Clinical Trial Results:
An Open-Label Phase II Study of the Safety and Efficacy of Doxorubicin and Cyclophosphamide in Combination with Bortezomib, Lenalidomide, and Dexamethasone for Treatment of Patients with Newly Diagnosed Multiple Myeloma
Summary
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EudraCT number |
2011-002751-34 |
Trial protocol |
DK |
Global end of trial date |
28 Sep 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Apr 2019
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First version publication date |
07 Apr 2019
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Other versions |
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 |
8050
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Vejle Hospital
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Sponsor organisation address |
Kabbeltoft 25, 7100 Vejle, Vejie, Denmark,
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Public contact |
Lena Bjerre, Vejle Hospital, 45 79406316, lena.bjerre.haarbo@slb.regionsyddanmark.dk
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Scientific contact |
Lena Bjerre, Vejle Hospital, 45 79406316, lena.bjerre.haarbo@slb.regionsyddanmark.dk
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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 |
30 Aug 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Aug 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Sep 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 |
To evaluate the efficacy and safety of the combination therapy of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in newly diagnosed multiple myeloma patients
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Protection of trial subjects |
The study was conducted in accordance with ethical principles founded in the Declaration of Helsinki. The EC reviewed all appropriate study documentation in order to safeguard the rights, safety and well-being of the patients. The study was conducted at site where EC approval had been obtained.
Patients had the right to withdraw from the study at any time for any reason, without prejudice to their medical care.
The patient’s confidentiality was maintained and would not be made publicly available to the extent permitted by the applicable laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Sep 2011
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Long term follow-up planned |
No
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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 |
Denmark: 35
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Worldwide total number of subjects |
35
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EEA total number of subjects |
35
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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) |
20
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 1 single site in 1 country. The date of first patient enrollment was 17 Nov 2011 and the date of last patient enrollment was 13 May 2014. A total of 35 subjects were enrolled in the study. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Patients enrolled in the study to evaluate the efficacy and safety of ACVDL in adult patients with newly diagnosed multiple myeloma | ||||||||||||||||||||||||
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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Arm title
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ACVDL | ||||||||||||||||||||||||
Arm description |
Combination therapy of Doxorubicin, Cyclophosphamide, Bortezomib, Dexamethasone and Lenalidomide (ACVDL) for 8 cycles with the exception of patients who attained a CR/PR after 4 cycles of the therapy and were eligible to stem cell mobilization and transplantation, and then 5 cycles bortezomib consolidation therapy for patients who did not attain mCR. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ACVDL
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Investigational medicinal product code |
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Other name |
Doxorubicin, Cyclophosphamide, Bortezomib, Dexamethasone, Lenalidomide
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Pharmaceutical forms |
Capsule, Concentrate and solvent for solution for infusion, Tablet
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Routes of administration |
Intravenous use, Oral use, Subcutaneous use
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Dosage and administration details |
8 cycles of ACVDL therapy was administered for patients with the exception of those who attained a CR/PR after 4 cycles of the therapy and were eligible to stem cell mobilization and transplantation. After the end of ACVDL therapy, 5 cycles of bortezomib consolidation therapy were administered for patients who did not attain mCR.
Each 21-day cycle of ACVDL therapy consisted of the following treatment regime:
-Doxorubicin (50mg/m^2/IV) and cyclophosphamide (750mg/m^2/IV) will be given on Day 1.
-Bortezomib will be given at 1.3 mg/m^2/IV as a 3-5 second IV push on Days 2 and 9 followed by a 10-day rest period.
-Lenalidomide will be given as a single daily oral dose of 15 mg on Days 1-14 followed by a 7-day rest period.
-Dexamethasone will be given as a single daily oral dose of 20mg/day on Days 2, 3, 9 and 10.
Each 35-day cycle of bortezomib consolidation therapy is as follows:
Bortezomib will be given at 1.6mg/m^2 subcutaneously on Day 1, 8, 15 and 22
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Baseline characteristics reporting groups
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Reporting group title |
ACVDL
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Reporting group description |
Combination therapy of Doxorubicin, Cyclophosphamide, Bortezomib, Dexamethasone and Lenalidomide (ACVDL) for 8 cycles with the exception of patients who attained a CR/PR after 4 cycles of the therapy and were eligible to stem cell mobilization and transplantation, and then 5 cycles bortezomib consolidation therapy for patients who did not attain mCR. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
It included subjects who completed one cycle of therapy. Subjects with protocol violations or those who withdrew from the study prematurely would also be included. However, subjects who violated the entry criteria that were clinically relevant to the outcome would be excluded.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
It included subjects fulfilling the following criteria:
a) Tumor remission measures available at the End of ACVDL and 4 weeks after completion of consolidation therapy (if applicable)
b) The absence of any major protocol violations including the violation of entry criteria
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
It included subjects who received the first dose of the study therapy.
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End points reporting groups
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Reporting group title |
ACVDL
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Reporting group description |
Combination therapy of Doxorubicin, Cyclophosphamide, Bortezomib, Dexamethasone and Lenalidomide (ACVDL) for 8 cycles with the exception of patients who attained a CR/PR after 4 cycles of the therapy and were eligible to stem cell mobilization and transplantation, and then 5 cycles bortezomib consolidation therapy for patients who did not attain mCR. | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
It included subjects who completed one cycle of therapy. Subjects with protocol violations or those who withdrew from the study prematurely would also be included. However, subjects who violated the entry criteria that were clinically relevant to the outcome would be excluded.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
It included subjects fulfilling the following criteria:
a) Tumor remission measures available at the End of ACVDL and 4 weeks after completion of consolidation therapy (if applicable)
b) The absence of any major protocol violations including the violation of entry criteria
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
It included subjects who received the first dose of the study therapy.
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End point title |
Response rate (mCR/sCR/CR/VGPR) [1] | ||||||||||||
End point description |
The response rate was reported as percentage of subjects achieving Molecular Complete Response (mCR), Stringent Complete Response (sCR), Complete Response (CR) or Very Good Partial Response (VGPR) at 4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan and after consolidation therapy. Analysis was performed on ITT and PP set.
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End point type |
Primary
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End point timeframe |
Baseline, Interim Assessment, End of ACVDL (4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan) and End of Consolidation Therapy
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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: The primary endpoint was estimation of parameter and therefore no statistical analyses were specified. |
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No statistical analyses for this end point |
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End point title |
Complete response rate (mCR/sCR/CR) | ||||||||
End point description |
The complete response rate was reported as percentage of subjects achieving Molecular Complete Response (mCR), Stringent Complete Response (sCR) or Complete Response (CR) at 4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan and after consolidation therapy. Analysis was performed on ITT set.
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End point type |
Secondary
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End point timeframe |
Baseline, Interim Assessment, End of ACVDL (4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan) and End of Consolidation Therapy
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No statistical analyses for this end point |
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End point title |
Very good partial response rate (VGPR) | ||||||||
End point description |
Very good partial response rate was reported as percentage of subjects achieving Very Good Partial Response (VGPR) at 4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan and after consolidation therapy. Analysis was performed on ITT set.
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End point type |
Secondary
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End point timeframe |
Baseline, Interim Assessment, End of ACVDL (4-weeks after completion of 8 cycles of ACVDL or 3 months after 4 cycles of ACVDL followed by high-dose melphalan) and End of Consolidation Therapy
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No statistical analyses for this end point |
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End point title |
Time to progression (TTP) | ||||||||
End point description |
Time to progression was defined as the time interval from date of first dose of the ACVDL therapy until the date of the first documentation of disease progression. Death due to cause other than progression was censored. Patient without an event was censored at date last known progression-free. Analysis was performed on ITT set using Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
Baseline, Interim Assessment, End of ACVDL, End of Consolidation Therapy, every 12 weeks up to the 4-year, or any other reason for study discontinuation
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No statistical analyses for this end point |
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End point title |
Progression-free survival (PFS) | ||||||||
End point description |
Progression free survival was defined as the time interval from date of first dose of the ACVDL therapy until the date of the first documentation of disease progression or death due to any cause, whichever occurred first. Patient without an event was censored at date last known progression-free. Analysis was performed on ITT set using Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
Baseline, Interim Assessment, End of ACVDL, End of Consolidation Therapy, every 12 weeks up to the 4-year, or any other reason for study discontinuation
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No statistical analyses for this end point |
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End point title |
Dose intensity for ACVDL cycle 1-4 (Non-SCT Patients) | ||||||||||||||||||
End point description |
The mean dose intensity measured for the first 4 cycles of ACVDL for Non-SCT Patients
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End point type |
Secondary
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End point timeframe |
Baseline, End of 4 cycles of ACVDL Therapy
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No statistical analyses for this end point |
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End point title |
Dose intensity for ACVDL cycle 1-8 (Non-SCT Patients) | ||||||||||||||||||
End point description |
The mean dose intensity measured for the cycles 1-8 of ACVDL Therapy for Non-SCT Patients
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End point type |
Secondary
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End point timeframe |
Baseline, End of 8 cycles of ACVDL Therapy
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No statistical analyses for this end point |
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End point title |
Dose intensity for consolidation therapy cycle 1-5 | ||||||||||
End point description |
The mean dose intensity measured for Cycles 1-5 of Consolidation Therapy
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End point type |
Secondary
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End point timeframe |
Start of Consolidation Therapy Cycle 1, End of Consolidation Therapy Cycle 5
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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 |
From the start of the first dose of any medication of the ACVDL therapy to 4 weeks after the last dose of ACVDL or 3 months post stem cell transplantation, or 4 weeks after the combination therapy.
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Adverse event reporting additional description |
ACVDL- or combination therapy- related SAEs were reported during the 4-year follow-up period.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
ACVDL
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Reporting group description |
Combination therapy of Doxorubicin, Cyclophosphamide, Bortezomib, Dexamethasone and Lenalidomide (ACVDL) for 8 cycles with the exception of patients who attained a CR/PR after 4 cycles of the therapy and were eligible to stem cell mobilization and transplantation, and then 5 cycles bortezomib consolidation therapy for patients who did not attain mCR. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Jul 2012 |
Addition of 5-cycles consolidation therapy with bortezomib for patients not attaining molecular complete response (mCR) at 4 weeks after the last dose of the combination therapy of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide (ACVDL) or 3 months after stem cell transplantation. |
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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 |