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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2013-004595-35
    Trial protocol
    		 GB   DE   NL   BE  
    Global end of trial date
    22 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2018
    First version publication date
    02 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY63-2521/17020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02170025
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    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 (applicable for part 2 only)
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    21
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    Screening details
    		 Of 31 participants who were screened, 10 failed screening, 21 were randomized.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat (Adempas, BAY63-2521)
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat (Adempas, BAY63-2521)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo tid.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo tid.

    Number of subjects in period 1
    		Riociguat (Adempas, BAY63-2521) Placebo
    Started
    14
    7
    Completed
    12
    7
    Not completed
    2
    0
         Adverse Event
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 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.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tid.

    Reporting group values
    		 Riociguat (Adempas, BAY63-2521) Placebo Total
    Number of subjects
    		 14 7 21
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.1 ± 6.9 29.1 ± 7.2 -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 10 6 16
    Sweat chloride content
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 96.33 ± 17.28 94.50 ± 12.82 -

    End points

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    End points reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 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.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tid.

    Subject analysis set title
    Pharmacodynamic analysis set (PDS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacodynamic analysis set (N=16) included patients who received the medication and who had valid sweat chloride data for efficacy analysis.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set (N=21) included patients who had taken at least one dose of the study medication.

    Primary: Change of sweat chloride content from baseline

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    End point title
    		 Change of sweat chloride content from baseline
    End point description
    Sweat chloride samples were obtained by using a Macroduct induction and collection device according to standard procedures.
    End point type
    Primary
    End point timeframe
    Baseline, at day 14 and day 28 in study part 1
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    9 [1]
    7 [2]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at day 14 in part 1
    7.06 ± 10.26
    8.71 ± 8.20
        Change at day 28 in part 1
    3.44 ± 11.04
    9.00 ± 12.71
    Notes
    [1] - PDS
    [2] - PDS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Bayesian analysis
    Point estimate
    -1.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 6
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    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.
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Bayesian analysis
    Point estimate
    -5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 2.4

    Secondary: Change of FEV1 from baseline

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    End point title
    		 Change of FEV1 from baseline
    End point description
    Spirometry was performed according to the American Thoracic Society Guidelines 1995 at the time points screening/ baseline, treatment period and follow up.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 14, Day 28 and Follow-up
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    9 [3]
    7 [4]
    Units: % predicted value
    arithmetic mean (standard deviation)
        Change at day 14
    0.86 ± 4.59
    2.00 ± 7.28
        Change at day 28
    -0.79 ± 6.04
    2.43 ± 9.55
        Change at follow-up visit
    -0.46 ± 5.51
    2.63 ± 9.50
    Notes
    [3] - PDS
    [4] - PDS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first treatment until 14 days after last treatment
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tid

    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 Participants received 0.5 mg three times daily (tid) BAY63-2521 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.

    Serious adverse events
    		 Placebo Riociguat (Adempas, BAY63-2521)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Riociguat (Adempas, BAY63-2521)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    13 / 14 (92.86%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 14 (14.29%)
         occurrences all number
    1
    2
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    3
    Immune system disorders
    Jarisch-Herxheimer reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 14 (21.43%)
         occurrences all number
    1
    3
    Sinus congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Sputum discoloured
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 14 (14.29%)
         occurrences all number
    1
    3
    Sputum increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
         occurrences all number
    1
    2
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Serum ferritin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Pseudomonas test positive
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Skin injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Face injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 14 (21.43%)
         occurrences all number
    4
    4
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Eye disorders
    Eye allergy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    4
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Faecal volume decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Faeces soft
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2015
    Amendment 5 (dated 15 Apr 2015) to the original clinical study protocol Version 1.0, forming current integrated protocol version 2.0. - A “positive sputum culture for Staphylococcus aureus either currently or within the previous year” was removed as exclusion criterion (part of exclusion criterion 5)
    28 Sep 2015
    Amendment 7 (dated 28 Sep 2015) to the integrated protocol version 2.0 (15 Apr 2015) - FEV1 range for inclusion extended from 60-90% predicted (p) to 40 to 100%p - The range of acceptable blood pressure for inclusion was extended (upper limit of SBP from 140 to 160 mmHg, upper limit of DBP from 90 to 100 mmHg. - Removal of two barrier methods as acceptable contraception - Switching 2 site visits into telephone contacts - NPD measurement was made optional (and related exclusion criterion removed) - Removal of determination of reticulocytes - Inclusion of pharmacokinetic (PK) data into DSMB assessment
    18 Aug 2016
    Amendment 8 (dated 18 Aug 2016) to protocol version 3.0 (28 Sep 2015) - Shortening of safety monitoring period from 12 to 4 h if DSMB review of the data of Cohort 1 did not reveal any safety concerns - LCI measurement was made optional and LCI as well as NPD were changed from secondary endpoints to additional endpoints - Potential combination of 2 visits on one calendar day in patients not performing LCI or NPD - Removal of upper limit of body mass index as inclusion criterion - Removal of cystatin C from the set of laboratory parameters

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Based on multiple factors, the design of part 2 is no longer appropriate. Study was terminated at the end of part 1. No safety concerns were identified.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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