Clinical Trial Results:
A Single Blind Phase IV Pharmacodynamic Study to Evaluate Neutrophil Distribution Kinetics and Function Following Single-Dose Tocilizumab Treatment in Healthy Subjects.
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Summary
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EudraCT number |
2013-002341-11 |
Trial protocol |
GB |
Global end of trial date |
06 Mar 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Feb 2016
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First version publication date |
26 Feb 2016
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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 |
WA29049
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01991990 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. HoffmannLa Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, CH4070, Basel, Switzerland,
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd, +41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd, +41 61 6878333, global.trial_information@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 |
06 Mar 2015
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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 |
06 Mar 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 |
This was a Phase IV, single-blind, two-arm study to explore the pharmacodynamics (PD) effects of tocilizumab (TCZ) on neutrophil redistribution, function, and survival in healthy participants, and to investigate differences between participants with greater than (>) 50% neutrophil count decrease at Day 4 relative to baseline and participants with less than or equal to (≤) 50% neutrophil count decrease at Day 4 relative to baseline.
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Protection of trial subjects |
This study was conducted in full conformance with the International Conference on Harmonization (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever afforded the greater protection to the individual. Studies conducted in the European Union/European Economic Area (EU/EEA) complied with the EU Clinical Trial Directive (2001/20/EC).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 May 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 |
United Kingdom: 18
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Worldwide total number of subjects |
18
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EEA total number of subjects |
18
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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) |
18
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
There was a substantial protocol amendment for this study on 20Dec2014, post the Global End of Trial Date (GETD) of 10Dec2014. An error is shown: "The amendment date is not allowed. Amendment dates must not be later than the global end of the trial date". In order to resolve this error, the GETD is reported as 06Mar2015 (Final Database lock [DBL]). | |||||||||
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Pre-assignment
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Screening details |
The screening visit was up to 3 weeks before randomization to the first dose of study medication. Out of 23 screened participants; 5 participants discontinued (4=met exclusion criteria; 1=withdrew), 18 participants were included. | |||||||||
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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 |
Randomised - controlled
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Blinding used |
Single blind | |||||||||
Roles blinded |
Subject | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||
Arm description |
Participants received a single dose of placebo-matched to tocilizumab on Day 0. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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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 |
Single dose of placebo injection was administered on Day 0
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Arm title
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Tocilizumab | |||||||||
Arm description |
Participants received a single dose of intravenous (IV) tocilizumab (TCZ) at a dose of 8 milligrams (mg) per kilogram (kg) body weight infusion over 1 hour on Day 0 | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Tocilizumab
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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 |
Participants received single IV infusion of tocilizumab based on their body weight on Day 0
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a single dose of placebo-matched to tocilizumab on Day 0. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tocilizumab
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Reporting group description |
Participants received a single dose of intravenous (IV) tocilizumab (TCZ) at a dose of 8 milligrams (mg) per kilogram (kg) body weight infusion over 1 hour on Day 0 | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a single dose of placebo-matched to tocilizumab on Day 0. | ||
Reporting group title |
Tocilizumab
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Reporting group description |
Participants received a single dose of intravenous (IV) tocilizumab (TCZ) at a dose of 8 milligrams (mg) per kilogram (kg) body weight infusion over 1 hour on Day 0 | ||
Subject analysis set title |
Tocilizumab (Polymorphonuclear Leukocyte [PMN])-High Group)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants who received a single dose of IV TCZ at a dose of 8 mg/kg body weight infusion over 1 hour on Day 0 and with ≤50% neutrophil count decrease at Day 4 relative to baseline were included in this group.
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Subject analysis set title |
Tocilizumab (PMN-Low Group)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants who received a single dose of IV TCZ at a dose of 8 mg/kg body weight infusion over 1 hour on Day 0 and with >50% neutrophil count decrease at Day 4 relative to baseline were included in this group.
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End point title |
Neutrophil Redistribution Analysis on Day 4 (Neutrophil Nadir) [1] [2] | ||||||||||||||||||||||||||||
End point description |
On Day 4 participants had neutrophils isolated from 100 milliliters (mL) of acid-citrate dextrose (ACD)-anti-coagulated autologous blood and labeled in autologous plasma with up to 2.5 megaBecquerel (MBq) 111 Indium (111In)-tropolonate before being reinjected. Participants rested for 45 minutes (min) post-injection for neutrophil equilibrium between the circulating and marginating neutrophil pools. Whole-body profiling performed with 2 highly sensitive scintillation detectors with the recorded counts corrected for the physical decay of 111In to allow measurement of the effect of TCZ on the normal redistribution pattern of neutrophils and assessment of margination of neutrophils in the presence of TCZ. Distribution of radiolabelled neutrophils on Day 4 (45 min post re-injection) in the blood, expressed as percentages of total body counts (TBCs). Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Day 4
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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: No statistical analysis was planned for this study. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| Notes [3] - 1 participant was excluded due to external contamination affecting profiling data. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Redistribution Analysis on Day 5 [4] [5] | ||||||||||||||||||||||||
End point description |
On Day 4 participants had neutrophils isolated from 100 mL of ACD-anti-coagulated autologous venous blood and labeled with up to 2.5 MBq 111In-tropolonate before being reinjected. Participants rested for 45 min post-injection to allow for neutrophil equilibrium between the circulating and marginating neutrophil pools. Whole-body profiling was performed in a heavily shielded dedicated whole-body counter with 2 highly sensitive scintillation detectors with the recorded counts corrected for the physical decay of 111In to allow measurement of the effect of TCZ on the normal redistribution pattern of neutrophils and assessment of margination of neutrophils in the presence of TCZ. Distribution of radiolabelled neutrophils and peak counts, on Day 5 (24-hours post re-injection) in liver/spleen (center) and pelvic bone marrow (right) were decay corrected and expressed as percentages of Day 4 (45 minutes post re-injection). Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Day 5
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| Notes [4] - 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: No statistical analysis was planned for this study. [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| Notes [6] - 1 participant was excluded due to external contamination affecting profiling data. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Neutrophil Redistribution Analysis on Day 10 [7] [8] | ||||||||||||||||||||||||
End point description |
On Day 4 participants had neutrophils isolated from 100 mL of ACD-anti-coagulated autologous venous blood and labeled with up to 2.5 MBq 111In-tropolonate before being reinjected. Participants rested for 45 min post-injection to allow for neutrophil equilibrium between the circulating and marginating neutrophil pools. Whole-body profiling was performed in a heavily shielded dedicated whole-body counter with 2 highly sensitive scintillation detectors with the recorded counts corrected for the physical decay of 111In to allow measurement of the effect of TCZ on the normal redistribution pattern of neutrophils and assessment of margination of neutrophils in the presence of TCZ. Distribution of radiolabelled neutrophils and peak counts, on Day 10 (6 days post re-injection) in liver/spleen (center) and pelvic bone marrow (right) were decay corrected and expressed as percentages of Day 4 (45 minutes post re-injection). Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Day 10
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| Notes [7] - 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: No statistical analysis was planned for this study. [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| Notes [9] - 1 participant was excluded due to external contamination affecting profiling data. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Neutrophil Phagocytosis: Change From Baseline to Nadir (Day 4) in the Percentage of eFluor670-Positive (eFluoro670+) Neutrophils [10] [11] | ||||||||||||||||||||||||||||
End point description |
Neutrophil phagocytosis was assessed by flow cytometry using heat-killed Staphylococcal pneumonia (S.pneumonia) bacteria labeled with eFluor670. Phagocytosis was quantified by measuring the eFluor670 fluorescence from neutrophils containing phagocytosed bacteria. Experiments were performed using neutrophils (PMN) only, PMN plus S. pneumonia at 4 degrees(˚) centigrade (C) (to control for non-specific bacterial adherence to PMN cell surface), and PMN plus S. pneumonia at 37˚C. Change from baseline in the percentage of eFluor670+ neutrophils was calculated on Day 4. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [10] - 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: No statistical analysis was planned for this study. [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Phagocytosis: Change From Baseline to Nadir (Day 4) in Median Fluorescence Intensity (MFI) of eFluor670+ Neutrophils [12] [13] | ||||||||||||||||||||||||||||
End point description |
Neutrophil phagocytosis was assessed by flow cytometry using heat-killed Staphylococcal pneumonia bacteria labeled with eFluor670. Phagocytosis was quantified by measuring the eFluor670 fluorescence from neutrophils containing phagocytosed bacteria. Experiments were performed using neutrophils (PMN) only, PMN plus S. pneumonia at 4˚C (to control for non-specific bacterial adherence to PMN cell surface), and PMN plus S. pneumonia at 37˚C. Change from baseline in the eFluor670+ MFI was calculated on Day 4. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [12] - 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: No statistical analysis was planned for this study. [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Respiratory Burst: Change From Baseline to Nadir (Day 4) in the Production of Reactive Oxygen Species as Measured by Chemiluminescence (Relative Light Units - Absolute) [14] [15] | ||||||||||||||||||||||||
End point description |
Neutrophils generate a respiratory burst using reactive oxygen species (ROS) to kill invading pathogens. When luminol is used as a substrate for ROS, a chemical reaction is produced resulting in photon emission (chemiluminescence) in primed and unprimed neutrophils following formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation which is quantifiable. fMLP stimulation of the respiratory burst is mediated through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in primed neutrophils. The maximal fMLP response is observed in primed neutrophils and is an ex vivo measure of the capacity of neutrophils to respond to pathogenic stimuli. In the current experiments, neutrophils were primed with tumor necrosis factor alpha (TNFα). Light emission was recorded on a luminometer. Absolute change from baseline in the production of ROS on Day 4 was reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [14] - 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: No statistical analysis was planned for this study. [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Neutrophil Survival: Change From Baseline to the Nadir (Day 4) in the Percentage of Apoptotic Neutrophils as Measured by Microscopic Morphololgy [16] [17] | ||||||||||||||||||||||||||||
End point description |
Neutrophil apoptosis was measured using microscopy method with slides stained with Diff-Quik (modified Wright Giemsa stain) and morphology examined under oil immersion light microscopy with 100 times magnification. Neutrophils constitutively undergo apoptosis when cultured ex vivo, and this can be delayed by the addition of agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or TNFα. Apoptotic neutrophils were characterized with dark and pyknotic nuclei compared to the viable neutrophils. Change from baseline in the percentage of apoptotic neutrophils on Day 4 measured by microscopy is reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [16] - 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: No statistical analysis was planned for this study. [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Survival: Change From Baseline to the Nadir in the Percentage of Apoptotic Neutrophils as Measured by Flow Cytometry [18] [19] | ||||||||||||||||||||||||||||
End point description |
Ageing neutrophils translocate phosphatidylserine from the inner leaflet of the plasma membrane to the outer leaflet during the early stages of apoptosis. This translocation can be measured due to the affinity of Annexin V (AV) to bind exposed phosphatidylserine. Propidium Iodide (PI) is normally membrane-impermeable but enters cells in late apoptosis when their plasma membrane becomes leaky. Neutrophils constitutively undergo apoptosis when cultured ex vivo, and this can be delayed by the addition of agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or TNFα. Apoptosis was assessed by flow cytometry with fluorescein isocyanate-labeled recombinant human AV (AV-FITC) and PI staining and the change from baseline in the percentage of apoptotic neutrophils on Day 4 measured by flow cytometry is reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [18] - 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: No statistical analysis was planned for this study. [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Morphology: Change From Baseline to Nadir in the Number of Neutrophils With Shape Change Measured Using Flow Cytometry [20] [21] | ||||||||||||||||||||||||||||
End point description |
Neutrophil shape change is an indicator of the chemotactic ability of neutrophils to respond to and migrate to sites of inflammation. For determination of neutrophil shape change, fresh (0 min control), phosphate-buffered saline (PBS) control (30 min control) and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimuated (30 min fMLP) PMNs (at 5 × 10^6 PMNs/ milliliter [mL]) were fixed with CellFIX, 90 microliters (μL) transferred to each sample tube, and cold PBS added to stop further reaction. Shape change was assessed by measuring forward scatter (FSC) on flow cytometry. Change from baseline in the number of neutrophils with shape change on Day 4 was reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [20] - 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: No statistical analysis was planned for this study. [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Morphology: Change From Baseline to the Nadir (Day 4) in the Percentage of Neutrophils With Shape Change Measured by Flow Cytometry (FSC-High Cells) [22] [23] | ||||||||||||||||||||||||||||
End point description |
Neutrophil shape change is an indicator of the chemotactic ability of neutrophils to respond to and migrate to sites of inflammation. For determination of neutrophil shape change, fresh (0 min control), PBS control (30 min control) and fMLP-stimuated (30 min fMLP) PMNs (at 5 × 10^6 PMNs/ mL) were fixed with CellFIX, 90 μL transferred to each sample tube, and cold PBS added to stop further reaction. Shape change was assessed by measuring FSC on flow cytometry. Change from baseline in the percentage of neutrophils with shape change on Day 4 was reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [22] - 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: No statistical analysis was planned for this study. [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Neutrophil Morphology: Change From Baseline to the Nadir (Day 4) in the Percentage of Neutrophils With Shape Change Measured by Microscopic Morphology [24] [25] | ||||||||||||||||||||||||||||
End point description |
Neutrophil shape change is an indicator of the chemotactic ability of neutrophils to respond to and migrate to sites of inflammation. For determination of neutrophil shape change, fresh (0 min control), PBS control (30 min control) and fMLP-stimuated (30 min fMLP) PMNs (at 5 × 10^6 PMNs/ mL) were fixed with CellFIX, 90 μL transferred to each sample tube, and cold PBS added to stop further reaction. Shape change was assessed by microscopy with neutrophils classified as shape-changed if they contained > 1 cell surface bleb or irregularity and change from baseline in percentage of neutrophil with shape change on Day 4 was reported. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 4
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| Notes [24] - 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: No statistical analysis was planned for this study. [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Absolute Median Fluorescence Intensities of Neutrophil Adhesion Molecules [26] [27] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Neutrophil surface receptor expression may be used to characterize the activation status of neutrophils. Fresh (0 min), PBS control (30 min) and fMLP-stimulated (30 min) PMNs (5 × 10^6 PMNs/mL) were fixed with CellFIX, and 90 μL transferred to each tube containing antibody mixture (2 μL cluster of differentiation [CD] 11b-brilliant violet (BV) 421, 2 μL CD16-FITC, 5 μL CD62L-allophycocyanin (APC) and 5 μL CD162-phycoerythrin [PE]) or isotype control mixture of equivalent volumes. After 30 minutes of incubation on ice and in the dark, cold PBS was added to stop further reaction. Surface marker expressions were quantified by flow cytometry. Safety analysis population used for analysis of this endpoint.
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End point type |
Primary
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End point timeframe |
Day 4
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| Notes [26] - 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: No statistical analysis was planned for this study. [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Tocilizumab arm was split in to two groups, "PMN-High Group" and "PMN-Low Group" and the results are reported for these 2 groups. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From baseline to 8 weeks of safety followup (approximately 8 months)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a single dose of placebo-matched to tocilizumab on Day 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tocilizumab
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Reporting group description |
Participants received a single dose of intravenous (IV) tocilizumab (TCZ) at a dose of 8 milligrams (mg) per kilogram (kg) body weight infusion over 1 hour on Day 0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Dec 2013 |
The protocol was amended to add a 24-hour window to the Day 10 study visit and clarify that the neutrophil killing assay was not considered a key outcome of the study. |
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07 Apr 2014 |
The protocol amendment corrected the TCZ dosing information for participants weighing more than 100 kg and aligned the maximum TCZ dose of 800 mg with the current TCZ Summary of Product Characteristics (SmPC). Weight cutoffs for participants ≤ 50 kg and > 50 kg to ≤ 100 kg were modified and a new weight category of > 50 kg to ≤ 75 kg was added. |
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20 Dec 2014 |
The protocol was amended to change the grouping of participants from grading according to Common Terminology Criteria (CTC) Grade (Grade 1 or 2 vs. Grade 3 or 4) neutrophil count to grouping by a relative reduction in absolute neutrophil counts of ≤ 50% or > 50% at the time of the expected neutrophil nadir in relation to baseline counts because of the lower than expected rate of CTC Grade 3 or 4 neutrophil counts. Preliminary review of the data indicated this would allow for analysis of neutrophil distribution in TCZ-treated participants while eliminating unnecessary exposure of participants to TCZ and 111In. Although this protocol amendment was decided prior to actual GETD (10Dec2014), formal agreement was received afterwards. |
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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. | |||
| The actual GETD was 10Dec2014. To resolve the error ("The amendment date is not allowed. Amendment dates must not be later than the global end of the trial date") related to protocol amendment on 20Dec2014, GETD is reported as 06Mar2015 (Final DBL). | |||
