Clinical Trial Results:
Trial of afatinib (BIBW 2992) in suspected or confirmed mutant EGFR lung cancer patients unfit for chemotherapy
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Summary
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EudraCT number |
2011-003608-19 |
Trial protocol |
GB |
Global end of trial date |
30 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Dec 2019
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First version publication date |
18 Dec 2019
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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 |
UCL/09/0426
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01415011 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
TIMELY Trial Co-ordinator, CR UK & UCL Cancer Trials Centre, +44 02076799284, ctc.timely@ucl.ac.uk
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Scientific contact |
TIMELY Trial Co-ordinator, University College London, +44 02076799284, ctc.timely@ucl.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 |
15 Nov 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Nov 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Nov 2018
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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 |
To examine the efficacy and safety of afatinib (BIBW 2992) in non-small cell lung cancer patients who had either suspected or confirmed EGFR mutation and were considered unfit for chemotherapy. The primary outcome measure is progression free survival at 6 months.
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Protection of trial subjects |
Regular Trial Management Group meetings and Independent Data Monitoring Committee meetings were held throughout the trial to monitor overall safety in the patient group. Pharmacovigilance requirements and safety compliance rules were detailed in the trial protocol with overall risk assessment, on-site monitoring and central monitoring conducted by the trial teams.
Patient data is stored in a secure manner and the trial is registered in accordance with the Data Protection Act.
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Background therapy |
In the TIMELY trial, loperamide was a named NIMP. At the time of initiation of treatment with afatinib (BIBW 2992), patients were given a supply of loperamide to keep with them at all times, and were counselled on the appropriate use. Loperamide was administered to the patients for management of diarrhoea adverse events associated with afatinib. | ||
Evidence for comparator |
No comparators where applicable in the trial design. | ||
Actual start date of recruitment |
01 Mar 2012
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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 |
United Kingdom: 39
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Worldwide total number of subjects |
39
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EEA total number of subjects |
39
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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) |
9
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From 65 to 84 years |
27
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85 years and over |
3
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Recruitment
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Recruitment details |
A total of 39 eligible patients were recruited to the study between 12th March 2013 and 13th August 2015. Patients were recruited from 13 different UK NHS hospital sites. | ||||||
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Pre-assignment
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Screening details |
Patient enrolled were non-small cell lung cancer patients with comorbidities precluding chemotherapy, with either (i) EGFR-mutation, PS 0-3, or (ii) suspected EGFR-mutation (tissue unavailable/failed genotyping), never/former-light smoker, adenocarcinoma, and performance status 0-2. | ||||||
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Period 1
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Period 1 title |
Overall trial
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
Not applicable.
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Arms
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Arm title
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Single arm - 40mg daily oral afatinib | ||||||
Arm description |
All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Afatinib
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Investigational medicinal product code |
BIBW 2992
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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 |
Each patient started afatinib at a dose of 40mg, once daily, orally, in the form of tablet. Each cycle of afatinib was administered every 28 days. Daily dosing continued until progression, unacceptable adverse events or other reason necessitating withdrawal.
30mg and 20mg doses were provided for patients who required protocol dose modifications due to adverse events.
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Period 2
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Period 2 title |
1 month
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Single arm - 40mg daily oral afatinib | ||||||
Arm description |
All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Afatinib
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Investigational medicinal product code |
BIBW 2992
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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 |
Each patient started afatinib at a dose of 40mg, once daily, orally, in the form of tablet. Each cycle of afatinib was administered every 28 days. Daily dosing continued until progression, unacceptable adverse events or other reason necessitating withdrawal.
30mg and 20mg doses were provided for patients who required protocol dose modifications due to adverse events.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Patients had any stage non-small cell lung cancer with either suspected or confirmed EGFR status and were unable to receive chemotherapy due to co-morbidity. At trial entry, patients were age 18 or over, were required to have adequate organ function and have no existing conditions that would exclude them from treatment with afatinib, such as interstitial lung disease, and cardiac abnormalities. Patients assessments were fortnightly for the first two cycles, then monthly for twelve months and two-monthly thereafter. After discontinuing afatinib (BIBW 2992), all patients were followed-up two-monthly during the first twelve months. Tumour response was evaluated by CT scan of the chest and abdomen (4 calendar weeks after the start date for treatment and then every 8 calendar weeks until disease progression). If after 1 year the patient was still on afatinib (BIBW 2992) CT scans were planned every 12 calendar weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Single arm - 40mg daily oral afatinib
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Reporting group description |
All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days. | ||
Reporting group title |
Single arm - 40mg daily oral afatinib
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Reporting group description |
All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days. | ||
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End point title |
Progression-free survival at 6 months [1] | ||||||||
End point description |
The end point value reported is the proportion of patients alive and progression free at 6 months with corresponding exact binomial 80% confidence interval.
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End point type |
Primary
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End point timeframe |
Progression-free survival at 6 months; calculated as the time between the date of registration and date of first progression or death (from any cause), whichever occured first. Patients who have not died or progressed were censored at the date last seen.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: TIMELY was a single arm study; the system is unable to accommodate the details required for statistical analysis for a single arm trial, therefore the analysis details have not been added. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Response | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Best response from initial response assessment for the whole duration of the trial.
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| No statistical analyses for this end point | |||||||||||
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End point title |
Overall Survival | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Overall survival is defined as the time from start of treatment to death from any cause. The median follow up time censoring for deaths was 42 months (range for survivors 32 to 65).
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Attachments |
OS all patients |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression free survival in patients aged 70 and over | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Defined as the time from start of treatment to progression or death from any cause in patient aged 70 and over.
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Attachments |
PFS by age |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Treatment Compliance | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Calculated from date of first dose to date of last known dose. Patients who were still on treatment at the time of analysis were censored at the date last seen.
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Attachments |
Time on treatment |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in performance status at 1 month | |||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline assessment at registration and one month after registration (+/- 1 week).
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Statistical analysis title |
Wilcoxon signed-rank test | |||||||||||||||||||||||||||
Comparison groups |
Single arm - 40mg daily oral afatinib v Single arm - 40mg daily oral afatinib
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | |||||||||||||||||||||||||||
P-value |
= 0.5 | |||||||||||||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||||||||||||||
Confidence interval |
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| Notes [2] - Wilcoxon signed-rank test to determine whether there is evidence of a change in performance status from registration to 1 month. |
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End point title |
Progression-free survival | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Progression-free survival is defined as the time from registration to the date of first progression or death (from any cause), whichever occurs first. Patients who have not died or progressed were censored at the date last seen.
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Attachments |
PFS all patients |
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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 |
All adverse events that occured between informed consent and 30 days post last administration of afatinib.
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Adverse event reporting additional description |
Adverse events were collected from patients through clinical assessment and review of self-reported patient diaries. For each type of adverse event, the maximum toxicity grade was obtained for each patient. Focus is on those with a grade 3 or 4 event. The proportion of patients with any grade 3 or 4 event are examined.
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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
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Reporting groups
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Reporting group title |
All trial subjects
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Reporting group description |
For each type of adverse event, the maximum toxicity grade was obtained for each patient. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 Mar 2013 |
Protocol version 2.0 dated 15th March 2013:
1. Updated Investigator's Brochure (IB)for afatinib implemented - version 13, dated 11th July 2012.
2. The IMP name BIBW 2992 was amended to afatinib (BIBW 2992) on all trial documents following generic name approval.
3. Participant Information sheet and Protocol updated to include new safety information described in the updated IB.
4. Reference Safety Information updated; all serious adverse reactions were evaluated, in order to determine whether they are suspected unexpected serious adverse reactions, using information contained in the current investigator brochure for Afatinib (BIBW 2992).
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05 Nov 2013 |
Protocol version 3 dated 12th November 2013:
1. Updated Afatinib Investigator's Brochure implemented - version 14 dated 4th July 2013.
2. Reference Safety Information; all serious adverse reactions were evaluated, in order to determine whether they are suspected unexpected serious adverse reactions, using information contained in the updated investigator brochure for afatinib (BIBW 2992) version 14 dated 04/07/2013 using the list of expected AEs under section 7.
3. The main change was to include patients with a known EGFR mutation. As a result the trial title has been amended on all trial documents to reflect the inclusion of this group of patients.
4. The Participant Information Sheet was updated to include an additional side effect referenced in the updated safety information.
5. Protocol updated to include confirmed EGFR patients and the safety profile of afatinib was updated with information from ongoing phase I and II trials.
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02 Jul 2014 |
Protocol version 4.0 dated 24th June 2014:
Clarification regarding eligibility of patients with WHO performance status (PS) 3 added. Patients with a confirmed activating EGFR mutation and WHO PS 0-3 were eligible, whereas patients who had suspected EGFR mutation were only eligible if WHO PS was 0-2. |
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12 Dec 2016 |
Protocol version 5 dated 9th August 2016:
1. End of trial definition updated.
2. Inclusion of central review of progression. |
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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. | |||
| 1. SAEs and non-serious grade 3+ AEs are listed under non-serious AE section. 2. Under non-serious AEs, only the highest grade experienced by patients was collected and therefore the 'subjects affected' number has been entered for 'occurrences'. | |||
