Clinical Trial Results:
A randomized phase II trial evaluating the endocrine activity and efficacy of neoadjuvant degarelix versus triptorelin in premenopausal patients receiving letrozole for locally advanced endocrine responsive breast cancer.
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Summary
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EudraCT number |
2012-005326-29 |
Trial protocol |
IT |
Global end of trial date |
25 Aug 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Apr 2020
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First version publication date |
01 Apr 2020
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Other versions |
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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 |
IBCSG 41-13 TREND
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02005887 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
IBCSG
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Sponsor organisation address |
Effingerstrasse 40, Bern, Switzerland, 3008
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Public contact |
IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 31389 93 91, regulatoryoffice@ibscg.org
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Scientific contact |
IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 31389 93 91, regulatoryoffice@ibscg.org
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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 |
05 Sep 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Aug 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Aug 2017
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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 |
This trial evaluated neoadjuvant endocrine therapy (degarelix [GnRH antagonist] versus triptorelin [GnRH agonist]) in combination with letrozole as treatment for premenopausal women diagnosed with endocrine responsive breast cancer.
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Protection of trial subjects |
- In compliance with GDPR.
- Adverse events were reported and in case of adverse events and treatment-related toxicities management guidance was provided in the study protocol to treat trial subjects in adequately manner.
- The safety of the trial treatment was regularly reviewed by the IBCSG Data Safety Monitoring Committee (DSMC).
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
28 Mar 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Italy: 51
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Worldwide total number of subjects |
51
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EEA total number of subjects |
51
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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) |
51
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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 |
The study was activated on 28 March 2013 and the first patient was enrolled on 24 February 2014. The trial was activated in seven participating centers in Italy. Three centers enrolled patients. Final enrollment was 51 patients. The study completed accrual on 10 January 2017 and closed on 12 January 2017. | |||||||||||||||
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Pre-assignment
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Screening details |
Premenopausal patients with histologically confirmed primary breast cancer and with primary tumor which is ER+ and PgR+ (>50%) and HER2-negative or not amplified | |||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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triptorelin + letrozole | |||||||||||||||
Arm description |
Triptorelin 3.75 mg i.m. on day 1 every 28 days for 6 cycles + letrozole 2.5 mg/day orally for 6 cycles | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Triptorelin
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Investigational medicinal product code |
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Other name |
decapeptyl
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Triptorelin 3.75 mg injected into the muscle on day 1 every 28 days for 6 cycles (1 cycle= 28 days)
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Arm title
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degarelix + letrozole | |||||||||||||||
Arm description |
Degarelix 240 mg s.c. on day 1 of cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg every day orally for 6 cycles | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Degarelix
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Investigational medicinal product code |
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Other name |
firmagon
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Degarelix 240 mg injected under the skin given as two injections of 120 mg on the first day of treatment, followed by injection of 80 mg on day 1 of cycles 2 to 6 (1 cycle=28 days)
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Baseline characteristics reporting groups
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Reporting group title |
triptorelin + letrozole
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Reporting group description |
Triptorelin 3.75 mg i.m. on day 1 every 28 days for 6 cycles + letrozole 2.5 mg/day orally for 6 cycles | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
degarelix + letrozole
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Reporting group description |
Degarelix 240 mg s.c. on day 1 of cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg every day orally for 6 cycles | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
triptorelin + letrozole
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Reporting group description |
Triptorelin 3.75 mg i.m. on day 1 every 28 days for 6 cycles + letrozole 2.5 mg/day orally for 6 cycles | ||
Reporting group title |
degarelix + letrozole
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Reporting group description |
Degarelix 240 mg s.c. on day 1 of cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg every day orally for 6 cycles | ||
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End point title |
Time to Optimal Ovarian Function Suppression | ||||||||||||
End point description |
Time from the first injection of degarelix or triptorelin to the first assessment of centrally assessed 17-β-estradiol (E2) level in the range of optimal ovarian function suppression (≤2.72 pg/mL or ≤10 pmol/L) during the 6 cycles of neoadjuvant treatments.
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End point type |
Primary
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End point timeframe |
up to 24 weeks
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Statistical analysis title |
Statistical analysis primary endpoint | ||||||||||||
Statistical analysis description |
The primary endpoint will be compared between the two treatment arms using a stratified two-sample log-rank test, with age as stratification factor. The distribution of the primary endpoint will be summarized using the method of Kaplan-Meier and the two-sided 95% confidence interval (CI) for the difference in proportion of patients who achieve optimal ovarian function suppression between the two treatment arms at the end of the 1st, 2nd and 4th cycle will also be provided.
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Comparison groups |
degarelix + letrozole v triptorelin + letrozole
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Number of subjects included in analysis |
51
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
3.05
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
1.65 | ||||||||||||
upper limit |
5.65 | ||||||||||||
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End point title |
Ki67 Proliferation Marker Changes | ||||||||||||
End point description |
The percent change in Ki67 expression from pre-treatment diagnostic (baseline) biopsy to surgery, calculated as (surgery-baseline)/baseline*100
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End point type |
Secondary
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End point timeframe |
Before day 1 of cycle 1 and surgery
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| Notes [1] - Four patients are not evaluable [2] - Four patients are not evaluable |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Preoperative Endocrine Prognostic Index (PEPI) Score | ||||||||||||
End point description |
Preoperative Endocrine Prognostic Index (PEPI) is the sum of the risk points (tumor size, nodal status, Ki67 level, ER status) with a 0-12 score representing the best prognostic feature (0 being the best score; 12 being the worst score), as previously determined to be associated with recurrence-free survival.
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End point type |
Secondary
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End point timeframe |
After 24 weeks or the time of surgery
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| Notes [3] - Two patients who did not have surgery were not evaluated |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Best Overall (Disease) Response | ||||||||||||
End point description |
Based on WHO tumor measurement and response criteria [1], measured from the start of treatment across all time points until disease progression or the end of 6 cycles of neoadjuvant therapies, whichever comes first. Response was determined by the IBCSG Head of Medical Affairs. An internal review (IR) form was created to record the final determination on best overall response. Confirmation of partial or complete response by an additional scan was not required in this trial. Best overall response was assessed based on changes in tumor size from baseline to the assessments after 3 and after 6 cycles (denoted as day 1 of cycle 4 and prior to surgery respectively) as measured physically by caliper or ruler and as measured by breast tumor imaging (i.e., bilateral mammography and breast ultrasound).
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End point type |
Secondary
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End point timeframe |
From day 1 of cycle 1 across all time points until disease progression
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Patients With Node-negative Disease at Surgery | ||||||||||||
End point description |
The number of lymph nodes assessed at surgery minus the number of positives nodes identified, equal to zero.
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End point type |
Secondary
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End point timeframe |
During surgery, an average of 2 hours
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Patients Who Underwent Breast-Conserving Surgery (BCS) | ||||||||||||
End point description |
Whether or not patient undergoes BCS (per Surgery form).
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End point type |
Secondary
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End point timeframe |
During surgery, an average of 2 hours
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| Notes [4] - Two patients who did not have surgery were not evaluated |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Patient-reported Symptoms (PRS) Outcomes | ||||||||||||
End point description |
The patient-reported symptoms (PRS) will be assessed using the Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-ES) comprising 18 items (each has score range from 0 to 4) with a possible minimum total score of 0 and maximum total score of 72 (72 is best). Functional Assessment of Chronic Illness Therapy (FACIT) guidelines will be used for scoring and interpretation of the FACT-ES total score.
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End point type |
Secondary
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End point timeframe |
At baseline, day 1 of cycle 2 and cycle 4 and prior to surgery; cycle 4 reported
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events (AE) forms were submitted at the end of every cycle (28 days) and 30 days after surgery. All patients submitted AE data during 6 cycles of treatment period when available.
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Adverse event reporting additional description |
Adverse events were collected using CTCAE v4.0. Each targeted AE will be classified according to the maximum grade of the event while on trial treatment (grade 0,1,2,3,4,5; where 0=no report). Other grade 3-5 AEs will be classified according to the maximum grade of any reported other AE.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
triptorelin + letrozole
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Reporting group description |
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Reporting group title |
degarelix + letrozole
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30589600 |
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