Clinical Trial Results:
Treatment of newly diagnosed moderate or severe chronic graft-versus-host disease with prednisone and everolimus (PredEver first)
- A prospective multicenterphase IIA study -
Summary
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EudraCT number |
2011-004847-35 |
Trial protocol |
DE |
Global end of trial date |
07 Feb 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jan 2022
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First version publication date |
22 Jan 2022
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Other versions |
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Summary report(s) |
Clinical study report Synopsis |
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 |
PredEver_first
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Universitätsklinikum Hamburg Eppendorf
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Sponsor organisation address |
Martinistrasse 52, Hamburg, Germany, 20246
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Public contact |
Coordinating Investigator, University Medical Center Hamburg-Eppendorf, 0049 407410 55250, ayuketang@uke.de
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Scientific contact |
Coordinating Investigator, University Medical Center Hamburg-Eppendorf, 0049 407410 55250, ayuketang@uke.de
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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 |
31 Mar 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Feb 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Feb 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 main objective of this study is to investigate the clinical benefit of treatment with prednisone and everolimus in patients with chronic GVHD.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good
Clinical Practice (GCP) regulations/guidelines, the general principles indicated in the Declaration of
Helsinki, and all applicable regulatory requirements. Prior to study initiation the study protocol was
reviewed and approved by an Independent Ethics Committee (IEC). The study, all study procedures and
the risks and benefits were explained to the subjects by responsible investigators and written informed
consent were collected prior to any study related examinations.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
06 Mar 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 36
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Worldwide total number of subjects |
36
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EEA total number of subjects |
36
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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) |
28
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From 65 to 84 years |
8
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at nine sites in Germany. The sites were loated at (university) hospital's departments of stem cell transplantation, internal medicine or hematology. Patient recruitment was performed on sites by trained investigators who provided written and verbal information before obtaining written informed consent. | ||||||||||||||||||
Pre-assignment
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Screening details |
Written informed consent before any study specific medical procedures, inclusion/exclusion citeria check, laboratory screening assessments, medical history and prior/concomitant medication recording, comprehensive assessment of organ involvement i.e. CGvHD disease status according to NIH criteria. Screening period = 14 days | ||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
38 [1] | ||||||||||||||||||
Number of subjects completed |
36 | ||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Screening failures: 2 | ||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 38 patients were consented and started the study screening, 2 patients were screening failures and did not enter the treatment period. 36 patients were enrolled for treatment. |
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Period 1
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Period 1 title |
overall trial (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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first line Prednisolon + Everolimus Treatment (PredEver first) | ||||||||||||||||||
Arm description |
In this single-arm study patients were allocated to combination therapy with prednisone and everolimus. After diagnosis of cGvHD patients received prednisone 1 mg/kg BW once daily in the morning (orally or I.V.) and everolimus 0.75 mg twice daily orally (targeted trough level 3-8 μg/l). In patients with abnormal liver function test results, the initial dose of everolimus was 0.25 mg twice daily. Depending on the patients's response (CR or PR) prednisone dose tapering was performed. Dose adjustments of everolimus were performed according to clinical judgement of the local physician. Patients were treated on the protocol for a maximum of 12 months. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Prednisone (merchandise)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
5 mg / 20 mg / 50 mg (merchandise), orally or intravenous, initial prednisone dose was 1 mg/kg body weight once daily in the morning for at least two weeks.
stepwise tapering upon CR: duration of each step 2 weeks (1.0 mg to 0.3 mg) or 4 weeks (0.2 mg - 0 mg), Steps: 1.0 mg, 0.8 mg, 0.6 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, 0.05 mg (every other day), 0.025 mg (every other day), 0 mg.
In case of flare, tapering may be halted or prednisone increased two to three steps back.
Stepwise tapering upon PR: Duration of each step 2 weeks (1.0 mg to 0.6 mg), 3 weeks (0.5 mg to 0.4 mg) or 4 weeks (0.3 mg – 0.05 mg [every other day])
Steps: 1.0 mg, 0.8 mg, 0.6 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, 0.05 mg (every other day).
In case of flare, tapering may be halted or prednisone increased two to three steps back.
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Investigational medicinal product name |
Everolimus
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Investigational medicinal product code |
RAD001
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Other name |
Certican
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
0.25 mg / 0.50 mg / 0.75 mg / 1.00 mg (provided by Novartis Pharma GmbH)
Whole tablets or dispersible tablets were admimistered, initial dose was 0,75 mg twice daily. The dose should have been adjusted to a
targeted trough serum level of 3-8 μg/l, measured by HPLC or immunoassay four to five days after the previous dose change. Dose adjustment was according to clinical judgement of the local physician depending on co-medication, toxicity and serum levels.
In patients with abnormal liver function test results, the initial dose of everolimus was 0.25 mg twice daily. Close monitoring of serum levels at start of treatment and after any dose change was performed for 2 weeks (twice weekly). Increment of daily dose should not have surpassed 0.5 mg within one week.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
first line Prednisolon + Everolimus Treatment (PredEver first)
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Reporting group description |
In this single-arm study patients were allocated to combination therapy with prednisone and everolimus. After diagnosis of cGvHD patients received prednisone 1 mg/kg BW once daily in the morning (orally or I.V.) and everolimus 0.75 mg twice daily orally (targeted trough level 3-8 μg/l). In patients with abnormal liver function test results, the initial dose of everolimus was 0.25 mg twice daily. Depending on the patients's response (CR or PR) prednisone dose tapering was performed. Dose adjustments of everolimus were performed according to clinical judgement of the local physician. Patients were treated on the protocol for a maximum of 12 months. |
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End point title |
Proportion of patients with treatment success at 6 months [1] | ||||||||
End point description |
Treatment success was defined as: Patient being alive and having achieved a CR or PR of cGvHD without addition of secondary systemic treatment for cGvHD and without development of relapse of underlying disease after 6 months from treatment first intake. Addition of any immunosuppressive or immunomodulatory systemic therapy aimed at treating or controlling symptoms of cGvHD is considered treatment failure.
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End point type |
Primary
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End point timeframe |
start of treatment till week 24 (6 months)
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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: descriptive analysis for rate of treatment success at 6 months was performed for primary endpoint |
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Notes [2] - final analysis |
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No statistical analyses for this end point |
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End point title |
Overall survival rate | ||||||||
End point description |
Proportion of patients experiencing death
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End point type |
Secondary
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End point timeframe |
from time of enrollment until end of follow-up.
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Notes [3] - final analysis |
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No statistical analyses for this end point |
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End point title |
Time to response (speed of first response) | ||||||||
End point description |
Speed of first response was defined as the weeks between the date of first study medication intake and the date of visit at which the first response (either CR or PR) occurred. Subjects without a response or who are discontinued before having it were considered as “censored” at the date of end of study.
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End point type |
Secondary
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End point timeframe |
Start of treatment until date of visit at which the first response occurred (evaluation until month 12 visit)
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Notes [4] - final analysis |
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No statistical analyses for this end point |
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End point title |
Time to treatment failure | ||||||||
End point description |
Treatment failure being defined as progression of cGvHD after ≥ 2 weeks in any organ, lack of response (CR/PR) after 12 weeks and/or addition of secondary systemic treatment for cGvHD. Subjects without an event or who are discontinued before having it were considered as “censored” at the date of end of study.
The revised analysis set only body systems eye, genitalia, gastrointestinal tract, joints, liver, mouth and skin were considered for the evaluation of ‘progression of cGvHD after or at two weeks in any organ’. Eosinophilia, oesophageal involvement and myositis were not considered.
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End point type |
Secondary
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End point timeframe |
start of treatment until two weeks (progression of cGvHD) and/or until twelve weeks (lack of response) and/or untill addition of secondary systemic treatment for cGVHD
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Notes [5] - final analysis |
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No statistical analyses for this end point |
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End point title |
Proportion of patients experiencing relapses | ||||||||
End point description |
This endpoint was the evaluation of the relapse rate of underlying malignancies of patients treated with prednisone and everolimus for cGvHD and was evaluated in the form of proportion of patients with relapses from enrollment until end of follow up.
Patients discontinuing treatment prematurely or discontinuing treatment phase for reasons other than a recurrence of malignancies were censored at the date of study discontinuation.
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End point type |
Secondary
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End point timeframe |
from start of treatment (enrollment) until end of follow up phase ( 1 year treatment + 1 year Follow-up)
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Notes [6] - final analysis |
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No statistical analyses for this end point |
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End point title |
Proportion of patients showing pre-defined side effects | ||||||
End point description |
This endpoint was the assessment of adverse events including the side effects of prednisone and everolimus in patients with cGvHD, with particular attention to the incident rates of thrombotic microangiopathy (TMA), non-infectious pneumonitis (NIP) and avascular osteonecrosis.
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End point type |
Secondary
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End point timeframe |
start of treatment until end of treatment
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Notes [7] - final analysis |
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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 AEs were collected from the time point of signed inform consent.
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Adverse event reporting additional description |
Primary analysis of safety was performed with the safety population, which included 36 patients. As 2 patients deemed screening failures retrospectively, received the study drug, it was decided to include also these patients in the safety analysis.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
first line Prednisolon + Everolimus Treatment (PredEver first)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0.05% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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22 May 2013 |
Subject of the first amendment was to simplify clinical trial routines as well as to correct minor inconsistencies in the protocol. A Data Safety Monitoring Board (DSMB) was created to ensure the safety of the participants, details concerning dose modification and concomitant medication were added, visit schedule was amended by safety visits for additional physical examination, clinical lab tests
and concomitant medication. Adaption of assessment of skin manifestation of cGvHD biopsy which was allowed to be organized as per local routine (a central review could still be arranged by each site), and adaption of adverse event documentation. |
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30 Jan 2014 |
Subject of the second amendment was to simplify clinical trial routines as well as to correct minor inconsistencies in the protocol. The number of centers was increased, the duration of the study was prolonged by one year, exclusion criteria 11 was clarified and CNI tapering was prolonged from 1 - 3 to 1 - 4 weeks. |
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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 |