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Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)

Lewis J. Rubin, Nazzareno Galiè, Friedrich Grimminger, Ekkehard Grünig, Marc Humbert, Zhi-Cheng Jing, Anne Keogh, David Langleben, Arno Fritsch, Flavia Menezes, Neil Davie, Hossein-Ardeschir Ghofrani
European Respiratory Journal 2015 45: 1303-1313; DOI: 10.1183/09031936.00090614
Lewis J. Rubin
1Dept of Medicine, University of California, San Diego, La Jolla, California, USA
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Nazzareno Galiè
2Dept of Experimental, Diagnostic and Specialty Medicine–DIMES, Bologna University Hospital, Bologna, Italy
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Friedrich Grimminger
3University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
4Member of the German Center of Lung Research (DZL)
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Ekkehard Grünig
5Centre for Pulmonary Hypertension, Thoraxclinic, University Hospital Heidelberg, Heidelberg, Germany
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Marc Humbert
6Université Paris-Sud, Le Kremlin-Bicêtre, France
7AP-HP Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
8INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis, Robinson, France
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Zhi-Cheng Jing
9State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Anne Keogh
10St Vincent's Hospital, Sydney, Australia
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David Langleben
11Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada
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Arno Fritsch
12Global Clinical Development, Bayer HealthCare Pharmaceuticals, Wuppertal, Germany
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Flavia Menezes
13Bayer HealthCare Pharmaceuticals, São Paulo, Brazil
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Neil Davie
12Global Clinical Development, Bayer HealthCare Pharmaceuticals, Wuppertal, Germany
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Hossein-Ardeschir Ghofrani
3University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
4Member of the German Center of Lung Research (DZL)
14Dept of Medicine, Imperial College London, London, UK
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  • Article
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Figures

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  • Additional Files
  • FIGURE 1
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    FIGURE 1

    Patient disposition and number of patients at selected time points during the PATENT-2 study.

  • FIGURE 2
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    FIGURE 2

    Mean change from baseline in 6-min walking distance (6MWD) in the PATENT-1 and PATENT-2 studies. Data are observed values and error bars represent standard error from the mean. #: Absolute value.

  • FIGURE 3
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    FIGURE 3

    The proportion of patients in whom World Health Organization functional class was improved, stabilised or worsened in the former riociguat 2.5 mg maximum patient group, the former riociguat 1.5 mg maximum patient group and the former placebo patient group. Data are observed values. Percentages may not add up to 100% due to rounding.

  • FIGURE 4
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    FIGURE 4

    Kaplan–Meier plots for a) clinical worsening and b) survival in the overall population during the PATENT-2 study. At 1 year, the estimated rate of clinical worsening-free survival was 88% (95% CI 84–91%) and the estimated survival rate was 97% (95% CI 94–98%). Using a worst-case analysis for clinical worsening, where patients who dropped out were assumed to have experienced clinical worsening, the rate of clinical worsening-free survival at 1 year was 84% (95% CI 80–87%). Using a worst-case analysis for survival, where patients who dropped out were assumed to have died, the rate of survival at 1 year was 90% (95% CI 87–93%).

Tables

  • Figures
  • Additional Files
  • TABLE 1

    Patient characteristics at the PATENT-1 study baseline

    CharacteristicFormer riociguat 2.5 mg maximumFormer riociguat 1.5 mg maximumFormer placeboTotal
    Patients n23156109396
    Age years50±1648±1649±1650±16
    Female186 (81)44 (79)87 (80)317 (80)
    Treatment naïve114 (49)30 (54)53 (49)197 (50)
    Pretreated117 (51)26 (46)56 (51)199 (50)
    PAH classification
     Idiopathic136 (59)35 (63)74 (68)245 (62)
     Familial7 (3)1 (2)1 (1)9 (2)
     Connective tissue disease-associated PAH63 (27)13 (23)18 (17)94 (24)
     Congenital heart disease-associated PAH14 (6)7 (13)12 (11)33 (8)
     Portal PH10 (4)02 (2)12 (3)
     Anorexigen/amphetamine-associated PAH1 (0.4)02 (2)3 (1)
    6MWD m364±67359±68378±66367±67
    WHO functional class
     I–IV patients n23156108395
     I/II/III/IV2/42/55/0#7/30/63/0#3/50/45/23/43/54/1#
    100101#
    • Data are presented as mean±sd, n (%) or %, unless otherwise stated. PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; 6MWD: 6-min walking distance; WHO: World Health Organization. #: data does not add up to 100% due to rounding.

  • TABLE 2

    Adverse events (AE) in the PATENT-2 study

    Former riociguat 2.5 mg maximumFormer riociguat 1.5 mg maximumFormer placeboTotal
    Patients23156109396
    Any AE222 (96)55 (98)107 (98)384 (97)
    Individual AEs in >10%  of patients
     Nasopharyngitis55 (24)13 (23)27 (25)95 (24)
     Dizziness53 (23)12 (21)28 (26)93 (23)
     Peripheral oedema50 (22)14 (25)25 (23)89 (22)
     Cough52 (23)6 (11)20 (18)78 (20)
     Diarrhoea32 (14)11 (20)27 (25)70 (18)
     Headache33 (14)8 (14)27 (25)68 (17)
     Nausea41 (18)6 (11)19 (17)66 (17)
     Vomiting30 (13)8 (14)19 (17)57 (14)
     Upper respiratory   tract infection29 (13)8 (14)17 (16)54 (14)
     Dyspnoea28 (12)11 (20)12 (11)51 (13)
     Dyspepsia29 (13)8 (14)10 (9)47 (12)
     Chest pain26 (11)6 (11)14 (13)46 (12)
     Epistaxis22 (10)10 (18)12 (11)44 (11)
    Drug-related AE123 (53)26 (46)66 (61)215 (54)
    Discontinued due to AE25 (11)4 (7)7 (6)36 (9)
    SAEs114 (49)30 (54)60 (55)204 (52)
    Discontinued due to SAE18 (8)4 (7)7 (6)29 (7)
    AEs of special interest  in >5% of patients
     Hypotension24 (10)6 (11)7 (6)37 (9)
     Syncope15 (6)3 (5)10 (9)28 (7)
    Other AEs of interest
     Haemoptysis/pulmonary   haemorrhage16 (7)2 (4)7 (6)25 (6)
    • Data are presented as n or n (%). The mean treatment duration was 95 weeks. SAE: serious AE.

  • TABLE 3

    Change from the PATENT-1 study baseline during the PATENT-1 study and the PATENT-2 study

    Former riociguat 2.5 mg maximumFormer riociguat 1.5 mg maximumPlaceboTotal population PATENT-2 1 year
    PATENT-1 week 12PATENT-2PATENT-1 week 12PATENT-2PATENT-1 week 12PATENT-2
    Week 121 yearWeek 121 yearWeek 121 year
    NT-proBNP
     Observed values pg mL-1−338±1031−322±1206−291±1612−447±954−520±944−235±1214134±809−410±1023−294±1945−284±1653
     Patients207201177464644959380301
    Borg dyspnoea score
     Observed values−0.55±1.52−0.58±1.84−0.52±1.98−0.43±1.19−0.52±1.64−0.18±1.58−0.15±1.88−0.54±1.90−0.45±2.06−0.45±1.94
     Patients22821819255544910810284325
    EQ-5D score
     Observed values0.05±0.210.06±0.220.06±0.240.10±0.260.15±0.240.13±0.240.02±0.220.03±0.240.07±0.200.07±0.23
     Patients22721219355525010610283326
    LPH score
     Observed values−7.6±16.8−11.0±18.9−11.8±16.1−14.3±18.9−2.7±15.1−2.1±15.7
     Patients224209#5554#10593#
    • Data are presented as mean±sd or n. NT-proBNP: N-terminal prohormone of brain natriuretic peptide; EQ-5D: Euro Qol Group 5-Dimension Self-Report Questionnaire. #: Week 8 data shown for Living with Pulmonary Hypertension (LPH) score.

  • TABLE 4

    Clinical worsening events during PATENT-2

    Former riociguatFormer placeboTotal
    2.5 mg maximum1.5 mg maximum
    Patients23156109396
    Patients with clinical worsening#49 (21)11 (20)24 (22)84 (21)
     Heart/lung transplantation1 (0.4)1 (2)02 (1)
     Hospitalisation due to PH25 (11)5 (9)11 (10)41 (10)
     Start of new PH treatment34 (15)9 (16)17 (16)60 (15)
     Decrease in 6MWD due to PH6 (3)1 (2)3 (3)10 (3)
     Persistent worsening in WHO FC due to PH4 (2)01 (1)5 (1)
     Died14 (6)4 (7)9 (8)27 (7)
    • Data are presented as n or n (%). PH: pulmonary hypertension; 6MWD: 6-min walking distance; WHO: World Health Organization; FC: functional class. #: one patient can experience more than one type of event. The mean treatment duration was 95 weeks.

Additional Files

  • Figures
  • Tables
  • Disclosures

    Files in this Data Supplement:

    • A. Fritsch
    • N. Galie
    • N. Davie
    • Z-C. Jing
    • A. Keogh
    • D. Langleben
    • E. Grunig
    • F. Grimminger
    • F. Menezes
    • H-A. Ghofrani
    • L.J. Rubin
    • M. Humbert
  • Supplementary material

    Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

    Files in this Data Supplement:

    • Supplementary text and tables - Text and tables
    • Supplementary figures - Figures S1-S4
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Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)
Lewis J. Rubin, Nazzareno Galiè, Friedrich Grimminger, Ekkehard Grünig, Marc Humbert, Zhi-Cheng Jing, Anne Keogh, David Langleben, Arno Fritsch, Flavia Menezes, Neil Davie, Hossein-Ardeschir Ghofrani
European Respiratory Journal May 2015, 45 (5) 1303-1313; DOI: 10.1183/09031936.00090614

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Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)
Lewis J. Rubin, Nazzareno Galiè, Friedrich Grimminger, Ekkehard Grünig, Marc Humbert, Zhi-Cheng Jing, Anne Keogh, David Langleben, Arno Fritsch, Flavia Menezes, Neil Davie, Hossein-Ardeschir Ghofrani
European Respiratory Journal May 2015, 45 (5) 1303-1313; DOI: 10.1183/09031936.00090614
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