Clinical Trial Results:
A Phase 1/2 Open-label Study in Patients with Arginase I Deficiency to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous AEB1102
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Summary
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EudraCT number |
2017-003851-45 |
Trial protocol |
GB PT |
Global end of trial date |
28 Feb 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jun 2021
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First version publication date |
12 Jun 2021
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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 |
CAEB1102-101A
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02488044 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Aeglea BioTherapeutics, Inc.
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Sponsor organisation address |
805 Las Cimas Parkway, Suite 100, Austin, United States, 78736
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Public contact |
Arg1-D Trial Information, Aeglea Biotherapeutics, Inc., +1 512 942-2935, raredisease@aegleabio.com
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Scientific contact |
Arg1-D Trial Information, Aeglea Biotherapeutics, Inc., +1 512 942-2935, raredisease@aegleabio.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 |
28 Feb 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Feb 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Feb 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of intravenous (IV) administration of AEB1102 in patients with Arginase I deficiency and hyperargininemia
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Protection of trial subjects |
The study was conducted in accordance with the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical Practice (GCP), the ethical principles that have their origins in the Declaration of Helsinki and local regulations. The protocol, all amendments and the informed consent forms (ICFs) / patient information sheets (PIS) were reviewed and approved relevant ethics committee (EC) in each participating country.
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Background therapy |
All 16 patients included in the trial were managed prior to and during the study with dietary protein restriction and essential amino acid supplementation, and 14 patients were also taking ammonia scavengers prior to and during the study. Patients had individual elevated mean plasma arginine levels ranging from 238 to 566 µM at baseline prior to pegzilarginase treatment. | ||
Evidence for comparator |
No comparator used | ||
Actual start date of recruitment |
25 Aug 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Portugal: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
United States: 10
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Country: Number of subjects enrolled |
Canada: 3
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Worldwide total number of subjects |
16
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EEA total number of subjects |
3
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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) |
6
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
5
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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 |
This study was conducted globally and enrolled subjects at 9 clinical sites • 6 centers in the United States (US) • 1 center in the United Kingdom (UK) • 1 center in Portugal • 1 center in Canada | ||||||||||
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Pre-assignment
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Screening details |
Eligibility for the study was determined during the screening period, which was up to 6 weeks in duration. Subjects who signed the ICF, were assigned a unique subject identification and were screened. The total number of subjects who were screened was 17, and 1 of those subjects did not enter the study. A total of 16 subjects were eligible. | ||||||||||
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Pre-assignment period milestones
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Number of subjects started |
17 [1] | ||||||||||
Number of subjects completed |
16 | ||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Did not meet the eligibility criteria: 1 | ||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 17 subjects were screened, 1 subject did not meet the eligibility criteria, 16 subject were enrolled into the study. |
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Period 1
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Period 1 title |
Single Ascending Dose Escalation
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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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AEB1102 Period 1 | ||||||||||
Arm description |
Each patient received single ascending doses of study drug with a 2-week washout/observation period between successive dose levels. For each individual subject, dose escalation continued in pre-defined steps until stopping rules were met or the highest allowed dose of 0.30 mg/kg was reached. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Pegzilarginase
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Investigational medicinal product code |
AEB1102
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Part 1 doses: Each subject received escalating doses of study drug in Part 1 with a 2-week washout/observation period between each successive dose level. The possible doses for each subject in Part 1 were 0.015, 0.03, 0.06, 0.10, 0.15, 0.20, and 0.30 mg/kg, at 2-week intervals as needed to optimize plasma arginine (over a maximum of 14 weeks).
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Period 2
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Period 2 title |
Repeat Dosing
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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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Arm title
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AEB1102 Period 2 | ||||||||||
Arm description |
This was a repeat-dosing period for subjects who completed Part 1 without a clinically significant reason to preclude continued dosing with study drug. Each patient received 8 weekly repeat doses of study drug with the starting dose chosen based on dose response from Part 1. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Pegzilarginase
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Investigational medicinal product code |
AEB1102
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Part 2: Part 2 was a repeat-dosing period for subjects who completed Part 1 without a clinically significant reason to preclude continued dosing of study drug. The starting dose level was based on PK of study drug and plasma arginine levels from single- and repeat-dose results available at the time the subject completed Part 1. No doses in Part 2 exceeded the highest dose used in any subject in Part 1 (Once weekly for a period of 7 weeks (8 doses)
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Baseline characteristics reporting groups
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Reporting group title |
Single Ascending Dose Escalation
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Reporting group description |
A total of 16 subjects were eligible to participate in the study, received study drug, and were included in the Full Analysis Set. Baseline data for this group applied to both periods. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Full Analysis Set (FAS) included all subjects who received study drug. The FAS was used for evaluating subject characteristics, study drug administration, and safety endpoints.
The Pharmacodynamic Analysis Set (PD Set) included all subjects in the FAS who were enrolled (consented) in the study and had any valid arginine concentration-time data. All subjects in the FAS were also in the PD Set; therefore, separate analyses were not performed for the PD Set.
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End points reporting groups
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Reporting group title |
AEB1102 Period 1
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Reporting group description |
Each patient received single ascending doses of study drug with a 2-week washout/observation period between successive dose levels. For each individual subject, dose escalation continued in pre-defined steps until stopping rules were met or the highest allowed dose of 0.30 mg/kg was reached. | ||
Reporting group title |
AEB1102 Period 2
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Reporting group description |
This was a repeat-dosing period for subjects who completed Part 1 without a clinically significant reason to preclude continued dosing with study drug. Each patient received 8 weekly repeat doses of study drug with the starting dose chosen based on dose response from Part 1. | ||
Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set (FAS) included all subjects who received study drug. The FAS was used for evaluating subject characteristics, study drug administration, and safety endpoints.
The Pharmacodynamic Analysis Set (PD Set) included all subjects in the FAS who were enrolled (consented) in the study and had any valid arginine concentration-time data. All subjects in the FAS were also in the PD Set; therefore, separate analyses were not performed for the PD Set.
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End point title |
Number of subjects with Adverse Events [1] | ||||||||||||||||||||||||
End point description |
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent adverse events (TEAEs) were defined as those events which are newly occurring or worsening from Baseline (ie, on or after the first dose of study drug). All TEAEs were coded using MedDRA Version 19.0 terminology. The incidence of AEs was summarized and tabulated by MedDRA SOC and PT.
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End point type |
Primary
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End point timeframe |
Weekly throughout the study, from screening up to week 14 plus FUP in Period 1 and up to week 8 plus FUP in Period 2
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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 performed. For detailed breakdown of AEs see Adverse events section. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Adverse Events by Maximum Severity [2] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Weekly throughout the study, from screening up to week 14 plus FUP in Period 1 and up to week 8 plus FUP in Period 2
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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 analysis was performed. For detailed break down of AEs see Adverse events section. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Baseline to week 14
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Attachments |
Summary of PK parameters Part 1 Summary of PK parameters Part 2 Concentration versus Time Profile Part 1 Concentration versus Time Profile Part 2 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Baseline to week 14
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Baseline to week 14
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Baseline to week 14
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 1 Part 2
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| No statistical analyses for this end point | |||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 1 Part 2
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 1 Part 2
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 1 Part 2
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| No statistical analyses for this end point | |||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 8 Part 2
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| No statistical analyses for this end point | |||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 8 Part 2
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 8 Part 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Pharmacokinetic evaluation of AEB1102 | ||||||||||
End point description |
Serum concentration versus time data were analyzed by noncompartmental analysis (NCA) with PhoenixTM WinNonlin® Version 8.0, using an IV infusion administration model. Actual (elapsed) sampling, actual infusion times and dose assignments in the clinical database were used in the analysis; when there was missing dosing or sampling information (and the actual time could not be calculated), the corresponding nominal time(s) was used.
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End point type |
Secondary
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End point timeframe |
Week 8 Part 2
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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 |
The reporting period for non-serious AEs and SAEs was the period from the first dose of study drug continuing through the last study Follow-up Visit (weekly throughout the study, up to week 14 in Part 2)
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Adverse event reporting additional description |
The Investigator assessed AEs for severity, for relationship to study drug (not related, unlikely, possibly related, probably related, or definitely related), and whether the event met one or more of the definitions of an SAE. Adverse events reported spontaneously by the subject, in response to an open-ended question, or revealed by observation.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Full Analysis Set
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Reporting group description |
The Full Analysis Set (FAS) included all subjects who received at least one dose of study medication. The FAS was used for evaluating subject characteristics, treatment administration, and safety endpoints. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 Jan 2016 |
Amendment 1 (US only): Addressed comments received from the US FDA and clarified the timing of study procedures |
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01 Nov 2016 |
Amendment 2 (US and Canada only): Converted the study into a Phase 1/2 study that increased the potential maximum dose that a subject could have received in the dose-escalation period, thereby increasing the total number of single escalating doses to 7 from the current 4, added a repeat-dose phase, and expanded enrollment to include pediatric subjects. |
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30 Jun 2017 |
Amendment 2.1 (US and UK only): Specified DSMB assessment of specific clinical data from subjects aged ≥ 14 years at informed consent prior to dosing the youngest subjects (aged 2 to 13 years) in Parts 1 and 2. • Minor revisions were made to objectives and endpoints, PK sampling, and sample collection times. |
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31 Dec 2017 |
Amendment 2.2 (UK only): Addressed requests from the MHRA in the UK regarding language related to birth control requirements for female and male subjects and language related to the potential (based on animal studies) for testicular toxicity in male study subjects |
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23 Jan 2018 |
Amendment 2.3 (US only): Provided for dosing adjustments in response to infusion-related adverse events, in particular, hypersensitivity reactions. Additionally, stricter language was added regarding birth control requirements for female and male subjects. |
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17 May 2018 |
Amendment 3 (Global): Harmonised several other amendments (2.0, 2.2, and 2.3) that were active in different countries. |
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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 | |||
