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Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)

Sponsor
EMD Serono (Industry)
Overall Status
Completed
CT.gov ID
NCT00093964
Collaborator
(none)
81
Enrollment
17
Locations
2
Arms
72.2
Actual Duration (Months)
4.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will investigate clinical activity, safety, and tolerability of the anti-angiogenic compound cilengitide (EMD 121974) in the treatment of first recurrence of glioblastoma multiforme (GBM).

Condition or Disease Intervention/Treatment Phase
  • Drug: Cilengitide 500 mg
  • Drug: Cilengitide 2000 mg
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
81 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Open-label, Randomized, Uncontrolled, Phase IIa Trial in Subjects With Recurrent Glioblastoma Multiforme to Investigate the Clinical Activity, Safety, and Tolerability of Cilengitide (EMD 121,974) Administered as a Single Agent.
Actual Study Start Date :
Oct 13, 2004
Actual Primary Completion Date :
Oct 28, 2005
Actual Study Completion Date :
Oct 21, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cilengitide 500 Milligram (mg)

Drug: Cilengitide 500 mg
Subjects will receive 1-hour intravenous infusion of 500 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
Other Names:
  • EMD 121974

    		•
    Experimental: Cilengitide 2000 mg

    Drug: Cilengitide 2000 mg
    Subjects will receive 1-hour intravenous infusion of 2000 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Other Names:
  • EMD 121974

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Subjects With Progression-free Survival [Month 6]

      Progression-free survival was defined as subjects who survived greater than or equal to (>=) 180 days without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.

    Secondary Outcome Measures

    1. Percentage of Subjects With Overall Response Rate [From the start of treatment up to 6 years]

      Overall response rate was defined as percentage of subjects who had best response during the study which was either complete response (CR: disappearance of all tumors, no new lesions and stable or improved neurological examination) or partial response (PR: >= reduction in the sum of the products of the largest perpendicular diameters compared to the baseline sum, no worsening of evaluable lesion and stable or improved neurological examination). CR or PR was confirmed within 31 days with a repeat neuroimaging.

    2. Time to Disease Progression [From the start of treatment until disease progression (assessed up to a maximum of 6 years)]

      Time to disease progression was defined as the number of days between the first dose and the date of first assessment of progressive disease during the study or until death. Surviving subjects without progressive disease were censored at the time of the last visit and the subject was known to be non-progressing. Disease progression was assessed as per independent central blinded radiology assessment.

    3. Overall Survival Time [From the start of treatment until death (assessed up to a maximum of 6 years)]

      Survival time was defined as the number of months between the date of randomization and the date of death or the last date the subject was known to be alive.

    4. Percentage of Subjects With 1-year of Survival Rate [From the start of treatment up to 1 year]

      1-year survival rate was defined as percentage of subjects who survived for >=365 days with or without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.

    5. Maximum Observed Plasma Concentration (Cmax) [Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2]

      Cmax is the maximum observed plasma concentration of cilengitide after administration.

    6. Time to Reach Maximum Plasma Concentration (Tmax) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide.

    7. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      AUC 0-infinity is the area under the curve for the plot showing plasma concentration against time from time zero to the time of the last quantifiable concentration of cilengitide.

    8. Apparent Terminal Rate Constant (Lambda z) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

    9. Terminal Half-life (t1/2) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      The t1/2 is the time taken to eliminate half the amount of cilengitide.

    10. Mean Residence Time of Drug in the Body (MRT) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      MRT is defined as the mean duration of time a drug molecule is present in the systemic circulation.

    11. Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity.

    12. Apparent Volume of Distribution During the Terminal Phase (Vz) [Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2]

      Vz was calculated as Dose/(AUC0-infinity multiplied by elimination rate constant [lambda z]) following single dose.

    13. Apparent Volume of Distribution at Steady State (Vss) [Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2]

      Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state.

    14. Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From the start of treatment up to 6 years]

      An AE was any untoward medical occurrence in a subject which did not necessarily have a causal relationship with the study drug. A TEAE was any AE that started on or any time after the day of first dose of cilengitide during the treatment phase or within the safety follow-up after last dose of cilengitide. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly.

    Eligibility Criteria

    Criteria

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

    • Written informed consent obtained before undergoing any study-related activities.

    • Males or females 18 years of age or older who can be treated in an outpatient setting.

    • Histologically proven GBM, which is recurrent or progressive following surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy (Gliadel wafer therapy is not considered systemic chemotherapy). Malignancy is to be documented with a previous histopathological report.

    • Subjects initially diagnosed with other conditions similar to GBM (such as anaplastic astrocytoma [AA] or low grade glioma) that subsequently progressed to histologically proven GBM and have had surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy for the original diagnosis are eligible if they meet all inclusion criteria.

    • GBM recurring only in the contralateral hemisphere must be histologically confirmed by biopsy. GBM recurring bilaterally does not need to be histologically confirmed by biopsy (i.e., if recurrence is ipsilateral and contralateral).

    • Archived tumor tissue specimens from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of angiogenic markers (e.g. αvβ3 and αvβ5 integrins).

    • Measurable disease (solid contrast-enhancing lesion greater than or equal to (>=)1 cm in any dimension) evaluated by gadolinium-enhanced magnetic resonance imaging (Gd MRI) within 2 weeks prior to the first dose of EMD 121974.

    • At least 12 weeks have elapsed since the last radiation treatment, and at least 4 weeks have elapsed since the last chemotherapy dose (at least 6 weeks for nitrosourea-containing chemotherapy) prior to the first dose of EMD 121974.

    • If the subject underwent recent surgery, status must be >=2 weeks post surgery or >=1 week post biopsy, in stable condition, and maintained on a stable corticosteroid regimen for >=5 days prior to first dose of EMD 121974.

    • Karnofsky Performance Score (KPS) of >=70%.

    • Subjects with the potential for pregnancy or impregnating their partner must agree to follow acceptable methods of birth control to avoid conception during the study and for at least 6 months after receiving the last dose of study drug.

    • Women of childbearing potential must have a negative pregnancy test at screening.

    • Laboratory values (within 1 week prior to the first dose of EMD 121974, except for blood count and Prothrombin time (PT)/Partial thromboplastin time (PTT), which are to be within 72 hours of the first dose): Absolute neutrophil count >=1500/millimeter (mm)3. Platelets >=100,000/mm3. Creatinine less than or equal to (<=) 1.5 milligram/deciliter (mg/dL) or creatinine clearance >=60 mL/min. Hematocrit >=30%. Prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits. Hemoglobin >=10 mg/dL. Total bilirubin <=1.5 times the upper limit of normal. Aspartate aminotransferase and alanine aminotransferase <=2.5 times above upper limit of normal.

    • No more than 8 weeks have elapsed since recurrence was detected

    Exclusion Criteria:

    • Prior radiation therapy greater than (>) 66 Gray.

    • Subject anticipates undergoing elective surgery, dental extraction, or invasive dental procedures.

    • History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment.

    • History of prior malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for ≥5 years are eligible for this study.

    • History of coagulation disorder associated with bleeding or recurrent thrombotic events.

    • Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety.

    • Subject is pregnant, anticipates becoming pregnant within 6 months after study participation, or is currently breast-feeding.

    • Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of EMD 121974.

    • Prior antiangiogenic therapy.

    • Placement of Gliadel wafer at surgery for recurrence.

    • Unable to undergo Gd MRI.

    • Current known alcohol dependence or drug abuse.

    • Requiring concomitant chemotherapy.

    • Treatment with a prohibited concomitant medication.

    • Known hypersensitivity to the study treatment.

    • Legal incapacity or limited legal capacity.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama at Birmingham Birmingham Alabama United States 35294-3280
    2 Barrow Neurological Institute Phoenix Arizona United States 85013
    3 UCLA Medical Center Los Angeles California United States 90095
    4 Denise Damek Aurora Colorado United States 80010
    5 Northwestern University Chicago Illinois United States 60611
    6 Indiana University Medical Center Indianapolis Indiana United States 46202
    7 Massachusetts General Hospital Boston Massachusetts United States 02114
    8 University of Massachusetts Worcester Massachusetts United States 01655
    9 Henry Ford Health System Detroit Michigan United States 48202
    10 Washington University Saint Louis Missouri United States 63110
    11 Memorial Sloan Kettering Cancer Center New York New York United States 10021
    12 Duke University Medical Center Durham North Carolina United States 27710
    13 Good Samaritan Hospital/Tri Health Hatton Center Cincinnati Ohio United States 45206
    14 Baylor University Medical Center at Dallas Dallas Texas United States 75246
    15 University of Texas MD Anderson Cancer Center Houston Texas United States 77030
    16 University of Vermont/Fletcher Allen Healthcare Burlington Vermont United States 05401
    17 University of Virginia Health System Charlottesville Virginia United States 22903

    Sponsors and Collaborators

    • EMD Serono

    Investigators

    • Study Director: Medical Responsible, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    EMD Serono
    ClinicalTrials.gov Identifier:
    NCT00093964
    Other Study ID Numbers:
    • EMD 121974-009
    • NCT00103064
    • NCT00119288
    First Posted:
    Oct 11, 2004
    Last Update Posted:
    Apr 16, 2019
    Last Verified:
    Jan 1, 2019
    Keywords provided by EMD Serono
    Brain cancer
    Brain tumor
    Additional relevant MeSH terms:
    Glioblastoma

    Study Results

    Participant Flow

    Recruitment Details First/Last subject in: 13 October 2004/28 October 2005. Data analysis cut-off: 21 October 2010
    Pre-assignment Detail
    Arm/Group Title Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received 1-hour intravenous infusion of 500 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received 1-hour intravenous infusion of 2000 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Period Title: Overall Study
    STARTED 41 40
    COMPLETED 41 40
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg Total
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Total of all reporting groups
    Overall Participants 41 40 81
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53.0
    (12.11)
    54.6
    (11.4)
    53.8
    (11.59)
    Sex: Female, Male (Count of Participants)
    Female
    18
    43.9%
    12
    30%
    30
    37%
    Male
    23
    56.1%
    28
    70%
    51
    63%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Subjects With Progression-free Survival
    Description Progression-free survival was defined as subjects who survived greater than or equal to (>=) 180 days without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.
    Time Frame Month 6

    Outcome Measure Data

    Analysis Population Description
    The intention-to-treat (ITT) population included all randomized subjects who had received at least 1 intravenous administration of cilengitide. Here,"Number of participants analyzed" signifies those subjects who were evaluable for this outcome measure.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 40 40
    Number (95% Confidence Interval) [percentage of subjects]
    7.5
    15.0
    2. Secondary Outcome
    Title Percentage of Subjects With Overall Response Rate
    Description Overall response rate was defined as percentage of subjects who had best response during the study which was either complete response (CR: disappearance of all tumors, no new lesions and stable or improved neurological examination) or partial response (PR: >= reduction in the sum of the products of the largest perpendicular diameters compared to the baseline sum, no worsening of evaluable lesion and stable or improved neurological examination). CR or PR was confirmed within 31 days with a repeat neuroimaging.
    Time Frame From the start of treatment up to 6 years

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide. Here,"Number of participants analysed" signifies those subjects who were evaluable for this outcome measure.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 40 40
    Number (95% Confidence Interval) [percentage of subjects]
    5.0
    12.5
    3. Secondary Outcome
    Title Time to Disease Progression
    Description Time to disease progression was defined as the number of days between the first dose and the date of first assessment of progressive disease during the study or until death. Surviving subjects without progressive disease were censored at the time of the last visit and the subject was known to be non-progressing. Disease progression was assessed as per independent central blinded radiology assessment.
    Time Frame From the start of treatment until disease progression (assessed up to a maximum of 6 years)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 41 40
    Median (Full Range) [months]
    1.81
    1.91
    4. Secondary Outcome
    Title Overall Survival Time
    Description Survival time was defined as the number of months between the date of randomization and the date of death or the last date the subject was known to be alive.
    Time Frame From the start of treatment until death (assessed up to a maximum of 6 years)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 41 40
    Median (Full Range) [months]
    6.54
    9.91
    5. Secondary Outcome
    Title Percentage of Subjects With 1-year of Survival Rate
    Description 1-year survival rate was defined as percentage of subjects who survived for >=365 days with or without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.
    Time Frame From the start of treatment up to 1 year

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 41 40
    Number (95% Confidence Interval) [percentage of subjects]
    22.0
    37.5
    6. Secondary Outcome
    Title Maximum Observed Plasma Concentration (Cmax)
    Description Cmax is the maximum observed plasma concentration of cilengitide after administration.
    Time Frame Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    40.4
    (24.4)
    105.7
    (14.1)
    Cycle 2
    35.4
    (20.6)
    169.7
    (20.7)
    7. Secondary Outcome
    Title Time to Reach Maximum Plasma Concentration (Tmax)
    Description Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    1.13
    1.33
    Cycle 2
    1.17
    1.00
    8. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity)
    Description AUC 0-infinity is the area under the curve for the plot showing plasma concentration against time from time zero to the time of the last quantifiable concentration of cilengitide.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    92.7
    (60.4)
    346.5
    (50.3)
    Cycle 2
    84.6
    (33.2)
    429.3
    (27.4)
    9. Secondary Outcome
    Title Apparent Terminal Rate Constant (Lambda z)
    Description Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    0.320
    (0.080)
    0.204
    (0.010)
    Cycle 2
    0.325
    (0.107)
    0.211
    (0.008)
    10. Secondary Outcome
    Title Terminal Half-life (t1/2)
    Description The t1/2 is the time taken to eliminate half the amount of cilengitide.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    2.24
    3.38
    Cycle 2
    2.04
    3.21
    11. Secondary Outcome
    Title Mean Residence Time of Drug in the Body (MRT)
    Description MRT is defined as the mean duration of time a drug molecule is present in the systemic circulation.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    2.76
    (0.66)
    3.98
    (0.25)
    Cycle 2
    2.92
    (0.74)
    3.42
    (0.18)
    12. Secondary Outcome
    Title Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF)
    Description CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,"Overall Number of participants analyzed" = subjects evaluable for this outcome and "Number analyzed" = subjects evaluable for the specified category.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    6.85
    (4.47)
    5.85
    (0.86)
    Cycle 2
    6.75
    (3.25)
    4.67
    (0.31)
    13. Secondary Outcome
    Title Apparent Volume of Distribution During the Terminal Phase (Vz)
    Description Vz was calculated as Dose/(AUC0-infinity multiplied by elimination rate constant [lambda z]) following single dose.
    Time Frame Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population included the subjects who had received cilengitide and who had had blood samples drawn in Week 1 and/or 5 that provided drug concentration for non-compartmental PK evaluation. Here, "Number of participants analysed" signifies those subjects who were evaluable for this outcome measure.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    20.3
    (8.9)
    28.9
    (5.5)
    Cycle 2
    21.0
    (6.8)
    22.1
    (1.2)
    14. Secondary Outcome
    Title Apparent Volume of Distribution at Steady State (Vss)
    Description Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state.
    Time Frame Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The PK population included the subjects who had received cilengitide and who had blood samples drawn in Week 1 and/or 5 that provided drug concentration for non-compartmental PK evaluation. Here, "Number of participants analysed" signifies those subjects who were evaluable for this outcome measure.
    Arm/Group Title Cilengitide 500 Milligrams (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 5 6
    Cycle 1
    17.4
    (7.8)
    23.3
    (4.1)
    Cycle 2
    19.3
    (8.3)
    15.9
    (0.9)
    15. Secondary Outcome
    Title Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    Description An AE was any untoward medical occurrence in a subject which did not necessarily have a causal relationship with the study drug. A TEAE was any AE that started on or any time after the day of first dose of cilengitide during the treatment phase or within the safety follow-up after last dose of cilengitide. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly.
    Time Frame From the start of treatment up to 6 years

    Outcome Measure Data

    Analysis Population Description
    The safety population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
    Arm/Group Title Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received 1-hour intravenous infusion of 500 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received 1-hour intravenous infusion of 2000 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    Measure Participants 41 40
    TEAEs
    41
    39
    SAEs
    16
    18

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Arm/Group Description Subjects received 1-hour intravenous infusion of 500 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. Subjects received 1-hour intravenous infusion of 2000 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
    All Cause Mortality
    Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 16/41 (39%) 18/40 (45%)
    Blood and lymphatic system disorders
    Lymphopenia 0/41 (0%) 1/40 (2.5%)
    Cardiac disorders
    Atrial fibrillation 1/41 (2.4%) 1/40 (2.5%)
    Supraventricular tachycardia 0/41 (0%) 1/40 (2.5%)
    Eye disorders
    Diplopia 0/41 (0%) 1/40 (2.5%)
    Gastrointestinal disorders
    Nausea 1/41 (2.4%) 0/40 (0%)
    Splenic artery aneurysm 1/41 (2.4%) 0/40 (0%)
    Vomiting 1/41 (2.4%) 0/40 (0%)
    General disorders
    Asthenia 2/41 (4.9%) 1/40 (2.5%)
    Chest pain 0/41 (0%) 1/40 (2.5%)
    Fatigue 1/41 (2.4%) 1/40 (2.5%)
    Gait disturbance 0/41 (0%) 1/40 (2.5%)
    Generalised oedema 0/41 (0%) 1/40 (2.5%)
    Oedema peripheral 0/41 (0%) 1/40 (2.5%)
    Infections and infestations
    Aspergillosis 0/41 (0%) 1/40 (2.5%)
    Brain abscess 1/41 (2.4%) 0/40 (0%)
    Cellulitis 1/41 (2.4%) 1/40 (2.5%)
    Clostridium colitis 1/41 (2.4%) 0/40 (0%)
    Herpes zoster 1/41 (2.4%) 1/40 (2.5%)
    Sepsis 1/41 (2.4%) 0/40 (0%)
    Investigations
    Blood glucose increased 0/41 (0%) 1/40 (2.5%)
    Musculoskeletal and connective tissue disorders
    Muscular weakness 1/41 (2.4%) 0/40 (0%)
    Nervous system disorders
    Amnesia 1/41 (2.4%) 0/40 (0%)
    Aphasia 2/41 (4.9%) 3/40 (7.5%)
    Ataxia 1/41 (2.4%) 1/40 (2.5%)
    Brain oedema 2/41 (4.9%) 0/40 (0%)
    Cerebral haemorrhage 1/41 (2.4%) 0/40 (0%)
    Convulsion 5/41 (12.2%) 8/40 (20%)
    Grand mal convulsion 1/41 (2.4%) 0/40 (0%)
    Headache 5/41 (12.2%) 2/40 (5%)
    Hemiparesis 1/41 (2.4%) 1/40 (2.5%)
    Hemiplegia 1/41 (2.4%) 0/40 (0%)
    Motor dysfunction 1/41 (2.4%) 0/40 (0%)
    Neurologic neglect syndrome 0/41 (0%) 1/40 (2.5%)
    Neuropathy 1/41 (2.4%) 0/40 (0%)
    Peripheral sensory neuropathy 1/41 (2.4%) 0/40 (0%)
    Postictal paralysis 1/41 (2.4%) 0/40 (0%)
    Somnolence 1/41 (2.4%) 0/40 (0%)
    Psychiatric disorders
    Affective disorder 1/41 (2.4%) 0/40 (0%)
    Confusional state 1/41 (2.4%) 0/40 (0%)
    Mental status changes 2/41 (4.9%) 1/40 (2.5%)
    Renal and urinary disorders
    Renal failure 1/41 (2.4%) 0/40 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration 1/41 (2.4%) 1/40 (2.5%)
    Pulmonary embolism 0/41 (0%) 3/40 (7.5%)
    Pulmonary oedema 1/41 (2.4%) 0/40 (0%)
    Vascular disorders
    Deep vein thrombosis 2/41 (4.9%) 2/40 (5%)
    Other (Not Including Serious) Adverse Events
    Cilengitide 500 Milligram (mg) Cilengitide 2000 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 41/41 (100%) 39/40 (97.5%)
    Blood and lymphatic system disorders
    Haemoglobinaemia 1/41 (2.4%) 0/40 (0%)
    Leukopenia 0/41 (0%) 1/40 (2.5%)
    Lymphopenia 2/41 (4.9%) 2/40 (5%)
    Neutropenia 1/41 (2.4%) 1/40 (2.5%)
    Thrombocytopenia 2/41 (4.9%) 1/40 (2.5%)
    Ear and labyrinth disorders
    Deafness 1/41 (2.4%) 0/40 (0%)
    Ear pain 2/41 (4.9%) 2/40 (5%)
    Middle ear effusion 1/41 (2.4%) 0/40 (0%)
    Otorrhoea 1/41 (2.4%) 0/40 (0%)
    Tinnitus 1/41 (2.4%) 1/40 (2.5%)
    Tympanic membrane perforation 0/41 (0%) 1/40 (2.5%)
    Vertigo 1/41 (2.4%) 0/40 (0%)
    Endocrine disorders
    Cushingoid 5/41 (12.2%) 3/40 (7.5%)
    Hirsutism 1/41 (2.4%) 0/40 (0%)
    Eye disorders
    Cataract 0/41 (0%) 1/40 (2.5%)
    Conjunctival haemorrhage 0/41 (0%) 1/40 (2.5%)
    Conjunctivitis 1/41 (2.4%) 1/40 (2.5%)
    Diplopia 1/41 (2.4%) 2/40 (5%)
    Dry eye 1/41 (2.4%) 0/40 (0%)
    Eye irritation 1/41 (2.4%) 0/40 (0%)
    Eye pain 0/41 (0%) 1/40 (2.5%)
    Eyelid oedema 0/41 (0%) 1/40 (2.5%)
    Gaze palsy 0/41 (0%) 1/40 (2.5%)
    Glaucoma 0/41 (0%) 1/40 (2.5%)
    Lacrimation increased 1/41 (2.4%) 0/40 (0%)
    Ophthalmoplegia 1/41 (2.4%) 0/40 (0%)
    Papilloedema 1/41 (2.4%) 1/40 (2.5%)
    Photophobia 1/41 (2.4%) 0/40 (0%)
    Scleral haemorrhage 1/41 (2.4%) 0/40 (0%)
    Vision blurred 5/41 (12.2%) 3/40 (7.5%)
    Visual acuity reduced 5/41 (12.2%) 1/40 (2.5%)
    Vitreous floaters 1/41 (2.4%) 0/40 (0%)
    Gastrointestinal disorders
    Abdominal distension 3/41 (7.3%) 1/40 (2.5%)
    Abdominal pain 2/41 (4.9%) 3/40 (7.5%)
    Abdominal pain upper 1/41 (2.4%) 1/40 (2.5%)
    Chapped lips 0/41 (0%) 1/40 (2.5%)
    Constipation 3/41 (7.3%) 4/40 (10%)
    Diarrhoea 7/41 (17.1%) 5/40 (12.5%)
    Dry mouth 0/41 (0%) 1/40 (2.5%)
    Dyspepsia 3/41 (7.3%) 3/40 (7.5%)
    Dysphagia 0/41 (0%) 1/40 (2.5%)
    Faecal incontinence 1/41 (2.4%) 0/40 (0%)
    Flatulence 3/41 (7.3%) 0/40 (0%)
    Gastrooesophageal reflux disease 1/41 (2.4%) 1/40 (2.5%)
    Gingival hypertrophy 1/41 (2.4%) 0/40 (0%)
    Gingivitis 0/41 (0%) 1/40 (2.5%)
    Haematochezia 1/41 (2.4%) 0/40 (0%)
    Haemorrhoids 1/41 (2.4%) 1/40 (2.5%)
    Lip disorder 0/41 (0%) 1/40 (2.5%)
    Lip dry 0/41 (0%) 1/40 (2.5%)
    Loose stools 1/41 (2.4%) 1/40 (2.5%)
    Nausea 10/41 (24.4%) 6/40 (15%)
    Stomach discomfort 0/41 (0%) 1/40 (2.5%)
    Toothache 1/41 (2.4%) 0/40 (0%)
    Vomiting 3/41 (7.3%) 2/40 (5%)
    General disorders
    Abasia 1/41 (2.4%) 0/40 (0%)
    Adverse drug reaction 1/41 (2.4%) 0/40 (0%)
    Asthenia 1/41 (2.4%) 6/40 (15%)
    Catheter related complication 0/41 (0%) 1/40 (2.5%)
    Catheter site haemorrhage 2/41 (4.9%) 0/40 (0%)
    Catheter site oedema 1/41 (2.4%) 0/40 (0%)
    Catheter site pain 1/41 (2.4%) 2/40 (5%)
    Chest discomfort 1/41 (2.4%) 0/40 (0%)
    Chest pain 0/41 (0%) 1/40 (2.5%)
    Chills 1/41 (2.4%) 1/40 (2.5%)
    Cyst 0/41 (0%) 2/40 (5%)
    Difficulty in walking 1/41 (2.4%) 1/40 (2.5%)
    Facial pain 0/41 (0%) 1/40 (2.5%)
    Fatigue 11/41 (26.8%) 18/40 (45%)
    Gait disturbance 4/41 (9.8%) 6/40 (15%)
    Influenza like illness 1/41 (2.4%) 0/40 (0%)
    Infusion site pain 0/41 (0%) 1/40 (2.5%)
    Infusion site reaction 1/41 (2.4%) 0/40 (0%)
    Malaise 0/41 (0%) 1/40 (2.5%)
    Mucosal inflammation 1/41 (2.4%) 0/40 (0%)
    Oedema 1/41 (2.4%) 0/40 (0%)
    Oedema peripheral 12/41 (29.3%) 10/40 (25%)
    Pitting oedema 1/41 (2.4%) 0/40 (0%)
    Pyrexia 2/41 (4.9%) 3/40 (7.5%)
    Temperature intolerance 1/41 (2.4%) 1/40 (2.5%)
    Venipuncture site bruise 1/41 (2.4%) 0/40 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/41 (0%) 1/40 (2.5%)
    Immune system disorders
    Hypersensitivity 1/41 (2.4%) 1/40 (2.5%)
    Seasonal allergy 2/41 (4.9%) 0/40 (0%)
    Infections and infestations
    Bacteriuria 1/41 (2.4%) 0/40 (0%)
    Body tinea 1/41 (2.4%) 0/40 (0%)
    Candidiasis 0/41 (0%) 2/40 (5%)
    Cellulitis 1/41 (2.4%) 2/40 (5%)
    Conjunctivitis infective 1/41 (2.4%) 0/40 (0%)
    Cystitis 1/41 (2.4%) 0/40 (0%)
    Dental caries 1/41 (2.4%) 0/40 (0%)
    Eczema infected 0/41 (0%) 1/40 (2.5%)
    Escherichia urinary tract infection 1/41 (2.4%) 0/40 (0%)
    Eye infection 1/41 (2.4%) 1/40 (2.5%)
    Folliculitis 0/41 (0%) 1/40 (2.5%)
    Gastroenteritis 2/41 (4.9%) 0/40 (0%)
    Herpes simplex 1/41 (2.4%) 0/40 (0%)
    Herpes zoster 1/41 (2.4%) 0/40 (0%)
    Hordeolum 1/41 (2.4%) 0/40 (0%)
    Influenza 0/41 (0%) 1/40 (2.5%)
    Localised infection 0/41 (0%) 1/40 (2.5%)
    Nasopharyngitis 2/41 (4.9%) 1/40 (2.5%)
    Oral infection 1/41 (2.4%) 0/40 (0%)
    Otitis externa 0/41 (0%) 1/40 (2.5%)
    Otitis media 0/41 (0%) 1/40 (2.5%)
    Respiratory tract infection 1/41 (2.4%) 0/40 (0%)
    Rhinitis 1/41 (2.4%) 0/40 (0%)
    Sialoadenitis 1/41 (2.4%) 0/40 (0%)
    Sinusitis 3/41 (7.3%) 2/40 (5%)
    Tooth abscess 1/41 (2.4%) 0/40 (0%)
    Upper respiratory tract infection 5/41 (12.2%) 2/40 (5%)
    Urinary tract infection 4/41 (9.8%) 3/40 (7.5%)
    Viral upper respiratory tract infection 0/41 (0%) 1/40 (2.5%)
    Injury, poisoning and procedural complications
    Arthropod bite 1/41 (2.4%) 0/40 (0%)
    Back injury 0/41 (0%) 1/40 (2.5%)
    Blood blister 0/41 (0%) 1/40 (2.5%)
    Contusion 3/41 (7.3%) 3/40 (7.5%)
    Excoriation 2/41 (4.9%) 0/40 (0%)
    Fall 6/41 (14.6%) 3/40 (7.5%)
    Hand fracture 1/41 (2.4%) 0/40 (0%)
    Joint sprain 0/41 (0%) 1/40 (2.5%)
    Post procedural pain 1/41 (2.4%) 0/40 (0%)
    Rib fracture 0/41 (0%) 1/40 (2.5%)
    Skin laceration 1/41 (2.4%) 3/40 (7.5%)
    Tibia fracture 0/41 (0%) 1/40 (2.5%)
    Tooth injury 1/41 (2.4%) 0/40 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/41 (0%) 1/40 (2.5%)
    Activated partial thromboplastin time shortened 0/41 (0%) 1/40 (2.5%)
    Alanine aminotransferase increased 2/41 (4.9%) 2/40 (5%)
    Anticonvulsant drug level increased 2/41 (4.9%) 1/40 (2.5%)
    Aspartate aminotransferase increased 0/41 (0%) 2/40 (5%)
    Bacteria urine 3/41 (7.3%) 0/40 (0%)
    Blood alkaline phosphatase increased 1/41 (2.4%) 1/40 (2.5%)
    Blood cholesterol increased 2/41 (4.9%) 1/40 (2.5%)
    Blood glucose increased 1/41 (2.4%) 0/40 (0%)
    Blood iron decreased 1/41 (2.4%) 0/40 (0%)
    Blood potassium decreased 0/41 (0%) 1/40 (2.5%)
    Blood urea increased 2/41 (4.9%) 0/40 (0%)
    Cardiac murmur 0/41 (0%) 1/40 (2.5%)
    Electrocardiogram ST segment elevation 1/41 (2.4%) 0/40 (0%)
    Electrocardiogram abnormal 1/41 (2.4%) 0/40 (0%)
    Haemoglobin decreased 1/41 (2.4%) 0/40 (0%)
    Neutrophil count decreased 0/41 (0%) 1/40 (2.5%)
    Neutrophil count increased 2/41 (4.9%) 0/40 (0%)
    Nuclear magnetic resonance imaging abnormal 1/41 (2.4%) 0/40 (0%)
    Platelet count decreased 1/41 (2.4%) 0/40 (0%)
    Prothrombin time 0/41 (0%) 1/40 (2.5%)
    Red blood cell count decreased 1/41 (2.4%) 0/40 (0%)
    Tandem gait test abnormal 1/41 (2.4%) 1/40 (2.5%)
    Weight decreased 0/41 (0%) 1/40 (2.5%)
    Weight increased 1/41 (2.4%) 2/40 (5%)
    White blood cell count decreased 0/41 (0%) 1/40 (2.5%)
    White blood cells urine positive 2/41 (4.9%) 0/40 (0%)
    Metabolism and nutrition disorders
    Anorexia 1/41 (2.4%) 0/40 (0%)
    Dehydration 2/41 (4.9%) 0/40 (0%)
    Diabetes mellitus 0/41 (0%) 1/40 (2.5%)
    Hypercholesterolaemia 0/41 (0%) 2/40 (5%)
    Hyperglycaemia 1/41 (2.4%) 5/40 (12.5%)
    Hyperkalaemia 1/41 (2.4%) 0/40 (0%)
    Hypernatraemia 1/41 (2.4%) 0/40 (0%)
    Hyperphosphataemia 1/41 (2.4%) 0/40 (0%)
    Hypoalbuminaemia 1/41 (2.4%) 0/40 (0%)
    Hypocalcaemia 1/41 (2.4%) 0/40 (0%)
    Hypokalaemia 4/41 (9.8%) 0/40 (0%)
    Hypomagnesaemia 1/41 (2.4%) 0/40 (0%)
    Hyponatraemia 1/41 (2.4%) 1/40 (2.5%)
    Hypophosphataemia 1/41 (2.4%) 0/40 (0%)
    Increased appetite 0/41 (0%) 1/40 (2.5%)
    Markedly reduced dietary intake 1/41 (2.4%) 0/40 (0%)
    Tetany 0/41 (0%) 1/40 (2.5%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 9/41 (22%) 2/40 (5%)
    Arthritis 1/41 (2.4%) 0/40 (0%)
    Back pain 4/41 (9.8%) 8/40 (20%)
    Bone pain 1/41 (2.4%) 0/40 (0%)
    Joint effusion 1/41 (2.4%) 0/40 (0%)
    Joint stiffness 1/41 (2.4%) 0/40 (0%)
    Joint swelling 1/41 (2.4%) 0/40 (0%)
    Muscle cramp 2/41 (4.9%) 3/40 (7.5%)
    Muscle spasms 0/41 (0%) 1/40 (2.5%)
    Muscular weakness 5/41 (12.2%) 4/40 (10%)
    Musculoskeletal chest pain 1/41 (2.4%) 0/40 (0%)
    Musculoskeletal discomfort 1/41 (2.4%) 0/40 (0%)
    Myalgia 2/41 (4.9%) 0/40 (0%)
    Myopathy steroid 1/41 (2.4%) 1/40 (2.5%)
    Neck pain 0/41 (0%) 1/40 (2.5%)
    Pain in extremity 3/41 (7.3%) 2/40 (5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma 1/41 (2.4%) 0/40 (0%)
    Nervous system disorders
    Amnesia 8/41 (19.5%) 5/40 (12.5%)
    Aphasia 5/41 (12.2%) 9/40 (22.5%)
    Ataxia 1/41 (2.4%) 3/40 (7.5%)
    Aura 2/41 (4.9%) 0/40 (0%)
    Balance disorder 7/41 (17.1%) 2/40 (5%)
    Brain oedema 0/41 (0%) 1/40 (2.5%)
    Cognitive disorder 2/41 (4.9%) 1/40 (2.5%)
    Convulsion 7/41 (17.1%) 4/40 (10%)
    Coordination abnormal 2/41 (4.9%) 1/40 (2.5%)
    Cranial nerve disorder 1/41 (2.4%) 2/40 (5%)
    Cranial neuropathy 3/41 (7.3%) 1/40 (2.5%)
    Disturbance in attention 3/41 (7.3%) 0/40 (0%)
    Dizziness 7/41 (17.1%) 7/40 (17.5%)
    Dysarthria 3/41 (7.3%) 1/40 (2.5%)
    Dysgeusia 1/41 (2.4%) 0/40 (0%)
    Dysgraphia 0/41 (0%) 1/40 (2.5%)
    Dyskinesia 0/41 (0%) 1/40 (2.5%)
    Dysphasia 0/41 (0%) 1/40 (2.5%)
    Facial palsy 1/41 (2.4%) 3/40 (7.5%)
    Facial paresis 5/41 (12.2%) 0/40 (0%)
    Grand mal convulsion 1/41 (2.4%) 1/40 (2.5%)
    Headache 14/41 (34.1%) 14/40 (35%)
    Hemianopia homonymous 1/41 (2.4%) 0/40 (0%)
    Hemiparesis 3/41 (7.3%) 4/40 (10%)
    Hemiplegia 1/41 (2.4%) 0/40 (0%)
    Hyperaesthesia 0/41 (0%) 1/40 (2.5%)
    Hyperreflexia 0/41 (0%) 1/40 (2.5%)
    Hypoaesthesia 2/41 (4.9%) 2/40 (5%)
    Lethargy 2/41 (4.9%) 1/40 (2.5%)
    Memory impairment 4/41 (9.8%) 5/40 (12.5%)
    Motor dysfunction 4/41 (9.8%) 2/40 (5%)
    Neurologic neglect syndrome 2/41 (4.9%) 1/40 (2.5%)
    Neuropathic pain 0/41 (0%) 1/40 (2.5%)
    Neuropathy 2/41 (4.9%) 0/40 (0%)
    Nystagmus 1/41 (2.4%) 2/40 (5%)
    Paraesthesia 2/41 (4.9%) 2/40 (5%)
    Partial seizures 1/41 (2.4%) 1/40 (2.5%)
    Peripheral sensory neuropathy 0/41 (0%) 3/40 (7.5%)
    Peroneal nerve palsy 0/41 (0%) 1/40 (2.5%)
    Pyramidal tract syndrome 1/41 (2.4%) 0/40 (0%)
    Reflex sympathetic dystrophy 1/41 (2.4%) 0/40 (0%)
    Sensory disturbance 1/41 (2.4%) 1/40 (2.5%)
    Simple partial seizures 1/41 (2.4%) 2/40 (5%)
    Sinus headache 1/41 (2.4%) 0/40 (0%)
    Somnolence 1/41 (2.4%) 2/40 (5%)
    Speech disorder 4/41 (9.8%) 3/40 (7.5%)
    Tremor 4/41 (9.8%) 4/40 (10%)
    Upper motor neurone lesion 2/41 (4.9%) 0/40 (0%)
    Visual field defect 1/41 (2.4%) 0/40 (0%)
    Psychiatric disorders
    Affect lability 1/41 (2.4%) 1/40 (2.5%)
    Aggression 0/41 (0%) 1/40 (2.5%)
    Agitation 2/41 (4.9%) 1/40 (2.5%)
    Anxiety 2/41 (4.9%) 3/40 (7.5%)
    Cognitive deterioration 0/41 (0%) 1/40 (2.5%)
    Confusional state 8/41 (19.5%) 7/40 (17.5%)
    Depression 3/41 (7.3%) 6/40 (15%)
    Disorientation 0/41 (0%) 1/40 (2.5%)
    Insomnia 4/41 (9.8%) 6/40 (15%)
    Irritability 2/41 (4.9%) 0/40 (0%)
    Mental status changes 1/41 (2.4%) 0/40 (0%)
    Mood altered 2/41 (4.9%) 1/40 (2.5%)
    Nervousness 1/41 (2.4%) 0/40 (0%)
    Personality change 1/41 (2.4%) 2/40 (5%)
    Psychomotor retardation 1/41 (2.4%) 0/40 (0%)
    Psychotic disorder 0/41 (0%) 1/40 (2.5%)
    Renal and urinary disorders
    Haematuria 1/41 (2.4%) 1/40 (2.5%)
    Leukocyturia 1/41 (2.4%) 0/40 (0%)
    Micturition urgency 2/41 (4.9%) 1/40 (2.5%)
    Nephrolithiasis 1/41 (2.4%) 1/40 (2.5%)
    Pollakiuria 2/41 (4.9%) 0/40 (0%)
    Proteinuria 4/41 (9.8%) 0/40 (0%)
    Renal salt-wasting syndrome 0/41 (0%) 1/40 (2.5%)
    Urinary incontinence 4/41 (9.8%) 4/40 (10%)
    Reproductive system and breast disorders
    Breast pain 1/41 (2.4%) 0/40 (0%)
    Menstrual disorder 1/41 (2.4%) 0/40 (0%)
    Nipple pain 0/41 (0%) 1/40 (2.5%)
    Polymenorrhoea 1/41 (2.4%) 0/40 (0%)
    Prostatitis 1/41 (2.4%) 0/40 (0%)
    Sexual dysfunction 1/41 (2.4%) 2/40 (5%)
    Respiratory, thoracic and mediastinal disorders
    Cough 2/41 (4.9%) 4/40 (10%)
    Dyspnoea 1/41 (2.4%) 5/40 (12.5%)
    Hoarseness 0/41 (0%) 1/40 (2.5%)
    Hypoxia 0/41 (0%) 1/40 (2.5%)
    Nasal congestion 2/41 (4.9%) 0/40 (0%)
    Nasal dryness 0/41 (0%) 1/40 (2.5%)
    Pharyngolaryngeal pain 2/41 (4.9%) 0/40 (0%)
    Respiratory tract congestion 1/41 (2.4%) 0/40 (0%)
    Sinus congestion 1/41 (2.4%) 0/40 (0%)
    Snoring 1/41 (2.4%) 0/40 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 1/41 (2.4%) 0/40 (0%)
    Dermal cyst 0/41 (0%) 1/40 (2.5%)
    Dermatitis contact 1/41 (2.4%) 1/40 (2.5%)
    Dry skin 2/41 (4.9%) 1/40 (2.5%)
    Ecchymosis 2/41 (4.9%) 1/40 (2.5%)
    Erythema 1/41 (2.4%) 0/40 (0%)
    Face oedema 0/41 (0%) 1/40 (2.5%)
    Hyperhidrosis 0/41 (0%) 1/40 (2.5%)
    Photosensitivity reaction 0/41 (0%) 1/40 (2.5%)
    Pruritus 2/41 (4.9%) 1/40 (2.5%)
    Rash 6/41 (14.6%) 7/40 (17.5%)
    Rash erythematous 1/41 (2.4%) 0/40 (0%)
    Rash generalised 1/41 (2.4%) 0/40 (0%)
    Rash pruritic 1/41 (2.4%) 0/40 (0%)
    Skin discolouration 0/41 (0%) 1/40 (2.5%)
    Skin fragility 0/41 (0%) 1/40 (2.5%)
    Vascular disorders
    Deep vein thrombosis 2/41 (4.9%) 0/40 (0%)
    Hypertension 1/41 (2.4%) 0/40 (0%)
    Hypotension 0/41 (0%) 2/40 (5%)
    Petechiae 2/41 (4.9%) 1/40 (2.5%)
    Phlebitis 0/41 (0%) 1/40 (2.5%)
    Phlebitis superficial 0/41 (0%) 1/40 (2.5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Results Point of Contact

    Name/Title Merck KGaA Communication Center
    Organization Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany
    Phone +49-6151-72-5200
    Email service@merckgroup.com
    Responsible Party:
    EMD Serono
    ClinicalTrials.gov Identifier:
    NCT00093964
    Other Study ID Numbers:
    • EMD 121974-009
    • NCT00103064
    • NCT00119288
    First Posted:
    Oct 11, 2004
    Last Update Posted:
    Apr 16, 2019
    Last Verified:
    Jan 1, 2019