Clinical Trial Results:
Avastin Randomised Trial with neo-adjuvant chemotherapy for patients with early HER2- negative breast cancer
Summary
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EudraCT number |
2008-002322-11 |
Trial protocol |
GB |
Global end of trial date |
19 Jun 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jul 2016
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First version publication date |
31 Jul 2015
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Other versions |
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Summary report(s) |
Artemis Article Artemis SupplementaryAppendix |
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 |
ARTemis
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Additional study identifiers
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ISRCTN number |
ISRCTN68502941 | ||
US NCT number |
NCT01093235 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
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Sponsor organisation address |
R&D, Box 277, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ
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Public contact |
Louise Grybowicz
, Cambridge University Hospitals NHS Foundation Trust, +44 1223 348447, louise.grybowicz@addenbrookes.nhs.uk
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Scientific contact |
Dr. Helena Earl, University of Cambridge
, hme22@cam.ac.uk
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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 |
16 Oct 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Mar 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Jun 2014
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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 |
A phase III, randomised trial to determine whether the addition to neo-adjuvant chemotherapy (3 cycles of docetaxel followed by 3 cycles of 5-fluorouracil, epirubicin and cyclophosphamide) of 4 cycles of an anti-angiogenic agent bevacizumab given concurrently with the chemotherapy is more effective than standard chemotherapy alone in terms of short-term and long-term outcome in patients presenting with high risk HER2-negative early breast cancer.
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Protection of trial subjects |
Protocol design: Prevention of AEs included cardiac monitoring (LVEF and BP) mandated before, during and after treatment; G-CSF strongly recommended for use alongside treatment; schedule of chemotherapy reversed to be less cardiotoxic and more efficacious; mandatory treatment washout period before surgery; early interim safety analysis of toxicities on first 200 patients; various exclusion criteria, screening, and on-treatment investigations conducted to ascertain and maintain knowledge of patients' fitness to receive the treatment; on-study toxicity management guidelines; and continuous monitoring and dissemination of the safety data for the treatments used throughout the trial, and of the patients themselves.
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Background therapy |
5-Fluorouracil 500mg/m2, Epirubicin 100mg/m2 and Cyclophosphamide 500mg/m2: every 3 weeks for 3 cycles. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 May 2009
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
10 Years | ||
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 |
United Kingdom: 800
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Worldwide total number of subjects |
800
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EEA total number of subjects |
800
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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) |
758
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From 65 to 84 years |
42
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were approached, consented, and recruited at hospital oncology clinics for recently-diagnosed, HER-2 negative, early (non-metastatic) breast cancer. Recruitment period was from May 2009 to Jan 2013. | |||||||||||||||||||||
Pre-assignment
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Screening details |
HER2, ER, FBC, biochem, BP, Pregnancy, Urine, Coagulation, LVEF, Staging inflammatory/LN+ Exclusions: Cardiac-related or Thromboembolic disease, Inflammatory GI disease, Bleeding diathesis, Nephritic/nephrotic syndrome, Infection, Major surgery/trauma, Non-healing wound/fracture, Anticoagulants, LHRH-agonists, Other chemo/bio agent or malignancy. | |||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
800 | |||||||||||||||||||||
Number of subjects completed |
800 | |||||||||||||||||||||
Period 1
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Period 1 title |
Primary endpoint analysis (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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Arm B | |||||||||||||||||||||
Arm description |
Research | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Bevacizumab (Avastin)
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Investigational medicinal product code |
Bev
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
15mg/kg; IV infusion every 3 weeks, for 4 cycles.
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Investigational medicinal product name |
Docetaxel
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Investigational medicinal product code |
D
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
100mg/m2, every 3 weeks for 3 cycles.
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Arm title
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Arm A | |||||||||||||||||||||
Arm description |
Standard treatment | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Docetaxel
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Investigational medicinal product code |
D
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
100mg/m2, every 3 weeks for 3 cycles.
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Baseline characteristics reporting groups
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Reporting group title |
Arm B
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Reporting group description |
Research | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm A
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Reporting group description |
Standard treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomised patients.
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End points reporting groups
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Reporting group title |
Arm B
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Reporting group description |
Research | ||
Reporting group title |
Arm A
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Reporting group description |
Standard treatment | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomised patients.
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End point title |
Complete pathological response (pathCR) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy. | |||||||||||||||
End point description |
No residual invasive carcinoma within the breast (DCIS permitted) AND no evidence of metastatic disease within the lymph nodes {Pinder, 2007 #86}
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End point type |
Primary
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End point timeframe |
Period of assessment: 02July2013 - 11Mar2014
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Statistical analysis title |
Complete pathological response (pathCR) rates. | |||||||||||||||
Statistical analysis description |
No residual invasive carcinoma within the breast (DCIS permitted) AND no evidence of metastatic disease within the lymph nodes {Pinder, 2007 #86}
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Comparison groups |
Arm A v Arm B
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Number of subjects included in analysis |
781
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.03 [1] | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
1.53
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
1.04 | |||||||||||||||
upper limit |
2.26 | |||||||||||||||
Notes [1] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors." |
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End point title |
pCR and Minimal Residual Disease (MRD) | |||||||||||||||
End point description |
Complete pathological response (pathCR) and Minimal Residual Disease (MRD) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.
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End point type |
Secondary
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End point timeframe |
Period of assessment: 02July2013 - 11Mar2014
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Statistical analysis title |
pCR and Minimal Residual Disease (MRD) | |||||||||||||||
Statistical analysis description |
Complete pathological response (pathCR) and Minimal Residual Disease (MRD) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.
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Comparison groups |
Arm B v Arm A
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Number of subjects included in analysis |
782
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.03 [2] | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
1.43
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
1.03 | |||||||||||||||
upper limit |
1.98 | |||||||||||||||
Notes [2] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors." |
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Statistical analysis title |
pCR in breast only | |||||||||||||||
Statistical analysis description |
pCR in all breast tumours
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Comparison groups |
Arm B v Arm A
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Number of subjects included in analysis |
782
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.02 [3] | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
1.54
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
1.06 | |||||||||||||||
upper limit |
2.24 | |||||||||||||||
Notes [3] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors." |
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Adverse events information
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Timeframe for reporting adverse events |
From randomisation of the first trial patient, to 6 weeks after the final infusion of the final patient (or longer if considered related to treatment or protocol).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
All patients randomised into the trial | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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30 Nov 2009 |
Administrative changes & clarifications to Protocol & Patient Information Sheets; addition of screening tests and time limits to pre-randomisation tests; long-term follow-up increased to 10 years.
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22 Jun 2010 |
New reference safety information (Summary of Product Characteristics) for IMP docetaxel
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18 Oct 2010 |
Change of distributor of IMP Bevacizumab - outsourced by the manufacturer.
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27 Sep 2011 |
Administrative changes & clarifications to Protocol & Patient Information Sheets; addition of eligibility criteria; interim saftey analysis complete, requirement to report specific AEs lifted. |
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29 Oct 2013 |
Addition of a translational sample collection sub-study; clarification of primary endpoint; clarification of definition of end of trial. |
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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 | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/25975632 |