Clinical Trial Results:
DETECT III – A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus Lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells
Summary
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EudraCT number |
2010-024238-46 |
Trial protocol |
DE |
Global end of trial date |
20 Jan 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
10 May 2024
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First version publication date |
10 May 2024
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Other versions |
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Summary report(s) |
Müller et al. 2021_ESMO_prognostic relevance of HER2 status Fehm et. al_ClinChem_2024 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D-III
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01619111 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Universitätsklinik Ulm
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Sponsor organisation address |
Albert-Einstein-Allee 29, Ulm, Germany, 89075
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Public contact |
Studienzentrale , Universitätsklinikum Ulm - Klinik für Frauenheilkunde und Geburtshilfe, 0049 73150058652, Studienzentrale.UFK@uniklinik-ulm.de
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Scientific contact |
Prof. Wolfgang Janni, Universitätsklinikum Ulm - Klinik für Frauenheilkunde und Geburtshilfe, 3150058652 73150058652, Studienzentrale.UFK@uniklinik-ulm.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Jan 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Jan 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the trial was to prove the clinical efficacy of lapatinib (as assessed by the CTC clearance rate) in patients with metastasizing breast cancer who exhibit HER2-positive circulating tumor cells (CTC) although the primary tumor tissue and/or biopsies from metastatic sites were investigated for HER2 status and showed HER2-negativity.
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Protection of trial subjects |
Safety and tolerability were assessed by evaluation of adverse event (AE) and serious adverse event (SAE) reports using the international Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The safety population (which is equivalent to mITT population) comprised all randomized subjects who received at least one dose of the respective study treatment.
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Background therapy |
Reference therapy was standard therapy, to be selected from the mono-chemotherapies or endocrine therapies | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
24 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 101
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Worldwide total number of subjects |
101
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EEA total number of subjects |
101
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
101
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with HER2-neg. metastatic breast cancer, | |||||||||
Pre-assignment
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Screening details |
positive HER2-status of circulating tumor cells (CTCs) | |||||||||
Pre-assignment period milestones
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Number of subjects started |
101 | |||||||||
Number of subjects completed |
101 | |||||||||
Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Standard Therapy plus Lapatinib | |||||||||
Arm description |
Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Lapatinib Tyverb
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
daily dose of lapatinib may have been adjusted dependent on the dose regimen of the standard chemo- or endocrine therapy and on the occurrence of adverse events.
In any case, the maximum daily dose was 1500 mg, the minimum daily dose was 750 mg. Duration of lapatinib therapy was 12 months
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Arm title
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Standard therapy | |||||||||
Arm description |
During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not | |||||||||
Arm type |
Standard therapy | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Standard Therapy plus Lapatinib
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Reporting group description |
Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard therapy
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Reporting group description |
During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Randomized ITT population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized subjects who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib).
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End points reporting groups
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Reporting group title |
Standard Therapy plus Lapatinib
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Reporting group description |
Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol). | ||
Reporting group title |
Standard therapy
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Reporting group description |
During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not | ||
Subject analysis set title |
Randomized ITT population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomized subjects who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib).
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End point title |
CTC clearance rates at the time of first CTC assessment | ||||||||||||
End point description |
A first follow-up CTC assessment could be performed in 69 patients (30 and 39 patients in the standard and lapatinib
arms, respectively) after a median time of 73 days (interquartile range 64–87 days, range 22–215 days). CTC clearance
was observed in 8 (26.7%, 95% CI 10.8% - 42.5%) patients in the standard arm and in 12 (30.8%, 95% CI 16.3% -
45.3%) patients in the lapatinib arm; the difference was not statistically significant (p = 0.710;
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End point type |
Primary
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End point timeframe |
CTC clearance rates at the time of first CTC assessment
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Attachments |
ctc clearance rate after first asessment |
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Statistical analysis title |
non-parametric | ||||||||||||
Comparison groups |
Standard Therapy plus Lapatinib v Standard therapy
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.71 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Confidence interval |
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End point title |
CTC clearance rates after study treatment | ||||||||||||
End point description |
The primary endpoint, i.e., the CTC clearance rate, was calculated as the proportion of patients with at least one CTC detected in 7.5 ml of peripheral blood drawn before treatment that showed no evidence of CTCs in the blood after study treatment (i.e., at the time of the closure visit, which took place either after a patient had received one year of study treatment or at the time the study treatment had to be stopped because of progress, toxicity or patient wish).
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End point type |
Primary
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End point timeframe |
A first follow-up CTC assessment after study treatment
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Attachments |
ctc clearance rate after study treatment |
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Statistical analysis title |
non-parametric | ||||||||||||
Comparison groups |
Standard Therapy plus Lapatinib v Standard therapy
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.156 [2] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
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Notes [1] - The primary endpoint CTC clearance rate will be evaluated using non-parametric statistical methods appropriate for the analysis of frequencies and rates (i.e. Chi-square tests and modifications thereof). The proportion of pa-tients that show no evidence of CTCs in the blood after the study treatment will be compared between the two treatment arms, and relative risks, odds ratios and their 95% confidence intervals will be reported. [2] - All p values will be two-sided if not stated otherwise. The statistical methods described in this section are suited for the data and distributions usually expected in this type of trials. The suitability will be checked after data entry. If necessar |
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End point title |
OS | ||||||||||||
End point description |
Patients with no evidence of CTCs at the first follow-up CTC assessment (i.e., patients with CTC clearance at the first
follow-up) showed better OS than patients with CTCs (CTC clearance: median OS 42.4 months; no CTC clearance:
median OS 14.1 months; HR 0.34; 95% CI 0.16–0.70; p = 0.004; Figure 5). Patients showing CTC clearance at the
first follow-up CTC assessment also had numerically longer PFS, but the difference was not significant (CTC
clearance: median PFS 10.1 months; no CTC clearance: median PFS 6.2 months; HR 0.56; 95% CI 0.29–1.07; p =
0.078).
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End point type |
Secondary
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End point timeframe |
overall survival according to CTC clearance at the time of first follow-up CTC assessment.
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Attachments |
Untitled (Filename: overal survival OS-CTC clearance.pptx) |
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No statistical analyses for this end point |
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End point title |
PFS | ||||||||||||
End point description |
progression-free survival according to randomization arm
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End point type |
Secondary
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End point timeframe |
progression-free survival according to randomization arm
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Attachments |
PFS randomization arm |
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Statistical analysis title |
PFS | ||||||||||||
Comparison groups |
Standard Therapy plus Lapatinib v Standard therapy
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
P-value |
= 0.092 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.67
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.42 | ||||||||||||
upper limit |
1.07 | ||||||||||||
Variability estimate |
Standard deviation
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Notes [3] - PFS data were available for 87 patients. The median PFS follow-up time for patients without progression was 4.6 months. Progressive disease occurred in 34 of 40 patients in the standard arm and in 36 of 47 patients in the lapatinib arm. Patients in the lapatinib arm showed a numerically but not significantly better PFS than patients in the standard arm |
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End point title |
OS according to randomization | ||||||||||||
End point description |
Survival according to randomization arm
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End point type |
Secondary
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End point timeframe |
End of study
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Attachments |
OS randomization arm |
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Statistical analysis title |
OS randomization arm | ||||||||||||
Comparison groups |
Standard Therapy plus Lapatinib v Standard therapy
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.008 [4] | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Confidence interval |
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Notes [4] - This was evident based on univariable Cox regression analysis (HR 0.53; 95% CI 0.33–0.84; p = 0.008) and multivariable Cox regression analysis adjusted for the metastasis-free interval (<12 months, >12 months), type of metastases (visceral, non-visce |
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Adverse events information
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Timeframe for reporting adverse events |
start of study - first dose of study treatment until end of study
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Adverse event reporting additional description |
The safety evaluation was performed in the Safety Population, defined as all randomized patients who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib). The safety set comprised 101 patients (48 patients in the standard arm, 53 patients in the lapatin
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Standard arm
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Reporting group description |
In conclusion, types and frequencies of adverse events observed in the DETECT III study were as expected for the treatments given in this study, with diarrhea in the lapatinib arm being the most common side effect observed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lapatinib arm
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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25 Oct 2012 |
Change of sponsor from University Hospital Düsseldorf to University Hospital Ulm |
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30 Sep 2014 |
Subsequent changes in protocol |
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09 Jun 2015 |
Administrative changes in the protocol |
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16 Mar 2016 |
Acknowledgement of administrative changes in the trial protocol and patient information |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |