Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis, delta F508, Safety, Tolerability, Sweat Chloride, Pharmacokinetics
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
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.
Interventions
DRUGRiociguat (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.
DRUGPlacebo
Participants received matching placebo tid.
Sponsors
Merck Sharp & Dohme LLC
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Sweat Chloride Content From Baseline | 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
| Measure | Time frame | Description |
|---|---|---|
| Change of FEV1 From Baseline | 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. |
Countries
Belgium, Canada, France, Germany, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at multiple centers in 7 countries worldwide between 30-Sep-2014 (first subject first visit) and 31-Jan-2017 (last subject last visit).
Pre-assignment details
Of 31 participants who were screened, 10 failed screening, 21 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 14 |
| Placebo Participants received matching placebo tid | 7 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Riociguat (Adempas, BAY63-2521) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 27.1 Years STANDARD_DEVIATION 6.9 | 29.1 Years STANDARD_DEVIATION 7.2 | 27.8 Years STANDARD_DEVIATION 6.9 |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
| Sweat chloride content | 96.33 mmol/L STANDARD_DEVIATION 17.28 | 94.50 mmol/L STANDARD_DEVIATION 12.82 | 95.53 mmol/L STANDARD_DEVIATION 15.03 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 13 / 14 |
| serious Total, serious adverse events | 1 / 7 | 1 / 14 |
Outcome results
Primary
Change of Sweat Chloride Content From Baseline
Sweat chloride samples were obtained by using a Macroduct induction and collection device according to standard procedures.
Time frame: Baseline, at day 14 and day 28 in study part 1
Population: Pharmacodynamic analysis set (N=16) included patients who received the medication and who had valid sweat chloride data for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change of Sweat Chloride Content From Baseline | Change at day 14 in part 1 | 7.06 mmol/L | Standard Deviation 10.26 |
| Riociguat (Adempas, BAY63-2521) | Change of Sweat Chloride Content From Baseline | Change at day 28 in part 1 | 3.44 mmol/L | Standard Deviation 11.04 |
| Placebo | Change of Sweat Chloride Content From Baseline | Change at day 14 in part 1 | 8.71 mmol/L | Standard Deviation 8.2 |
| Placebo | Change of Sweat Chloride Content From Baseline | Change at day 28 in part 1 | 9.00 mmol/L | Standard Deviation 12.71 |
Comparison: Treatment effect describes the difference in outcomes between 0.5 mg riociguat and placebo on Day 14. This was an exploratory analysis. For sample size determination a probabilistic assessment on predicted point estimates and width of credible intervals was performed.90% CI: [-8.7, 6]
Comparison: Treatment effect describes the difference in outcomes between 1.0 mg riociguat and placebo on Day 28. This was an exploratory analysis. For sample size determination a probabilistic assessment on predicted point estimates and width of credible intervals was performed.90% CI: [-12.4, 2.4]
Secondary
Change of FEV1 From Baseline
Spirometry was performed according to the American Thoracic Society Guidelines 1995 at the time points screening/ baseline, treatment period and follow up.
Time frame: From Baseline to Day 14, Day 28 and Follow-up
Population: Pharmacodynamic analysis set (N=16) included patients who received the medication and who had valid sweat chloride data for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change of FEV1 From Baseline | Change at day 14 | 0.86 % predicted value | Standard Deviation 4.59 |
| Riociguat (Adempas, BAY63-2521) | Change of FEV1 From Baseline | Change at day 28 | -0.79 % predicted value | Standard Deviation 6.04 |
| Riociguat (Adempas, BAY63-2521) | Change of FEV1 From Baseline | Change at follow-up visit | -0.46 % predicted value | Standard Deviation 5.51 |
| Placebo | Change of FEV1 From Baseline | Change at day 14 | 2.00 % predicted value | Standard Deviation 7.28 |
| Placebo | Change of FEV1 From Baseline | Change at day 28 | 2.43 % predicted value | Standard Deviation 9.55 |
| Placebo | Change of FEV1 From Baseline | Change at follow-up visit | 2.63 % predicted value | Standard Deviation 9.5 |