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MabCute: A Study Comparing Maintenance Subcutaneous Rituximab With Observation Only in Participants With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma Who Had Responded to Rituximab-based Immunochemotherapy Induction and 2-year Maintenance With Subcutaneous Rituximab

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01461928
Collaborator
(none)
692
Enrollment
180
Locations
2
Arms
77.4
Actual Duration (Months)
3.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This multicenter, randomized, open-label, parallel-group study will evaluate the efficacy and safety of subcutaneously administered rituximab in comparison with observation only as maintenance therapy in participants with relapsed or refractory indolent Non-Hodgkin's lymphoma (NHL). All participants will receive induction therapy with rituximab (375 milligrams per square meter [mg/m^2] intravenously [IV] in Cycle 1, then 1400 mg subcutaneous [SC] every 3-4 weeks) plus standard chemotherapy for 6-8 months; followed by 24 months of maintenance I period with rituximab (1400 mg SC every 8 weeks). Participants completing therapy and showing partial or complete response will be randomized to receive either rituximab (1400 mg SC every 8 weeks) or observation with no treatment during maintenance II period and will be followed for at least 15 months. Anticipated time on study treatment is until disease progression, unacceptable toxicity or end of study, whichever occurs first.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
692 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Study Comparing Maintenance Therapy With Subcutaneous Rituximab Continued Until Progression With Observation Only in Patients With Relapsed or Refractory, Indolent Non-Hodgkin's Lymphoma Who Completed and Responded to Rituximab-based Immunochemotherapy Induction and Initial 2-year Rituximab Maintenance Therapy Administered Subcutaneously
Actual Study Start Date :
Dec 20, 2011
Actual Primary Completion Date :
Jun 2, 2018
Actual Study Completion Date :
Jun 2, 2018

Arms and Interventions

Arm Intervention/Treatment
Other: Maintenance II Period Observation Only

Participants will receive standard chemotherapy regimen in combination with 375 mg/m^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); no treatment in Maintenance II period until disease progression or end of study, whichever occurs first.

Drug: Chemotherapy (Induction Period)
Participants will receive standard combination chemotherapy every 3-4 weeks for 6 to 8 months. The chemotherapy regimen will be selected at Investigator's discretion, for individual participant. Study protocol does not enforce any particular chemotherapy regimen.

Drug: Rituximab
Participants will receive rituximab according to the regimen specified in individual arm.
Other Names:
  • Rituxan
  • MabThera
  • RO0452294

    		•
    Experimental: Maintenance II Period Rituximab

    Participants will receive standard chemotherapy regimen in combination with 375 mg/m^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); 1400 mg rituximab SC every 8 weeks until disease progression or end of study, whichever occurs first (Maintenance II period).

    Drug: Chemotherapy (Induction Period)
    Participants will receive standard combination chemotherapy every 3-4 weeks for 6 to 8 months. The chemotherapy regimen will be selected at Investigator's discretion, for individual participant. Study protocol does not enforce any particular chemotherapy regimen.

    Drug: Rituximab
    Participants will receive rituximab according to the regimen specified in individual arm.
    Other Names:
  • Rituxan
  • MabThera
  • RO0452294

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maintenance II: Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia [From randomization (Maintenance II) up to disease progression or death, whichever occurs first (up to approximately 24 months)]

      Progression free survival from randomization (PFSrand) is defined as the time from date of randomization to the date of first documented disease progression or death, whichever occurs first. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed. The Observation arm did not include one participant with AE outcome of death reported retrospectively 2 months after discontinuation from study (censored as having no event on Day 456 post-randomization).

    Secondary Outcome Measures

    1. Number of Participants With Adverse Events (AEs), Serious AEs, and Infusion/Administration-related Reactions (IRRs/ARRs) [From day of first rituximab induction dose up to day of disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)]

      An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 (obtained retrospectively) were collected for this arm. Therefore arms are not comparable overall.

    2. Event-free Survival (Time to Treatment Failure) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia [From day of first rituximab induction dose up to day of any treatment failure, including disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)]

      Event-Free Survival was measured from the day of first rituximab Induction dose through Maintenance I and Maintenance II rituximab arm until the date of any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g. disease progression, toxicity, patient preference, initiation of new anti-lymphoma treatment, or death). Treatment discontinuation was considered as an event and was not applicable to the randomized observation arm.

    3. Time to Next Lymphoma Treatment (TNLT) [From day of first rituximab induction dose up to any new lymphoma treatment (up to approximately 87 months)]

      Time to next lymphoma treatment (TNLT) is defined as the time from date of first rituximab induction dose to the date date of first documented intake of any new antilymphoma treatment (chemotherapy, radiotherapy, immunotherapy, etc.).

    4. Overall Survival [From day of first rituximab induction dose up to death (up to approximately 87 months)]

      Overall survival from first induction treatment (OSRegist) is defined as the time from date of first rituximab induction dose to the date of death, irrespective of cause. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed.

    5. Maintenance II: Overall Survival [From randomization (Maintenance II) up to death (up to approximately 24 months)]

      Overall survival from randomization (OSrand) is defined as the time from date of randomization to the date of death, irrespective of cause.

    6. Percentage of Participants With Partial or Complete Tumor Response (PR/CR) Assessment at End of Induction Using 1999 International Working Group Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia [From day of first rituximab induction dose up to end of induction period (up to approximately 8 months)]

      Overall response rate is defined as the proportion of responders at the end of the Induction period. A responder is defined as a participant experiencing either CR or PR tumor response according to the Cheson response criteria for indolent lymphoma or the recommendations for Waldenström's macroglobulinemia.

    7. Maintenance I: Percentage of Participants With Conversion of PR to CR Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia [From day of first rituximab induction dose up to end of Maintenance I period (up to approximately 32 months)]

    8. Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia [From day of first rituximab induction dose up to disease progression or death, whichever occurs first (up to approximately 87 months)]

      Progression free survival from first induction treatment (PFSregist) is defined as the time from date of first rituximab induction dose to the date of first documented disease progression or death by any cause, whichever occurs first.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically confirmed Cluster of Differentiation 20-positive (CD20+) follicular NHL Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma) according to World Health Organization (WHO) classification system

    • Participants must have received and must have relapsed or been refractory to, one or more lines of adequate therapy prior to enrollment, including at least one line consisting of immunotherapy and/or chemotherapy and/or radiotherapy

    • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 2

    Exclusion Criteria:

    • Transformation to high-grade lymphoma

    • Aggressive lymphoma (for example, mantle cell lymphoma [MCL])

    • Presence or history of central nervous system (CNS) lymphomatous disease

    • Other malignancy within 5 years prior to enrollment, except for curatively treated carcinoma in situ of the cervix, squamous cell carcinoma of the skin or basal cell skin cancer, or cervical carcinoma Stage 1B or less, breast cancer in situ or localized prostate cancer Stage T1c if treated with curative intent and relapse- and metastasis-free for at least 2 years prior to enrollment

    • Inadequate hematological, hepatic or renal function

    • Known human immunodeficiency virus (HIV) infection

    • Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B or C)

    • Pregnant or breastfeeding women

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University "Mother Theresa" Hospital Center; Oncology Department Tirana Albania 1000
    2 CEMIC Saavedra Buenos Aires Argentina 1431
    3 Instituto Damic Cordoba Argentina X5003DCE
    4 Hospital Privado de Comunidad; Oncology Mar Del Plata Argentina 7600
    5 Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie Graz Austria 8036
    6 Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie Innsbruck Austria 6020
    7 Kepler Universitätskliniken GmbH - Med Campus III; III. Medizinische Abteilung Linz Austria 4020
    8 Landeskrankenhaus Rankweil; Interne E Rankweil Austria 6830
    9 Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Hämatologie & Hämostaseologie Wien Austria 1090
    10 Centro de Tratamento Oncologico - CETRON Rio de janeiro RJ Brazil 22250-906
    11 Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia Passo Fundo RS Brazil 99010-260
    12 Hospital das Clinicas - UFRGS Porto Alegre RS Brazil 90035-003
    13 Centro de Pesquisas Oncologicas - CEPON Florianopolis SC Brazil 88034-000
    14 Hospital de Cancer de Barretos Barretos SP Brazil 14784-400
    15 Instituto de Ensino e Pesquisa Sao Lucas - IEP Sao Paulo SP Brazil 01236-030
    16 Hospital das Clinicas - FMUSP; Hematologia Sao Paulo SP Brazil 05403-000
    17 Hospital Santa Marcelina;Oncologia Sao Paulo SP Brazil 08270-070
    18 UMHAT Dr Georgi Stranski; Hematology Pleven Bulgaria 5800
    19 Tokuda Hospital Sofia; Hematology department Sofia Bulgaria 1407
    20 UMHAT Alexandrovska EAD; Hematology Sofia Bulgaria 1431
    21 Centro Javeriano de Oncología Bogota Colombia
    22 Fundacion Santa Fe de Bogotá Bogota Colombia
    23 Instituto Nacional de Cancerologia; Hematology Bogota Colombia
    24 Hospital Abel Gilbert Ponton; Oncology Guayaquil Ecuador EC090104
    25 Teodoro Maldonado Carbo Hospital; Oncology Service Guayaquil Ecuador EC090150
    26 Hospital Solca Portoviejo; Oncologia Portoviejo Ecuador EC130104
    27 Hospital Solca Quito; Oncologia Quito Ecuador EC170124
    28 Kasr Eieny Uni Hospital; Oncology (Nemrock) Cairo Egypt 11562
    29 Centre Hospitalier Uni Ire; Service Des Maladies Du Sang Angers Cedex 9 France 49933
    30 CH Henri Mondor; Med Interne Neuro Endocrinologie Aurillac France 15000
    31 Centre Hospitalier de La Cote Basque; Hematologie Bayonne France 64109
    32 Hopital Jean Minjoz; Hematologie Besancon France 25030
    33 Hopital Augustin Morvan; Hematologie Brest France 29609
    34 Institut d'Hématologie de Basse Normandie Caen France 14000
    35 CH Metropole de Savoie CHAMBERY Cedex France 73011
    36 Chu Estaing; Hematologie Clinique Adultes Clermont Ferrand France 63003
    37 Ch Sud Francilien; Hematologie Oncologie Corbeil Essonnes France 91000
    38 Hopital Henri Mondor Creteil France 94010
    39 Chu Site Du Bocage;Hematologie Clinique Dijon France 21079
    40 Centre Hospitalier Departemental Les Oudairies La Roche Sur Yon France 85925
    41 Hôpital Albert Michallon; Hematologie Clinique La Tronche France 38700
    42 Hopital Andre Mignot; Hematologie - Oncologie Le Chesnay France 78157
    43 Ch Du Mans; Medecine Hematologie Oncologie Le Mans France 72037
    44 Hopital Claude Huriez; Hematologie Lille France 59037
    45 Hopital Uni Ire Dupuytren; Hematologie Limoges France 87042
    46 Hopital Nord; Laboratoire D'Hematologie Marseille France 13015
    47 Hôpital Lapeyronie; Hématologie Oncologie Médicale Montpellier France 34295
    48 Hopital Emile Muller; Hematologie Mulhouse France 68070
    49 Hopital Hotel Dieu Et Hme; Clinique Dermatologique Nantes France 44093
    50 Centre Antoine Lacassagne;B4 Hematologie Cancerologie Nice France 06189
    51 Hopital Pitie Salpetriere; Hematologie Clinique Paris France 75651
    52 Hopital De Haut Leveque; Hematologie Clinique Pessac France 33604
    53 Centre Henri Becquerel; Hematologie Rouen France 76038
    54 Hopital Purpan; Hematologie Clinique Toulouse France 31059
    55 Gemeinschaftspraxis Dr. Bueckner und Dr. Nueckel Bochum Germany 44787
    56 Klinikum Darmstadt GmbH; Med. Klinik V; Onkologie & Hämatologie Darmstadt Germany 64283
    57 St. Johannes Hospital; Abt. für Hämatologie und Onkologie Dortmund Germany 44137
    58 BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie Dresden Germany 01307
    59 Gemeinschaftspraxis Dr. med. J. Mohm und Dr. med. G. Prange-Krex; Fachaerzte fuer Innere Medizin Dresden Germany 01307
    60 Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik Greifswald Germany 17475
    61 Internistisch-Onkologische Gemeinschaftspraxis; Dres. Rohrberg, Hurtz, Schma usw. Halle Germany 06110
    62 OncoResearch Lerchenfeld GmbH Hamburg Germany 22081
    63 Onkologische Schwerpunktpraxis (Eps-Gmbh) Jena Germany 07743
    64 Dres. Richard Hansen Susanne Pfitzner-Dempfle und Manfred Reeb Kaiserslautern Germany 67655
    65 Dres. Barbara Tschechne Stefanie Luft und Wolf-Oliver Jordan Lehrte Germany 31275
    66 Onkologische Schwerpunktpraxis Lübeck Lübeck Germany 23562
    67 Onkologische Gemeinschaftspraxis Magdeburg Germany 39104
    68 Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach Marburg Germany 35037
    69 Dres. Michael Maasberg Marion Schmitz und Maria Theresia Keller Mayen Germany 56727
    70 Klinikum Grosshadern der LMU Muenchen Germany 81377
    71 Staedtisches Krankenhaus Muenchen-Schwabing, Haematologie & Onkolgie München Germany 80804
    72 Hamatol Onkol Praxisgemeinschaft Dres H H-D Schick/D Schick München Germany 81241
    73 Klinikum rechts der Isar der TU München; III. Medizinischen Klinik (Hämatologie/Onkologie) München Germany 81675
    74 Praxis Dr.med. Jens Uhlig Naunhof Germany 04683
    75 Oncologianova GmbH Recklinghausen Germany 45659
    76 Klinik der Uni Regensburg; Hämatologie/Onkologie, Studienzentrale Regensburg Germany 93053
    77 Dres. Andreas Hübner, Andreas Lück und Petra Bruhn Rostock Germany 18107
    78 Dres. Ulrich Banhardt und Thomas Fietz Singen Germany 78224
    79 Dres. Emil Höring Matthias Respondek und Ulrike Schwinger Stuttgart Germany 70190
    80 General Hospital of Athens Evangelismos; Hematology Athens Greece 106 76
    81 Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine Athens Greece 115 27
    82 University Hospital of Ioannina; Hematology Ioannina Greece 455 00
    83 University Hospital of Larissa; Hematology Dept. Larissa Greece 411100
    84 University Hospital Of Patras; Dept. Of Internal Medicine-Hematology Division Patras Greece 265 00
    85 Semmelweis University, First Dept of Medicine Budapest Hungary 1083
    86 St Laszlo Hospital, Pharmacy Budapest Hungary 1097
    87 National Institute of Oncology, A Dept of Internal Medicine Budapest Hungary 1122
    88 Uni of Debrecen; 2Nd Clinic of Internal Medicine Debrecen Hungary 4004
    89 University of Pecs, I st Dept of Internal Medicine Pecs Hungary 7624
    90 A.O. Universitaria Federico II Di Napoli; Oncologia Ed Endocrinologia Clinica Napoli Campania Italy 80131
    91 Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica Napoli Campania Italy 80131
    92 Ospedale Cardarelli; Divisione Di Ematologia Napoli Campania Italy 80131
    93 A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna Bologna Emilia-Romagna Italy 40138
    94 A.O.U. Policlinico di Modena-Dipartimento di Medicina Diagnostica, Clinica e di Sanità pubblica Modena Emilia-Romagna Italy 41100
    95 A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica Udine Friuli-Venezia Giulia Italy 33100
    96 Universita' Degli Studi La Sapienza-Ist.Di Ematologia; Dip Biot Cel e Ematol Roma Lazio Italy 00161
    97 A.O. Universitaria S. Martino Di Genova; Ematologia 1 Genova Liguria Italy 16132
    98 Ospedale Maggiore Di Milano; U.O. Ematologia I - Padiglione Marcora Milano Lombardia Italy 20122
    99 Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia Milano Lombardia Italy 20162
    100 A.O. Universitaria S. Giovanni Battista-Molinette Di Torino; Ematologia 1 Torino Piemonte Italy 10126
    101 Uni Degli Studi Di Bari, Policlinico; Cattedra Di Ematologia,Dipart. Di Medicina Interna E Publica Bari Puglia Italy 70124
    102 Ospedale Ferrarotto; Divisione Di Ematologia Via S. Sofia 78 Sicilia Italy 95123
    103 Az. Osp. Di Careggi; Divisione Di Ematologia Firenze Toscana Italy 50135
    104 Ospedale Santa Chiara; Unita Operativa Di Ematologia Pisa Toscana Italy 56100
    105 A.O. Universitaria Senese; Ematologia Siena Toscana Italy 53100
    106 Azienda Sanitaria Di Bolzano; Ematologia E Centro Trapianto Mid.Osseo Bolzano Trentino-Alto Adige Italy 39100
    107 Uni Degli Studi; Dip.Med.Clinica E Sperim. Ematologia Padova Veneto Italy 35128
    108 Ospedale Ca Foncello; Ematologia Treviso Veneto Italy 31100
    109 Uni Di Verona Policlinico G.B. Rossi; Divisione E Cattedra Di Ematologia Verona Veneto Italy 37130
    110 Seamen' Hospital' Dept. of haematology Klaipeda Lithuania 92288
    111 Haukeland Universitetssykehus Bergen Norway 5021
    112 Oslo Universitetssykehus HF; Radiumhospitalet Oslo Norway 0310
    113 Helse Stavanger HF, Stavanger Universitetssjukehus; Klinikk for Blod og kreftsykdommer Stavanger Norway 4011
    114 St. Olavs Hospital HF, Kreftavdelingen, Gastrosentret Trondheim Norway 7030
    115 Policlinica de Diagnostic Rapid Brasov Romania 500152
    116 County Clinical Emergency Hospital Brasov Brasov Romania 500360
    117 Institutul Clinic Fundeni; Hematologie Bucharest Romania 022338
    118 Spitalul Clinic Coltea; Clinica de Hematologie Bucuresti Romania 030171
    119 Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie Targu-mures Romania 540136
    120 Spitalul Clinic municipal de Urgenta Timisoara; Clinica de Hematologie Timisoara Romania 300079
    121 Regional Oncology Center Chelyabinsk Russian Federation 454087
    122 N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis Moscow Russian Federation 115478
    123 Rus Med Academy for Postgraduate Education; Oncology Department Moscow Russian Federation 123995
    124 City Clin Hosp n.a. S.P.Botkin Moscow Russian Federation 125101
    125 Regional Clinical Hospital N.A. Semashko; Hematology Nizhny Novgorod Russian Federation 603126
    126 Leningrad Regional Clinical Hospital St Petersburg Russian Federation 194291
    127 Petrov Research Inst. of Oncology St Petersburg Russian Federation 197758
    128 SRI of Hematology and Transfusiology St. Petersburg Russian Federation 191024
    129 National Oncology Inst. ; Dept. of Haematology Bratislava Slovakia 833 10
    130 Uni Hospital ; Dept. of Haematol. & Transfusion Medicine Martin Slovakia 036 59
    131 Institute of Oncology Ljubljana Ljubljana Slovenia 1000
    132 Hospital General Universitario de Elche; Servicio de Oncologia Elche Alicante Spain 03203
    133 Hospital Univ. Central de Asturias; servicio de Hematologia Oviedo Asturias Spain 33011
    134 Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia Badalona Barcelona Spain 08915
    135 Hospital de Jerez de la Frontera; Servicio de Hematologia Jerez de La Frontera Cadiz Spain 11407
    136 Hospital Universitario Son Espases Palma De Mallorca Islas Baleares Spain 07014
    137 Hospital Quiron de Madrid; Servicio de Hematologia Pozuelo de Alarcon Madrid Spain 28223
    138 Hospital Universitario de Canarias;servicio de Hematologia La Laguna Tenerife Spain 38320
    139 Hospital Universitario de Canarias;servicio de Oncologia La Laguna Tenerife Spain 38320
    140 Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia Barcelona Spain 08025
    141 Hospital Universitari Vall d'Hebron; Servicio de Hematologia Barcelona Spain 08035
    142 Hospital Duran i Reynals; Servicio de Hematologia Barcelona Spain 08907
    143 Hospital San Pedro De Alcantara; Servicio de Hematologia Caceres Spain 10003
    144 Hospital Universitario San Cecilio; Servicio de Oncologia Granada Spain 18003
    145 Complejo Hospitalario de Jaen- Hospital Universitario Medico Quirurgico; Servicio de Hematologia Jaen Spain 23007
    146 HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia Madrid Spain 28050
    147 Hospital Clinico Universitario Virgen de la Victoria; Servicio de Hematologia Malaga Spain 29010
    148 Complejo Hospitalario Universitario de Ourense, Servicio de Hematologia Orense Spain 32005
    149 Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia Valencia Spain 46015
    150 Complejo Hospitalario Zamora- H. Virgen de la Concha; Servicio de Hematología Zamora Spain 49002
    151 Hospital Royo Villanova; Servicio de Hematologia Zaragoza Spain 50015
    152 Laenssjukhuset; Medicinkliniken/Hematologsektionen Halmstad Sweden 30185
    153 Sunderby Sjukhus; Medicinkliniken Luleå Sweden S-971 80
    154 Capio, S:T Gorans Hospital; Dept of Medicine Stockholm Sweden 112 81
    155 Södersjukhuset, Medicinkliniken/Sektionen för Hematologi Stockholm Sweden 118 83
    156 Uddevalla Sjukhus; Medicinkliniken Uddevalla Sweden 45180
    157 Västmanlands sjukhus Västerås, Onkologmottagningen Västerås Sweden 72189
    158 Ospedale San Giovanni; Oncologia Bellinzona Switzerland 6500
    159 UniversitätsSpital Zürich; Zentrum für Hämatologie und Onkologie, Klinik für Onkologie Zürich Switzerland 8091
    160 GATA (Gulhane Military Medical School) Ankara Turkey 06010
    161 Hacettepe Uni Medical Faculty; Hematology Ankara Turkey 06100
    162 Gazi Uni Medical School; Hematology Ankara Turkey 06500
    163 Istanbul Uni Capa Medical Faculty; Inst. of Oncology Istanbul Turkey 34093
    164 Marmara University Pendik Training and Research Hospital, Hematology Department Istanbul Turkey 34300
    165 Erciyes Uni ; Hematology Kayseri Turkey 38039
    166 Birmingham Heartlands Hospital; Department of Haematology Birmingham United Kingdom B9 5SS
    167 Royal Bournemouth General Hospital; Haematology Bournemouth United Kingdom BH7 7DW
    168 Addenbrookes Hospital; Haematology Cambridge United Kingdom CB2 0QQ
    169 Kent & Canterbury Hospital; Clinical Haematology Canterbury United Kingdom CT1 3NG
    170 Uni Hospital of Wales; Dept of Haematology Cardiff United Kingdom CF14 4XW
    171 Leicester Royal Infirmary; Dept of Haematology Leicester United Kingdom LE1 5WW
    172 Royal Liverpool Uni Hospital; Haematology Liverpool United Kingdom L7 8XP
    173 University College London, Department of Haematology London United Kingdom NW1 2PG
    174 The Royal Marsden Hospital; Dept of Medicine London United Kingdom SW3 5PT
    175 Freeman Hospital Newcastle upon Tyne United Kingdom NE7 7DN
    176 Norfolk & Norwich Hospital; Dept of Haematology Norwich United Kingdom NR4 7UY
    177 Nottingham City Hospital; Dept of Haematology Nottingham United Kingdom NG5 1PB
    178 Churchill Hospital; Oxford Cancer and Haematology Centre Oxford United Kingdom OX3 7LJ
    179 Derriford Hospital; Haematology Plymouth United Kingdom PL6 8DH
    180 Royal Marsden Hospital; Dept. of Medicine Sutton United Kingdom SM2 5PT

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01461928
    Other Study ID Numbers:
    • MO25455
    • 2010-023407-95
    First Posted:
    Oct 28, 2011
    Last Update Posted:
    Aug 6, 2019
    Last Verified:
    Jul 1, 2019
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:
    Lymphoma
    Lymphoma, Non-Hodgkin
    Rituximab

    Study Results

    Participant Flow

    Recruitment Details Participants were identified for potential recruitment using pre-screening enrolment logs.
    Pre-assignment Detail Participants were treated with an induction regimen (6 months) and received SC rituximab at a dose of 375 mg/m2 with chemotherapy followed by 2 years of Maintenance I SC rituximab of 1400 mg alone. Responding participants at the end of Maintenance I were randomized to either Maintenance II rituximab treatment or observation only.
    Arm/Group Title All Participants Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm). Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were randomized to no longer receive SC rituximab but observed until the end of study.
    Period Title: Induction (up to 8 Months)
    STARTED 692 0 0
    COMPLETED 494 0 0
    NOT COMPLETED 198 0 0
    Period Title: Induction (up to 8 Months)
    STARTED 494 0 0
    COMPLETED 276 0 0
    NOT COMPLETED 218 0 0
    Period Title: Induction (up to 8 Months)
    STARTED 0 138 138
    COMPLETED 0 115 111
    NOT COMPLETED 0 23 27

    Baseline Characteristics

    Arm/Group Title All Participants
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Overall Participants 692
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    64.6
    (11.14)
    Sex: Female, Male (Count of Participants)
    Female
    346
    50%
    Male
    346
    50%
    Race/Ethnicity, Customized (Number) [Number]
    Caucasian
    579
    83.7%
    Black
    7
    1%
    Asian
    5
    0.7%
    Other
    32
    4.6%
    Not applicable as per local regulation
    69
    10%

    Outcome Measures

    1. Primary Outcome
    Title Maintenance II: Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
    Description Progression free survival from randomization (PFSrand) is defined as the time from date of randomization to the date of first documented disease progression or death, whichever occurs first. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed. The Observation arm did not include one participant with AE outcome of death reported retrospectively 2 months after discontinuation from study (censored as having no event on Day 456 post-randomization).
    Time Frame From randomization (Maintenance II) up to disease progression or death, whichever occurs first (up to approximately 24 months)

    Outcome Measure Data

    Analysis Population Description
    The primary efficacy analysis population was the ITT population (ITTrand), which included only randomised participants (Maintenance II only) and was used for the analysis of the primary efficacy endpoint of PFS and the secondary analysis endpoint overall survival (OS). The PFS end point was not reached.
    Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
    Arm/Group Description Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were randomized to no longer receive SC rituximab but observed until the end of study.
    Measure Participants 138 138
    Median (95% Confidence Interval) [Months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Maintenance II - Arm A (Rituximab), Maintenance II - Arm B (Observation Only)
    Comments The stratified log rank test p-value was derived using the following randomization stratification strata : Follicular Lymphoma International Prognostic Index (FLIPI) risk category (low, intermediate, high) and indolent NHL subtype (follicular lymphoma, non-follicular lymphoma). Power at time of final analysis was less than 40%. Final analysis was not able to address it's primary objective.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.410
    Comments Power at time of final analysis was less than 40%. Final analysis was not able to address its primary objective.
    Method Stratified Long-rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.76
    Confidence Interval (2-Sided) 95%
    0.37 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Number of Participants With Adverse Events (AEs), Serious AEs, and Infusion/Administration-related Reactions (IRRs/ARRs)
    Description An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 (obtained retrospectively) were collected for this arm. Therefore arms are not comparable overall.
    Time Frame From day of first rituximab induction dose up to day of disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)

    Outcome Measure Data

    Analysis Population Description
    The safety population included all participants who received at least one dose of study drug and had a safety assessment performed post randomization.
    Arm/Group Title All Participants
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 692
    Number of Participants with Adverse Events
    643
    92.9%
    Number of Participants with Serious Adverse Events
    339
    49%
    Number of Participants with IRRs/ARRs
    330
    47.7%
    3. Secondary Outcome
    Title Event-free Survival (Time to Treatment Failure) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
    Description Event-Free Survival was measured from the day of first rituximab Induction dose through Maintenance I and Maintenance II rituximab arm until the date of any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g. disease progression, toxicity, patient preference, initiation of new anti-lymphoma treatment, or death). Treatment discontinuation was considered as an event and was not applicable to the randomized observation arm.
    Time Frame From day of first rituximab induction dose up to day of any treatment failure, including disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)

    Outcome Measure Data

    Analysis Population Description
    All participants who were enrolled into the given study period and had received at least one dose of study treatment at any time were included in the ITT population for each period of the study; Induction, Maintenance I and Maintenance I
    Arm/Group Title Maintenance II - Arm A (Rituximab) All Participants
    Arm/Group Description Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 138 692
    Median (95% Confidence Interval) [Months]
    65.38
    24.99
    4. Secondary Outcome
    Title Time to Next Lymphoma Treatment (TNLT)
    Description Time to next lymphoma treatment (TNLT) is defined as the time from date of first rituximab induction dose to the date date of first documented intake of any new antilymphoma treatment (chemotherapy, radiotherapy, immunotherapy, etc.).
    Time Frame From day of first rituximab induction dose up to any new lymphoma treatment (up to approximately 87 months)

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the randomised ITT population (ITTrand), which included only randomised participants (Maintenance II only) as well as the ITT population, that included all participants who had completed a Baseline visit and at least one on-treatment assessment (Induction, Maintenance I and Maintenance II).
    Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only) All Participants
    Arm/Group Description Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were randomized to no longer receive SC rituximab but observed until the end of study. Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 138 138 692
    Median (95% Confidence Interval) [Months]
    NA
    NA
    NA
    5. Secondary Outcome
    Title Overall Survival
    Description Overall survival from first induction treatment (OSRegist) is defined as the time from date of first rituximab induction dose to the date of death, irrespective of cause. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed.
    Time Frame From day of first rituximab induction dose up to death (up to approximately 87 months)

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
    Arm/Group Title All Participants
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 692
    Median (95% Confidence Interval) [Months]
    NA
    6. Secondary Outcome
    Title Maintenance II: Overall Survival
    Description Overall survival from randomization (OSrand) is defined as the time from date of randomization to the date of death, irrespective of cause.
    Time Frame From randomization (Maintenance II) up to death (up to approximately 24 months)

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the randomised ITT population (ITTrand), which included only randomised participants (Maintenance II only) and was used for the analysis of the primary efficacy endpoint of PFS and the secondary analysis endpoint overall survival (OS).
    Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
    Arm/Group Description Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were randomized to no longer receive SC rituximab but observed until the end of study.
    Measure Participants 138 138
    Median (95% Confidence Interval) [Months]
    NA
    NA
    7. Secondary Outcome
    Title Percentage of Participants With Partial or Complete Tumor Response (PR/CR) Assessment at End of Induction Using 1999 International Working Group Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
    Description Overall response rate is defined as the proportion of responders at the end of the Induction period. A responder is defined as a participant experiencing either CR or PR tumor response according to the Cheson response criteria for indolent lymphoma or the recommendations for Waldenström's macroglobulinemia.
    Time Frame From day of first rituximab induction dose up to end of induction period (up to approximately 8 months)

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
    Arm/Group Title All Participants
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 692
    Number (95% Confidence Interval) [Percentage of Participants]
    84.7
    12.2%
    8. Secondary Outcome
    Title Maintenance I: Percentage of Participants With Conversion of PR to CR Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
    Description
    Time Frame From day of first rituximab induction dose up to end of Maintenance I period (up to approximately 32 months)

    Outcome Measure Data

    Analysis Population Description
    The Maintenance I participant analysis group consisted of a subgroup of responding participants who completed Induction and successfully enrolled into Maintenance I. Participants who had partial response (PR) at the end of Induction were included in this analysis.
    Arm/Group Title Maintenance I
    Arm/Group Description Participants received 12 cycles of rituximab administered as a single SC injection of 1400 mg without chemotherapy every 8 weeks for 2 years
    Measure Participants 357
    Number (95% Confidence Interval) [Percentage]
    21.6
    9. Secondary Outcome
    Title Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
    Description Progression free survival from first induction treatment (PFSregist) is defined as the time from date of first rituximab induction dose to the date of first documented disease progression or death by any cause, whichever occurs first.
    Time Frame From day of first rituximab induction dose up to disease progression or death, whichever occurs first (up to approximately 87 months)

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
    Arm/Group Title All Participants
    Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    Measure Participants 692
    Median (95% Confidence Interval) [Months]
    59.33

    Adverse Events

    Time Frame From Baseline up to 47 months
    Adverse Event Reporting Description The SAF population included all participants who had received at least one dose of rituximab during the study (Induction, Maint I, Maint II) and were assigned to treatment groups. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 were collected for this arm, therefore arms are not comparable overall. All AEs reported in Arm A and Arm B are also included in All Participants.
    Arm/Group Title Arm A Arm B (Observation Only) All Participants
    Arm/Group Description Subjects received SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Subjects did not receive further rituximab treatment until the end of study. Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
    All Cause Mortality
    Arm A Arm B (Observation Only) All Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/138 (7.2%) 8/138 (5.8%) 161/692 (23.3%)
    Serious Adverse Events
    Arm A Arm B (Observation Only) All Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 59/138 (42.8%) 58/138 (42%) 339/692 (49%)
    Blood and lymphatic system disorders
    Thrombocytopenia 0/138 (0%) 0 1/138 (0.7%) 1 5/692 (0.7%) 5
    Neutropenia 1/138 (0.7%) 1 6/138 (4.3%) 12 22/692 (3.2%) 29
    Lymphopenia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Leukopenia 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Hyperviscosity syndrome 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Febrile Neutropenia 4/138 (2.9%) 5 2/138 (1.4%) 2 36/692 (5.2%) 42
    Bone marrow failure 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Anaemia 0/138 (0%) 0 1/138 (0.7%) 1 8/692 (1.2%) 10
    Cardiac disorders
    Ventricular tachycardia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Myocardial ischaemia 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Myocardial infarction 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Coronary artery disease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Congestive cardiomyopathy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cardiopulmonary failure 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Cardiac failure congestive 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cardiac failure acute 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Cardiac failure 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Cardic arrest 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Atrial fibrillation 2/138 (1.4%) 2 2/138 (1.4%) 2 7/692 (1%) 7
    Aortic valve incompetence 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Aortic valve calcification 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Acute myocardial infarction 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Acute coronary syndrome 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Congenital, familial and genetic disorders
    Atrial septal defect 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ear and labyrinth disorders
    Vertigo positional 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Vertigo 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Endocrine disorders
    Thyrotxic crisis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Goitre 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eye disorders
    Dacryostenosis acquired 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cataract 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal disorders
    Vomiting 1/138 (0.7%) 1 0/138 (0%) 0 4/692 (0.6%) 4
    Retroperitoneal haematoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Proctitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pancreatitis acute 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Pancreatitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Oesophagitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Intestinal pseudo-obstruction 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Inflammatory bowel disease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haemorrhoidal haemorrhage 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Gastrooesophageal reflux disease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal toxicity 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Gastritis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dyspepsia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Duodenal ulcer 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Diverticular perporation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Diarrhoea 1/138 (0.7%) 1 2/138 (1.4%) 2 10/692 (1.4%) 12
    Crohn's disease 1/138 (0.7%) 1 1/138 (0.7%) 2 2/692 (0.3%) 3
    Colitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Ascites 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Abdominal pain upper 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Abdominal pain 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    General disorders
    Sudden death 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Pyrexia 1/138 (0.7%) 1 3/138 (2.2%) 3 11/692 (1.6%) 16
    Oedema peripheral 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Malaise 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site reaction 0/138 (0%) 0 1/138 (0.7%) 1 5/692 (0.7%) 5
    Injection site pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site induration 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site haematoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site erythema 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Infusion site erythema 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 5
    Inflammation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    General physical health deterioration 0/138 (0%) 0 0/138 (0%) 0 5/692 (0.7%) 5
    Feeling hot 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Face oedema 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Death 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Chills 0/138 (0%) 0 0/138 (0%) 0 4/692 (0.6%) 4
    Chest pain 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Hepatobiliary disorders
    Liver disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Jaundice 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic steatosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic failure 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cholecystitis acute 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cholecystitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cholangitis acute 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bile duct stone 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Immune system disorders
    Immunosupression 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypersensitivity 2/138 (1.4%) 2 0/138 (0%) 0 4/692 (0.6%) 5
    Drug hypersensitivity 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Infections and infestations
    Viral upper respiratory tract infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Viral infection 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Varicella 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Urosepsis 1/138 (0.7%) 2 0/138 (0%) 0 2/692 (0.3%) 3
    Urinary tract infection 3/138 (2.2%) 4 2/138 (1.4%) 2 12/692 (1.7%) 13
    Upper respiratory tract infection 0/138 (0%) 0 3/138 (2.2%) 4 8/692 (1.2%) 9
    Tracheobronchitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Soft tissue infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Skin infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Septic shock 1/138 (0.7%) 1 1/138 (0.7%) 1 6/692 (0.9%) 6
    Sepsis syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Sepsis 3/138 (2.2%) 3 2/138 (1.4%) 2 18/692 (2.6%) 18
    Salmonellosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Respiratory tract infection 1/138 (0.7%) 1 2/138 (1.4%) 2 9/692 (1.3%) 9
    Pyelonephritis chronic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary sepsis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pseudomonas infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Progressive multifocal leukoencephalopathy 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Pneumonia 14/138 (10.1%) 14 6/138 (4.3%) 7 54/692 (7.8%) 65
    Pneumocystis Jirovecii pneumonia 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Pneumococcal infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pharyngitis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Periorbital cellulitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Perineal cellulitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Paraspinal abscess 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Neutropenic sepsis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Necrotising fasciitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Myocarditis septic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Myocarditis infectious 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Meningitis aseptic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lung infection 2/138 (1.4%) 2 4/138 (2.9%) 4 7/692 (1%) 7
    Lower respiratory tract infection 1/138 (0.7%) 1 5/138 (3.6%) 6 10/692 (1.4%) 11
    Kidney infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Intestinal sepsis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Influenza 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Infective exacerbation of chronic obstructive airways disease 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Infection 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Herpes zoster 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 5
    Hepatitis viral 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatitis C 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic candidiasis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haemophilus infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastroenteritis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Escherichia urinary tract infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Erysipelas 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Enterobacter sepsis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Diverticulitis 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 4
    Device related sepsis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cytomegalovirus infection 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Cellulitis 1/138 (0.7%) 2 0/138 (0%) 0 2/692 (0.3%) 4
    Candida infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Campylobacter gastroenteritis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bronchopulmonary aspergillosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bronchitis 0/138 (0%) 0 4/138 (2.9%) 4 5/692 (0.7%) 5
    Appendicitis 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Abscess 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Abdominal wall abscess 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Abdominal infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Injury, poisoning and procedural complications
    Upper limb fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Tooth avulsion 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Subarachnoid haemorrhage 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spinal compression fracture 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Pubis fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lumbar vertebral fracture 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Infusion related reaction 3/138 (2.2%) 3 0/138 (0%) 0 7/692 (1%) 7
    Hip fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Head injury 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Femur fracture 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Femoral neck fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Fall 0/138 (0%) 0 2/138 (1.4%) 3 3/692 (0.4%) 4
    Complications of bone marrow transplant 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Chest injury 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ankle fracture 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Anastomotic leak 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Investigations
    Neutrophil count decreased 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lymphocyte count decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Metabolism and nutrition disorders
    Tumour lysis syndrome 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Hypophosphataemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hyponatraemia 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Hyperglycaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spinal column stenosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Pain in extremity 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Osteoporotic fracture 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Osteoarthritis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Neck pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Musculoskeletal chest pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Intervertebral disc protrusion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Haemarthrosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Compartment syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bone pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Back pain 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Arthralgia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Transitional cell carcinoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Squamous cell carcinoma of skin 1/138 (0.7%) 1 2/138 (1.4%) 4 5/692 (0.7%) 7
    Squamous cell carcinoma of lung 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Squamous cell carcinoma 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Small intestine adenocarcinoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Refractory Anaemia With An Excess Of Blasts 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rectal cancer 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Prostatic adenoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Prostate cancer 2/138 (1.4%) 2 0/138 (0%) 0 4/692 (0.6%) 4
    Pancreatic carcinoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nodal Marginal Zone B-Cell Lymphoma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Neuroendocrine tumour 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Naevoid melanoma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Myeloid leukaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Myelodysplastic syndrome 1/138 (0.7%) 1 2/138 (1.4%) 2 9/692 (1.3%) 9
    Metastatic squamous cell carcinoma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Malignant melanoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lung neoplasm malignant 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lung adenocarcinoma 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Lentigo maligna 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Large cell lung cancer 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Invasive ductal breast carcinoma 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Hodgkin's disease 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hepatocellular Carcinoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Colorectal cancer 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cholangiocarcinoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Carcinoid tumour of the stomach 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Breast cancer 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Bowen's disease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bladder cancer 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Basal cell carcinoma 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 3
    Anaplastic astrocytoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Anal squamous cell carcinoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Adenocarcinoma pancreas 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Adenocarcinoma of colon 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Acute myeloid leukaemia 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 4
    Nervous system disorders
    Transient ischaemic attack 0/138 (0%) 0 1/138 (0.7%) 2 1/692 (0.1%) 2
    Syncope 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 4
    Presyncope 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Peripheral sensory neuropathy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ischaemic stroke 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Hemiplegic migraine 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Headache 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Haemorrhage intracranial 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cognitive disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cerebrovascular disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cerebrovascular accident 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 4
    Cerebral infarction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Cerebral haemorrhage 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Cerebral atrophy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Carotid artery stenosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Psychiatric disorders
    Depression 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Delirium 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Renal and urinary disorders
    Urethral haemorrhage 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Ureterolithiasis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Haematuria 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nephrolithiasis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Acute kidney injury 0/138 (0%) 0 3/138 (2.2%) 3 6/692 (0.9%) 6
    Reproductive system and breast disorders
    Menometrorrhagia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Throat irritation 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Sleep apnoea syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Respiratory failure 0/138 (0%) 0 0/138 (0%) 0 4/692 (0.6%) 4
    Respiratory disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary embolism 1/138 (0.7%) 1 1/138 (0.7%) 1 5/692 (0.7%) 5
    Pleural effusion 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Oropharyngeal pain 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lung disorder 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Haemoptysis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Dyspnoea 1/138 (0.7%) 1 0/138 (0%) 0 6/692 (0.9%) 7
    Chronic obstructive pulmonary disease 2/138 (1.4%) 5 0/138 (0%) 0 3/692 (0.4%) 6
    Bronchospasm 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bronchiectasis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 3
    Asthma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Acute respiratory failure 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Acute pulmonary oedema 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Skin and subcutaneous tissue disorders
    Urticaria 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Toxic skin eruption 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Skin reaction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rash papular 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rash 0/138 (0%) 0 0/138 (0%) 0 5/692 (0.7%) 5
    Pruritus 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Peau D'orange 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Erythema 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Surgical and medical procedures
    Venous thrombosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Vena cava thrombosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Phlebitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Peripheral arterial occlusive disease 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Orthostatic hypotension 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Jugular vein thrombosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypotension 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypertension 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Haemorrhagic vasculitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haematoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Flushing 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Deep vein thrombosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Abdominal hernia repair 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Other (Not Including Serious) Adverse Events
    Arm A Arm B (Observation Only) All Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 133/138 (96.4%) 133/138 (96.4%) 643/692 (92.9%)
    Blood and lymphatic system disorders
    Thrombocytopenia 9/138 (6.5%) 12 10/138 (7.2%) 13 49/692 (7.1%) 75
    Pancytopenia 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 4
    Neutropenia 48/138 (34.8%) 134 51/138 (37%) 173 226/692 (32.7%) 604
    Microcytosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lymphopenia 4/138 (2.9%) 13 1/138 (0.7%) 1 16/692 (2.3%) 34
    Lymphocytosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lymphadenopathy 0/138 (0%) 0 3/138 (2.2%) 3 3/692 (0.4%) 3
    Lymph node pain 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Leukopenia 14/138 (10.1%) 47 9/138 (6.5%) 18 52/692 (7.5%) 126
    Leukocytosis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Iron deficiency anaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypoglobulinaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypochromic anaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haematotoxicity 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Febrile neutropenia 3/138 (2.2%) 3 2/138 (1.4%) 8 15/692 (2.2%) 22
    Eosinophilia 0/138 (0%) 0 0/138 (0%) 0 4/692 (0.6%) 4
    Coagulopathy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Anaemia 23/138 (16.7%) 35 21/138 (15.2%) 32 106/692 (15.3%) 172
    Agranulocytosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cardiac disorders
    Vantricular arrhythmia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Tachycardia 0/138 (0%) 0 4/138 (2.9%) 4 10/692 (1.4%) 10
    Supraventricular tachycardia 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Sinus tachycardia 2/138 (1.4%) 3 0/138 (0%) 0 3/692 (0.4%) 4
    Sinus bradycardia 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Pericardial effusion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Palpitations 3/138 (2.2%) 3 4/138 (2.9%) 5 9/692 (1.3%) 11
    Myocardial ischaemia 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Mitral valve incompetence 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Left ventricular failure 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Left ventricular dysfunction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hyperkinetic heart syndrome 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Extrasystoles 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cardiac failure congestive 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Cardiac failure chronic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cardiac failure 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Bundle branch block left 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bradycardia 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Atrioventricular block complete 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Atrial tachycardia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Atrial fibrillation 2/138 (1.4%) 3 2/138 (1.4%) 2 8/692 (1.2%) 12
    Atrial flutter 0/138 (0%) 0 1/138 (0.7%) 2 3/692 (0.4%) 4
    Arrhythmia supraventricular 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Arrhythmia 3/138 (2.2%) 3 0/138 (0%) 0 5/692 (0.7%) 5
    Aortic valve incompetence 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Angina pectoris 1/138 (0.7%) 1 4/138 (2.9%) 5 7/692 (1%) 8
    Acute coronary syndrome 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Congenital, familial and genetic disorders
    Porokeratosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Thyroglossal cyst 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ear and labyrinth disorders
    Vestibular disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Vertigo 7/138 (5.1%) 10 2/138 (1.4%) 2 18/692 (2.6%) 21
    Tympanic membrane disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Tinnitus 5/138 (3.6%) 6 2/138 (1.4%) 2 9/692 (1.3%) 10
    Middle ear inflammation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypoacusis 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 4
    Ear pain 4/138 (2.9%) 4 2/138 (1.4%) 2 11/692 (1.6%) 12
    Deafness unilateral 0/138 (0%) 0 2/138 (1.4%) 2 3/692 (0.4%) 3
    Deafness 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Endocrine disorders
    Hypothyroidism 2/138 (1.4%) 3 2/138 (1.4%) 2 4/692 (0.6%) 5
    Autoimmune thyroiditis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Goitre 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hypoaldosteronism 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Thyroid disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Thyroid mass 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Thyroiditis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hyperthyroidism 0/138 (0%) 0 0/138 (0%) 0 4/692 (0.6%) 4
    Inappropriate antidiuretic hormone secretion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Eye disorders
    Vitreous floaters 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Visual impairment 2/138 (1.4%) 2 1/138 (0.7%) 1 6/692 (0.9%) 6
    Visual acuity reduced 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Vision blurred 2/138 (1.4%) 2 1/138 (0.7%) 1 5/692 (0.7%) 5
    Periorbital oedema 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Ocular hyperaemia 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Noninfective conjunctivitis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Lacrimation increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Glaucoma 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Eyelid swelling 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Eyelid oedema 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Eye pruritus 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Eye pain 4/138 (2.9%) 4 0/138 (0%) 0 6/692 (0.9%) 6
    Eye irritation 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Eye inflammation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eye discharge 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Entropion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dry eye 3/138 (2.2%) 3 0/138 (0%) 0 5/692 (0.7%) 5
    Diabetic retinopathy 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Conjunctivitis allergic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Conjunctival hyperaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Chalazion 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cataract 2/138 (1.4%) 3 1/138 (0.7%) 2 5/692 (0.7%) 8
    Gastrointestinal disorders
    Vomiting 23/138 (16.7%) 32 16/138 (11.6%) 31 96/692 (13.9%) 160
    Umbilical hernia 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Toothache 5/138 (3.6%) 5 2/138 (1.4%) 2 9/692 (1.3%) 9
    Tooth loss 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Tooth disorder 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Tooth development disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Tongue ulceration 0/138 (0%) 0 2/138 (1.4%) 2 4/692 (0.6%) 4
    Tongue geographic 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Tongue coated 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Stomatitis 5/138 (3.6%) 5 3/138 (2.2%) 4 17/692 (2.5%) 18
    Sensitivity of teeth 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Salivary hypersecretion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rectal polyp 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Rectal haemorrhage 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Proctalgia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Perianal erythema 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Paraesthesia oral 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Pancreatic duct dilatation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pancreatic cyst 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Oral pain 3/138 (2.2%) 3 5/138 (3.6%) 5 15/692 (2.2%) 16
    Oral disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Oesophagitis 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Odynophagia 1/138 (0.7%) 1 2/138 (1.4%) 5 7/692 (1%) 10
    Noninfective gingivitis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Nausea 45/138 (32.6%) 63 37/138 (26.8%) 65 199/692 (28.8%) 312
    Mouth ulceration 3/138 (2.2%) 4 3/138 (2.2%) 4 12/692 (1.7%) 15
    Melaena 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lower gastrointestinal haemorrhage 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Lip ulceration 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Large intestinal ulcer 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Irritable bowel syndrome 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Intestinal obstruction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Inguinal hernia 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Impaired gastric emptying 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ileal ulcer 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hiatus hernia 2/138 (1.4%) 2 1/138 (0.7%) 1 4/692 (0.6%) 4
    Haemorrhoids thrombosed 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Haemorrhoids 0/138 (0%) 0 3/138 (2.2%) 3 12/692 (1.7%) 12
    Haemorrhoidal haemorrhage 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 4
    Haematochezia 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Gingival bleeding 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Gastrooesophageal reflux disease 11/138 (8%) 13 7/138 (5.1%) 9 20/692 (2.9%) 24
    Gastrointestinal toxicity 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal sounds abnormal 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal inflammation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal hypomotility 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Gastrointestinal disorder 2/138 (1.4%) 2 2/138 (1.4%) 2 5/692 (0.7%) 5
    Gastritis 1/138 (0.7%) 1 6/138 (4.3%) 6 12/692 (1.7%) 12
    Gastric ulcer 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Food poisoning 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Flatulence 1/138 (0.7%) 1 1/138 (0.7%) 1 7/692 (1%) 7
    Faeces soft 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Faecaloma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eructation 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Epigastric discomfort 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Enterocolitis 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Dysphagia 1/138 (0.7%) 1 1/138 (0.7%) 1 10/692 (1.4%) 10
    Dyspepsia 10/138 (7.2%) 10 7/138 (5.1%) 7 26/692 (3.8%) 27
    Dyschezia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dry mouth 1/138 (0.7%) 1 1/138 (0.7%) 1 10/692 (1.4%) 10
    Diverticulum intestinal 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Diarrhoea 35/138 (25.4%) 50 28/138 (20.3%) 36 143/692 (20.7%) 211
    Defaecation urgency 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Crohn's disease 0/138 (0%) 0 1/138 (0.7%) 2 1/692 (0.1%) 2
    Constipation 21/138 (15.2%) 26 15/138 (10.9%) 22 98/692 (14.2%) 129
    Colitis 3/138 (2.2%) 5 0/138 (0%) 0 6/692 (0.9%) 8
    Chronic gastritis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Change in bowel habit 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ascites 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 4
    Aphthous ulcer 0/138 (0%) 0 3/138 (2.2%) 3 6/692 (0.9%) 6
    Anal haemorrhage 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Anal fissure 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 3
    Abdominal tenderness 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Abdominal pain upper 11/138 (8%) 16 4/138 (2.9%) 5 39/692 (5.6%) 49
    Abdominal pain lower 1/138 (0.7%) 1 1/138 (0.7%) 2 2/692 (0.3%) 3
    Abdominal pain 13/138 (9.4%) 15 13/138 (9.4%) 23 57/692 (8.2%) 74
    Abdominal distension 2/138 (1.4%) 2 1/138 (0.7%) 1 7/692 (1%) 8
    Abdominal discomfort 0/138 (0%) 0 2/138 (1.4%) 2 5/692 (0.7%) 5
    General disorders
    Xerosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Vessel puncture site haematoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Unevaluable event 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Thirst 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Swelling 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Pyrexia 32/138 (23.2%) 45 29/138 (21%) 49 159/692 (23%) 258
    Puncture site pain 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Puncture site erythema 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Polyp 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Peripheral swelling 2/138 (1.4%) 2 0/138 (0%) 0 7/692 (1%) 8
    Performance status decreased 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Pain 3/138 (2.2%) 3 2/138 (1.4%) 2 8/692 (1.2%) 8
    Oedema peripheral 6/138 (4.3%) 6 7/138 (5.1%) 8 38/692 (5.5%) 40
    Oedema 3/138 (2.2%) 3 2/138 (1.4%) 2 9/692 (1.3%) 9
    Mucosal inflammation 6/138 (4.3%) 6 7/138 (5.1%) 8 25/692 (3.6%) 27
    Malaise 2/138 (1.4%) 2 1/138 (0.7%) 1 10/692 (1.4%) 10
    Localised oedema 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Injection site warmth 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site thrombosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Injection site swelling 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Injection site reaction 1/138 (0.7%) 2 1/138 (0.7%) 1 10/692 (1.4%) 13
    Injection site rash 0/138 (0%) 0 1/138 (0.7%) 1 8/692 (1.2%) 9
    Injection site pruritus 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Injection site plaque 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site pain 3/138 (2.2%) 3 6/138 (4.3%) 7 24/692 (3.5%) 34
    Injection site oedema 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site mass 0/138 (0%) 0 2/138 (1.4%) 3 2/692 (0.3%) 3
    Injection site irritation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Injection site inflammation 0/138 (0%) 0 3/138 (2.2%) 3 8/692 (1.2%) 9
    Injection site induration 3/138 (2.2%) 9 1/138 (0.7%) 2 5/692 (0.7%) 17
    Injection site hypersensitivity 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Injection site haematoma 1/138 (0.7%) 2 0/138 (0%) 0 4/692 (0.6%) 5
    Injection site erythema 10/138 (7.2%) 11 9/138 (6.5%) 14 38/692 (5.5%) 46
    Injection site discomfort 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Injection site discolouration 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Injection site bruising 1/138 (0.7%) 1 1/138 (0.7%) 1 5/692 (0.7%) 5
    Infusion site rash 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 3
    Infusion site pain 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Infusion site inflammation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Infusion site haematoma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Infusion site extravasation 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Infusion site erythema 1/138 (0.7%) 6 0/138 (0%) 0 4/692 (0.6%) 16
    Influenza like illness 6/138 (4.3%) 24 6/138 (4.3%) 9 20/692 (2.9%) 45
    Inflammation 0/138 (0%) 0 1/138 (0.7%) 1 5/692 (0.7%) 6
    Implant site haematoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypothermia 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 7
    Hyperthermia 3/138 (2.2%) 4 1/138 (0.7%) 1 7/692 (1%) 8
    Haemorrhagic cyst 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Granuloma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    General physical health deterioration 3/138 (2.2%) 3 0/138 (0%) 0 5/692 (0.7%) 5
    Feeling of body temperature change 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Feeling hot 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 5
    Feeling cold 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Feeling abnormal 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Fatigue 30/138 (21.7%) 46 19/138 (13.8%) 25 115/692 (16.6%) 157
    Facial pain 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Face oedema 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Discomfort 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cyst 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Chills 8/138 (5.8%) 8 9/138 (6.5%) 9 40/692 (5.8%) 47
    Chest pain 11/138 (8%) 12 7/138 (5.1%) 7 27/692 (3.9%) 29
    Chest discomfort 3/138 (2.2%) 3 3/138 (2.2%) 3 10/692 (1.4%) 10
    Catheter site thrombosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Catheter site haemorrhage 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Axillary pain 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Asthenia 27/138 (19.6%) 43 19/138 (13.8%) 28 113/692 (16.3%) 167
    Application site pain 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Application site erythema 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Administration site pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Administration site inflammation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Administration site extravasation 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 6
    Hepatobiliary disorders
    Biliary colic 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Chloangitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Choleithiasis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hepatocellular injury 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 6
    Hepatotoxicity 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Liver disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cholestasis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 4
    Cholecystitis chronic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic cyst 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic function abnormal 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic lesion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic steatosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hyperbilirubinaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Immune system disorders
    Seasonal allergy 1/138 (0.7%) 1 2/138 (1.4%) 2 4/692 (0.6%) 4
    Sarcoidosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Iodine allergy 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Immunodeficiency 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Immune system disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypogammaglobulinaemia 9/138 (6.5%) 9 9/138 (6.5%) 9 26/692 (3.8%) 26
    Hypersensitivity 3/138 (2.2%) 3 0/138 (0%) 0 7/692 (1%) 7
    Drug hypersensitivity 0/138 (0%) 0 0/138 (0%) 0 5/692 (0.7%) 7
    Cytokine release syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Infections and infestations
    Wound infection 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Vulvovaginal mycotic infection 1/138 (0.7%) 3 1/138 (0.7%) 2 2/692 (0.3%) 5
    Vulvitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Viral upper respiratory tract infection 3/138 (2.2%) 3 0/138 (0%) 0 7/692 (1%) 7
    Viral pharyngitis 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Viral parotitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Viral infection 7/138 (5.1%) 8 2/138 (1.4%) 2 11/692 (1.6%) 12
    Varicella zoster virus infection 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Vaginal infection 2/138 (1.4%) 3 1/138 (0.7%) 1 3/692 (0.4%) 4
    Urinary tract infection 11/138 (8%) 14 14/138 (10.1%) 22 55/692 (7.9%) 73
    Ureaplasma infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Upper respiratory tract infection 24/138 (17.4%) 36 20/138 (14.5%) 26 63/692 (9.1%) 85
    Trichomoniasis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Tracheobronchitis 4/138 (2.9%) 4 1/138 (0.7%) 1 6/692 (0.9%) 6
    Tracheitis 3/138 (2.2%) 3 3/138 (2.2%) 3 8/692 (1.2%) 8
    Tooth infection 1/138 (0.7%) 2 2/138 (1.4%) 2 5/692 (0.7%) 6
    Tooth abscess 2/138 (1.4%) 2 1/138 (0.7%) 1 5/692 (0.7%) 5
    Tonsillitis 3/138 (2.2%) 3 2/138 (1.4%) 3 5/692 (0.7%) 6
    Tinea pedis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Superinfection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Subcutaneous abscess 2/138 (1.4%) 2 2/138 (1.4%) 6 5/692 (0.7%) 9
    Staphylococcal infection 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Skin infection 1/138 (0.7%) 1 3/138 (2.2%) 3 4/692 (0.6%) 4
    Sinusitis bacterial 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Sinusitis 14/138 (10.1%) 27 16/138 (11.6%) 21 45/692 (6.5%) 67
    Sepsis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rhinitis 19/138 (13.8%) 21 9/138 (6.5%) 9 42/692 (6.1%) 46
    Respiratory tract infection viral 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 4
    Respiratory tract infection 4/138 (2.9%) 5 10/138 (7.2%) 19 24/692 (3.5%) 36
    Respiratory syncytial virus infection 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Rectal abscess 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rash pustular 1/138 (0.7%) 1 1/138 (0.7%) 1 5/692 (0.7%) 5
    Pyoderma 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Pyelonephritis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Puncture site abscess 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pulpitis dental 0/138 (0%) 0 3/138 (2.2%) 3 3/692 (0.4%) 3
    Pseudomonas infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pseudomembranous colitis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Proteus infection 1/138 (0.7%) 3 0/138 (0%) 0 1/692 (0.1%) 3
    Postoperative wound infection 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Pneumonia fungal 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pneumonia bacterial 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pneumonia 17/138 (12.3%) 22 10/138 (7.2%) 13 44/692 (6.4%) 55
    Pharyngotonsillitis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Pharyngitis 3/138 (2.2%) 4 3/138 (2.2%) 6 9/692 (1.3%) 13
    Pertussis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Periorbital infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Paronychia 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 6
    Parainfluenzae virus infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Otitis media 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Otitis externa 0/138 (0%) 0 1/138 (0.7%) 2 1/692 (0.1%) 2
    Oral infection 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Oral herpes 9/138 (6.5%) 17 4/138 (2.9%) 5 25/692 (3.6%) 35
    Oral fungal infection 2/138 (1.4%) 2 1/138 (0.7%) 2 5/692 (0.7%) 7
    Oral candidiasis 3/138 (2.2%) 3 3/138 (2.2%) 4 14/692 (2%) 15
    Orchitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Onychomycosis 2/138 (1.4%) 2 1/138 (0.7%) 2 4/692 (0.6%) 5
    Oesophageal candidiasis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nasopharyngitis 29/138 (21%) 55 24/138 (17.4%) 36 72/692 (10.4%) 120
    Nasal herpes 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Nail infection 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Mucosal infection 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Meningitis 0/138 (0%) 0 0/138 (0%) 0 1/1 (100%) 1
    Lymphangitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lung infection 10/138 (7.2%) 15 5/138 (3.6%) 5 24/692 (3.5%) 32
    Lower respiratory tract infection viral 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Lower respiratory tract infection 17/138 (12.3%) 37 9/138 (6.5%) 14 46/692 (6.6%) 76
    Lip infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Laryngitis 2/138 (1.4%) 2 0/138 (0%) 0 4/692 (0.6%) 4
    Labyrinthitis 1/138 (0.7%) 2 0/138 (0%) 0 2/692 (0.3%) 3
    Injection site cellulitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Influenza 20/138 (14.5%) 23 14/138 (10.1%) 18 56/692 (8.1%) 65
    Infectious colitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Infection 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Infected bite 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hordeolum 2/138 (1.4%) 3 0/138 (0%) 0 2/692 (0.3%) 3
    Herpes zoster oticus 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Herpes zoster infection neurological 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Herpes zoster 16/138 (11.6%) 18 12/138 (8.7%) 12 46/692 (6.6%) 50
    Herpes virus infection 1/138 (0.7%) 1 1/138 (0.7%) 2 3/692 (0.4%) 4
    Herpes simplex 2/138 (1.4%) 2 1/138 (0.7%) 1 4/692 (0.6%) 4
    Hepatitis viral 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hepatitis B 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic infection fungal 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Helicobacter gastritis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Haemophilus infection 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Gingivitis 2/138 (1.4%) 3 2/138 (1.4%) 2 5/692 (0.7%) 6
    Genital herpes simplex 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Gastrointestinal infection 2/138 (1.4%) 2 1/138 (0.7%) 1 3/692 (0.4%) 3
    Gastrointestinal fungal infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastroenteritis viral 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Gastroenteritis salmonella 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Gastroenteritis 2/138 (1.4%) 2 7/138 (5.1%) 7 11/692 (1.6%) 12
    Furuncle 1/138 (0.7%) 1 1/138 (0.7%) 4 4/692 (0.6%) 7
    Fungal skin infection 1/138 (0.7%) 2 2/138 (1.4%) 3 3/692 (0.4%) 5
    Fungal infection 1/138 (0.7%) 1 1/138 (0.7%) 1 6/692 (0.9%) 6
    Folliculitis 1/138 (0.7%) 1 2/138 (1.4%) 5 8/692 (1.2%) 12
    Eyelid infection 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eye infection 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Escherichia urinary tract infection 1/138 (0.7%) 2 2/138 (1.4%) 4 5/692 (0.7%) 8
    Erysipelas 1/138 (0.7%) 1 2/138 (1.4%) 2 4/692 (0.6%) 4
    Epstein-Barr virus infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Endocarditis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Ear infection 3/138 (2.2%) 4 4/138 (2.9%) 4 14/692 (2%) 17
    Diverticulitis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Diarrhoea infectious 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Device related sepsis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Device related infection 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Dacryocanaliculitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cytomegalovirus infection 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Cystitis Escherichia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cystitis 4/138 (2.9%) 4 0/138 (0%) 0 6/692 (0.9%) 6
    Conjunctivitis 12/138 (8.7%) 14 4/138 (2.9%) 5 24/692 (3.5%) 27
    Chlamydial infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cellulitis 1/138 (0.7%) 1 2/138 (1.4%) 2 8/692 (1.2%) 9
    Candida infection 3/138 (2.2%) 3 0/138 (0%) 0 5/692 (0.7%) 5
    Campylobacter infection 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Campylobacter gastroenteritis 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Campylobacter colitis 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Bronchitis 24/138 (17.4%) 55 21/138 (15.2%) 27 78/692 (11.3%) 126
    Body tinea 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Blastocystis infection 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bartholinitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Balanitis candida 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bacteriuria 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bacterial infection 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Arthritis infective 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Arthritis bacterial 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Application site cellulitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Angular cheilitis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Anal abscess 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Acute sinusitis 5/138 (3.6%) 6 1/138 (0.7%) 1 7/692 (1%) 7
    Abscess oral 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Abdominal infection 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Injury, poisoning and procedural complications
    Wrist fracture 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Upper limb fracture 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Traumatic haematoma 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Toxicity to various agents 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Tooth fracture 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 4
    Tooth avulsion 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Thermal burn 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Spinal fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spinal compression fracture 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Skin abrasion 2/138 (1.4%) 3 0/138 (0%) 0 2/692 (0.3%) 3
    Scratch 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rib fracture 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Radius fracture 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Radiation skin injury 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Radiation injury 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Procedural site reaction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Procedural pain 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Post-traumatic pain 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Post procedural haematoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pelvic fracture 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Muscle strain 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Muscle rupture 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Medication error 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lumbar vertebral fracture 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Limb injury 1/138 (0.7%) 1 0/138 (0%) 0 5/692 (0.7%) 5
    Ligament sprain 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Ligament rupture 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Laceration 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Joint injury 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Joint dislocation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Infusion related reaction 4/138 (2.9%) 4 3/138 (2.2%) 3 23/692 (3.3%) 24
    Humerus fracture 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Head injury 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Hand fracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Fracture 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Foot fracture 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Fall 1/138 (0.7%) 1 4/138 (2.9%) 4 11/692 (1.6%) 12
    Epicondylitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Dental restoration failure 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Craniocerebral injury 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Contusion 4/138 (2.9%) 4 0/138 (0%) 0 6/692 (0.9%) 6
    Arthropod bite 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Animal bite 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Administration related reaction 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Investigations
    White blood cell count increased 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    White blood cell count decreased 11/138 (8%) 19 13/138 (9.4%) 21 46/692 (6.6%) 72
    Weight increased 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 6
    Weight decreased 6/138 (4.3%) 7 4/138 (2.9%) 4 25/692 (3.6%) 27
    Transferrin saturation decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Transaminases increased 1/138 (0.7%) 2 1/138 (0.7%) 1 5/692 (0.7%) 6
    Pulse abnormal 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Prostatic specific antigen increased 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Polymerase chain reaction positive 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Platelet count increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Platelet count decreased 14/138 (10.1%) 20 10/138 (7.2%) 13 59/692 (8.5%) 96
    Oxygen saturation decrease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Neutrophil count increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Neutrophil count decreased 28/138 (20.3%) 65 29/138 (21%) 60 113/692 (16.3%) 289
    Lymphocyte count increased 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Lymphocyte count decreased 13/138 (9.4%) 17 14/138 (10.1%) 23 45/692 (6.5%) 80
    Liver palpable 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Liver function test increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    International normalised ratio increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    International normalised ratio decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Immunoglobulins decreased 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Hypophonesis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Histamine level increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hepatic enzyme increased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 2
    Haemoglobin decreased 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Gamma-glutamyltransferase increased 1/138 (0.7%) 1 0/138 (0%) 0 6/692 (0.9%) 8
    Eosinophil count increased 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Electrocardiogram QT prolonged 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Ejection fraction decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Coagulation time prolonged 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cardiac murmur 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    CD4 lymphocytes decreased 0/138 (0%) 0 3/138 (2.2%) 3 3/692 (0.4%) 3
    C-reactive protein increased 3/138 (2.2%) 3 2/138 (1.4%) 2 17/692 (2.5%) 17
    Body temperature increased 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Blood urea increased 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Blood sodium decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Blood pressure increased 1/138 (0.7%) 3 1/138 (0.7%) 1 2/692 (0.3%) 4
    Blood pressure abnormal 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Blood potassium decreased 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Blood phosphorus decreased 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Blood magnesium decreased 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Blood lactate dehydrogenase increased 4/138 (2.9%) 4 1/138 (0.7%) 1 14/692 (2%) 16
    Blood iron decreased 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Blood immunoglobulin M decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Blood immunoglobulin G decreased 1/138 (0.7%) 1 0/138 (0%) 0 5/692 (0.7%) 5
    Blood glucose increased 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Blood folate decreased 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Blood creatinine increased 4/138 (2.9%) 4 4/138 (2.9%) 5 12/692 (1.7%) 17
    Blood creatine increased 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Blood cholesterol increased 2/138 (1.4%) 2 1/138 (0.7%) 1 3/692 (0.4%) 3
    Blood bilirubin increased 2/138 (1.4%) 2 2/138 (1.4%) 2 6/692 (0.9%) 6
    Blood alkaline phosphatase increased 1/138 (0.7%) 1 1/138 (0.7%) 1 8/692 (1.2%) 9
    Biopsy prostate 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Aspartate aminotransferase increased 3/138 (2.2%) 3 3/138 (2.2%) 4 11/692 (1.6%) 13
    Alanine aminotransferase increased 3/138 (2.2%) 3 3/138 (2.2%) 7 11/692 (1.6%) 20
    Metabolism and nutrition disorders
    Vitamin D deficiency 2/138 (1.4%) 2 1/138 (0.7%) 1 4/692 (0.6%) 4
    Vitamin B12 deficiency 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Type 2 diabetes mellitus 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Tumour lysis syndrome 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Tetany 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Obesity 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Metabolic disorder 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Metabolic acidosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Malnutrition 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lactose intolerance 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Iron deficiency 1/138 (0.7%) 2 0/138 (0%) 0 2/692 (0.3%) 3
    Increased appetite 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hypovitaminosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypouricaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypoproteinaemia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypophosphataemia 2/138 (1.4%) 2 0/138 (0%) 0 7/692 (1%) 9
    Hypophagia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hyponatraemia 1/138 (0.7%) 1 0/138 (0%) 0 4/692 (0.6%) 5
    Hypomagnesaemia 0/138 (0%) 0 1/138 (0.7%) 1 6/692 (0.9%) 9
    Hypokalaemia 7/138 (5.1%) 10 1/138 (0.7%) 1 22/692 (3.2%) 31
    Hypoglycaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypocalcaemia 0/138 (0%) 0 0/138 (0%) 0 5/692 (0.7%) 7
    Hypoalbminaemia 0/138 (0%) 0 0/138 (0%) 0 5/692 (0.7%) 5
    Hyperuricaemia 6/138 (4.3%) 9 3/138 (2.2%) 3 10/692 (1.4%) 13
    Hypertriglyceridaemia 2/138 (1.4%) 2 1/138 (0.7%) 1 3/692 (0.4%) 3
    Hyperphosphataemia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypernatraemia 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Hyperlipidaemia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hyperkalaemia 2/138 (1.4%) 3 0/138 (0%) 0 6/692 (0.9%) 8
    Hyperglycaemia 2/138 (1.4%) 5 2/138 (1.4%) 2 8/692 (1.2%) 11
    Hypercholesterolaemia 0/138 (0%) 0 2/138 (1.4%) 2 4/692 (0.6%) 4
    Hypercalcaemia 1/138 (0.7%) 1 1/138 (0.7%) 1 6/692 (0.9%) 6
    Gout 2/138 (1.4%) 2 1/138 (0.7%) 1 6/692 (0.9%) 6
    Folate deficiency 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Fluid retention 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Fluid overload 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dyslipidaemia 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Diabetes mellitus 3/138 (2.2%) 3 3/138 (2.2%) 3 7/692 (1%) 7
    Decreased appetite 7/138 (5.1%) 9 7/138 (5.1%) 9 48/692 (6.9%) 56
    Cachexia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Musculoskeletal and connective tissue disorders
    Tenosynovitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Tendonitis 3/138 (2.2%) 3 1/138 (0.7%) 1 4/692 (0.6%) 4
    Tendon disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Synovial cyst 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Spondylitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spinal pain 1/138 (0.7%) 1 0/138 (0%) 0 4/692 (0.6%) 4
    Spinal osteoarthritis 2/138 (1.4%) 2 1/138 (0.7%) 1 4/692 (0.6%) 4
    Spinal column stenosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Sjogren's syndrome 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Rotator cuff syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Polyarthritis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Periostitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Periarthritis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pain in jaw 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Pain in extremity 10/138 (7.2%) 10 10/138 (7.2%) 11 43/692 (6.2%) 46
    Osteoporosis 4/138 (2.9%) 4 1/138 (0.7%) 1 7/692 (1%) 8
    Osteopenia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Osteochondrosis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Osteoarthritis 3/138 (2.2%) 3 5/138 (3.6%) 5 14/692 (2%) 15
    Osteitis deformans 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Neck pain 4/138 (2.9%) 5 3/138 (2.2%) 3 11/692 (1.6%) 12
    Myofascial pain syndrome 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Myalgia 5/138 (3.6%) 5 5/138 (3.6%) 5 16/692 (2.3%) 17
    Musculoskeletal stiffness 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Musculoskeletal pain 5/138 (3.6%) 5 6/138 (4.3%) 6 22/692 (3.2%) 22
    Musculoskeletal discomfort 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Musculoskeletal chest pain 2/138 (1.4%) 2 2/138 (1.4%) 2 5/692 (0.7%) 5
    Muscular weakness 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Muscle tightness 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Muscle spasms 10/138 (7.2%) 10 5/138 (3.6%) 7 25/692 (3.6%) 28
    Muscle fatigue 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Muscle contracture 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Mobility decreased 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Limb mass 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Limb discomfort 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Joint swelling 2/138 (1.4%) 3 3/138 (2.2%) 3 7/692 (1%) 8
    Joint stiffness 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Intervertebral disc protrusion 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Groin pain 1/138 (0.7%) 1 1/138 (0.7%) 2 3/692 (0.4%) 4
    Foot deformity 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Flank pain 1/138 (0.7%) 1 1/138 (0.7%) 1 5/692 (0.7%) 6
    Exostosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Chondrocalcinosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bursitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bone pain 2/138 (1.4%) 2 3/138 (2.2%) 3 17/692 (2.5%) 17
    Back pain 14/138 (10.1%) 16 13/138 (9.4%) 19 62/692 (9%) 72
    Axillary mass 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Arthritis 0/138 (0%) 0 2/138 (1.4%) 2 5/692 (0.7%) 5
    Arthralgia 15/138 (10.9%) 22 14/138 (10.1%) 23 52/692 (7.5%) 68
    Ankylosing spondylitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Sweat gland tumour 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Squamous cell carcinoma of skin 1/138 (0.7%) 1 2/138 (1.4%) 2 6/692 (0.9%) 6
    Squamous cell carcinoma 2/138 (1.4%) 2 1/138 (0.7%) 1 7/692 (1%) 8
    Skin papilloma 1/138 (0.7%) 3 0/138 (0%) 0 1/692 (0.1%) 3
    Seborrhoeic keratosis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Prostate cancer 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Paget's disease of nipple 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Myelodysplastic syndrome 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Melanocytic naevus 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Lobular breast carcinoma in situ 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Lipoma 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Leiomyoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Large intestine benign neoplasm 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Large cell lung cancer 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Keratoacanthoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Breast cancer 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Bowen's disease 0/138 (0%) 0 2/138 (1.4%) 2 3/692 (0.4%) 3
    Bladder transitional cell carcinoma 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Basal cell carcinoma 5/138 (3.6%) 5 5/138 (3.6%) 5 17/692 (2.5%) 19
    Acrochordon 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Nervous system disorders
    Vertebrobasilar insufficiency 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Tremor 3/138 (2.2%) 3 3/138 (2.2%) 4 13/692 (1.9%) 15
    Tension headache 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Syncope 3/138 (2.2%) 3 2/138 (1.4%) 2 10/692 (1.4%) 10
    Somnolence 0/138 (0%) 0 3/138 (2.2%) 3 4/692 (0.6%) 4
    Sensory disturbance 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Sensorimotor disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Seizure 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Sciatica 3/138 (2.2%) 3 4/138 (2.9%) 5 12/692 (1.7%) 14
    Presyncope 4/138 (2.9%) 4 1/138 (0.7%) 1 5/692 (0.7%) 5
    Post herpetic neuralgia 1/138 (0.7%) 1 2/138 (1.4%) 2 5/692 (0.7%) 5
    Polyneuropathy 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Peripheral sensory neuropathy 4/138 (2.9%) 4 3/138 (2.2%) 3 10/692 (1.4%) 10
    Peripheral sensorimotor neuropathy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Parosmia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Parkinsonism 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Paraesthesia 5/138 (3.6%) 5 9/138 (6.5%) 9 29/692 (4.2%) 29
    Nystagmus 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Neuropathy peripheral 8/138 (5.8%) 9 7/138 (5.1%) 8 23/692 (3.3%) 25
    Neuromuscular pain 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Neuralgia 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 4
    Nerve root compression 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nerve compression 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Memory impairment 2/138 (1.4%) 2 2/138 (1.4%) 2 6/692 (0.9%) 6
    Lumbar radiculopathy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Lethargy 1/138 (0.7%) 2 0/138 (0%) 0 4/692 (0.6%) 5
    Intention tremor 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypotonia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypokinesia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypoaesthesia 1/138 (0.7%) 1 2/138 (1.4%) 3 6/692 (0.9%) 8
    Hypersomnia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hemiparesis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Headache 16/138 (11.6%) 24 18/138 (13%) 25 68/692 (9.8%) 92
    Formication 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Facial paralysis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Facial neuralgia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dysgraphia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Dysgeusia 7/138 (5.1%) 11 3/138 (2.2%) 3 17/692 (2.5%) 21
    Dysaesthesia 1/138 (0.7%) 1 3/138 (2.2%) 3 6/692 (0.9%) 6
    Dizziness 16/138 (11.6%) 21 8/138 (5.8%) 8 36/692 (5.2%) 42
    Disturbance in attention 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Diabetic neuropathy 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cluster headache 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cerebral microangiopathy 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Cerebral ischaemia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Carpal tunnel syndrome 3/138 (2.2%) 3 0/138 (0%) 0 3/692 (0.4%) 3
    Carotid arteriosclerosis 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Burning sensation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Balance disorder 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Ataxia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Arachnoid cyst 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Aphonia 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Aphasia 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Anosmia 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Amnesia 3/138 (2.2%) 3 1/138 (0.7%) 1 5/692 (0.7%) 5
    Ageusia 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Product Issues
    Device occlusion 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Thrombosis in device 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Psychiatric disorders
    Stress 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Sleep disorder 2/138 (1.4%) 2 1/138 (0.7%) 1 5/692 (0.7%) 5
    Restlessness 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Panic attack 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Mood altered 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Loss of libido 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Insomnia 7/138 (5.1%) 8 5/138 (3.6%) 5 31/692 (4.5%) 33
    Feeling of despair 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Depression 8/138 (5.8%) 8 2/138 (1.4%) 2 20/692 (2.9%) 20
    Depressed mood 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Delirium 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Confusional state 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Anxiety disorder 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Anxiety 1/138 (0.7%) 1 9/138 (6.5%) 9 22/692 (3.2%) 23
    Agitation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Adjustment disorder with depressed mood 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Renal and urinary disorders
    Urinary tract pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Urinary tract obstruction 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Urinary retention 3/138 (2.2%) 3 1/138 (0.7%) 1 5/692 (0.7%) 5
    Urinary incontinence 1/138 (0.7%) 1 1/138 (0.7%) 3 5/692 (0.7%) 7
    Urethral haemorrhage 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Strangury 0/138 (0%) 0 2/138 (1.4%) 2 3/692 (0.4%) 3
    Renal pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Renal impairment 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Renal failure 0/138 (0%) 0 2/138 (1.4%) 2 8/692 (1.2%) 9
    Renal cyst 1/138 (0.7%) 1 2/138 (1.4%) 2 3/692 (0.4%) 3
    Renal colic 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Renal atrophy 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Polyuria 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pollakiuria 3/138 (2.2%) 3 1/138 (0.7%) 1 9/692 (1.3%) 10
    Nocturia 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Nephrolithiasis 1/138 (0.7%) 1 3/138 (2.2%) 3 6/692 (0.9%) 6
    Nephroangiosclerosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Micturition urgency 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Leukocyturia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Hypertonic bladder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Haematuria 2/138 (1.4%) 2 1/138 (0.7%) 1 5/692 (0.7%) 5
    Dysuria 2/138 (1.4%) 2 6/138 (4.3%) 6 13/692 (1.9%) 14
    Cystitis haemorrhagic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Chronic kidney disease 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Bladder hypertrophy 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bladder disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Azotaemia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Acute kidney injury 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Reproductive system and breast disorders
    Vulvovaginal erythema 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Vaginal discharge 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Testicular pain 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Testicular oedema 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Pruritus genital 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Premature menopause 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Pelvic pain 1/138 (0.7%) 2 1/138 (0.7%) 1 2/692 (0.3%) 3
    Pelvic discomfort 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Ovarian cyst 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Menstrual disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Erectile dysfunction 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Dysmenorrhoea 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cystocele 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Benign prostatic hyperplasia 4/138 (2.9%) 4 0/138 (0%) 0 5/692 (0.7%) 5
    Amenorrhoea 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Prostatic disorder 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Breast mass 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Genital rash 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Menometrorrhagia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Menorrhagia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Prostatitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spermatic cord mass 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spermatic cord pain 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Testicular swelling 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Vulvovaginal inflammation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Wheezing 0/138 (0%) 0 2/138 (1.4%) 2 4/692 (0.6%) 4
    Upper respiratory tract inflammation 1/138 (0.7%) 2 0/138 (0%) 0 2/692 (0.3%) 3
    Upper airway obstruction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Upper-airway cough syndrome 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Tracheomalacia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Throat tightness 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Throat irritation 2/138 (1.4%) 2 2/138 (1.4%) 2 5/692 (0.7%) 5
    Sneezing 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Sleep apnoea syndrome 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Sinus polyp 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Sinus disorder 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Sinus congestion 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Rhonchi 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Rhinorrhoea 6/138 (4.3%) 6 2/138 (1.4%) 2 14/692 (2%) 14
    Rhinitis atrophic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rhinitis allergic 3/138 (2.2%) 3 2/138 (1.4%) 2 11/692 (1.6%) 11
    Rales 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary mass 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary hypertension 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary fibrosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pulmonary embolism 1/138 (0.7%) 1 1/138 (0.7%) 1 5/692 (0.7%) 5
    Pulmonary arterial hypertension 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Productive cough 5/138 (3.6%) 5 8/138 (5.8%) 8 25/692 (3.6%) 28
    Pneumonia aspiration 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pleuritic pain 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Pleurisy 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Pleural effusion 2/138 (1.4%) 2 2/138 (1.4%) 2 6/692 (0.9%) 6
    Pharyngeal parasthesia 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Pharyngeal inflammation 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Painful respiration 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Orthopnoea 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Oropharyngeal pain 15/138 (10.9%) 15 5/138 (3.6%) 5 39/692 (5.6%) 40
    Oropharyngeal discomfort 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Obstructive airways disorder 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Obliterative bronchiolitis 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Noninfective bronchitis 0/138 (0%) 0 0/138 (0%) 0 4/692 (0.6%) 4
    Nasal pruritus 0/138 (0%) 0 1/138 (0.7%) 2 1/692 (0.1%) 2
    Nasal polyps 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nasal obstruction 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Nasal congestion 2/138 (1.4%) 2 2/138 (1.4%) 2 8/692 (1.2%) 8
    Lung disorder 1/138 (0.7%) 1 2/138 (1.4%) 2 4/692 (0.6%) 4
    Larynx irritation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Laryngospasm 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Laryngeal pain 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Interstitial lung disease 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Increased upper airway secretion 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hiccups 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haemoptysis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Epistaxis 3/138 (2.2%) 3 3/138 (2.2%) 3 12/692 (1.7%) 15
    Emphysema 2/138 (1.4%) 2 0/138 (0%) 0 3/692 (0.4%) 3
    Dyspnoea exertional 0/138 (0%) 0 1/138 (0.7%) 1 6/692 (0.9%) 7
    Dyspnoea 6/138 (4.3%) 7 11/138 (8%) 11 55/692 (7.9%) 62
    Dysphonia 6/138 (4.3%) 7 3/138 (2.2%) 4 14/692 (2%) 18
    Dry throat 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Cough 47/138 (34.1%) 72 24/138 (17.4%) 37 135/692 (19.5%) 185
    Chronic obstructive pulmonary disease 5/138 (3.6%) 5 2/138 (1.4%) 2 9/692 (1.3%) 10
    Catarrh 0/138 (0%) 0 1/138 (0.7%) 1 3/692 (0.4%) 3
    Bronchospasm 1/138 (0.7%) 1 2/138 (1.4%) 2 7/692 (1%) 7
    Bronchomalacia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Bronchitis chronic 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bronchiectasis 1/138 (0.7%) 1 0/138 (0%) 0 2/692 (0.3%) 2
    Bronchial obstruction 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Bronchial hyperreactivity 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Bronchial disorder 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Atelectasis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Asthmatic crisis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Asthma 2/138 (1.4%) 2 2/138 (1.4%) 3 5/692 (0.7%) 6
    Adenoidal hypertrophy 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Acute pulmonary oedema 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Skin and subcutaneous tissue disorders
    Urticaria 3/138 (2.2%) 3 2/138 (1.4%) 7 15/692 (2.2%) 20
    Swelling face 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Stasis dermatitis 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Skin ulcer 1/138 (0.7%) 1 3/138 (2.2%) 3 4/692 (0.6%) 4
    Skin swelling 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Skin reaction 1/138 (0.7%) 1 2/138 (1.4%) 2 5/692 (0.7%) 6
    Skin mass 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Skin lesion 3/138 (2.2%) 3 7/138 (5.1%) 8 19/692 (2.7%) 22
    Skin exfoliation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Skin disorder 1/138 (0.7%) 2 0/138 (0%) 0 1/692 (0.1%) 2
    Seborrhoeic dermatitis 1/138 (0.7%) 1 1/138 (0.7%) 3 3/692 (0.4%) 5
    Sebaceous hyperplasia 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rosacea 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Rash pruritic 0/138 (0%) 0 0/138 (0%) 0 3/692 (0.4%) 3
    Rash papular 0/138 (0%) 0 1/138 (0.7%) 1 6/692 (0.9%) 8
    Rash maculo-papular 0/138 (0%) 0 2/138 (1.4%) 3 8/692 (1.2%) 10
    Rash macular 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Rash generalised 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Rash follicular 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Rash erythematous 2/138 (1.4%) 2 1/138 (0.7%) 1 7/692 (1%) 7
    Rash 19/138 (13.8%) 24 18/138 (13%) 23 76/692 (11%) 97
    Purpura 2/138 (1.4%) 2 2/138 (1.4%) 2 4/692 (0.6%) 4
    Psoriasis 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Pruritus generalised 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 4
    Pruritus allergic 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Pruritus 11/138 (8%) 14 9/138 (6.5%) 12 51/692 (7.4%) 61
    Prurigo 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Pityriasis rosea 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Perioral dermatitis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Panniculitis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Pain of skin 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Night sweats 3/138 (2.2%) 5 3/138 (2.2%) 4 19/692 (2.7%) 22
    Neurodermatitis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Nail discolouration 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Macule 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Intertrigo 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Hypertrichiosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hyperkeratosis 2/138 (1.4%) 2 2/138 (1.4%) 2 8/692 (1.2%) 8
    Hyperhidrosis 3/138 (2.2%) 3 2/138 (1.4%) 2 15/692 (2.2%) 15
    Granulomatous rosacea 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Exfoliative rash 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Erythema nodosum 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Erythema multiforme 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eczema nummular 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Ecchymosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Eczema 3/138 (2.2%) 3 4/138 (2.9%) 4 12/692 (1.7%) 14
    Erythema 6/138 (4.3%) 7 6/138 (4.3%) 7 29/692 (4.2%) 39
    Dry skin 4/138 (2.9%) 5 3/138 (2.2%) 3 10/692 (1.4%) 11
    Drug eruption 1/138 (0.7%) 1 0/138 (0%) 0 5/692 (0.7%) 5
    Dermatomyositis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Dermatitis bullous 1/138 (0.7%) 4 0/138 (0%) 0 1/692 (0.1%) 4
    Dermatitis atopic 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Dermatitis allergic 2/138 (1.4%) 2 2/138 (1.4%) 2 6/692 (0.9%) 6
    Dermatitis 2/138 (1.4%) 2 2/138 (1.4%) 2 5/692 (0.7%) 5
    Dermal cyst 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Decubitus ulcer 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Blood blister 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Angioedema 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Alopecia 6/138 (4.3%) 6 6/138 (4.3%) 7 23/692 (3.3%) 26
    Actinic keratosis 2/138 (1.4%) 2 3/138 (2.2%) 3 10/692 (1.4%) 11
    Acne 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Surgical and medical procedures
    Tooth extraction 2/138 (1.4%) 2 0/138 (0%) 0 2/692 (0.3%) 2
    Skin neoplasm excision 0/138 (0%) 0 1/138 (0.7%) 1 4/692 (0.6%) 6
    Shoulder arthroplasty 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Nephrostomy 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Mass excision 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hip arthroplasty 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Foot operation 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Cholecystectomy 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Central venous catheter removal 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Cataract operation 1/138 (0.7%) 1 4/138 (2.9%) 5 6/692 (0.9%) 8
    Astringent therapy 1/138 (0.7%) 1 1/138 (0.7%) 1 3/692 (0.4%) 3
    Cancer surgery 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Vascular operation 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Wisdom teeth removal 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Vascular disorders
    Venous thrombosis limb 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Venous thrombosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Varicose vein 1/138 (0.7%) 1 1/138 (0.7%) 1 4/692 (0.6%) 4
    Varicose ulceration 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Thrombosis 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Thrombophlebitis superficial 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Thrombophlebitis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2
    Subclavian vein thrombosis 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Spider vein 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Poor venous access 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Phlebitis superficial 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Phlebitis 2/138 (1.4%) 2 2/138 (1.4%) 3 6/692 (0.9%) 7
    Peripheral venous disease 3/138 (2.2%) 4 1/138 (0.7%) 1 4/692 (0.6%) 5
    Peripheral ischaemia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Peripheral coldness 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Peripheral arterial occlusive disease 0/138 (0%) 0 2/138 (1.4%) 2 2/692 (0.3%) 2
    Pallor 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Orthostatic hypotension 0/138 (0%) 0 0/138 (0%) 0 2/692 (0.3%) 2
    Ischaemia 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Intermittent claudication 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Hypotension 2/138 (1.4%) 2 3/138 (2.2%) 3 19/692 (2.7%) 21
    Hypertensive crisis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Hypertension 18/138 (13%) 27 5/138 (3.6%) 6 45/692 (6.5%) 57
    Hyperaemia 1/138 (0.7%) 1 1/138 (0.7%) 1 2/692 (0.3%) 2
    Hot flush 1/138 (0.7%) 1 1/138 (0.7%) 1 8/692 (1.2%) 16
    Haemorrhage 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Haematoma 2/138 (1.4%) 2 1/138 (0.7%) 1 5/692 (0.7%) 5
    Flushing 2/138 (1.4%) 2 2/138 (1.4%) 2 8/692 (1.2%) 8
    Essential hypertension 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Embolism 0/138 (0%) 0 1/138 (0.7%) 1 1/692 (0.1%) 1
    Deep vein thrombosis 1/138 (0.7%) 1 0/138 (0%) 0 3/692 (0.4%) 3
    Aortic stenosis 0/138 (0%) 0 1/138 (0.7%) 1 0/692 (0%) 0
    Aortic arteriosclerosis 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Aortic aneurysm 0/138 (0%) 0 0/138 (0%) 0 1/692 (0.1%) 1
    Angiopathy 1/138 (0.7%) 1 0/138 (0%) 0 1/692 (0.1%) 1
    Arteriosclerosis 0/138 (0%) 0 1/138 (0.7%) 1 2/692 (0.3%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmann-La Roche
    Phone 800 821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01461928
    Other Study ID Numbers:
    • MO25455
    • 2010-023407-95
    First Posted:
    Oct 28, 2011
    Last Update Posted:
    Aug 6, 2019
    Last Verified:
    Jul 1, 2019