Clinical Trial Results:
Multiple, fixed-dose, comparative efficacy and safety evaluation of RGB-02 and Neulasta® in patients undergoing chemotherapy treatment known to induce neutropenia.
Summary
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EudraCT number |
2013-003166-14 |
Trial protocol |
CZ HU BG HR |
Global end of trial date |
08 Apr 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Jun 2022
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First version publication date |
26 Jun 2022
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Other versions |
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 |
RGB-02-101
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Gedeon Richter Plc
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Sponsor organisation address |
Gyömrői út 19-21, Budapest, Hungary, H-1103
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Public contact |
Dr. Balázs Lázár, Gedeon Richter Plc., +36 1 432 6437, RA.ctaRichter@richter.hu
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Scientific contact |
Medical Information Scientific Service, Gedeon Richter Plc., +36 1 5057032, medinfo@richter.hu
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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 |
30 Jun 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Apr 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Apr 2015
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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 aim of this study was to assess and compare the efficacy and safety of RGB-02 versus Neulasta® (both subcutaneous [s.c.] injections) in breast cancer patients receiving myelosuppressive chemotherapy.
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Protection of trial subjects |
This study was conducted in compliance with Independent Ethics Committee (IEC) and the International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP-E6) Guidelines, in accordance with applicable regulations regarding clinical safety data management (E2A, E2B[R3]), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and E10). In addition, this study was compliant to all local regulatory requirements, and requirements for data protection. Before initiating the study, the Investigator/institution had to have written and dated approval/favorable opinion from the IEC for the study protocol, written Informed Consent Form (ICF), any consent form updates, patient recruitment procedures (e.g., advertisements) and any written information to be provided to patients, and a statement from the IEC that they complied with GCP requirements. The IEC approval had to identify the protocol version as well as the documents reviewed.
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Background therapy |
On Day 1 of each cycle, patients received 60 mg/m2 doxorubicin intravenous (i.v.) infusion followed approximately 1 hour later by i.v. infusion of 75 mg/m2 docetaxel. Chemotherapy was repeated every 3 weeks for up to 4 cycles. In each cycle, all patients received standard oral corticosteroid premedication on 3 consecutive days starting on Day -1 (the day before chemotherapy was administered). | ||
Evidence for comparator |
RGB-02 (pegfilgrastim) is an investigational medicinal product (IMP) under development as a biosimilar to the pegfilgrastim Neulasta® which has been approved in the European Union (EU) since 2002 for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes). The active substance of RGB-02 and Neulasta® is a covalent conjugate of recombinant human granulocyte-colony stimulating factor (G-CSF, filgrastim) with a single 20 kDa polyethylene glycol (PEG). | ||
Actual start date of recruitment |
28 Jan 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Croatia: 5
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Country: Number of subjects enrolled |
Bulgaria: 12
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Country: Number of subjects enrolled |
Czech Republic: 8
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Country: Number of subjects enrolled |
Hungary: 48
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Country: Number of subjects enrolled |
Romania: 15
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Country: Number of subjects enrolled |
Russian Federation: 84
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Country: Number of subjects enrolled |
Serbia: 12
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Country: Number of subjects enrolled |
Ukraine: 55
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Worldwide total number of subjects |
239
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EEA total number of subjects |
88
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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) |
234
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Between 28 January 2014 (first patient first visit) and 08 April 2015 (last patient last visit) a total of 270 patients were screened at 35 of the 40 sites that were opened for this study. Of these, 239 were randomized at 32 sites (in Russia, Hungary, Ukraine, Romania, Czech Republic, Serbia, Bulgaria, Croatia). | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The study started with a 21-day screening period. During the screening period, the eligibility of the patients to participate in the study was assessed. The randomization was performed on Day -1 or Day 1 of Cycle 1, before chemotherapy administration. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
All randomized subjects (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
The treatment was administered in a double-blind manner during the first 2 cycles. After the second cycle (from Cycle 3 onwards), the treatment administration became open-label.
Relabeling of Neulasta® syringes and overlabeling of the needle caps of both the test and reference products was used to ensure the blinding. Due to the blinding solution, the syringes for both IMPs were properly blinded so that they were not identifiable either by the pharmacist, the IMP administrator, or the patient
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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RGB-02 | |||||||||||||||||||||||||||
Arm description |
All subjects randomized to receive RGB-02 (test product) during Cycles 1-4. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
RGB-02
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Investigational medicinal product code |
RGB-02
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Other name |
pegfilgrastim 6 mg/0.6 mL (test product)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A single dose of RGB-02 pre-filled syringes 6 mg/0.6 mL for subcutaneous (s.c.) administration during Cycles 1-4. Administrated on Day 2 of the cycle approximately 24h after chemotherapy.
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Arm title
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Neulasta® + RGB-02 | |||||||||||||||||||||||||||
Arm description |
All subjects randomized to receive Neulasta® (reference product) during Cycles 1 and 2 under double-blind conditions and who were switched to receive RGB-02 (test product) under open label conditions starting with Cycle 3. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. . A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Neulasta®
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Investigational medicinal product code |
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Other name |
pegfilgrastim 6 mg/0.6 mL
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A single dose of Neulasta® pre-filled syringes 6 mg/0.6 mL for subcutaneous (s.c.) administration during Cycles 1 and 2. Administrated on Day 2 of the cycle approximately 24h after chemotherapy.
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Investigational medicinal product name |
RGB-02
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Investigational medicinal product code |
RGB-02
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Other name |
pegfilgrastim 6 mg/0.6 mL (test product)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A single dose of RGB-02 pre-filled syringes 6 mg/0.6 mL for subcutaneous (s.c.) administration during Cycles 3 and 4. Administrated on Day 2 of the cycle approximately 24h after chemotherapy.
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Baseline characteristics reporting groups
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Reporting group title |
RGB-02
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Reporting group description |
All subjects randomized to receive RGB-02 (test product) during Cycles 1-4. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Neulasta® + RGB-02
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Reporting group description |
All subjects randomized to receive Neulasta® (reference product) during Cycles 1 and 2 under double-blind conditions and who were switched to receive RGB-02 (test product) under open label conditions starting with Cycle 3. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. . A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | ||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
RGB-02
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Reporting group description |
All subjects randomized to receive RGB-02 (test product) during Cycles 1-4. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | ||
Reporting group title |
Neulasta® + RGB-02
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Reporting group description |
All subjects randomized to receive Neulasta® (reference product) during Cycles 1 and 2 under double-blind conditions and who were switched to receive RGB-02 (test product) under open label conditions starting with Cycle 3. In addition to the 4 cycles of chemotherapy, 2 additional cycles (Cycles 5-6) with the same regimen were allowed if deemed necessary by the Investigator. For those patients who received more than 4 cycles, RGB-02 was administered as supportive therapy. 3-weeks per cycle. . A Follow-up Visit was performed 6 months (± 10 days) after the first IMP administration. | ||
Subject analysis set title |
Per Protocol - RGB-02 (Cycle 1)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per Protocol populations were defined cycle by cycle (Cycles 1 to 4). The PP population for the respective cycle included all patients in the FAS who had no major protocol deviations with a possible impact on the efficacy variables prior to completion of that cycle within the RGB-02 arm.
FAS = Full Analysis Set
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Subject analysis set title |
Per Protocol - Neulasta® + RGB-02 (Cycle 1)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per Protocol populations were defined cycle by cycle (Cycles 1 to 4). The PP population for the respective cycle included all patients in the FAS who had no major protocol deviations with a possible impact on the efficacy variables prior to completion of that cycle within the Neulasta® + RGB-02 arm.
FAS = Full Analysis Set
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Subject analysis set title |
Full Analysis Set - RGB-02
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All randomized subjects who had data for at least one efficacy endpoint within the RGB-02 arm.
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Subject analysis set title |
Full Analysis Set - Neulasta® + RGB-02
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All randomized subjects who had data for at least one efficacy endpoint within the Neulasta® + RGB-02 arm.
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End point title |
DSN (duration of severe neutropenia) in Cycle 1 | ||||||||||||||||||||
End point description |
Duration of severe neutropenia was defined as the number of days from the time of the first ANC value < 0.5 x10^9/L until the time of the first ANC value after this where the ANC value was ≥ 0.5 x10^9/L.
ANC=absolute neutrophil count
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End point type |
Primary
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End point timeframe |
Cycle 1.
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Statistical analysis title |
LS Mean difference (RGB-02 vs Neulasta®) for FAS | ||||||||||||||||||||
Statistical analysis description |
The estimated difference in mean duration of severe neutropenia between the 2 treatment arms and the 2-sided 95% CI for the difference between means were calculated using an analysis of covariance (ANCOVA) model with treatment, country, chemotherapy treatment setting (neoadjuvant or adjuvant), and baseline ANC value as factors in the model.
FAS = Full Analysis Set population
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Comparison groups |
Full Analysis Set - RGB-02 v Full Analysis Set - Neulasta® + RGB-02
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Number of subjects included in analysis |
238
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||||||||||
Method |
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Parameter type |
Least Squares mean difference | ||||||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.2 | ||||||||||||||||||||
upper limit |
0.4 | ||||||||||||||||||||
Notes [1] - If the upper limit of the 95% CI for the difference in means is ≤ 1 day and the lower bound of the 95% CI for the difference in means is ≥ -1 day, then the means in the 2 groups will be considered equivalent. |
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Statistical analysis title |
LS Mean difference (RGB-02 vs Neulasta®) for PP | ||||||||||||||||||||
Statistical analysis description |
The estimated difference in mean duration of severe neutropenia between the 2 treatment arms and the 2-sided 95% CI for the difference between means were calculated using an analysis of covariance (ANCOVA) model with treatment, country, chemotherapy treatment setting (neoadjuvant or adjuvant), and baseline ANC value as factors in the model.
PP = Per Protocol population
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Comparison groups |
Per Protocol - RGB-02 (Cycle 1) v Per Protocol - Neulasta® + RGB-02 (Cycle 1)
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Number of subjects included in analysis |
223
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [2] | ||||||||||||||||||||
Method |
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Parameter type |
Least Squares mean difference | ||||||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.2 | ||||||||||||||||||||
upper limit |
0.4 | ||||||||||||||||||||
Notes [2] - If the upper limit of the 95% CI for the difference in means is ≤ 1 day and the lower bound of the 95% CI for the difference in means is ≥ -1 day, then the means in the 2 groups will be considered equivalent. |
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Adverse events information
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Timeframe for reporting adverse events |
Overall trial
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
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Reporting groups
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Reporting group title |
Safety population - RGB-02 (Cycle 1-2)
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Reporting group description |
All randomized subjects who received at least 1 dose of RGB-02 during Cycle 1 and 2 within RGB-02 arm. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safety population - Neulasta® (Cycle 1-2)
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Reporting group description |
All randomized subjects who received at least 1 dose of Neulasta® during Cycle 1 and 2 within Neulasta® + RGB-02 arm. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 |