adempas, BAY63-2521); Participants received 0.5 mg BAY63-2521 three times daily (tid) for 14 days. The dose would be increased to 1 mg BAY63-2521 for an additional 14 days, if this was considered safe and tolerable on the basis of the available data for a given patient.	Drug: Riociguat (Adempas, BAY63-2521); Participants received 0.5 mg BAY63-2521 three times daily (tid) for 14 days. The dose would be increased to 1 mg BAY63-2521 for an additional 14 days, if this was considered safe and tolerable on the basis of the available data for a given patient.
Experimental: Placebo; Participants received matching placebo tid.	Drug: Placebo; Participants received matching placebo tid.

Outcome Measures

Primary Outcome Measures :

1. Change of Sweat Chloride Content From Baseline [ Time Frame: Baseline, at day 14 and day 28 in study part 1 ]
   Sweat chloride samples were obtained by using a Macroduct induction and collection device according to standard procedures.

Secondary Outcome Measures :

1. Change of FEV1 From Baseline [ Time Frame: From Baseline to Day 14, Day 28 and Follow-up ]
   Spirometry was performed according to the American Thoracic Society Guidelines 1995 at the time points screening/ baseline, treatment period and follow up.

Eligibility Criteria

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

Criteria

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 40 and 100% 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 kg/ m² (calculated by dividing the patient's weight by the square of his/ her height [kg/ m2])

Inclusion criterion valid for study part 1 only:

- 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 criteria valid for study part 2 only:

• 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
• 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 (patients on Lumacaftor and/or Ivacaftor are excluded in part 1)

Exclusion Criteria:

• Patients with Cystic Fibrosis with any background other than homozygous deltaF508 mutation
• Exclusion criterion only valid for study part 1: Patients receiving treatment with Lumacaftor and/ or 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 abscessus 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 hypertension
• 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

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States, 35233-1711

United States, Colorado

Denver, Colorado, United States, 80206

United States, Missouri

Saint Louis, Missouri, United States, 63110

Belgium

Bruxelles - Brussel, Belgium, 1090

Canada, Ontario

Toronto, Ontario, Canada, M5B 1W8

France

Paris, France, 75674

Germany

Berlin, Germany, 13353

Netherlands

Rotterdam, Netherlands, 3015 CE

United Kingdom

Belfast, North Ireland, United Kingdom, BT12 7AB

London, United Kingdom, SW3 6NP

Sponsors and Collaborators

Bayer

Merck Sharp & Dohme LLC

Investigators

• Study Director: Bayer Study Director; Bayer

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Derichs N, Taylor-Cousar JL, Davies JC, Fajac I, Tullis E, Nazareth D, Downey DG, Rosenbluth D, Malfroot A, Saunders C, Jensen R, Solomon GM, Vermeulen F, Kaiser A, Willmann S, Saleh S, Droebner K, Sandner P, Bear CE, Hoffmann A, Ratjen F, Rowe SM; Rio-CF Study Group. Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis. J Cyst Fibros. 2021 Nov;20(6):1018-1025. doi: 10.1016/j.jcf.2021.07.015. Epub 2021 Aug 19.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02170025
• Other Study ID Numbers: 17020; 2013-004595-35 ( EudraCT Number )
• First Posted: June 23, 2014
• Results First Posted: March 29, 2018
• Last Update Posted: September 13, 2018
• Last Verified: August 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:

Cystic fibrosis; delta F508; Safety; Tolerability; Sweat Chloride; Pharmacokinetics

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Riociguat; Enzyme Activators; Molecular Mechanisms of Pharmacological Action