Clinical Trial Results:
An Open-label, non-Comparative Study to Evaluate the Steady-State Pharmacokinetics, Safety, and Efficacy of Mexiletine in Adolescents and Children with Myotonic Disorders
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Summary
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EudraCT number |
2019-003757-28 |
Trial protocol |
FR |
Global end of trial date |
13 Jun 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Dec 2024
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First version publication date |
25 Dec 2024
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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 |
MEX-NM-301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04624750 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Lupin Europe GmbH
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Sponsor organisation address |
Hanauer Landstraße 139-143, Frankfurt, Germany, 60314
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Public contact |
Senior Regulatory Affairs Manager, Lupin Healthcare (UK) Ltd. , +44 1565751378, EU-RA@lupin.com
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Scientific contact |
Senior Regulatory Affairs Manager, Lupin Healthcare (UK) Ltd. , +44 1565751378, EU-RA@lupin.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-002012-PIP01-16 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Oct 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
13 Jun 2024
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Global end of trial reached? |
Yes
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Global end of trial date |
13 Jun 2024
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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 |
Primary
• To evaluate the safety of mexiletine in adolescents (aged 12 to <18 years) and children (aged 6 to <12 years) for the treatment of myotonia
• To evaluate the efficacy of mexiletine for the treatment of myotonia Secondary
Secondary
• To evaluate the efficacy of mexiletine for the treatment of myotonia as assessed by patient-reported outcomes
• To evaluate efficacy and tolerability of mexiletine as measured by Clinical Global Impression (CGI) scale indices
• To determine changes in health-related quality-of-life as measured by the PedsQL Quality of Life and Neuromuscular module.
• To determine the steady-state pharmacokinetics (PK) of mexiletine in children (6 to <12 years) and adolescents (aged 12 to <18 years)
• To assess the acceptability of the capsule formulation.
• Palatability of alternative administration (capsule content with milk/juice or sprinkled on food) by 5-point facial hedonic
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Protection of trial subjects |
The nature and purpose of the study was fully explained to each patient (or their legally responsible guardian). Before each patient was enrolled into the study, informed consent was obtained from the patient (or his/ her legally authorized representative) according to the most current applicable regulatory and legal requirements. The consent was obtained on the IEC approved and most recent version of consent form in language best comprehended by the patient.
This study was conducted in compliance with the protocol and with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the
World Medical Association Declaration of Helsinki (2013) and in compliance to the specific local regulatory requirements wherever applicable and required. The study was conducted according to Good Clinical Practice (GCP) principles as required by Directive 2001/20/EC, as amended.
Subject Confidentiality requirements as stated in the Data Protection legislation
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Sep 2021
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research | ||
Long term follow-up duration |
22 Months | ||
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 |
France: 12
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Worldwide total number of subjects |
12
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EEA total number of subjects |
12
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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) |
5
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Adolescents (12-17 years) |
7
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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 |
The study was conducted at 2 sites in France. | |||||||||
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Pre-assignment
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Screening details |
The study comprised a screening period of 30 days. A total of 12 subjects were enrolled in the study treatment. | |||||||||
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Period 1
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Period 1 title |
Baseline
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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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Cohort 1 | |||||||||
Arm description |
Patients aged 12 to < 18 years. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Namuscla (mexiletine)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Namuscla (mexiletine) was started as a once-a-day (QD) treatment regimen (weeks 1 to 2), and the dose was escalated every 2 weeks as per investigator judgement (twice daily; BID at Day 14, and thrice daily; TID at Day 28) as per body weight of the patient.
Dose selection was based on body weight.
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Arm title
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Cohort 2 | |||||||||
Arm description |
Patients aged 6 to < 12 years. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Namuscla (mexiletine)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Namuscla (mexiletine) was started as a once-a-day (QD) treatment regimen (weeks 1 to 2), and the dose was escalated every 2 weeks as per investigator judgement (twice daily; BID at Day 14, and thrice daily; TID at Day 28) as per body weight of the patient.
Dose selection was based on body weight.
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Period 2
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Period 2 title |
Treatment period
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Is this the baseline period? |
No | |||||||||
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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Cohort 1 | |||||||||
Arm description |
Patients aged 12 to < 18 years. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Namuscla (mexiletine)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Namuscla (mexiletine) was started as a once-a-day (QD) treatment regimen (weeks 1 to 2), and the dose was escalated every 2 weeks as per investigator judgement (twice daily; BID at Day 14, and thrice daily; TID at Day 28) as per body weight of the patient.
Dose selection was based on body weight.
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Arm title
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Cohort 2 | |||||||||
Arm description |
Patients aged 6 to < 12 years. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Namuscla (mexiletine)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Namuscla (mexiletine) was started as a once-a-day (QD) treatment regimen (weeks 1 to 2), and the dose was escalated every 2 weeks as per investigator judgement (twice daily; BID at Day 14, and thrice daily; TID at Day 28) as per body weight of the patient.
Dose selection was based on body weight.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Patients aged 12 to < 18 years. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Patients aged 6 to < 12 years. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Patients aged 12 to < 18 years. | ||
Reporting group title |
Cohort 2
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Reporting group description |
Patients aged 6 to < 12 years. | ||
Reporting group title |
Cohort 1
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Reporting group description |
Patients aged 12 to < 18 years. | ||
Reporting group title |
Cohort 2
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Reporting group description |
Patients aged 6 to < 12 years. | ||
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End point title |
Frequency of adverse events [1] | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Throughout the study while on treatment with Namuscla
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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 analyses for this end point |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number and frequency of serious adverse events [2] | |||||||||
End point description |
A SAE is defined as, any untoward medical occurrence that at any dose:
• Results in death.
• Is life-threatening (defined as a participant at immediate risk of death at the time of the event). It does not include an event that, had it occurred in a more severe form, might have caused death.
• Requires in-patient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/ incapacity.
• Is a congenital anomaly/ birth defect.
• Consists of any other medically important condition.
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End point type |
Primary
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End point timeframe |
Throughout the study while on treatment with Namuscla
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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: No statistical analyses for this end point |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Incidence of adverse events of special interest (AESI) [3] | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Throughout the study while on treatment with Namuscla
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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: No statistical analyses for this end point |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Mean change in Visual Analogue Scale (VAS) score for muscle stiffness from baseline to days 56 [4] | ||||||||||||
End point description |
This endpoint is a secondary measure in the study and a primary measure of efficacy, specifically addressing myotonia severity, and complementing the main focus of the study which was on safety.
Efficacy of Namuscla treatment on the clinical outcomes.
Change from baseline - Intent to Treat population (ITT)
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End point type |
Primary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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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 analyses for this end point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean change in Faces (FAS) score for muscle stiffness from baseline to days 56 [5] | ||||||||
End point description |
This endpoint is a secondary measure in the study and a primary measure of efficacy, specifically addressing myotonia severity, and complementing the main focus of the study which was on safety.
Efficacy of Namuscla treatment on the clinical outcomes.
Change from baseline - Intent to Treat population (ITT)
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End point type |
Primary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| Notes [5] - 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 analyses for this end point |
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| Notes [6] - FAS scale only utilized in children aged 6 to 8 yo. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in the score of handgrip myotonia from baseline to Days 56 [7] | ||||||||||||
End point description |
This endpoint is a secondary measure in the study and a primary measure of efficacy, specifically addressing myotonia severity, and complementing the main focus of the study which was on safety.
The score of hand grip is quantitatively measured using a commercially available grip dynamometer and computerised capture system in standardised conditions.
Change from baseline - Intent to Treat population (ITT)
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End point type |
Primary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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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 analyses for this end point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Changes in ECG assessments from baseline to day 56 [8] | |||||||||||||||||||||||||||
End point description |
Safety population - results in milliseconds
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End point type |
Primary
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End point timeframe |
From baseline to day 56
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| Notes [8] - 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 analyses for this end point |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Number of adverse events (AEs) [9] | |||||||||
End point description |
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can, therefore, be any unfavourable and unintended sign, symptom or disease (including intercurrent illness), deterioration of a pre-existing illness, accident, any suspected drug reaction, or a clinically relevant change of laboratory values temporally associated with the use of a medicinal (investigation) product, whether or not related to the medicinal (investigational) product and/ or study treatment.
A treatment emergent AE (TEAE) will be defined as an AE that begins or that worsens in severity after at least one dose of study drug has been administered.
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End point type |
Primary
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End point timeframe |
Throughout the study while on treatment with Namuscla
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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: No statistical analyses for this end point |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Mean change in VAS score for muscle pain from baseline to Days 56 | ||||||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean change in VAS for weakness and fatigue from baseline to Days 56 | ||||||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean change in Faces score for muscle pain from baseline to Days 56 | ||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| Notes [10] - FAS scale only utilized in children aged to 6 to 8 yo. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Mean change in Faces score for weakness and fatigue from baseline to Days 56 | ||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| Notes [11] - FAS scale only utilized in children aged 6 to 8 yo. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Mean change in time to open the eyes after forced eye closure from baseline to Days 56 | ||||||||||||
End point description |
This end point is measured on a stopwatch when eyelid myotonia is present.
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in the right hand flexor muscles from baseline to Days 56 | ||||||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean change in time to perform Timed-up and go (TUG) test from baseline to Days 56 | ||||||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 14, 28, 42 and 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean change from baseline to Day 56 in Paediatric Quality of Life (PedsQL) score | ||||||||||||
End point description |
Changes in health-related quality-of-life as measured by the PedsQLTM Quality of Life (version 4.0) and Neuromuscular modules (version 3.0). These multidimensional scales assess the frequency of health problems using generic and disease-specific approaches, respectively.
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Days 56.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Global Impression (CGI) scores (efficacy and tolerability) evaluated by the patient, a parent or proxy and by the investigator at Day 56 | |||||||||
End point description |
Only CGI scores of "very efficient" or "good" are reported. Unit represents number of subjects with CGI score of "very efficient" or "good".
Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
Only Day 56
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| No statistical analyses for this end point | ||||||||||
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End point title |
Mean change from baseline to Day 56 in Myotonia Behaviour Scale (MBS) scores | ||||||||||||
End point description |
Change from baseline - Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
From baseline to Day 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Acceptability of the capsule formulation with respect to the swallowability determined at Day 56 | ||||||||||||
End point description |
It will be assessed by interviewing patients and their caregivers on Day 56, using a scale ranging from 1 (extremely easy) to 7 (extremely difficult) to evaluate swallowability
Intent to Treat population (ITT)
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End point type |
Secondary
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End point timeframe |
Only at Day 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical laboratory evaluations from baseline to day 56 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Safety population.
Each clinical laboratory results have a different units.
When mean and SD are equal to 0, it means that clinical laboratory results were not evaluable.
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End point type |
Secondary
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End point timeframe |
From baseline to day 56
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Steady-state pharmacokinetic | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
PK population.
Cmax-ss (peak concentrations during the dosing interval at steady-state) and AUC0-tau (area under the concentration time curve for one dosing interval at steady-state) are determined in µg/L.
If mean is equal to 0, it means results were not evaluable. The average artithmetic is presented.
Results are presented by total daily dose :
- 186 (62 mg 1 capsule 3 times per day)
- 248 (2 capsules of 62 mg twice a day )
- 249 (83 mg 1 capsule 3 times per day)
- 334 (167 mg 1 capsule twice a day)
- 372 (2 capsules of 62 mg 3 times a day)
- 501 (167 mg 1 capsule 3 times per day)
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End point type |
Secondary
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End point timeframe |
At day 42
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| Notes [12] - PK results have been determined for 2 subjects in the total daily dose 248 & 501 ; 1 for 186 & 362. [13] - PK results have been determined for 3 subjects in the total daily dose 186 ; 2 for 249. |
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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 |
Throughout the study
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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 |
24.0
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Reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Patients aged 12 to < 18 years. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Patients aged 6 to < 12 years. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | |||
