Clinical Trial Results:
A Phase 1, Multicenter, Open-Label, Single-Arm, Multiple Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Natalizumab in Pediatric Subjects with Relapsing Remitting Multiple Sclerosis
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Summary
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EudraCT number |
2012-005082-13 |
Trial protocol |
IT |
Global end of trial date |
24 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Feb 2016
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First version publication date |
04 Apr 2015
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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 |
101MS328
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01884935 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biogen Idec
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Sponsor organisation address |
225 Binney Street , Cambridge, United States, 02142
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Public contact |
Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.com
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Scientific contact |
Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001095-PIP02-12 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Sep 2014
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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 |
24 Sep 2014
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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 primary objective of the study is to determine the pharmacokinetic (PK) profile of multiple doses of natalizumab in pediatric subjects with relapsing remitting multiple sclerosis (RRMS).
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Protection of trial subjects |
Parents or legal guardians must provide written, informed consent, and subjects may provide written assent (if appropriate), before any screening tests or assessments are performed. Subjects must remain in the clinic for 1 hour after the infusion of study treatment is complete for observation and for collection of samples for PK and pharmacodynamic (PD) analyses (if applicable). Epinephrine for subcutaneous injection, diphenhydramine for intravenous (IV) injection, and any other medications and resuscitation equipment for the emergency management of anaphylactic reactions must be available in the room where the infusions are being performed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jul 2013
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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 |
Italy: 13
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Worldwide total number of subjects |
13
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EEA total number of subjects |
13
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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) |
1
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Adolescents (12-17 years) |
12
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Adults (18-64 years) |
0
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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 |
- | ||||||
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Pre-assignment
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Screening details |
Subjects were screened for a maximum of 4 weeks prior to first study infusion. | ||||||
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Period 1
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Period 1 title |
Natalizumab (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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Arm title
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Natalizumab | ||||||
Arm description |
300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses) | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
natalizumab
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Investigational medicinal product code |
BG00002
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Other name |
Tysabri
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Natalizumab is supplied as a sterile liquid in vials containing 300 mg natalizumab per vial (15 mL of a 20 mg/mL solution). One vial of natalizumab contains a sufficient volume for a single IV infusion following dilution in 100 mL 0.9% sodium chloride for injection.
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Baseline characteristics reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
300 mg intravenous (IV) natalizumab every 4 weeks for 16 weeks (a total of 5 doses) | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses) | ||
Subject analysis set title |
PK Population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The PK population is defined as all subjects who received at least 1 dose of natalizumab and have at least 1 post-baseline measurement of natalizumab concentration.
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Subject analysis set title |
PD Population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The PD population is defined as all subjects who received at least 1 dose of natalizumab and have at least 1 post-baseline measurement of the PD parameter being assessed.
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Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety population was defined as all subjects who received at least 1 dose of natalizumab and had at least 1 post-baseline assessment of the safety parameter being analyzed.
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End point title |
Maximum Plasma Concentration (Cmax) [1] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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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: Summary statistics for each PK parameter are presented in the data table. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Predose (Trough) Concentrations (Cpredose) From Multiple Dosing [2] | ||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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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: Summary statistics for each PK parameter are presented in the data table. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Area Under the Plasma Concentration Curve From Time of First to Last Dose (AUClast) [3] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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| Notes [3] - 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: Summary statistics for each PK parameter are presented in the data table. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration Curve From Time of First Dose to Infinity (AUC0-inf) [4] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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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: Summary statistics for each PK parameter are presented in the data table. |
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| Notes [5] - 4 subjects were excluded as their terminal phase could not be adequately characterized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Maximum Plasma Concentration (Tmax) [6] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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| Notes [6] - 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: Summary statistics for each PK parameter are presented in the data table. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance (Cl) [7] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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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: Summary statistics for each PK parameter are presented in the data table. |
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| Notes [8] - 4 subjects were excluded as their terminal phase could not be adequately characterized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution [9] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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| Notes [9] - 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: Summary statistics for each PK parameter are presented in the data table. |
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| Notes [10] - 4 subjects were excluded as their terminal phase could not be adequately characterized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Elimination Half-life (t1/2) [11] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
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| Notes [11] - 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: Summary statistics for each PK parameter are presented in the data table. |
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| Notes [12] - 4 subjects were excluded as their terminal phase could not be adequately characterized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Summary of Alpha4 Integrin Saturation Values | ||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline; 15 minutes post-dose; Days 2, 8, 15, and 22; Weeks 4, 8, 12, and 16
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| Notes [13] - n=subjects with an assessment at given time point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Overall Summary of Adverse Events (AEs) | ||||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject administered study drug and that does not necessarily have a causal relationship with this treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital anomaly or birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. AEs were categorized as related or not related to study drug; severity was categorized as mild, moderate, or severe.
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End point type |
Secondary
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End point timeframe |
From first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Number of Infusion Reactions and Acute Infusion-related Hypersensitivity Reactions | ||||||||||
End point description |
Infusion reactions were defined as those AEs occurring within 2 hours after the start of natalizumab infusion. If the start time of an AE or infusion was missing, but the AE occurred on the same day as the infusion, it was to be assumed to be an infusion reaction.
Acute infusion-related hypersensitivity reactions were defined as hypersensitivity reactions that occurred within 2 hours after the start of natalizumab infusion with preferred terms of: hypersensitivity not otherwise specified (NOS), anaphylactic reaction, anaphylactoid reaction, dermatitis allergic, drug hypersensitivity, urticaria NOS, vasoconstriction, urticaria generalized, and erythema multiforme.
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End point type |
Secondary
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End point timeframe |
From first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
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| Notes [14] - number of subjects with a reaction=1 |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Anti-natalizumab Antibody Summary | ||||||||||||||
End point description |
Number of subjects with positive and negative anti-natalizumab antibody tests at Day 1 and Week 16.
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End point type |
Secondary
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End point timeframe |
Day 1 through Week 16
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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 first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
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Adverse event reporting additional description |
Overall summary for treatment-emergent adverse events (TEAEs) is presented. A TEAE was defined as any AE that had onset on or after the first infusion of study treatment, or any pre-existing condition that had worsened after the first infusion of study treatment.
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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 |
17
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Reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Mar 2013 |
• Included a more restrictive criterion regarding eligibility for treatment with natalizumab in accordance with the clinical requirements, as outlined in the Italian Tysabri Registry.
• Clarified that all blood samples and magnetic resonance imaging scans collected from the subjects are to be stored for 15 years and destroyed thereafter.
• Clarified that, although the 24-hour sampling period was expected to provide the Cmax and Tmax data for most if not all of the study subjects, the assessments of Cmax and Tmax included samples from the entire sampling schedule as specified in the Schedule of Events. The Cmax and Tmax values presented are representative of the entire sampling schedule and not just of the 24 hour sampling period.
• Removed the measurement of serum concentration of soluble vascular adhesion molecule 1 (sVCAM-1). Soluble VCAM-1 was found to be suppressed after administration of natalizumab and was thought to provide an alternative measurement to α4 integrin saturation. However, a consistent relationship between sVCAM-1 serum concentration and α4 integrin saturation could not be established. Therefore, PD assessments in this study were limited to well understood markers of natalizumab therapy.
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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 | |||
