Clinical Trial Results:
Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for initial therapy of Waldenstrőm macroglobulinaemia: a randomised phase II study.
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Summary
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EudraCT number |
2011-005156-34 |
Trial protocol |
GB |
Global end of trial date |
02 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Aug 2021
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First version publication date |
20 Aug 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
UCL/11/0353
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01592981 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
Haematology Trials Group, Cancer Research UK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
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Scientific contact |
Haematology Trials Group, Cancer Research UK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Aug 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Aug 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Aug 2020
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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 |
This was a Phase II trial of bortezomib / cyclophosphamide / rituximab (BCR) in initial therapy of Waldenstrom's Macroglobulinaemia (WM). The overall aim was to make a preliminary examination of the safety and efficacy of the proposed BCR combination in patients with symptomatic, previously untreated WM and determine whether BCR warrants further investigation in a randomised phase III setting.
During the first non-randomised stage of the trial, the number and severity of adverse events experienced by patients treated with BCR were analysed.
Only when the BCR combination was considered tolerable (as defined in the study protocol), the trial continued to a randomised second stage where efficacy of BCR was assessed in terms of response to treatment and a second arm of fludarabine, cyclophosphamide and rituximab (FCR) was added to the design. The two arms were randomised in a 2:1 ratio.
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Protection of trial subjects |
The risks to the safety of the trial subjects were those generally associated with chemotherapy. With limited published data on the BCR combination of drugs in WM, a safety run-in phase was designed to assess the safety and tolerability of the regimen. This included 6 patients with regular monitoring of the laboratory and safety data. A formal review followed after the 6th patient reached day 1 of the second treatment cycle. The IDMC confirmed the study could continue with the laboratory and safety data continuing to be monitored regularly by trials unit staff and the TMG, with an annual review by the IDMC. The protocol contained specific instructions regarding clinical assessments for potential side effects, including neuropathy, and resultant dose modifications, or cessation of treatment. The protocol also had instructions on medications that should be used with caution and those that could be prescribed for specific conditions at the discretion of the treating physician.
Patients were counselled about the potential side effects prior to starting treatment. Pregnant or lactating women were excluded from the study. Women of childbearing potential and male patients were informed they must use an effective form of contraception during the course of the study.
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Background therapy |
Supportive care for this study was as per local guidelines with the following recommendations: • Aciclovir prophylaxis should be given whilst patients are receiving treatment because of the increased incidence of herpes zoster infection reported in patients treated on a similar regimen • Anti-emetic prophylaxis is recommended for at least 5 days with a 5 HT3 antagonist • Allopurinol is advised for the first cycle of therapy | ||
Evidence for comparator |
There is no agreed standard on first-line therapy of WM but a consensus panel of international experts has provided treatment recommendations based on the most recently published clinical trial results. Combination therapy of rituximab with purine analogues with or without alkylators or with cyclophosphamide based therapies have been recommended in the front-line setting with comparable response rates for both Fludarabine, Cyclophosphamide, Rituximab (FCR) and Dexamethasone, Rituximab, Cyclophosphamide (DRC). Within the UK, experience is greatest with FCR which is favoured by the participating centres as the non-comparative control arm following the results of a national survey. | ||
Actual start date of recruitment |
01 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 60
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Worldwide total number of subjects |
60
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EEA total number of subjects |
0
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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) |
23
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From 65 to 84 years |
36
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85 years and over |
1
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Recruitment
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Recruitment details |
The 60 trial subjects were recruited between 20/02/2013 and 04/09/2015 from 24 trial hospitals. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Treatment-naïve patients with symptomatic WM were enrolled. Patients aged ≥18 years with a confirmed diagnosis of WM according to World Health Organisation (WHO) criteria and ECOG Performance Status 0-2 were included. | ||||||||||||||||||||||||
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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 |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BCR (experimental) arm | ||||||||||||||||||||||||
Arm description |
BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Bortezomib
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Investigational medicinal product code |
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Other name |
Velcade
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
1.6 mg/m2.
- Based on body surface area (BSA) calculated using actual body weight according to local policy
- Calculated prior to each cycle and remained the same throughout each cycle and if a patient experienced a notable change in weight (e.g. loss or gain of 8lbs or 3.6kg or 5% change in weight) within a cycle
Administration:
Suggested anatomical areas were the thighs or abdomen and injection sites were rotated within a treatment cycle.
Intravenous bortezomib administration was allowed if a patient did not tolerate subcutaneous administration (e.g. >grade 2 local reaction). The change of administration route would have been approved by the Chief Investigator. Patients who switched to the IV route maintained this route for the remaining treatment.
Where bortezomib needed to be administered intravenously, the most recent SPC was checked for details on diluent, volume, duration of infusion, stability and storage of bortezomib.
Schedule:
Days 1, 8 and 15 of each cycle
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Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet, Powder for solution for injection
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Routes of administration |
Oral use, Intravenous use
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Dosage and administration details |
250mg/m2 - based on BSA calculated using actual body weight according to local policy
Administration:
Oral
If the oral preparation of cyclophosphamide is not tolerated this can be given intravenously at the same dose (250 mg/m2).
Schedule:
BCR (experimental) arm: days 1, 8 and 15 of each cycle
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Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
375mg/m2
Administration:
i.v infusion
If the IgM paraprotein is ≥ 50g/L at the time of the first treatment, prophylactic use of plasmapheresis is recommended before the administration of rituximab because of the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity.
If the IgM paraprotein is ≥ 50g/L but plasmapheresis is not available, Rituximab administration should be delayed to cycle 3 and 6.
Administration of rituximab including pre-medications (paracetamol, anti-histamines, steroids) and infusion rates during the first and subsequent infusions are according to the site local guidelines and policies.
Rituximab must not be administered as an intravenous bolus injection.
Schedule:
days 1, 8, 15 and 22 of cycles 2 and 5 only
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Arm title
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FCR (control) arm | ||||||||||||||||||||||||
Arm description |
Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Fludarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
40mg/m2
Based on BSA calculated using actual body weight according to local policy.
Administration:
Oral
If the oral preparation of fludarabine is not tolerated this can be given intravenously at 25 mg/m2.
Schedule:
days 1, 2 and 3 of each cycle
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Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
250mg/m2 - based on BSA calculated using actual body weight according to local policy
Administration:
Oral
If the oral preparation of cyclophosphamide is not tolerated this can be given intravenously at the same dose (250 mg/m2).
Schedule:
BCR (experimental) arm: days 1, 8 and 15 of each cycle
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Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
375mg/m2
Administration:
i.v infusion
If the IgM paraprotein is ≥ 50g/L at the time of the first treatment, prophylactic use of plasmapheresis is recommended before the administration of rituximab because of the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity.
If the IgM paraprotein is ≥ 50g/L but plasmapheresis is not available, Rituximab administration should be delayed to cycle 3 and 6.
Administration of rituximab including pre-medications (paracetamol, anti-histamines, steroids) and infusion rates during the first and subsequent infusions are according to the site local guidelines and policies.
Rituximab must not be administered as an intravenous bolus injection.
Schedule:
days 1, 8, 15 and 22 of cycles 2 and 5 only
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
Patient Inclusion Criteria -Age ≥ 18 years -Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein -Previously untreated disease at any stage requiring therapy -Performance status grade 0 - 2 -Life expectancy of greater than 6 months -Informed consent -Agreed compliance with recommended contraceptive precautions where appropriate Exclusion Criteria -Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein -Severe pre-existing neuropathy (> grade 2) -Autoimmune cytopenias -Evidence of active Hepatitis B or C infection -Serological positivity for HIV -Pregnant or lactating women -Life expectancy severely limited by other illness -Diagnosed or treated for a malignancy other than WM within 5 years -Renal failure -Severe impairment of liver function -Concurrent treatment with another investigational agent -Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BCR (experimental) arm
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Reporting group description |
BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | ||
Reporting group title |
FCR (control) arm
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Reporting group description |
Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | ||
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End point title |
Overall response rate [1] | |||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline to end of treatment
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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: This endpoint is the number/proportion of patients in each of the response categories. No specific statistical analyses are required to establish the percentage of patients. This can be calculated using the number of patients who were in the trial and the number of patients in each response category. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Speed of response | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Start of treatment to 25% reduction (minor response) in serum IgM
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progression free survival | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to two and three year follow up
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Time to next treatment | |||||||||
End point description |
Number of patients receiving further treatment within 61.2 months
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End point type |
Secondary
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End point timeframe |
Baseline to a median follow up of 61.2 months
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| No statistical analyses for this end point | ||||||||||
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End point title |
Toxicity | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to End of Trial
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Overall surivival | |||||||||
End point description |
Number of patients who died
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End point type |
Secondary
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End point timeframe |
Baseline to End of Trial
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| No statistical analyses for this end point | ||||||||||
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End point title |
Quality of life | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to End of Trial
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Duration of response | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Response to two or three year follow up
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| No statistical analyses for this end point | ||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All adverse events, and all serious adverse events (SAEs), that occurred between informed consent and 30 days post last trial treatment administration (or after this date if thought to be related to trial treatment) had to be reported.
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Adverse event reporting additional description |
Adverse events were recorded in the patient notes and trial Case Report Forms. Those meeting the definition of a Serious Adverse Event were also reported to UCL CTC using the trial specific SAE Report Form.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
NCI-CTCAE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
BCR (experimental) arm
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Reporting group description |
BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
FCR (control) arm
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Reporting group description |
Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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11 Jan 2013 |
Documents updated:
Protocol v2.0 30/11/2012
PIS-stage1 v2.0 30/11/2012
PIS-stage2 v2.0 30/11/2012
Pregnancy Monitoring IS (patient) v1 30/11/2012
Pregnancy Monitoring IS (partner) v1 30/11/2012
Pregnancy Monitoring IC (patient) v1 30/11/2012
Pregnancy Monitoring IC (partner) v1 30/11/2012
Main Changes:
Protocol - Details for patients who may need to switch to IV bortezomib added, removal of NHS number from sample label, clarification to analysis of 'speed and duration of response', list of expected AEs for sc bortezomib removed and replaced with reference to the current SPC as it covers both sc and iv administration, reference to bortezomib IB removed and replaced with current SPC
PIS:
- Section on bortezomib side effects expanded as requested by company supplying bortezomib
- Removal of statement regarding 'commercial use' of biological samples as this may be misleading
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13 Sep 2013 |
Documents updated: Protocol v3.0 08/08/2013
PIS-stage1 v3.0 08/08/2013
PIS-stage2 v3.0 08/08/2013
CTA
Main Changes:
Protocol - Paragraph clarifying whether interpreter may be required to be provided by the site to obtain informed consent
- Clarification that patients must be consented before any trial specific screening investigations are carried out
- Clarification that FBC can be performed 1 day before D1 and 8 of each cycle, and that patients in the FCR arm need checked only on D1 (or -1)
- Neutropenia changed from unusual to common side effect to reflect changes in the SPC
- Addition of optional plasma viscosity test for cycle 1-3
- Removing requirement for Sites to have written procedures for informing Sponsor of Serious Breaches
- Clarification to 'failure to start cycle 2 on time' when due to grade 3 or 4 heamatological toxicities
- Reducing number of blood samples to be sent to Leeds during treatment and follow up
- Serum samples for SFLC/ HeveyLite analysis to be sent to HMDS Leeds instead of Binding Site, Birmingham
- NHS number to be listed on biological sample label (if applicable)
- Clarification that either M protein or serum IgM can be used to assess changes in serum IgM level
PIS:
- Statement that Quality of Life questionnaire will be completed at 3 visits added
- Addition of PML as a rare side effect of bortezomib
- Details added to the paragraph on confidentiality that NHS numbers will be used
- Reference to the Binding Site in Birmingham removed |
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11 Apr 2014 |
Documents changed:
Protocol v4.0 18/02/2014
PIS-stage2 v4.0 18/02/2014
Main Changes:
Protocol - 1. Clarification that the Hep B serology tests include HBsAg, HBsAb and HBcAB; HBV DNA test required if HBcAb
result is positive (Prerandomisation
evaluation section 5.1 of protocol).
2. Details regarding rituximab administration (premedication, infusion rates during 1st and subsequent infusion)
removed and sites referred to their local policy (Treatment details section 7.3 Rituximab).
3. Addition that dose banding and dose capping for IMPs is allowed according to the site’s standard
practice’ (Treatment details section 7.3 of protocol).
4. Addition of details regarding ‘dose attenuation’ at treatment start for patients with cytopenia or PS=2 randomised
to FCR (Dose modifications section 7.4 of protocol).
5. Clarification on FBC timing during treatment (within 3 days of D1 and D8 of each cycle, repeated on the day if
abnormal) (sections 7.4.1 Haematological toxicity and 8.2 Assessments during treatment).
6. Clarification that nonhaematological
treatmentrelated
grade 3 or higher adverse events are used to assess the
toxicity rate (Interim analyses section 15.6 of protocol).
7. Correction of error in the ‘number of patients’ corresponding to toxicity rate of 20% in the second randomised
stage of the study (Interim analyses section 15.6 of protocol).
8. Addition of ‘febrile neutropenia’ and ‘fever’ to the list of expected AEs for the FCR regimen, and of ‘rituximab
related infusion reactions’ to the BCR arm (Expected Adverse Events Appendix 5 of protocol).
PIS:
1. Addition of 'hyperaemia' as uncommon side effect and of thrombocytosis, amyloidosis, erythrosis, cough
syndrome, coma and multiorgan failure as rare side effects of bortezomib.
2. Addition of hypogammaglobulinaemia and increased risk of infection as a side effect of rituximab |
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24 Oct 2014 |
Documents updated:
PIS
RSI update
Main changes:
PIS - Further information on rituximab side effects added
RSI - Cyclophosphamide SPC tablets changed from Pharmacia to the SPC from Baxter as the section on 'undesirable effects' in the latter contained a more comprehensive and detailed list of the known side effects using the System Organ Class and frequency
- Bortezomib and rituximab SPCs changed to the most recent (at the time) of bortezomib (10/01/2014) and rituximab (23/05/2014). |
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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. | |||
| Serious and non-serious adverse events are listed under non-serious adverse events Non-serious AEs:'Occurrences all number' cannot be provided-only the highest grade experienced by patients was collected. Subjects affected number is entered instead. | |||
