Clinical Trial Results:
A Randomized, Open-Label, Multi-Centre Study to Evaluate Patient Preference With Subcutaneous Administration of Rituximab Versus Intravenous Rituximab in Previously Untreated Patients With CD20+ Diffuse Large B-Cell Lymphoma or CD20+ Follicular Non-Hodgkin’s Lymphoma Grades 1, 2, or 3A
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Summary
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EudraCT number |
2012-003230-17 |
Trial protocol |
DE HU NL IT PT SE AT DK HR |
Global end of trial date |
20 Dec 2016
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Results information
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Results version number |
v3(current) |
This version publication date |
03 Jan 2018
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First version publication date |
19 May 2016
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Other versions |
v1 , v2 |
Version creation reason |
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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 |
MO28457
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01724021 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Hoffman La-Roche
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland,
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Public contact |
Head of Clin. Ops Italy, Roche S.p.A., +39 039 247 5070, ITALY.INFO_CTA@ROCHE.COM
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Scientific contact |
Head of Clin. Ops Italy, Roche S.p.A., +39 039 247 5070, ITALY.INFO_CTA@ROCHE.COM
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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 |
20 Dec 2016
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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 |
20 Dec 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the proportion of subjects indicating an overall preference via a Patient Preference Questionnaire (PPQ) for either the subcutaneous (SC) or the intravenous (IV) route of rituximab administration.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Dec 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
24 Months | ||
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 |
Netherlands: 12
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Country: Number of subjects enrolled |
Portugal: 10
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Country: Number of subjects enrolled |
Romania: 31
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Country: Number of subjects enrolled |
Sweden: 17
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Country: Number of subjects enrolled |
Croatia: 2
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Country: Number of subjects enrolled |
Austria: 15
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Country: Number of subjects enrolled |
Denmark: 13
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Country: Number of subjects enrolled |
Germany: 201
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Country: Number of subjects enrolled |
Hungary: 24
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Country: Number of subjects enrolled |
Italy: 60
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Country: Number of subjects enrolled |
Argentina: 10
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Country: Number of subjects enrolled |
Australia: 49
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Country: Number of subjects enrolled |
Brazil: 26
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Country: Number of subjects enrolled |
Canada: 20
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Country: Number of subjects enrolled |
Chile: 10
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Country: Number of subjects enrolled |
Colombia: 3
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Country: Number of subjects enrolled |
Dominican Republic: 4
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Country: Number of subjects enrolled |
Egypt: 10
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Country: Number of subjects enrolled |
El Salvador: 11
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Country: Number of subjects enrolled |
Guatemala: 8
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Country: Number of subjects enrolled |
Hong Kong: 8
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Country: Number of subjects enrolled |
Indonesia: 23
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Country: Number of subjects enrolled |
Korea, Republic of: 31
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Country: Number of subjects enrolled |
Malaysia: 20
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Country: Number of subjects enrolled |
New Zealand: 5
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Country: Number of subjects enrolled |
Panama: 22
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Country: Number of subjects enrolled |
Peru: 10
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Country: Number of subjects enrolled |
Philippines: 18
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Country: Number of subjects enrolled |
Taiwan: 16
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Country: Number of subjects enrolled |
Thailand: 30
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Country: Number of subjects enrolled |
Turkey: 15
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Country: Number of subjects enrolled |
Vietnam: 6
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Worldwide total number of subjects |
740
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EEA total number of subjects |
385
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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) |
459
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From 65 to 84 years |
281
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 743 subjects were randomized across all the sites and were included in the intent to treat (ITT) population. Three enrolled subjects were died prior to receiving study medication and were not included in the safety population. The Participant Flow represents the safety population. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A | ||||||||||||||||||||||||||||||
Arm description |
Subjects in Arm A received one cycle of rituximab 375 milligram per metre square (mg/m^2) intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclcophosphamie, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituximab SC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received three cycles of rituximab 1400 mg SC on Day 1 of each treament cycle. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Investigational medicinal product name |
Rituximab IV
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received one cycle of rituximab 375 mg/m^2 IV, and four cycles of rituximab 375 mg/m^2 IV on Day 1 of each treatment cycle. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Arm title
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Arm B | ||||||||||||||||||||||||||||||
Arm description |
Subjects in Arm B received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400 mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituximab SC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received four cycles of rituximab 1400 mg SC on Day 1 of each treament cycle. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Investigational medicinal product name |
Rituximab IV
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received four cycles of rituximab 375 mg/m^2 IV n Day 1 of each treatment cycle. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Baseline characteristics reporting groups
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Reporting group title |
Arm A
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Reporting group description |
Subjects in Arm A received one cycle of rituximab 375 milligram per metre square (mg/m^2) intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclcophosphamie, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B
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Reporting group description |
Subjects in Arm B received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400 mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A
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Reporting group description |
Subjects in Arm A received one cycle of rituximab 375 milligram per metre square (mg/m^2) intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclcophosphamie, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||
Reporting group title |
Arm B
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Reporting group description |
Subjects in Arm B received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400 mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||
Subject analysis set title |
Rituximab Intravenous (IV)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Rituximab was administered at a dose of 375 mg/m2 body surface area (BSA) as a single IV infusion, followed by administration of chemotherapy. At Cycle 1, Day 1, the first rituximab dose for both Arms A and B was always administered as a slow IV infusion, according to local standard practice. Faster infusion rates were permitted after Cycle 1, according to local practice. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Subject analysis set title |
Rituximab Subcutaneous (SC)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Each treatment cycle consisted of a single SC injection of rituximab administered at a fixed dose of 1400 mg. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator.
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Subject analysis set title |
Arm A (ITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received one cycle of rituximab 375 mg/m^2 IV, then three cycles of rituximab 1400mg SC, followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. The analysed intent-to treat (ITT) population included all subjects who were randomised in the study.
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Subject analysis set title |
Arm B (ITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. The analysed ITT population included all subjects who were randomised in the study.
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End point title |
Percentage of Subjects Indicating a Preference for Rituximab Subcutaneous (SC) Over Rituximab Intravenously (IV) at Cycle 6 [1] | ||||||||||||
End point description |
Subjects who preferred rituximab SC over rituximab IV, along with the corresponding 95% confidence interval (CI), were estimated using the patient preference questionnaire (PPQ) after completing Cycle 6. Intent-to treat (ITT) population included all subjects who were randomised in the study.
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End point type |
Primary
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End point timeframe |
Cycle 6 (Up to 24 weeks)
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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: Only descriptive analysis was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects Indicating a Preference for Rituximab Subcutaneous (SC) Over Rituximab Intravenously (IV) at Cycle 8 [2] | ||||||||||||
End point description |
Subjects who preferred rituximab SC over rituximab IV, along with the corresponding 95% CI, were estimated using the patient preference questionnaire (PPQ) after completing Cycle 8. ITT population included all subjects who were randomised in the study.
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End point type |
Primary
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End point timeframe |
Cycle 8 (Up to 32 weeks)
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| Notes [2] - 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: Only descriptive analysis was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Treatment Emergent Adverse Events (AEs) | |||||||||
End point description |
An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The safety population included all subjects who received at least one dose of rituximab.
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End point type |
Secondary
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End point timeframe |
Randomization of first subject to clinical cutoff date(Up to 4 years)
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time Required for Rituximab Administration (Subcutaneous [SC] or Intravenous [IV]) | ||||||||||||
End point description |
Administration time was defined as the time from start to end of the SC injection or from start to end of the IV infusion. ITT population included all subjects who were randomised in the study.
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End point type |
Secondary
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End point timeframe |
Cycle 1-4, Cycle 5-8 for both SC and IV (Up to 32 weeks)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Cancer Therapy Satisfaction Questionnaire (CTQS) Score | |||||||||||||||||||||
End point description |
CTSQ is a validated 16-item questionnaire that measures three domains related to subject's satisfaction with cancer therapy. These include expectations of therapy, feelings about side effects, and satisfaction with therapy. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all subjects. ITT population included all subjects who were randomised in the study. Here, n specifies the number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
During Cycle 4, 8 of treatment (Up to 32 weeks)
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Rituximab Administration Satisfaction Questionnaire (RASQ) Score | |||||||||||||||||||||||||||
End point description |
RASQ is a 20-item questionnaire that measures five domains related to the impact of treatment administration. These include physical impact, psychological impact, impact on activities of daily living (ADLs), convenience, and satisfaction. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all subjects. ITT population included all subjects who were randomised in the study. Here, n specifies the number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
During Cycle 4, 8 of treatment (Up to 32 weeks)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Complete Response (CR) Rate | ||||||||||||
End point description |
CR rate was assessed according to the International Working Group (IWG) Response Criteria (CHESON ET AL 1999) and included CR and CR unconfirmed (CRu). CR: complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. Cru: disappearance of clinical and radiographic evidence of disease and absence of splenomegaly, with regression of lymph nodes by > 75 % but still >1.5 cm in size, and indeterminate bone marrow assessment. Assessments were based on CT scans with contrast of the neck, chest, and abdomen or other diagnostic means, if applicable. Other methods (e.g. MRI) were acceptable for subjects in whom contrast CT scans were contraindicated. ITT population included all subjects who were randomised in the study.
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End point type |
Secondary
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End point timeframe |
28 (± 3 days) after Day 1 of the last dose of induction treatment
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| Notes [3] - Number of subjects analysed specifies number of subjects who were evaluable for this endpoint. [4] - Number of subjects analysed specifies number of subjects who were evaluable for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Event-free Survival (EFS) | ||||||||||||
End point description |
EFS was defined as the time from randomisation to first occurrence of progression or relapse according to IWG. IWG criteria uses the following categories: CR: complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms; partial response (PR): at least 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses; stable disease (SD): subject fails to attain a CR or PR, but does not reach progressive disease (PD); PD: Lymph nodes considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. Lymph node has a long axis of 1.1 to 1.5 cm, it is considered abnormal if its short axis is more than 1.0. Lymph nodes <= 1.0 × <= 1.0 cm would not be considered as abnormal for PD. ITT population included all subjects who were randomised in the study. Here, 99999 indicates median and upper and lower limits of CI (99999 and -99999) since they were not reached for this endpoint.
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End point type |
Secondary
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End point timeframe |
From the time of randomisation until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Disease-free Survival (DFS) | ||||||||||||
End point description |
DFS was defined as the period from the data of the initial CR/CRu until the date of relapse or death from any cause, whichever occurred first. ITT population included all subjects who were randomised in the study. Here, 99999 indicates median and upper and lower limits of CI (99999 and -99999) since they were not reached for this endpoint.
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End point type |
Secondary
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End point timeframe |
From the time of randomisation until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progression-free Survival (PFS) | ||||||||||||
End point description |
PFS was defined as the time from randomization to the first occurrence of progression or relapse, according to the IWG response criteria. IWG criteria uses the following categories: CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy; PR: At least a 50% decrease in SPD of up to six of the largest dominant nodes or nodal masses; SD: subjects fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD; PD: Lymph nodes considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. Lymph node has a long axis of 1.1 to 1.5 cm, it is considered abnormal if its short axis is more than 1.0. Lymph nodes <= 1.0 × <= 1.0 cm would not be considered as abnormal for PD. ITT population included all subjects who were randomised in the study. Here, 99999 indicates median and upper and lower limits of CI (99999 and -99999) since they were not reached for this endpoint.
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End point type |
Secondary
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End point timeframe |
From the time of randomisation until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall Survival (OS) | ||||||||||||
End point description |
OS was defined as the time from randomisation to death from any cause. ITT population included all subjects who were randomised in the study. Here, 99999 indicates median and upper and lower limits of CI (99999 and -99999) since they were not reached for this endpoint.
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End point type |
Secondary
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End point timeframe |
From the time of randomisation until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years)
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| No statistical analyses for this end point | |||||||||||||
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||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects With Anti-Rituximab Antibodies Over Time | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The safety population included all subjects who received at least one dose of rituximab. Here, n specifies the number of subjects who were evaluable at specified time points.
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|||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies Over Time | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The safety population included all subjects who received at least one dose of rituximab. Here, n specifies the number of subjects who were evaluable at specified time points.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years)
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|||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Summary of Observed Serum Rituximab Concentration | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The safety population included all subjects who received at least one dose of rituximab. Here, n specifies the number of subjects who were evaluable at specified time points.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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|
Adverse events information
|
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Timeframe for reporting adverse events |
Randomization of first subject to clinical cutoff date (Up to 4 years)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Arm A
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects in Arm A received one cycle of rituximab 375 milligram per metre square (mg/m^2) intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclcophosphamie, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects in Arm B received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400 mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Feb 2013 |
1. For each anti-rituximab sample taken, drug-concentration analysis was added as a requirement at each scheduled time point. 2. The 30-minute postdose anti-rHuPH20 samples were removed from every cycle. 3. Additional anti-rituximab and anti-rHuPH20 samples were required during the follow up period (i.e., at 6 and 12 months). 4. The screening/baseline anti-rituximab sample was removed (because the Cycle 1 predose sample could also act as the baseline sample). 5. The Schedule of Assessments and applicable footnotes were revised to reflect the above changes and to correct some inconsistencies. Immunogenicity sampling schedules for Treatment Arms A and B were included for ease of reference during the study. 6. The prephase corticosteroid example was increased from 3 days to 5 days in subjects with aggressive NHL. 7. The reporting requirements for SAEs and AEs of special interest after the end of study were revised in alignment with recent global requirements. 8. The needle gauge was revised to include both 25- and 27-gauge needles. 9. The word “MabThera” (trade name) was replaced with the word “rituximab” (generic name) in the PPQ for consistency within the protocol. |
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02 Jun 2014 |
1. It was originally anticipated that the proportion of subjects preferring rituximab SC would be approximately 60%. In order to have a sample size of 720 subjects for analysis of the primary endpoint, the enrollment target was originally 900. However, a preplanned interim analysis revealed that approximately 80% of subjects preferred rituximab SC. After a discussion with the IDMC, the sample size was recalculated, decreasing the required number of subjects from 720 to 560 subjects and the enrollment target to 700 subjects. 2. Although subjects with active hepatitis B or hepatitis C virus were excluded from the study, some hepatitis-related conditions were permitted. 3. As the blastic variant of mantle cell lymphoma is neither DLBCL nor NHL, this was removed as an exclusion criterion from the study. 4. Subjects receiving prior intrathecal methotrexate for central nervous system prophylaxis in DLBCL were not excluded. 5. For study entry, subjects must have had histologically confirmed, previously untreated CD20+ DLBCL or CD20+ follicular NHL Grade 1, 2, or 3a, according to the World Health Organization (WHO) classification system. The patient’s diagnosis was to be histologically confirmed prior to randomization. It was clarified that fine-needle aspiration samples were not be used as the sole material for pathological diagnosis. Lymph node excision or adequate core biopsy was required for the diagnosis of diffuse large B cell lymphoma or follicular NHL. 6. For assessment of hematologic function for study eligibility criteria, it was clarified that transfusions were not permitted within 2 weeks prior to the start of study drug administration. 7. The acceptable length of a cycle delay was increased from 10 days to 3 weeks, making it consistent with the 3-week window allowed for the treatment of toxicities and/or AEs. |
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02 Jun 2014 |
8. To allow investigators to decide how best to manage specific hematologic and non-hematologic AEs associated with rituximab-CHOP treatment, the protocol “guidelines” were changed to be considered as “recommendations.” Patient management decisions that did not adhere to these recommendations were no longer to be considered as major protocol violations. 9. To comply with doxorubicin’s prescribing information, subjects receiving rituximab-CHOP treatment who had a bilirubin value in the range of 20–50 micro mol per liter had their dose of doxorubicin reduced by 50%. 10. Corticosteroids could now be given as part of premedication to reduce the incidence and severity of injection-related reactions. 11. It was clarified that long-term treatment (>1 month) with intermittent corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of autoimmune conditions was permitted. 12. To comply with the guidance given in the current rituximab SC Investigator’s Brochure, subjects were now to be observed for at least 15 minutes following rituximab SC administration. A longer period may have been appropriate in subjects with an increased risk of hypersensitivity reactions. 13. To conform to standards of clinical practice, subjects with a high risk of central nervous system involvement could now receive prophylactic intrathecal methotrexate. Intrathecal methotrexate was to be administered according to local standards. 14. To better follow clinical practice, subjects were weighed prior to each treatment so that BSA could be recalculated if necessary. Cyclophosphamide, vincristine, doxorubicin, and bendamustine doses were to be recalculated only if the patient’s weight changed by more than ± 10% from baseline. 15. It was clarified that non-investigational medicinal products given as part of the subject’s chemotherapy must have been approved for this indication. |
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02 Jun 2014 |
16. Additional chemotherapy regimens of CHOP every 14 days × 8 cycles, CHOP every 28 days × 8 cycles, CVP every 21 days × 6 cycles, and CVP every 28 days × 6 cycles were now permitted. 17. The wording about stability and storage of rituximab SC was updated according to the latest Investigator’s Brochure. 18. It was clarified that the end-of-treatment response assessment, including radiology and imaging report, must have been obtained 28 (± 3) days after Day 1 of the last dose of induction treatment. The protocol previously stated that this must have been obtained between 4 and 8 weeks after Day 1 of the last treatment cycle, which was inconsistent with other parts of the protocol describing the final staging assessment. 19. As some study sites were only able to perform an international normalized ratio test, coagulation tests now included at least one of the following tests: international normalized ratio, prothrombin time, and activated partial thromboplastin time. 20. Lactate dehydrogenase (LDH) was previously only required to be tested at screening. However, as normalization of LDH was part of the response assessment according to the International Working Group (Cheson et al. 1999), subjects with an abnormal LDH at screening also had LDH included as part of their interim and final staging assessments. In addition, subjects with abnormal alkaline phosphatase, albumin, blood urea nitrogen, or C reactive protein at screening had these tests repeated as part of their interim and final staging assessments. 21. Neutrophil and lymphocyte counts were added to hematology tests to better monitor safety and to be consistent with other rituximab clinical trial protocols. 22. It was clarified that it was acceptable for subjects to have an MRI if they had a contraindication to CT scans (e.g., subjects with contrast allergy or impaired renal clearance). |
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02 Jun 2014 |
23. It was clarified that CT scans of the pelvis need only be done if clinically indicated. CT scans of the neck, chest, and abdomen continued to be required for all study subjects. 24. To minimize discrepancy between the calculation of follow-up visit dates and CT scan intervals, the wording was modified to allow sites to follow the CT frequency according to local standard of care. 25. The follow-up of subjects after induction treatment occurred every 3 months (± 2 weeks). It was clarified that the visit schedule would be calculated based on Visit 9. 26. The wording around the timing of Visit 5 (interim staging) was clarified. All interim staging and Visit 5 must have occurred prior to Visit 6 (initiation of Cycle 5), regardless of whether the CHOP regimen was given every 14 or 21 days. 27. To reduce redundant sampling, if Visit 5 (interim staging) was within 7 days of Visit 6 (initiation of Cycle 5), there was no need to collect the samples for Visit 6, i.e., only Visit 5 samples were to be collected and labeled as Visit 5. 28. During the post-treatment follow-up (observation) period, laboratory assessments and physical examinations were performed only if clinically indicated. 29. In the definition of disease-free and PFS, it was clarified that in terms of the event (relapse, progression, or death as relevant), these outcomes were to be assessed based on the event that occurred first. 30. The protocol wording was updated to reflect the latest Roche protocol template regarding the following: a) If an adverse event worsened in severity and became serious b) If the electronic data capture system was not available and a pregnancy reporting form needed to be submitted c) Investigators were to document and explain any protocol deviations 31. If new anti-lymphoma treatment had been started, any response to therapy was documented in electronic Case Report Form; however, it was clarified that response assessments were not specifically mandated by this study. |
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02 Jun 2014 |
32. It was clarified that CT scans of the pelvis need only be done if clinically indicated. CT scans of the neck, chest, and abdomen continued to be required for all study subjects. 33. To minimize discrepancy between the calculation of follow-up visit dates and CT scan intervals, the wording was modified to allow sites to follow the CT frequency according to local standard of care. 34. The follow-up of subjects after induction treatment occurred every 3 months (± 2 weeks). It was clarified that the visit schedule would be calculated based on Visit 9. 35. The wording around the timing of Visit 5 (interim staging) was clarified. All interim staging and Visit 5 must have occurred prior to Visit 6 (initiation of Cycle 5), regardless of whether the CHOP regimen was given every 14 or 21 days. 36. To reduce redundant sampling, if Visit 5 (interim staging) was within 7 days of Visit 6 (initiation of Cycle 5), there was no need to collect the samples for Visit 6, i.e., only Visit 5 samples were to be collected and labeled as Visit 5. 37. During the post-treatment follow-up (observation) period, laboratory assessments and physical examinations were performed only if clinically indicated. 38. In the definition of disease-free and PFS, it was clarified that in terms of the event (relapse, progression, or death as relevant), these outcomes were to be assessed based on the event that occurred first. 39. The protocol wording was updated to reflect the latest Roche protocol template regarding the following: a) If an adverse event worsened in severity and became serious b) If the electronic data capture system was not available and a pregnancy reporting form needed to be submitted c) Investigators were to document and explain any protocol deviations 40. If new anti-lymphoma treatment had been started, any response to therapy was documented in electronic Case Report Form; however, it was clarified that response assessments were not specifically mandated by this study. |
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02 Jun 2014 |
41. After study closure initiation, unrelated AEs/SAEs occurring in an off-study patient who had started a new anti-cancer treatment did not need to be reported. 42. Based on current recruitment rates, the study recruitment period was increased from 12 to 18 months, and the study duration was correspondingly adjusted from 3.5 to 4 years. 43. Additional minor changes were made to improve clarity and consistency. |
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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 | |||
