Clinical Trial Results:
“Ibrutinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP for the treatment of elderly patients (age 61-80 years) with CD20+ diffuse large B-cell lymphoma, IPI ≥ 2”
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Summary
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EudraCT number |
2015-003429-32 |
Trial protocol |
DE AT |
Global end of trial date |
12 Nov 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Oct 2025
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First version publication date |
30 Oct 2025
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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 |
ImbruVeRCHOP-Trial
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03129828 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité - Universitätsmedizin Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
Dr. med. Sophy Denker, M.D., Campus Virchow Clinicum (CVK), Hematology, Oncology and Tumor Immunology, +49 30450 653 569, sophy.denker@charite.de
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Scientific contact |
Prof. Dr. Clemens Schmitt, Campus Virchow Clinicum (CVK), Hematology, Oncology and Tumor, +49 30450 553 896, clemens.schmitt@charite.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 |
29 Nov 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Nov 2024
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Nov 2024
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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 clinical trial is to assess the efficacy of the treatment determined as the 2-year PFS for patients with DLBCL. The regimen will be considered unacceptable if ≤ 60 % of patients (i.e. ≤ 36 patients in a cohort of 60 patients) are progression-free at 2 years. With this decision rule, the regimen will be correctly rejected with at least 95% power if true 2-year PFS rate falls below 50%. If true 2-year PFS rate is 75%, the treatment will be rejected erroneously with a 0.007 probability. “Responders” (i.e. patients achieving a CR or a PR) vs. “Non-Responders” are based on the Revised Response Criteria for Malignant Lymphoma.
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Protection of trial subjects |
Following the principles of Good Clinical Practice and according to international (European) and German law the sponsor established a system to detect any safety signal and to take appropriate measures to protect patient’s safety. An immediate reaction to any risk given by the drug or the conduct of the trial is guaranteed.
The DSMB monitored the conduct of the study and the safety aspects of the trial on a regular basis, and had given recommendations to the sponsor whether to stop the trial or to change the trial protocol and have to decided about possible dose reductions of Ibrutinib and/or Bortezomib, especially during the safety run-in phase, if necessary.
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Background therapy |
Diffuse large B-cell lymphoma (DLBCL) account for about 30% of all Non-Hodgkin’s lymphoma (NHL) and 80% of aggressive NHL, and, thus, reflect the most frequent type of malignant lymphoma. The CHOP regimen (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) has been the standard of care for DLBCL since several decades, producing cures in about half of the patients. Given the still unsatisfying treatment results in DLBCL in general, and the particularly poor outcome in ABC DLBCL, there is urgent medical need to improve the current standard of care, i.e. R-CHOP-like immunochemotherapy, for the entire population of DLBCL patients, or, at least, a molecularly defined subset of patients at particular risk that would selectively benefit from this novel therapeutic concept. Addition of Bortezomib (Velcade®), the clinically approved first-in-class inhibitor of the proteasome with significant activity in multiple myeloma, may have the potential to contribute to this goal in the DLBCL arena.Another novel agent of interest is Ibrutinib (Imbruvica®; a.k.a. PCI-32765), an inhibitor of the Bruton’s Tyrosine Kinase (BTK), a signal mediator fairly upstream in the BCR/NF-B signaling cascade. For the treatment of DLBCL, ibrutinib is not yet approved. Based on the hypothesis that the combined addition of Ibrutinib and Bortezomib to R-CHOP may improve the outcome of those patients even further, we introduce here Ibrutinib-Bortezomib-Rituximab-CHOP (I-B-R-CHOP) – hereafter referred to as “ImbruVeRCHOP” – as an innovative study design that augments the standard. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Mar 2017
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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 |
Austria: 7
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Country: Number of subjects enrolled |
Germany: 31
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Worldwide total number of subjects |
38
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EEA total number of subjects |
38
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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) |
3
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From 65 to 84 years |
35
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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 8 study sites in Germany and in 4 study sites in Austria, between 17/03/2017 and 12/11/2024. | ||||||||||
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Pre-assignment
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Screening details |
The study was designed as a single-arm, open, prospective, multi-center, phase I/II study. Concept with no molecular pre selection for patients with newly diagnosed DLBCL, 61-80 years, higher risk profile IPI ≥ 2, good fitness level and available lymphoma lesions for re-biopsy. | ||||||||||
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Period 1
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Period 1 title |
Treatment group (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 | ||||||||||
Blinding implementation details |
no blinding
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Arms
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Arm title
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Treatment group | ||||||||||
Arm description |
The study was designed as a single-arm, open, prospective, multi-center, phase I/II study. Concept with no molecular pre selection for patients with newly diagnosed DLBCL, 61-80 years, higher risk profile IPI ≥ 2, good fitness level and available lymphoma lesions for re-biopsy. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Ibrutinib
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Investigational medicinal product code |
CAS 936563-96-1
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Other name |
Imbruvica
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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 |
During the reporting period, new findings on toxicity, reduced treatment adherence and poorer outcome were published in the PHOENIX study (NCT01855750). In the study, patients of a DLBCL subtype were randomized with ibrutinib plus R-CHOP against R-CHOP.
Because of those safety concerns related to the combination of the standard treatment R-CHOP with Ibrutinib, an adjustment of the dose of ibrutinib was made accordingly. Originally the patients received 560 mg of Ibrutinib. The dose was reduced to 420 mg on the 14th of July 2018.
patients received 420 mg (3 x 140 mg capsules) orally once a day, starting at Cycle 1, day d6 until cycle 6, d21
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Investigational medicinal product name |
Bortezomib
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Investigational medicinal product code |
CAS 179324-69-7
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Other name |
Velcade
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Bortezomib s.c. (1.3 mg/m2 C1 on d3 and d8, all other cycles d1 and d8) have been administered subcutaneously (at a concentration of 2.5 mg/ml)
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Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
Rituxan, anti-CD20 antibody
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
(375 mg/m2) was administered i.v. between 24 and 2 hours prior to start of CHOP (d0 or d1). Rituximab was administered 6 times synchronously with CHOP-21 (C1-6). Two additional 3-week cycles were administered after completion of CHOP-21 (C7-8). Patients received premedication consisting of Paracetamol (1,000 mg p.o.) and antihistamines (e.g. Dimetindenmaleat 4 mg i.v.) 30-60 minutes prior to the application of Rituximab. Rituximab was administered intravenously at an initial rate of 50 mg/hr.
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Investigational medicinal product name |
CHOP-21
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Investigational medicinal product code |
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Other name |
CYCLOPHOSPHAMIDE-DOXORUBICIN-PREDNISOLONE-VINCRISTINE (21)
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Pharmaceutical forms |
Infusion, Injection, Coated tablet
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Routes of administration |
Intravenous bolus use , Intravenous use, Oral use
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Dosage and administration details |
6 cycles - Cyclophosphamide i.v.,- infusion(750 mg/m2 d1); Doxorubicin; i.v. -infusion(50 mg/m2 d1), Vincristine 1 mg absolute, i.v. bolus, d1; Prednisone (100 mg absolute p.o. d1-5) as the standard of care for DLBCL.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment group (overall trial)
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Reporting group description |
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End points reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
The study was designed as a single-arm, open, prospective, multi-center, phase I/II study. Concept with no molecular pre selection for patients with newly diagnosed DLBCL, 61-80 years, higher risk profile IPI ≥ 2, good fitness level and available lymphoma lesions for re-biopsy. | ||
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End point title |
2-year progression-free survival (PFS) [1] | ||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Primary endpoint is the 2-year progression-free survival (2-year PFS) of DLBCL patients, calculated from d1 of C1 up to 40 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: The static analysis could not be entered because the study was only one-armed. The primary and secondary endpoints can be viewed as graphs in the charts. |
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Attachments |
Untitled (Filename: Results_EudraCT 2015-003429-32.pdf) |
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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 start of treatment until end of follow-up
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Adverse event reporting additional description |
AEs: Grade 1-2 and Grade 3-4 were documented in summary form.
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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 |
4.0
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Reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 Feb 2017 |
- update protocol V1.8 08-11-2016, Changes in interpretation of scientific documents/value of the trial |
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26 May 2017 |
- updated IBs: Investigators Broschure from Janssen-Cilag International Ibrutinib Ed 10, dated 29/08/2016; Ed 10.1,dated 08/12/2016; Ed 10.2 dated 03/02/2017 |
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15 Aug 2017 |
- addition of a new site (Würzburg) |
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28 Aug 2017 |
- addition of a new site (Freiburg) |
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19 Oct 2017 |
- addition of a new site at Campus Mitte Charité Berlin |
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26 Feb 2018 |
- addition of a new site (Frankfurt am Main) |
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13 Jun 2018 |
- updated version of IB of ibrutinib (Imbruvica) (Ed.11), new PICF, Adaption of the PICF due to the General Data Protection Regulation 2016/679 |
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05 Oct 2018 |
- update protocol V1.9_09/08/2018, The dosage of the IMP Ibrutinib has been changed from 560 mg p.o. to 420 mg p.o. daily, new document: PICF Pre-Sreening |
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21 May 2019 |
- addition of 4 new sites (Kiel/Luebeck/Marburg/Neumuenster) |
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14 Aug 2020 |
- update protocol V2.0 dated 02/06/2020, new nonclinical and clinical data; extension of the duration of the clinical trial due to problems in patient recruitment |
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12 May 2021 |
-update protocol V2.4 dated 30/12/2020 (inclusion criteria), update IB and SmPCs |
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23 May 2022 |
- update Investigator’s Brochure (V15 dated 10/12/2021) |
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21 Sep 2022 |
- update protocol V2.6 dated 29/08/2022, new recommendations to Ibrutinib dose modifications in case of cardiac failure ore cardiac arrhythmias |
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08 Dec 2022 |
-update protocol V2.7 dated 07/11/2022, extension of the study duration, PICF V 1.4.7 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/31903182 http://www.ncbi.nlm.nih.gov/pubmed/34414850 |
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