Clinical Trial Results:
A trial of de-escalation and stopping treatment in chronic myeloid leukaemia patients with excellent responses to tyrosine kinase inhibitor therapy DESTINY(De- Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel in chronic myeloid leukaemia)
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Summary
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EudraCT number |
2012-004025-24 |
Trial protocol |
GB |
Global end of trial date |
01 Aug 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Oct 2019
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First version publication date |
06 Oct 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 |
4203/UoL000893
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Additional study identifiers
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ISRCTN number |
ISRCTN74084226 | ||
US NCT number |
NCT01804985 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
The Royal Liverpool and Broadgreen University Hospitals NHS Trust
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Sponsor organisation address |
Prescot Street, Liverpool, United Kingdom, L7 8XP
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Public contact |
RD&I research Governance Manager, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, 0151 7063320, lucy.read@liverpool.ac.uk
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Scientific contact |
RD&I research Governance Manager, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, 0151 7063320, lucy.read@liverpool.ac.uk
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Sponsor organisation name |
University of Liverpool
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Sponsor organisation address |
2nd Floor Block D Waterhouse Building, Liverpool, United Kingdom, L69 3GA
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Public contact |
Research Support Manager, University of Liverpool, 0151 7948739, Sponsor@liverpool.ac.uk
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Scientific contact |
Research Support Manager, University of Liverpool, 0151 7948739, Sponsor@liverpool.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 |
13 Sep 2019
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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 |
01 Aug 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 |
The primary endpoint of the study is the proportion of patients who lose MMR during the trial observation period of 37 months. BCR-ABL1 will be assessed by standard PCR based molecular monitoring on blood. This is a routine part of clinical follow-up, but will be carried out more frequently than usual. It is not expected that any patient will undergo more serious relapse than loss of MMR, so there are no formal plans for routine marrow examinations. MR4 and MMR patients will receive the same strategy, but will be analysed separately.
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Protection of trial subjects |
The study involved a de-escalation of patient's prescribed medication for CLL, followed by stopping of their medication. As part of analysis, and as a continuous indication of patient health, monthly bloods were taken and analysed for relapse.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jun 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 |
United Kingdom: 174
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Worldwide total number of subjects |
174
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EEA total number of subjects |
174
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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) |
111
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From 65 to 84 years |
62
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85 years and over |
1
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Recruitment
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Recruitment details |
The trial opened to recruitment in December 2013 and closed in April 2015. Although the target number of patients was 168, 174 patients were enrolled in the study. This was due to ethical reasons as patients at different sites were still in the process of joining when the trial was approaching recruitment termination. | ||||||||||||||
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Pre-assignment
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Screening details |
A total of 336 patients were screened for the trial. Main reasons for decline included the commitment to monthly visits, the additional bone marrow test and reduction/cessation of treatment dose. Main reasons for exclusion included inadequate PCR lab results and higher or lower TKI doses than required. | ||||||||||||||
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Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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De-escalation | ||||||||||||||
Arm description |
- | ||||||||||||||
Arm type |
De-escalation | ||||||||||||||
Investigational medicinal product name |
Imatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
200mg once daily
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Investigational medicinal product name |
Nilotinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
200mg twice daily
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Investigational medicinal product name |
Dasatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
50mg once daily
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Period 2
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Period 2 title |
De-escalation
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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De-escalation | ||||||||||||||
Arm description |
- | ||||||||||||||
Arm type |
De-escalation | ||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 3
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Period 3 title |
Cessation
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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De-escalation | ||||||||||||||
Arm description |
- | ||||||||||||||
Arm type |
De-escalation | ||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: 4There were 6 patients (4 MMR and 2 MR4) that completed 12 months of de-escalation although they did not start cessation phase. The summaries in brackets refer to those patients. |
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
Baseline patients are summarised for the full cohort of 174 recruited patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
MMR
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
At least 3 molecular results over the preceding 12 months of registration, each with at least 10000 ABL1 control transcripts and BCR-ABL/ABL1 ratio of below or equal 0.1% (but above 0.01%).
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Subject analysis set title |
MR4
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
At least complete molecular remission MR4 (either (i) detectable disease ≤0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with ≥ 10,000 ABL or ≥ 24,000 GUS transcripts) for at least one year; at least three PCR-results with MR4 within the last year (+- 2 months) before study entry and no PCR-results > 0.01% during the same period.
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End points reporting groups
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Reporting group title |
De-escalation
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Reporting group description |
- | ||
Reporting group title |
De-escalation
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Reporting group description |
- | ||
Reporting group title |
De-escalation
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Reporting group description |
- | ||
Subject analysis set title |
MMR
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
At least 3 molecular results over the preceding 12 months of registration, each with at least 10000 ABL1 control transcripts and BCR-ABL/ABL1 ratio of below or equal 0.1% (but above 0.01%).
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Subject analysis set title |
MR4
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
At least complete molecular remission MR4 (either (i) detectable disease ≤0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with ≥ 10,000 ABL or ≥ 24,000 GUS transcripts) for at least one year; at least three PCR-results with MR4 within the last year (+- 2 months) before study entry and no PCR-results > 0.01% during the same period.
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End point title |
Relapse rate [1] | |||||||||
End point description |
The proportion of patients who can first de-escalate their treatment (to half the standard dose of their TKI) for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Losses to follow-up and complete withdrawals (prior experiencing relapse) from the trial are excluded from the number of available patients for analysis.
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End point type |
Primary
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End point timeframe |
Relapses are recorded from start of de-escalation phase until end of treatment cessation phase (3 years in total).
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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 website features do not allow the specify the primary endpoint analysis. No p-value was calculated but percentage estimate with 90% confidence interval, separately for the two subgroups. |
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Attachments |
Untitled (Filename: Primary Outcome.pdf) |
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| Notes [2] - Two patients withdrew consent. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Relapse on cessation | |||||||||
End point description |
Proportion of patients who can successfully de-escalate their treatment (to half the standard dose of their TKI), but who then lose MMR on complete TKI cessation.
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End point type |
Secondary
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End point timeframe |
Relapses occurred after the de-escalation phase within the treatment cessation phase (2 years in total).
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| Notes [3] - These are the number of patients who completed de-escalation without relapsing. [4] - These are the number of patients who completed de-escalation without relapsing. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Regain of MMR | |||||||||
End point description |
Proportion of patients who lose their MMR on de-escalation/stopping and regain MMR on resumption of their TKI.
Information on MMR recovery was not available on two patients (MR4 group) as they were censored shortly after relapse.
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End point type |
Secondary
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End point timeframe |
From point of relapse to regain of MMR or end of study.
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| Notes [5] - These is the number of patients who relapsed in MMR group. [6] - These is the number of patients who relapsed in MR4 group. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Molecular-free survival | ||||||||||||
End point description |
Molecular relapse-free survival (RFS); RFS is defined as the time from the first day of de-escalation to the date of confirmed loss of MMR (two consecutive BCR-ABL >0.1% IS).
For non-estimable values of median or lower/upper limit, the number zero has been used instead. The zeros and 10000000000 in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From start of de-escalation until end of cessation phase (3 years).
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Attachments |
Untitled (Filename: Figure3_KMPlot_RelapseFreeSurvival.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progression-free survival | ||||||||||||
End point description |
Progression-free survival (PFS); PFS is defined as the time from the first day of de-escalation to the date of progression to accelerated phase/ blast crisis or death from any cause (earliest occurrence)
Among the available data on progression, no disease progressions were experienced and only two patients died, both in MR4 group. One due to stenosis coronary atheroma and pulmonary heart disease with severe emphysema and the other because of ischaemic leg, after 35 and 3 months from starting de-escalation respectively. The number of events were too small and the analysis was not performed. The zeros in the value section are not informative.
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End point type |
Secondary
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End point timeframe |
From start of de-escalation to end of cessation phase.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall survival | ||||||||||||
End point description |
Overall survival (OS); OS is defined as the time from the first day of de-escalation to the date of death from any cause.
Only two patients died, both in MR4 group. One due to stenosis coronary atheroma and pulmonary heart disease with severe emphysema and the other because of ischaemic leg, after 35 and 3 months from starting de-escalation respectively. The number of events were too small and the analysis was not performed. The zeros in the value section are not informative.
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End point type |
Secondary
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End point timeframe |
From start of de-escalation phase to end of cessation phase.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Event-free survival | ||||||||||||
End point description |
Event-free survival (EFS); EFS is defined as the time from the first day of de-escalation to the date of confirmed loss of MMR, progression to AP/BC or death from any cause.
For non-estimable values of median or lower/upper limit, the number zero has been used instead. The zeros and 10000000000 in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From start of de-escalation to end of cessation phase.
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Attachments |
Untitled (Filename: Figure7_KMPlot_EventFreeSurvival.pdf) |
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Statistical analysis title |
Event-free survival | ||||||||||||
Statistical analysis description |
Estimates were calculated using Kaplan-Meier method. Median molecular-free survival estimate and 90% confidence intervals estimates are left blank where they were not estimable.
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Comparison groups |
MMR v MR4
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | ||||||||||||
P-value |
≤ 0.001 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
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| Notes [7] - A formal test was performed to assess if there was any statistically significant difference between MMR and MR4. |
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End point title |
Time to MMR recovery | ||||||||||||
End point description |
Time to MMR recovery (TTR); TTR is defined as the time from the date of confirmed loss of MMR to the date of MMR recovery.
Information on MMR recovery was not available on two patients (MR4 group) as they were censored shortly after relapse.
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End point type |
Secondary
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End point timeframe |
From relapse to restoration of MMR or end of study.
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Attachments |
Untitled (Filename: Figure8_CumInc_MMR.pdf) |
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| Notes [8] - These is the number of patients that relapsed in MMR group. [9] - These is the number of patients that relapsed in MR4 group. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Proportion of Mr4.5 prior study entry | |||||||||
End point description |
Proportion of MMR and MR4 patients in confirmed MR4.5 prior to entering the study.
Patients were evaluable for MR4.5 status if their most recent results prior entering the study showed at least 31,623 ABL1 control transcripts. Patients fulfilling this criteria with BCR-ABL ≤ 0.0032% IS were then considered as MR4.5 whereas patients fulfilling this criteria but with BCR-ABL > 0.0032% were considered as not MR4.5.
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End point type |
Secondary
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End point timeframe |
Prior patients being registered in the study.
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| Notes [10] - These are the number of patients evaluable. [11] - These are the number of patients evaluable. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Quality of life - EQ index | ||||||||||||
End point description |
EQ-index Score range: 0 – 100 (0: worst possible score, 100: best possible score)
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From baseline until end of cessation phase.
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Attachments |
Untitled (Filename: Figure9_EQ_index.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Quality of Life - EQ VAS | ||||||||||||
End point description |
EQ-VAS Score range: 0 – 100 (0: worst possible score, 100: best possible score).
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From baseline until end of cessation phase.
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Attachments |
Untitled (Filename: Figure10_EQ_VAS.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Quality of Life - FACT-BRMTOI | ||||||||||||
End point description |
FACT-BRMTOI Score range: 0 – 106 (0: worst possible score, 106: best possible score)
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
EQ-VAS Score range: 0 – 100 (0: worst possible score, 100: best possible score)
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Attachments |
Untitled (Filename: Figure11_FACT_BRMTOI.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Quality of Life - FACT-G | ||||||||||||
End point description |
FACT-G Score range: 0 – 106 (0: worst possible score, 106: best possible score)
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From baseline to end of cessation phase.
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Attachments |
Untitled (Filename: Figure12_FACT_G.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Quality of Life - FACT-BRM | ||||||||||||
End point description |
FACT –BRM Total Score range: 0 – 160 (0: worst possible score, 160: best possible score)
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Secondary
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End point timeframe |
From baseline to end of cessation phase.
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Attachments |
Untitled (Filename: Figure13_FACT_BRM.pdf) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
TKI related symptoms | |||||||||
End point description |
Data regarding TKI withdrawals-related symptoms.
Results were analysed over time not through a single estimate. The zeros in the results below are not informative, please see attachment instead.
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End point type |
Other pre-specified
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End point timeframe |
From baseline to the end of cessation phase.
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Attachments |
Untitled (Filename: Figure15_TKI_plot.pdf) |
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| No statistical analyses for this end point | ||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
From the date of informed consent until 28 days after last dose of treatment received in the de-escalation phase (or longer if felt to be a long-term side effect of trial treatment).
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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 |
Safety set
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Reporting group description |
All patients who received any trial treatment (started of de-escalation). Non-serious adverse events were not recorded in this trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Non-serious adverse events were not recorded for this study. |
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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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03 Feb 2014 |
• Clarification that reporting of molecular results should be to International Standard where possible and that potential patients without a standard BCR-ABL1 fusion transcript only may be eligible to participate.
• The criterion that excludes patients with previous higher than standard dose has been modified to include an exception to allow higher dose patients that participated in specific studies to be included as they do not demonstrate resistant disease.
• Clarification that patients who are already being treated with lower doses for tolerance reasons are allowed, providing their current dosage it at least 50% of the defined standard dose.
• Running order of exclusion criteria changed as result of the changes to allow a better reading ‘flow’.
• Clarification that samples should continue to be collected for relapsed patients until the molecular result at study entry is regained.
• Rewording for clarity of the primary endpoint.
• The line on there being no routine marrow examinations removed.
• Sample section has been updated so only patients recruited and treated at the Royal Liverpool Hospital are requested to provide blood samples for sending to the Liverpool labs.
• Sample collection time-points clarified and receptacles to be used, plus kits that are provided have been updated
• Additional samples from diagnostic blood tests being sent to Hammersmith has been updated to include all patients, rather than just those from the MR4 group, and clarified in the samples table.
• Accountability Procedures for Trial Treatment section has been re-written to confirm that the Trial is a ‘Type A’ and that no accountability is required.
• Confirmation that other treatment supply practices are allowed if the PI approves.
• Post month 37 PCR results (i.e. local) also being required has been added to this section
• Confirmation that enrolment to each molecular group will cease when its required number is reached added. |
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18 Dec 2014 |
Molecular Grouping:
• Deletion of statement ‘Enrolment to each molecular group will cease once the required number of patients for that particular group has been reached.’
• Reference to 2 equal groups of 84 MMR and MR4 patients removed throughout and replaced with 1 group of 168 MMR and MR4.
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16 Jan 2015 |
• Clarification that the central analysis definition of MMR is a BCR-ABL1/ABL1 ratio of ≤0.1% to International Standards (IS)
• Clarification that samples should continue to be collected for relapsed patients until MMR is regained
• Addition of extra medical expert who will assess SAE reports
• Exclusion criterion expanded to cover prior use of interferon
• ‘Objectives’ renamed ‘Outcomes’ and the secondary outcomes expanded
• Clarification that the study is a phase IIb
• Duplicated inclusion and exclusion criteria replaced with instruction to refer to the same in the protocol summary. Section numbering altered as a result.
• Updated to allow emailed registrations.
• Quantity of marrow tissue required updated to 1-2ml in table 1 to be consistent with rest of section
• Clarification that month 37 or relapse marrow samples should still be requested even if a baseline one wasn’t available, and that the quantity of marrow should be taken according to local practice
• Section re-worded for clarity and reference to ‘Type A’ trial removed as this is covered in the risk assessment section of the protocol.
• Clarified throughout that molecular monitoring is reported to international standards and not just where possible, and that samples should continue to be collected for relapsed patients until MMR is regained
• Schedule of trial procedures updated to include Hammersmith alert procedures and weight measurement requirement at all post screening visits
• Baseline marrow window extended to 1 calendar month prior to the commencement of de-escalation
• Table legend updated accordingly
• Addition to clarify that baseline samples are not included in the establishing of relapse
• Updated to include the reclassification of MR4 patients for statistical analysis purposes, plus rationale of same. Update to sample size.
• Update to analysis plan.
• Clarification and expansion in pharmacovigilance section.
• Risk assessment categories replaced.
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04 Jul 2016 |
• Update to protocol summary diagram.
• Changes to wording in overall design.
• Schedule of procedure updated to include relapse procedures.
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22 Mar 2017 |
• Update to diagram in protocol summary.
• Removal of bone marrow and 30mls blood at month 37. Addition of follow-up patients after month 37.
• Correction to references to Reference Safety Information.
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28 May 2018 |
• Removal of one secondary endpoint.
• Updated to contact details.
• Updated references to SmPCs. Clarified processes for non-protocol dosing. Removed wording relating to licenced indication, dosage and form. Confirmed method of dose reduction. |
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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 | |||
