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A Study of the Safety and Efficacy of Fabrazyme (Agalsidase Beta) as Compared to Placebo in Patients With Advanced Fabry Disease

Sponsor
Genzyme, a Sanofi Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00074984
Collaborator
(none)
82
Enrollment
26
Locations
2
Arms
35
Duration (Months)
3.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

People with Fabry disease have an alteration in their genetic material (DNA) which causes a deficiency of the a-galactosidase A enzyme. Fabrazyme (agalsidase beta) is a drug that helps to breakdown and remove certain types of fatty substances called "glycolipids." These glycolipids are normally present within the body in most cells. In Fabry disease, glycolipids build up in various tissues such as the liver, kidney, skin, and blood vessels because a-galactosidase A is not present, or is present in small quantities. The build up of glycolipid ("globotriaosylceramide" or "GL-3") levels in these tissues in particular is thought to cause the clinical symptoms that are common to Fabry disease. This study will test the safety and efficacy of Fabrazyme in the treatment of patients with Fabry disease.

Condition or Disease Intervention/Treatment Phase
  • Biological: Fabrazyme (agalsidase beta)
  • Biological: Placebo
 Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
82 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Fabrazyme on Progression of Renal Disease and Significant Clinical Events in Patients With Fabry Disease
Study Start Date :
Feb 1, 2001
Actual Primary Completion Date :
Jan 1, 2004
Actual Study Completion Date :
Jan 1, 2004

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo

Patients randomized to placebo

Biological: Placebo
1 mg/kg placebo intravenously every 2 weeks
Active Comparator: Fabrazyme (agalsidase beta)

Patients randomized to Fabrazyme (agalsidase beta).

Biological: Fabrazyme (agalsidase beta)
1mg/kg Fabrazyme (agalsidase beta) every 2 weeks
Other Names:
  • Fabrazyme

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients [up to 35 months]

      The primary efficacy endpoint was the time to the first occurrence of a clinically significant renal (33% increase in serum creatinine, dialysis or transplant), cardiac (myocardial infarction, significant change in cardiac status, i.e., angina, congestive heart failure or symptomatic arrhythmia requiring medication or surgery) or cerebrovascular (stroke or transient ischemic attack) event and/or death (due to any cause) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.

    Secondary Outcome Measures

    1. Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients [up to 35 months]

      Time to a clinically significant renal event (33% increase in serum creatinine, dialysis or transplant) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.

    2. Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients [up to 35 months]

      Summary of slopes of eGFR by baseline eGFR subgroups (>60 and <=60 mL/min/1.73m^2/year) comparing Placebo vs Fabrazyme (agalsidase beta) Patients.

    3. Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients [up to 35 months]

      Summary of slopes of inverse serum creatinine by baseline serum creatinine subgroups (> or <= 1.5 mg/dL) comparing Placebo vs Fabrazyme (agalsidase beta) patients.

    4. Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) [at 24 months]

      Neuropathic pain was assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire on a scale of 0 (no pain) to 10 (pain as bad as you can imagine)

    Eligibility Criteria

    Criteria

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

    • Patients must provide written informed consent

    • Patients must be at least 16 years old

    • Patients must have a current diagnosis of Fabry disease and have a clinical presentation consistent of Fabry disease (decreased sweating, Fabry pain, angiokeratoma, etc.)

    • Patients may not have received enzyme replacement therapy as a treatment for Fabry disease

    • Patients must have a documented plasma a-galactosidase A (aGAL) activity of < 1.5 nmol/hr/mL or a documented leukocyte aGAL activity of < 4 nmol/hr/mg

    • Patients must have one or more of the following: a serum creatinine measurement of 1.2 to 3 mg/dL (106.1 to 265 umol/L) OR estimated creatinine clearance < 80 mL/min only if the patient's serum creatinine measurement is < 1.2 mg/dL

    • Female patients of childbearing potential must have a negative pregnancy test prior to each dosing and all female patients must use a medically accepted form of contraception

    Exclusion Criteria:

    • Patient has undergone or is currently scheduled for kidney transplantation or is currently on dialysis

    • Patient has acute renal failure

    • Patient has participated in a study employing an investigational drug within 30 days of study entry

    • Patient has diabetes mellitus or presence of confounding renal disease

    • Patient has a history of transient ischemic attack (TIA) or ischemic stroke within 3 months of study entry documented by mild-to-moderate neurological deficit

    • Patient has critical coronary disease

    • Patient has congestive heart failure

    • Patient has severe residual neurological deficit that will confound the detection of new events as determined by an attending neurologist and/or Principal Investigator

    • Patient is unwilling to comply with the requirements of the protocol or the patient has a medical condition, serious intercurrent illness, or extenuating circumstances that would significantly decrease study compliance, including prescribed follow-up

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama at Birmingham Birmingham Alabama United States 35294
    2 Cedars-Sinai Medical Center Los Angeles California United States 90048
    3 University of San Francisco San Francisco California United States 94143
    4 University of Connecticut Health Partners Farmington Connecticut United States 06119
    5 Oncology Hematology Association Coral Springs Florida United States 33065
    6 Emory University School of Medicine Atlanta Georgia United States 30322
    7 Children's Memorial Hospital Chicago Illinois United States 60614
    8 University of Kansas Medical Center Kansas City Kansas United States 66160
    9 Massachusetts General Hospital Boston Massachusetts United States 02114
    10 Gene Therapy Center - Dept. of Pediatrics and Institute of Human Genetics Minneapolis Minnesota United States 55455
    11 Children's Hospital Buffalo New York United States 14209
    12 Mount Sinai School of Medicine New York New York United States 10029
    13 University of Rochester School of Medicine Rochester New York United States 14642
    14 Duke University Medical Center Durham North Carolina United States 27710
    15 Children's Hospital Medical Center Cincinnati Ohio United States 45229
    16 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    17 University of Pittsburgh Pittsburgh Pennsylvania United States 15261
    18 Baylor College of Medicine Houston Texas United States 77030
    19 University of Washington School of Medicine Seattle Washington United States 98195
    20 Queen Elizabeth II Health Center Halifax Nova Scotia Canada B3H 1V8
    21 North York General Hospital Toronto Ontario Canada M2K 1E1
    22 Hopital du Sacre-Coeur de Montreal Montreal Quebec Canada H4J 1C5
    23 University Hospital Prague Czech Republic 128 08
    24 Sopron Megyei Jogu Varos Erzsebet Korhaz Sopron Hungary 9400
    25 Klinika Chorob Metabolicznych Instytut Warsaw Poland 04-730
    26 Hope Hospital Manchester United Kingdom M6 8HD

    Sponsors and Collaborators

    • Genzyme, a Sanofi Company

    Investigators

    • Study Director: Medical Monitor, Genzyme Coorporation

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00074984
    Other Study ID Numbers:
    • AGAL-008-00
    First Posted:
    Dec 25, 2003
    Last Update Posted:
    Dec 27, 2013
    Last Verified:
    Dec 1, 2013
    Keywords provided by , ,
    a-Galactosidase A
    aGAL
    r-haGAL
    Fabry
    GL-3
    Fabrazyme
    Additional relevant MeSH terms:
    Fabry Disease

    Study Results

    Participant Flow

    Recruitment Details A total of 252 patients were screened for entry into the study and of these, 82 patients were eligible to be enrolled.
    Pre-assignment Detail
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Period Title: Overall Study
    STARTED 31 51
    COMPLETED 28 43
    NOT COMPLETED 3 8

    Baseline Characteristics

    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta) Total
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks. Total of all reporting groups
    Overall Participants 31 51 82
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    31
    100%
    49
    96.1%
    80
    97.6%
    >=65 years
    0
    0%
    2
    3.9%
    2
    2.4%
    Age, Customized (participants) [Number]
    <40 years
    8
    25.8%
    11
    21.6%
    19
    23.2%
    ≥40 years
    23
    74.2%
    40
    78.4%
    63
    76.8%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    44.3
    (9.23)
    46.9
    (9.75)
    45.9
    (9.58)
    Sex: Female, Male (Count of Participants)
    Female
    4
    12.9%
    6
    11.8%
    10
    12.2%
    Male
    27
    87.1%
    45
    88.2%
    72
    87.8%
    Race/Ethnicity (participants) [Number]
    Caucasian
    27
    87.1%
    45
    88.2%
    72
    87.8%
    Black
    0
    0%
    1
    2%
    1
    1.2%
    Hispanic
    2
    6.5%
    3
    5.9%
    5
    6.1%
    Asian
    1
    3.2%
    1
    2%
    2
    2.4%
    Other
    1
    3.2%
    1
    2%
    2
    2.4%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients
    Description The primary efficacy endpoint was the time to the first occurrence of a clinically significant renal (33% increase in serum creatinine, dialysis or transplant), cardiac (myocardial infarction, significant change in cardiac status, i.e., angina, congestive heart failure or symptomatic arrhythmia requiring medication or surgery) or cerebrovascular (stroke or transient ischemic attack) event and/or death (due to any cause) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.
    Time Frame up to 35 months

    Outcome Measure Data

    Analysis Population Description
    The Intent-to-treat (ITT) population consists of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Measure Participants 31 51
    Participants with a clinical event
    13
    41.9%
    14
    27.5%
    Participants with no clinical event
    18
    58.1%
    37
    72.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Fabrazyme (Agalsidase Beta)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1449
    Comments
    Method Log Rank
    Comments Comparison is based on a 2-sided log-rank test.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.574
    Confidence Interval (2-Sided) 95%
    0.269 to 1.222
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Fabrazyme (Agalsidase Beta)
    Comments Time to First Primary Endpoint Adjusting for Baseline Proteinuria using Cox Proportional Hazards Model
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0577
    Comments
    Method Wald Test
    Comments
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.465
    Confidence Interval (2-Sided) 95%
    0.211 to 1.025
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients
    Description Time to a clinically significant renal event (33% increase in serum creatinine, dialysis or transplant) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.
    Time Frame up to 35 months

    Outcome Measure Data

    Analysis Population Description
    The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Measure Participants 31 51
    Participants with a Renal event
    7
    22.6%
    10
    19.6%
    Participants with no Renal event
    24
    77.4%
    41
    80.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Fabrazyme (Agalsidase Beta)
    Comments Analysis of Time to First Renal Event for ITT population.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5261
    Comments
    Method Log Rank
    Comments 2-sided log-rank test
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.732
    Confidence Interval (2-Sided) 95%
    0.278 to 1.927
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients
    Description Summary of slopes of eGFR by baseline eGFR subgroups (>60 and <=60 mL/min/1.73m^2/year) comparing Placebo vs Fabrazyme (agalsidase beta) Patients.
    Time Frame up to 35 months

    Outcome Measure Data

    Analysis Population Description
    The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Measure Participants 31 51
    eGFR Total
    -3.62
    (3.38)
    -3.25
    (2.92)
    Baseline eGFR >60
    -5.09
    (3.52)
    -1.51
    (2.85)
    Baseline eGFR <= 60
    -3.02
    (3.21)
    -4.20
    (2.52)
    4. Secondary Outcome
    Title Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients
    Description Summary of slopes of inverse serum creatinine by baseline serum creatinine subgroups (> or <= 1.5 mg/dL) comparing Placebo vs Fabrazyme (agalsidase beta) patients.
    Time Frame up to 35 months

    Outcome Measure Data

    Analysis Population Description
    The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Measure Participants 31 51
    Total
    -0.038
    (0.037)
    -0.036
    (0.035)
    Baseline Serum Creatinine > 1.5
    -0.043
    (0.030)
    -0.050
    (0.028)
    Baseline Serum Creatinine <= 1.5
    -0.033
    (0.043)
    -0.022
    (0.035)
    5. Secondary Outcome
    Title Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst)
    Description Neuropathic pain was assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire on a scale of 0 (no pain) to 10 (pain as bad as you can imagine)
    Time Frame at 24 months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population
    Arm/Group Title Placebo Fabrazyme (Agalsidase Beta)
    Arm/Group Description Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks.
    Measure Participants 31 51
    Baseline (n=30, n=48)
    2.2
    (3.0)
    2.7
    (3.1)
    2 years (n=7, n=18)
    4.4
    (3.6)
    2.7
    (3.2)
    Change from baseline to 2 years (n=7, n=17)
    0.9
    (3.0)
    -0.8
    (3.2)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
    Arm/Group Title Fabrazyme (Agalsidase Beta) Placebo Total
    Arm/Group Description Patients randomized to Fabrazyme(agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks. Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks All patients.
    All Cause Mortality
    Fabrazyme (Agalsidase Beta) Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Fabrazyme (Agalsidase Beta) Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 18/51 (35.3%) 12/31 (38.7%) 30/82 (36.6%)
    Cardiac disorders
    Angina pectoris 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Angina unstable 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Atrial fibrillation 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Atrioventricular block second degree 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Bradycardia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Cardiac arrest 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Nodal arrhythmia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Ventricular tachycardia 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Ear and labyrinth disorders
    Meniere's disease 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gastrointestinal disorders
    Abdominal pain 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Constipation 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Vomiting 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    General disorders
    Chest pain 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Pyrexia 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Hepatobiliary disorders
    Cholelithiasis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Infections and infestations
    Cellulitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Erysipelas 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Localised infection 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Pneumonia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Streptococcal infection 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Injury, poisoning and procedural complications
    Femoral neck fracture 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hip fracture 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Medical device complication 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Procedural hypertension 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Investigations
    Blood creatinine increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Skin test positive 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Metabolism and nutrition disorders
    Dehydration 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Musculoskeletal and connective tissue disorders
    Aseptic necrosis bone 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Osteoarthritis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nervous system disorders
    Cerebrovascular accident 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Depressed level of consciousness 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Paraesthesia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Syncope 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Transient ischaemic attack 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Psychiatric disorders
    Affective disorder 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Alcoholism 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Depression 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Renal and urinary disorders
    Azotaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nephritis interstitial 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Surgical and medical procedures
    Drug therapy changed 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Vascular disorders
    Hypotension 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Other (Not Including Serious) Adverse Events
    Fabrazyme (Agalsidase Beta) Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 51/51 (100%) 29/31 (93.5%) 80/82 (97.6%)
    Blood and lymphatic system disorders
    Anaemia 6/51 (11.8%) 2/31 (6.5%) 8/82 (9.8%)
    Leukopenia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Lymphadenopathy 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nephrogenic anaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Cardiac disorders
    Angina pectoris 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Aortic valve sclerosis 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Arrhythmia 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Arrhythmia supraventricular 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Atrial fibrillation 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Bradycardia 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Bundle branch block 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Bundle branch block right 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Coronary artery disease 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dilatation atrial 2/51 (3.9%) 3/31 (9.7%) 5/82 (6.1%)
    Heart valve insufficiency 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Mitral valve incompetence 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Mitral valve prolapse 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Myocardial ischaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Palpitations 4/51 (7.8%) 1/31 (3.2%) 5/82 (6.1%)
    Sinus arrhythmia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Sinus bradycardia 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Supraventricular extrasystoles 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Tachyarrhythmia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Tachycardia 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Ventricular dysfunction 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Ventricular extrasystoles 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Ventricular hypertrophy 2/51 (3.9%) 3/31 (9.7%) 5/82 (6.1%)
    Ventricular tachycardia 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Ventricular wall thickening 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Ear and labyrinth disorders
    Cerumen impaction 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Deafness 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Deafness neurosensory 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Ear canal erythema 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Ear congestion 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Ear discomfort 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Ear pain 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Hearing impaired 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Hypoacusis 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Middle ear effusion 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Otorrhoea 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Tinnitus 6/51 (11.8%) 1/31 (3.2%) 7/82 (8.5%)
    Vertigo 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Endocrine disorders
    Hyperparathyroidism 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hypothalamo-pituitary disorders 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Eye disorders
    Binocular eye movement disorder 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Blepharitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blepharospasm 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Cataract 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Cataract subcapsular 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Conjunctivitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Diplopia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dry eye 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Eye irritation 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Eye pain 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Eyelid oedema 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Ocular hyperaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Retinopathy 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Scleral haemorrhage 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Vision blurred 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Visual acuity reduced 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Gastrointestinal disorders
    Abdominal discomfort 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Abdominal pain 8/51 (15.7%) 4/31 (12.9%) 12/82 (14.6%)
    Abdominal pain lower 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Abdominal pain upper 3/51 (5.9%) 4/31 (12.9%) 7/82 (8.5%)
    Abdominal rigidity 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Anal fistula 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Constipation 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Defaecation urgency 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Diarrhoea 12/51 (23.5%) 7/31 (22.6%) 19/82 (23.2%)
    Dry mouth 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Dyspepsia 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Faecal incontinence 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Faeces pale 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Flatulence 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Gastric disorder 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gastritis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gastrointestinal disorder 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gastrointestinal hypermotility 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gastrooesophageal reflux disease 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Gingival pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Haemorrhoids 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hypoaesthesia oral 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Lip blister 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Lip dry 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Mouth haemorrhage 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nausea 9/51 (17.6%) 10/31 (32.3%) 19/82 (23.2%)
    Oral pain 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Stomach discomfort 4/51 (7.8%) 0/31 (0%) 4/82 (4.9%)
    Stomatitis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Tooth disorder 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Toothache 4/51 (7.8%) 2/31 (6.5%) 6/82 (7.3%)
    Uvulitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Vomiting 14/51 (27.5%) 10/31 (32.3%) 24/82 (29.3%)
    General disorders
    Adverse event 8/51 (15.7%) 3/31 (9.7%) 11/82 (13.4%)
    Asthenia 5/51 (9.8%) 2/31 (6.5%) 7/82 (8.5%)
    Axillary pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Catheter site haematoma 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Catheter site pain 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Catheter site related reaction 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Chest discomfort 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Chest pain 5/51 (9.8%) 5/31 (16.1%) 10/82 (12.2%)
    Chills 20/51 (39.2%) 6/31 (19.4%) 26/82 (31.7%)
    Cyst 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Drug withdrawal syndrome 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Face oedema 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Fatigue 17/51 (33.3%) 4/31 (12.9%) 21/82 (25.6%)
    Feeling cold 4/51 (7.8%) 1/31 (3.2%) 5/82 (6.1%)
    Feeling hot 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Feeling hot and cold 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Feeling jittery 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Gait disturbance 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Influenza like illness 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Infusion site reaction 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Injection site thrombosis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Irritability 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Malaise 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Oedema peripheral 12/51 (23.5%) 9/31 (29%) 21/82 (25.6%)
    Pain 12/51 (23.5%) 7/31 (22.6%) 19/82 (23.2%)
    Pitting oedema 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Pyrexia 18/51 (35.3%) 9/31 (29%) 27/82 (32.9%)
    Suprapubic pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Thirst 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hepatobiliary disorders
    Cholelithiasis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Immune system disorders
    Hypersensitivity 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Multiple allergies 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Infections and infestations
    Bronchitis 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Bronchitis acute 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Candidiasis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Cellulitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Conjunctivitis infective 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dental caries 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Ear infection 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Fungal infection 4/51 (7.8%) 0/31 (0%) 4/82 (4.9%)
    Gastroenteritis 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Gastroenteritis viral 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Gingival abscess 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Gingival infection 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Herpes zoster 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Influenza 6/51 (11.8%) 4/31 (12.9%) 10/82 (12.2%)
    Kidney infection 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Labyrinthitis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Localised infection 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Lower respiratory tract infection 9/51 (17.6%) 1/31 (3.2%) 10/82 (12.2%)
    Mastoiditis 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Nail tinea 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nasopharyngitis 17/51 (33.3%) 6/31 (19.4%) 23/82 (28%)
    Oral candidiasis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Otitis externa fungal 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Otitis media 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Pharyngitis 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Pharyngitis streptococcal 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Postoperative infection 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Prostate infection 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Rectal abscess 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Respiratory tract infection 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Sinusitis 6/51 (11.8%) 3/31 (9.7%) 9/82 (11%)
    Skin infection 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Tooth abscess 4/51 (7.8%) 1/31 (3.2%) 5/82 (6.1%)
    Upper respiratory tract infection 16/51 (31.4%) 8/31 (25.8%) 24/82 (29.3%)
    Upper respiratory tract infection bacterial 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Urinary tract infection 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Vaginal candidiasis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Viral infection 5/51 (9.8%) 0/31 (0%) 5/82 (6.1%)
    Viral upper respiratory tract infection 6/51 (11.8%) 0/31 (0%) 6/82 (7.3%)
    Injury, poisoning and procedural complications
    Animal scratch 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Arthropod bite 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Back injury 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Contusion 4/51 (7.8%) 2/31 (6.5%) 6/82 (7.3%)
    Ear canal abrasion 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Electric shock 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Excoriation 7/51 (13.7%) 1/31 (3.2%) 8/82 (9.8%)
    Fall 4/51 (7.8%) 0/31 (0%) 4/82 (4.9%)
    Joint injury 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Muscle strain 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Open wound 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Operative haemorrhage 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Post procedural complication 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Post procedural nausea 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Postoperative wound complication 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Procedural pain 6/51 (11.8%) 0/31 (0%) 6/82 (7.3%)
    Road traffic accident 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Skin laceration 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Sunburn 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Thermal burn 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Tooth fracture 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Traumatic haematoma 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Vaccination complication 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Wound 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Wound secretion 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Investigations
    Albumin urine present 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Aspartate aminotransferase increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blood alkaline phosphatase increased 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Blood bicarbonate decreased 7/51 (13.7%) 4/31 (12.9%) 11/82 (13.4%)
    Blood bilirubin increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blood calcium decreased 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Blood chloride increased 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Blood creatinine increased 6/51 (11.8%) 2/31 (6.5%) 8/82 (9.8%)
    Blood glucose increased 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Blood phosphorus increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blood potassium decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blood potassium increased 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Blood pressure decreased 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Blood pressure increased 6/51 (11.8%) 2/31 (6.5%) 8/82 (9.8%)
    Blood sodium decreased 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Blood triglycerides increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blood urea increased 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Blood uric acid increased 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Body temperature increased 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Cardiac murmur 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Cardiac stress test abnormal 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Creatinine renal clearance decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Echocardiogram abnormal 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Ejection fraction decreased 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Electrocardiogram QT prolonged 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Electrocardiogram ST segment abnormal 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Electrocardiogram ST segment depression 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Electrocardiogram ST-T segment abnormal 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Electrocardiogram T wave amplitude increased 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Electrocardiogram T wave inversion 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Glomerular filtration rate decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Haematocrit decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Haemoglobin decreased 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Heart rate decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Heart rate increased 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Heart rate irregular 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hepatic enzyme increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    International normalised ratio increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nuclear magnetic resonance imaging abnormal 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Occult blood positive 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Platelet count decreased 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Platelet count increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Protein urine present 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Prothrombin time ratio increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Red blood cell count decreased 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Red blood cells urine positive 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Right ventricular systolic pressure increased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Tandem gait test abnormal 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Vibration test abnormal 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Weight decreased 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Metabolism and nutrition disorders
    Acidosis 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Anorexia 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Decreased appetite 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Gout 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Hyperchloraemia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Hyperkalaemia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Hyperphosphataemia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Hyperuricaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hypocalcaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hypokalaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Metabolic acidosis 1/51 (2%) 2/31 (6.5%) 3/82 (3.7%)
    Oral intake reduced 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 7/51 (13.7%) 7/31 (22.6%) 14/82 (17.1%)
    Arthritis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Aseptic necrosis bone 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Axillary mass 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Back pain 15/51 (29.4%) 4/31 (12.9%) 19/82 (23.2%)
    Bunion 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Buttock pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Chest wall pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Flank pain 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Groin pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Joint swelling 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Limb discomfort 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Mobility decreased 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Muscle spasms 6/51 (11.8%) 2/31 (6.5%) 8/82 (9.8%)
    Muscle twitching 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Muscular weakness 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Musculoskeletal discomfort 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Myalgia 7/51 (13.7%) 1/31 (3.2%) 8/82 (9.8%)
    Neck pain 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Pain in extremity 13/51 (25.5%) 5/31 (16.1%) 18/82 (22%)
    Pain in jaw 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Shoulder pain 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Epithelioma 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Lung neoplasm 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Malignant melanoma in situ 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Skin cancer 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Nervous system disorders
    Aphasia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Burning sensation 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Carpal tunnel syndrome 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Cerebellar syndrome 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Cerebral ischaemia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Coordination abnormal 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Dizziness 13/51 (25.5%) 4/31 (12.9%) 17/82 (20.7%)
    Dysgeusia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Encephalomalacia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Headache 21/51 (41.2%) 8/31 (25.8%) 29/82 (35.4%)
    Hyperaesthesia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Hypoaesthesia 8/51 (15.7%) 4/31 (12.9%) 12/82 (14.6%)
    Ischaemic stroke 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Loss of consciousness 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Memory impairment 0/51 (0%) 2/31 (6.5%) 2/82 (2.4%)
    Mental impairment 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Muscle contractions involuntary 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Nervous system disorder 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Neuropathy peripheral 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Nystagmus 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Paraesthesia 18/51 (35.3%) 8/31 (25.8%) 26/82 (31.7%)
    Reflexes abnormal 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Sciatica 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Somnolence 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Syncope vasovagal 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Tremor 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Psychiatric disorders
    Agitation 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Anxiety 4/51 (7.8%) 3/31 (9.7%) 7/82 (8.5%)
    Depressed mood 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Depression 4/51 (7.8%) 0/31 (0%) 4/82 (4.9%)
    Flat affect 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Insomnia 6/51 (11.8%) 2/31 (6.5%) 8/82 (9.8%)
    Mood altered 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Panic attack 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Post-traumatic stress disorder 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Sleep disorder 0/51 (0%) 3/31 (9.7%) 3/82 (3.7%)
    Renal and urinary disorders
    Azotaemia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dysuria 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Haematuria 0/51 (0%) 3/31 (9.7%) 3/82 (3.7%)
    Micturition disorder 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nocturia 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Proteinuria 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Renal impairment 5/51 (9.8%) 0/31 (0%) 5/82 (6.1%)
    Urethral meatus stenosis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Urethral stricture 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Urinary incontinence 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Reproductive system and breast disorders
    Breast discharge 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Breast discomfort 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dysmenorrhoea 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Nipple pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Scrotal angiokeratoma 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Testicular pain 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Respiratory, thoracic and mediastinal disorders
    Allergic cough 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Asthma 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Cough 22/51 (43.1%) 11/31 (35.5%) 33/82 (40.2%)
    Dyspnoea 5/51 (9.8%) 0/31 (0%) 5/82 (6.1%)
    Dyspnoea exacerbated 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dyspnoea exertional 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Epistaxis 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Nasal congestion 13/51 (25.5%) 7/31 (22.6%) 20/82 (24.4%)
    Painful respiration 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Paranasal sinus hypersecretion 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Pharyngolaryngeal pain 10/51 (19.6%) 8/31 (25.8%) 18/82 (22%)
    Pleural rub 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Productive cough 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Pulmonary hypertension 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Rales 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Respiratory tract congestion 5/51 (9.8%) 2/31 (6.5%) 7/82 (8.5%)
    Rhinitis allergic 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Rhinorrhoea 6/51 (11.8%) 4/31 (12.9%) 10/82 (12.2%)
    Rhonchi 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Sinus congestion 5/51 (9.8%) 4/31 (12.9%) 9/82 (11%)
    Sleep apnoea syndrome 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Sneezing 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Throat irritation 1/51 (2%) 3/31 (9.7%) 4/82 (4.9%)
    Throat tightness 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Upper respiratory tract congestion 2/51 (3.9%) 3/31 (9.7%) 5/82 (6.1%)
    Wheezing 3/51 (5.9%) 0/31 (0%) 3/82 (3.7%)
    Skin and subcutaneous tissue disorders
    Acne 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Alopecia 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Angiokeratoma 3/51 (5.9%) 2/31 (6.5%) 5/82 (6.1%)
    Angioneurotic oedema 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Anhidrosis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Blister 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Cold sweat 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Decubitus ulcer 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dermal cyst 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Dermatitis 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Dermatitis contact 4/51 (7.8%) 1/31 (3.2%) 5/82 (6.1%)
    Dry skin 2/51 (3.9%) 2/31 (6.5%) 4/82 (4.9%)
    Ecchymosis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Eczema 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Erythema 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Ingrown hair 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Livedo reticularis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Night sweats 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Pruritus 4/51 (7.8%) 2/31 (6.5%) 6/82 (7.3%)
    Pruritus allergic 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Pruritus generalised 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Psoriasis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Rash 7/51 (13.7%) 4/31 (12.9%) 11/82 (13.4%)
    Rash erythematous 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Rash maculo-papular 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Rash papular 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Rash pruritic 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Seborrhoeic dermatitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Skin discolouration 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Skin disorder 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Skin irritation 2/51 (3.9%) 0/31 (0%) 2/82 (2.4%)
    Skin lesion 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Skin nodule 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Skin ulcer 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Swelling face 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Urticaria 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Yellow skin 0/51 (0%) 1/31 (3.2%) 1/82 (1.2%)
    Vascular disorders
    Flushing 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Hot flush 3/51 (5.9%) 1/31 (3.2%) 4/82 (4.9%)
    Hypertension 2/51 (3.9%) 3/31 (9.7%) 5/82 (6.1%)
    Hypotension 2/51 (3.9%) 3/31 (9.7%) 5/82 (6.1%)
    Lymphoedema 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Pallor 1/51 (2%) 1/31 (3.2%) 2/82 (2.4%)
    Peripheral coldness 2/51 (3.9%) 1/31 (3.2%) 3/82 (3.7%)
    Raynaud's phenomenon 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Steal syndrome 1/51 (2%) 0/31 (0%) 1/82 (1.2%)
    Vasculitis 1/51 (2%) 0/31 (0%) 1/82 (1.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    In multi-site studies, PI can publish after Genzyme publishes or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.

    Results Point of Contact

    Name/Title Genzyme Medical Information
    Organization Genzyme Corporation
    Phone 800-745-4447
    Email
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00074984
    Other Study ID Numbers:
    • AGAL-008-00
    First Posted:
    Dec 25, 2003
    Last Update Posted:
    Dec 27, 2013
    Last Verified:
    Dec 1, 2013