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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled Phase 3 study of SGN-35 (brentuximab vedotin) and best supportive care (BSC) versus placebo and BSC in the treatment of patients at high risk of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT)

    Summary
    EudraCT number
    		 2009-016947-20
    Trial protocol
    		 FR   HU   ES   CZ   GB   BG   IT   DE  
    Global end of trial date
    27 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2021
    First version publication date
    08 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SGN35-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01100502
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PSI CRO Hungary Pharma Support LLC
    Sponsor organisation address
    Bank Center, Platina Tower, Szabadság tér 7, Budapest, Hungary,
    Public contact
    Clinical Operations, PSI CRO Hungary Pharma Support LLC, +36 1555 6755, rabudapest@psi-cro.com
    Scientific contact
    Clinical Operations, PSI CRO Hungary Pharma Support LLC, +36 1555 6755, rabudapest@psi-cro.com
    Sponsor organisation name
    Seagen Inc.
    Sponsor organisation address
    21823 30th Drive SE, Bothell/WA, United States, 98021
    Public contact
    Chief Medical Officer, Seagen Inc., 1 855-473-2436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seagen Inc., 1 855-473-2436, medinfo@seagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the progression-free survival (PFS) of brentuximab vedotin and best supportive care (BSC) versus placebo and BSC.
    Protection of trial subjects
    The protocol for this study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The conduct of all aspects of the study, including methods for obtaining informed consent, were also in accordance with principles enunciated in the declaration, the International Conference on Harmonisation (ICH) Good Clinical Practices (GCP), and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in Title 21 CFR Parts 11, 50, 54, 56, and 312. The consent form approved by each IRB/IEC included all elements required by the applicable regional laws and regulations, including a statement that Seattle Genetics, Inc. and authorities had access to patient records. Consent was obtained from all patients before any protocol-required procedures were performed, including any procedure not part of normal patient care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Apr 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Regulatory reason
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    United States: 135
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    Serbia: 9
    Worldwide total number of subjects
    329
    EEA total number of subjects
    146
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    321
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Apr 2010 to Aug 2014

    Pre-assignment
    Screening details
    		 Patients with HL who have received ASCT in the previous 30–45 days

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Brentuximab vedotin
    Arm description
    		 Brentuximab vedotin 1.8 mg/kg every 3 weeks by IV infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    ADCETRIS, SGN-35
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin 1.8 mg/kg every 3 weeks by IV infusion

    Arm title
    		 Placebo
    Arm description
    		 Placebo every 3 weeks by IV infusion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo every 3 weeks by IV infusion

    Number of subjects in period 1
    		Brentuximab vedotin Placebo
    Started
    165
    164
    Completed
    78
    81
    Not completed
    87
    83
         Adverse event, serious fatal
    2
    -
         Adverse event, non-fatal
    52
    10
         Patient decision, non-AE
    9
    4
         Progressive disease
    24
    69

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    		 Brentuximab vedotin 1.8 mg/kg every 3 weeks by IV infusion

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo every 3 weeks by IV infusion

    Reporting group values
    		 Brentuximab vedotin Placebo Total
    Number of subjects
    		 165 164 329
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 160 161 321
        From 65-84 years
    		 5 3 8
    Age continuous
    Units: years
        median (full range (min-max))
    		 33 (18 to 71) 32 (18 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 89 67 156
        Male
    		 76 97 173
    Race
    Units: Subjects
        Asian
    		 2 3 5
        Black or African American
    		 10 2 12
        White
    		 153 156 309
        Other
    		 0 3 3
    Eastern Cooperative Oncology Group Performance Status
    Zero = Normal activity One = Symptoms but ambulatory Two = In bed < 50% of the time
    Units: Subjects
        Zero
    		 87 97 184
        One
    		 77 67 144
        Two
    		 1 0 1
    HL status after frontline therapy
    Refractory/relapsed status after the end of frontline standard chemotherapy or a combined modality treatment program.
    Units: Subjects
        Refractory
    		 99 97 196
        Relapse <12 months
    		 53 54 107
        Relapse >=12 months with extranodal disease
    		 13 13 26
    Best response to salvage therapy pre-ASCT
    Units: Subjects
        Complete remission
    		 61 62 123
        Partial remission
    		 57 56 113
        Stable disease
    		 47 46 93

    End points

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    End points reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    		 Brentuximab vedotin 1.8 mg/kg every 3 weeks by IV infusion

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo every 3 weeks by IV infusion

    Subject analysis set title
    BV Arm - Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set includes all patients who received at least 1 dose of brentuximab vedotin or only received placebo: 2 patients randomized to placebo received a single dose of brentuximab vedotin and are included in the brentuximab vedotin arm; 2 patients randomized to placebo received no study treatment and are not included in the analysis

    Subject analysis set title
    Placebo Arm - Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set includes all patients who received at least 1 dose of brentuximab vedotin or only received placebo: 2 patients randomized to placebo received a single dose of brentuximab vedotin and are included in the brentuximab vedotin arm; 2 patients randomized to placebo received no study treatment and are not included in the analysis

    Primary: Progression-free survival by independent review

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    End point title
    		 Progression-free survival by independent review
    End point description
    Time from date of randomization to the first documentation of disease progression by independent review or to death due to any cause, whichever comes first.
    End point type
    Primary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Brentuximab vedotin Placebo
    Number of subjects analysed
    165 [1]
    164 [2]
    Units: Months
        median (confidence interval 95%)
    42.9 (30.4 to 42.9)
    24.1 (11.5 to 999)
    Notes
    [1] - Intention-to-treat
    [2] - 999 = Not available (follow-up is not long enough to assess an upper bound)
    Statistical analysis title
    		 Progression-free survival by independent review
    Statistical analysis description
    The primary analysis of PFS used a stratified log-rank test at a one-sided alpha level of 0.025. A stratified Cox regression model was used to estimate the HR and the corresponding 95% CI for the treatment effect. An HR <1 indicates that the duration of PFS is prolonged for patients on the brentuximab vedotin arm compared with patients on the placebo arm. The median PFS and its two-sided 95% CI for the median was calculated using the complementary log-log transformation method (Collett 1994).
    Comparison groups
    Brentuximab vedotin v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.571
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.404
         upper limit
    		 0.808
    Variability estimate
    Standard deviation

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    Counts of participants who had treatment-emergent adverse events, defined as newly occurring (not present at baseline) or worsening after first dose of study drug. Relatedness to study drug was assessed by the investigator. Serious adverse events are reported from the time of informed consent. All events are from study day 1 pre-dose to the end of the safety reporting period. Participants with multiple occurrences of an adverse event within a category are counted once within the category.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 BV Arm - Safety Analysis Set Placebo Arm - Safety Analysis Set
    Number of subjects analysed
    167
    160
    Units: Number of participants
        Any AE
    163
    142
        Treatment-related AE
    147
    79
        AE >=Grade 3
    93
    51
        Any SAE
    41
    20
        Any treatment-related SAE
    19
    7
        Discontinued treatment due to AE
    54
    10
    No statistical analyses for this end point

    Secondary: Incidence of anti-therapeutic antibodies (ATA) to brentuximab vedotin

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    End point title
    		 Incidence of anti-therapeutic antibodies (ATA) to brentuximab vedotin
    End point description
    Counts of participants with anti-brentuximab vedotin antibodies at any time during treatment.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 Brentuximab vedotin Placebo
    Number of subjects analysed
    157 [3]
    154 [4]
    Units: Number of participants
        Baseline (BL) negative
    138
    142
        - BL negative, negative post-BL
    92
    104
        - BL negative, transiently positive post-BL
    36
    27
        - BL negative, persistently positive post-BL
    10
    11
        Baseline (BL) positive
    19
    12
        - BL positive, negative post-BL
    7
    0
        - BL positive, transiently positive post-BL
    9
    5
        - BL positive, persistently positive post-BL
    3
    7
    Notes
    [3] - ATA-evaluable patients (i.e., patients with a baseline and at least one postbaseline sample)
    [4] - ATA-evaluable patients (i.e., patients with a baseline and at least one postbaseline sample)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Time from date of randomization to date of death due to any cause. Due to patients lost to follow up, patient withdrawal of consent and post ASCT therapies; there were less deaths on study than anticipated. Therefore, median OS was not reached. '999' is listed in lieu of "NA" due to requirement for numerical entry. Full Observed Range: Brentuximab Vedotin Arm: 1.31 to 117.88 months Placebo Arm: 0.03 to 119.23 months
    End point type
    Secondary
    End point timeframe
    Up to approximately 10 years
    End point values
    		 Brentuximab vedotin Placebo
    Number of subjects analysed
    165
    164
    Units: months
    999
    999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events were followed for up to 15 months. Serious adverse event data were collected for up to approximately 10 years (116 months).
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) defined as newly occurring (not present at baseline) or worsening after first dose of investigational product on Study SGN35-005
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 placebo every 3 weeks by IV infusion

    Reporting group title
    Brentuximab Vedotin
    Reporting group description
    		 brentuximab vedotin 1.8 mg/kg every 3 weeks by IV infusion

    Serious adverse events
    		 Placebo Brentuximab Vedotin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 160 (13.13%)
    43 / 167 (25.75%)
         number of deaths (all causes)
    2
    4
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Mantle cell lymphoma
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Anogenital warts
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 160 (1.25%)
    6 / 167 (3.59%)
         occurrences causally related to treatment / all
    0 / 5
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Asthma
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation myelopathy
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar migraine
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 160 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 160 (0.63%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 160 (0.63%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 160 (0.63%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute hepatitis b
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic candidiasis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 160 (2.50%)
    7 / 167 (4.19%)
         occurrences causally related to treatment / all
    0 / 7
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Brentuximab Vedotin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 160 (79.38%)
    151 / 167 (90.42%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 160 (2.50%)
    9 / 167 (5.39%)
         occurrences all number
    7
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 160 (4.38%)
    13 / 167 (7.78%)
         occurrences all number
    10
    13
    Chills
         subjects affected / exposed
    8 / 160 (5.00%)
    17 / 167 (10.18%)
         occurrences all number
    8
    21
    Fatigue
         subjects affected / exposed
    29 / 160 (18.13%)
    40 / 167 (23.95%)
         occurrences all number
    34
    68
    Non-cardiac chest pain
         subjects affected / exposed
    9 / 160 (5.63%)
    6 / 167 (3.59%)
         occurrences all number
    10
    8
    Oedema peripheral
         subjects affected / exposed
    10 / 160 (6.25%)
    8 / 167 (4.79%)
         occurrences all number
    14
    12
    Pain
         subjects affected / exposed
    5 / 160 (3.13%)
    11 / 167 (6.59%)
         occurrences all number
    5
    19
    Pyrexia
         subjects affected / exposed
    23 / 160 (14.38%)
    27 / 167 (16.17%)
         occurrences all number
    37
    49
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 160 (16.25%)
    35 / 167 (20.96%)
         occurrences all number
    33
    43
    Dyspnoea
         subjects affected / exposed
    10 / 160 (6.25%)
    21 / 167 (12.57%)
         occurrences all number
    11
    34
    Oropharyngeal pain
         subjects affected / exposed
    8 / 160 (5.00%)
    8 / 167 (4.79%)
         occurrences all number
    10
    9
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 160 (8.13%)
    14 / 167 (8.38%)
         occurrences all number
    14
    15
    Insomnia
         subjects affected / exposed
    5 / 160 (3.13%)
    14 / 167 (8.38%)
         occurrences all number
    5
    15
    Investigations
    Weight decreased
         subjects affected / exposed
    9 / 160 (5.63%)
    31 / 167 (18.56%)
         occurrences all number
    10
    64
    Weight increased
         subjects affected / exposed
    14 / 160 (8.75%)
    5 / 167 (2.99%)
         occurrences all number
    28
    5
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    3 / 160 (1.88%)
    9 / 167 (5.39%)
         occurrences all number
    3
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 160 (8.13%)
    19 / 167 (11.38%)
         occurrences all number
    18
    31
    Paraesthesia
         subjects affected / exposed
    2 / 160 (1.25%)
    16 / 167 (9.58%)
         occurrences all number
    2
    33
    Peripheral motor neuropathy
         subjects affected / exposed
    3 / 160 (1.88%)
    37 / 167 (22.16%)
         occurrences all number
    3
    39
    Peripheral sensory neuropathy
         subjects affected / exposed
    25 / 160 (15.63%)
    92 / 167 (55.09%)
         occurrences all number
    32
    220
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 160 (2.50%)
    14 / 167 (8.38%)
         occurrences all number
    11
    36
    Leukopenia
         subjects affected / exposed
    3 / 160 (1.88%)
    9 / 167 (5.39%)
         occurrences all number
    7
    18
    Neutropenia
         subjects affected / exposed
    18 / 160 (11.25%)
    58 / 167 (34.73%)
         occurrences all number
    36
    163
    Thrombocytopenia
         subjects affected / exposed
    3 / 160 (1.88%)
    12 / 167 (7.19%)
         occurrences all number
    7
    39
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 160 (3.13%)
    20 / 167 (11.98%)
         occurrences all number
    7
    30
    Constipation
         subjects affected / exposed
    5 / 160 (3.13%)
    20 / 167 (11.98%)
         occurrences all number
    5
    27
    Diarrhoea
         subjects affected / exposed
    15 / 160 (9.38%)
    33 / 167 (19.76%)
         occurrences all number
    25
    47
    Dyspepsia
         subjects affected / exposed
    6 / 160 (3.75%)
    11 / 167 (6.59%)
         occurrences all number
    6
    17
    Nausea
         subjects affected / exposed
    12 / 160 (7.50%)
    34 / 167 (20.36%)
         occurrences all number
    18
    61
    Vomiting
         subjects affected / exposed
    11 / 160 (6.88%)
    24 / 167 (14.37%)
         occurrences all number
    14
    35
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    7 / 160 (4.38%)
    10 / 167 (5.99%)
         occurrences all number
    9
    10
    Night sweats
         subjects affected / exposed
    18 / 160 (11.25%)
    12 / 167 (7.19%)
         occurrences all number
    19
    13
    Pruritus
         subjects affected / exposed
    14 / 160 (8.75%)
    22 / 167 (13.17%)
         occurrences all number
    18
    40
    Rash
         subjects affected / exposed
    5 / 160 (3.13%)
    14 / 167 (8.38%)
         occurrences all number
    6
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 160 (9.38%)
    30 / 167 (17.96%)
         occurrences all number
    16
    42
    Back pain
         subjects affected / exposed
    16 / 160 (10.00%)
    15 / 167 (8.98%)
         occurrences all number
    17
    22
    Muscle spasms
         subjects affected / exposed
    9 / 160 (5.63%)
    18 / 167 (10.78%)
         occurrences all number
    10
    20
    Muscular weakness
         subjects affected / exposed
    1 / 160 (0.63%)
    8 / 167 (4.79%)
         occurrences all number
    2
    10
    Myalgia
         subjects affected / exposed
    7 / 160 (4.38%)
    15 / 167 (8.98%)
         occurrences all number
    7
    17
    Pain in extremity
         subjects affected / exposed
    8 / 160 (5.00%)
    11 / 167 (6.59%)
         occurrences all number
    9
    12
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 160 (6.25%)
    10 / 167 (5.99%)
         occurrences all number
    13
    10
    Herpes zoster
         subjects affected / exposed
    3 / 160 (1.88%)
    10 / 167 (5.99%)
         occurrences all number
    3
    12
    Pharyngitis
         subjects affected / exposed
    4 / 160 (2.50%)
    8 / 167 (4.79%)
         occurrences all number
    4
    10
    Sinusitis
         subjects affected / exposed
    10 / 160 (6.25%)
    4 / 167 (2.40%)
         occurrences all number
    10
    6
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 160 (23.13%)
    43 / 167 (25.75%)
         occurrences all number
    57
    68
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 160 (5.63%)
    20 / 167 (11.98%)
         occurrences all number
    9
    25
    Hypokalaemia
         subjects affected / exposed
    6 / 160 (3.75%)
    10 / 167 (5.99%)
         occurrences all number
    6
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2009
    The sample size was increased to 322 patients to enable detection of a hazard ratio of 0.667 in favor of brentuximab vedotin. Based on regulatory guidance, more frequent CT scanning and lymphoma assessments were incorporated to better characterize the primary endpoint of PFS. To better inform patient care after disease progression, the protocol was revised to allow unblinding of a patient’s treatment assignment once disease progression had occurred. Investigator assessment of response to prior salvage therapy was added as a stratification factor to ensure that patients with different outcomes to salvage therapy were equally distributed between the treatment arms. Based on regulatory and investigator guidance and because of the blinded nature of the study, the prospective pathology review for confirmation of HL was removed.
    16 Aug 2010
    Administration of the EQ-5D health questionnaire and collection of MRU data was added to conduct exploratory health economics and outcomes research. A recommendation was added such that patients who experienced Grade 2 neuropathy were to resume treatment at 1.2 mg/kg to minimize additional or worsening events of neuropathy. The follow-up period for events of peripheral neuropathy and other AEs of interest was extended beyond the 30-day post-treatment reporting period to better characterize their resolution.
    03 Oct 2011
    The eligibility criteria were clarified to ensure exclusion of patients with PML. In addition, information and guidance were provided on the signs and symptoms of PML and diagnostic work-up/recommendations for suspending or discontinuing treatment with brentuximab vedotin in the event of PML.
    29 Nov 2011
    The safety assessments section was revised to better define the different subcategories of adverse events and provide guidance on their relative safety reporting periods; and to clarify sponsor safety reporting requirements in the US. The study assessments section was revised to require that any CT scans performed as standard of care after the 24-month scan were submitted for central review and study visits for patients who discontinued treatment before 16 cycles included all required assessments including CT scans and lymphoma assessments.
    07 Jun 2012
    The procedure for emergency unblinding was revised to allow investigators who needed treatment assignment information (for safety reasons or for clinical decision-making) to directly obtain treatment assignment information through the IWRS without having to first contact the sponsor. This change was made to better align with the recommendations of the EMA GCP Inspector’s Working Group and Clinical Trial Facilitation Group.
    13 Dec 2013
    The timing of the primary efficacy analysis was changed after an evaluation of blinded, pooled PFS data from the current study showed a flattening of the PFS curve after 24 months; thus, it was unlikely that additional follow up after 24 months would provide significant additional events. The primary efficacy analysis was therefore changed to occur after all study scheduled CT scans had been performed. At this time, all patients had been off therapy for at least one year. The IDMC was consulted regarding this change to the primary analysis and they agreed that the scientific integrity of the study should remain intact.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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