Clinical Trial Results:
A Phase 1/2, Multi-Center, Open-Label, Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of Olipudase Alfa in Pediatric Subjects Aged <18 Years with Acid Sphingomyelinase Deficiency
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Summary
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EudraCT number |
2014-003198-40 |
Trial protocol |
GB IT FR DE Outside EU/EEA |
Global end of trial date |
09 Dec 2019
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Results information
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Results version number |
v1 |
This version publication date |
20 Jun 2020
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First version publication date |
20 Jun 2020
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Other versions |
v2 |
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 |
DFI13803
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02292654 | ||
WHO universal trial number (UTN) |
U1111-1160-6469 | ||
Other trial identifiers |
Study Name: ASCEND-Peds | ||
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Sponsors
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Sponsor organisation name |
Genzyme Corporation, a Sanofi company
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Sponsor organisation address |
50 Binney St, Cambridge, MA, United States, 02142
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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-001600-PIP01-13 | ||
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 |
03 Jan 2020
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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 |
09 Dec 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 olipudase alfa administered intravenously in pediatric subjects every 2 weeks for 64 weeks
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Protection of trial subjects |
The study was conducted by investigators experienced in the treatment of pediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 May 2015
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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 |
United Kingdom: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Brazil: 2
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Country: Number of subjects enrolled |
United States: 6
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Worldwide total number of subjects |
20
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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) |
1
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Children (2-11 years) |
15
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Adolescents (12-17 years) |
4
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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 6 sites in 6 countries between 01 May 2015 and 09 December 2019. | ||||||||||||
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Pre-assignment
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Screening details |
A total of 23 subjects were screened out of which 20 subjects were included and treated in this study. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
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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Olipudase alfa: Adolescent Cohort | ||||||||||||
Arm description |
Subjects aged 12 to less than (<) 18 years received intravenous (IV) infusion of olipudase alfa once in every 2 weeks (Q2W) for 64 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Olipudase alfa
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Investigational medicinal product code |
GZ402665
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Other name |
recombinant human acid sphingomyelinase or rhASM
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 milligram per kilogram (mg/kg). The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of 64 treatment weeks.
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Arm title
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Olipudase alfa: Child cohort | ||||||||||||
Arm description |
Subjects aged 6 to <12 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Olipudase alfa
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Investigational medicinal product code |
GZ402665
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Other name |
recombinant human acid sphingomyelinase or rhASM
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of 64 treatment weeks.
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Arm title
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Olipudase alfa: Infant/Early Child cohort | ||||||||||||
Arm description |
Subjects aged <6 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Olipudase alfa
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Investigational medicinal product code |
GZ402665
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Other name |
recombinant human acid sphingomyelinase or rhASM
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of 64 treatment weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Olipudase alfa: Adolescent Cohort
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Reporting group description |
Subjects aged 12 to less than (<) 18 years received intravenous (IV) infusion of olipudase alfa once in every 2 weeks (Q2W) for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Olipudase alfa: Child cohort
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Reporting group description |
Subjects aged 6 to <12 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Olipudase alfa: Infant/Early Child cohort
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Reporting group description |
Subjects aged <6 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Total Subjects
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All subjects received IV infusion of olipudase alfa Q2W for 64 weeks. Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of 64 treatment weeks.
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End points reporting groups
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Reporting group title |
Olipudase alfa: Adolescent Cohort
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Reporting group description |
Subjects aged 12 to less than (<) 18 years received intravenous (IV) infusion of olipudase alfa once in every 2 weeks (Q2W) for 64 weeks. | ||
Reporting group title |
Olipudase alfa: Child cohort
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Reporting group description |
Subjects aged 6 to <12 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||
Reporting group title |
Olipudase alfa: Infant/Early Child cohort
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Reporting group description |
Subjects aged <6 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||
Subject analysis set title |
Total Subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects received IV infusion of olipudase alfa Q2W for 64 weeks. Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of 64 treatment weeks.
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) [1] | |||||||||||||||||||||||||||||||||||
End point description |
TEAEs were defined as adverse events (AEs) that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product [IMP]) administration until end of study. Analysis was performed on safety population that included all subjects who received at least 1 infusion (partial or total) of olipudase alfa.
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End point type |
Primary
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End point timeframe |
From baseline up End of Study (64 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Infusion-Associated Reactions (IARs) [2] | |||||||||||||||
End point description |
IARs were defined as AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Protocol-defined IAR: all AEs that were identified as an IAR by the investigator. Events occurring greater than or equal to (>=) 24 hours after the start of an infusion may have been judged an IAR at the discretion of the investigator or sponsor. Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Within up to 24 hours after start of any infusion (during the treatment period i.e. from baseline up to 64 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Number of Subjects With Change in Physical Examination [3] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Change from Normal assessment (at baseline) to Abnormal assessment (at Week 52) was reported. Physical examinations included following observations/measurements: examination of the skin, head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Abnormality in physical examinations was based on investigator’s discretion. Analysis was performed on safety population. One subject may be counted in multiple categories.
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End point type |
Primary
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End point timeframe |
Baseline, Week 52 (last complete assessment)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Change in Neurological Examination [4] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Change from Normal assessment (at baseline) to Abnormal assessment (at Week 52) was reported. Neurological examination included: coordination examination, cranial nerve examination, extrapyramidal features, fundoscopy, gait and coordination examination, motor examination, tone peripheral nervous system, reflexes examination, sensory examination, strength examination, mental status. Analysis was performed on safety population. One subject may be counted in multiple categories.
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End point type |
Primary
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End point timeframe |
Baseline, Week 52 (last assessment)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Abnormal Liver Function laboratory Values at the End of Study [5] | |||||||||||||||||||||||||||||||||||
End point description |
Abnormal values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase were reported. Analysis was performed on safety population. One subject may be counted in multiple categories.
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End point type |
Primary
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End point timeframe |
At End of Study (Week 64)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Potentially Clinically Significant Vital Sign Abnormalities [6] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant vital sign abnormalities: •Systolic blood pressure (SBP) supine: <=95 mmHg and decrease from baseline (DFB) >=20 mmHg (= SBP Low); >=160 mmHg and increase from baseline (IFB) >=20 mmHg (= SBP High)•Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg (= DBP Low) ; >=110 mmHg and IFB ≥10 mmHg (= DBP High) •Heart rate (HR) supine: <=50 beats per minute (bpm) and DFB >=20 bpm (= HR High); >=120 bpm and IFB >=20 bpm. Analysis was performed on safety population. One subject may be counted in multiple categories.
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End point type |
Primary
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End point timeframe |
From Baseline up to End of Study (64 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With potentially Clinically Significant Electrocardiogram (ECG) Abnormalities [7] | ||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant ECG abnormalities:
High PR Interval: >=180 milliseconds (ms) in adolescents, 170 ms in children, 160 ms in early children, and 140 ms in infants;
High QRS Interval: >=110 ms in adolescents, 100 ms in children, 95 ms in early children and 85 ms in infants;
Prolonged QTc Fridericia (QTc F): >450 ms in male adolescents, children, early children and infants or 470 ms in female adolescents,;
QTc F >500 ms;
QTc F increase from baseline >60 ms
Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
From Baseline up to End of Study (64 weeks)
|
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker Level: high sensitivity C Reactive Protein (hsCRP) at Week 64 [8] | ||||||||||||||||||||
End point description |
Analysis was performed on safety population. Here, number of subjects analysed=subjects with available data for this endpoint.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 64 (pre-infusion)
|
||||||||||||||||||||
| 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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 [9] | ||||||||||||||||||||
End point description |
Analysis was performed on safety population.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 64 (pre-infusion)
|
||||||||||||||||||||
| 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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker: Iron at Week 64 [10] | ||||||||||||||||||||
End point description |
Analysis was performed on safety population. Here number of subjects analysed=subjects with available data for this endpoint.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 64 (pre-infusion)
|
||||||||||||||||||||
| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 [11] | ||||||||||||||||||||||||||||||
End point description |
Analysis was performed on safety population. Here 'n' = number of subjects with available data for specified categories.
|
||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 64 (pre-infusion)
|
||||||||||||||||||||||||||||||
| 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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 [12] [13] | ||||||||||||||||||||||||
End point description |
Analysis was performed on safety population. Here 'n' = number of subjects with available data for specified categories. For the arm "Olipudase alfa: Infant/Early Child cohort" data was not collected in subjects <6 years old, per protocol.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Week 24 (pre-infusion, last assessment)
|
||||||||||||||||||||||||
| Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For the arm "Olipudase alfa: Infant/Early Child cohort" data was not collected in subjects <6 years old, per protocol. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Safety Biomarker: Calcitonin at Week 64 [14] | ||||||||||||||||||||
End point description |
Analysis was performed on safety population.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 64 (pre-infusion)
|
||||||||||||||||||||
| Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Doppler Echocardiogram: Absolute Change from Baseline in Left Ventricular Ejection Fraction at Week 52 [15] | ||||||||||||||||||||
End point description |
Analysis was performed on safety population. Here, number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||||||||||
| Notes [15] - 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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Treatment-Emergent, Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) [16] | ||||||||||||||||||||||||||||||||||||||||
End point description |
Serum samples for immunogenicity assessment were analyzed to detect ADA. ADA response were categorized as: treatment induced and treatment boosted response. A subject whose ADA status was positive anytime post-baseline and was negative or missing at baseline was considered to have treatment-induced ADA. A subject whose ADA status is positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline is significantly higher than that at baseline is considered to have treatment boosted ADA. Positive samples in the ADA assay were further analyzed in the NAb assay as positive NAb inhibition of catalytic activity and positive NAb inhibition of cellular uptake. Analysis was performed on safety population.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From baseline up to Week 64
|
||||||||||||||||||||||||||||||||||||||||
| Notes [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
|||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||
End point title |
Number of Subjects With Abnormalities in Liver Ultrasound Doppler at Week 52 [17] | |||||||||||||||
End point description |
Evidence of portal hypertension was assessed by portal vein direction from liver ultrasound doppler. Analysis was performed on safety population.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Week 52 (last assessment)
|
|||||||||||||||
| Notes [17] - 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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
||||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of infusion (Ceoi) | ||||||||||||||||||||||||
End point description |
Ceoi was defined as the plasma concentration at the end of infusion (EOI). Data collected for child and Infant/child age groups at 0-30 min was considered at end of infusion. Analysis was performed on PK population which included all subjects who received at least 1 infusion of study medication and had evaluable PK data.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At the end of infusion of the first 3.0 mg/kg dose and at Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of olipudase alfa | ||||||||||||||||||||||||
End point description |
Cmax: maximum plasma concentration observed. Analysis was performed on PK population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | ||||||||||||||||||||||||||||||||
End point description |
AUClast: Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to the time of last measured concentration real time. AUC(0-tau): area under the plot of the drug concentration versus the time curve from time “0” to the end of the dosing interval (tau), where dosing interval was 2 weeks. Analysis was performed on PK population.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | ||||||||||||||||||||||||
End point description |
Half-life is the time measured for the plasma concentration of drug to decrease by one half. Analysis was performed on PK population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: Total body clearance (CL) of Olipudase Alfa | ||||||||||||||||||||||||
End point description |
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Total body clearance of a drug from the plasma calculated using equations below: CL = Dose / AUC after the first dose. Analysis was performed on PK population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | ||||||||||||||||||||||||
End point description |
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Analysis was performed on PK population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Pharmacokinetic Parameter: Time to Reach Cmax (tmax) of Olipudase Alfa | ||||||||||||||||||||||||
End point description |
tmax: time to reach maximum plasma concentration observed. Analysis was performed on PK population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | ||||||||||||||||||||||||||||||
End point description |
Spleen and liver volumes was assessed by abdominal magnetic resonance imaging (MRI). Analysis was performed on modified intent-to-treat (mITT) population which included all subjects who were exposed to IMP, regardless of the amount of treatment administered (partial or total).
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 for Both Lungs | ||||||||||||||||||||
End point description |
Pulmonary imaging of chest using HRCT was obtained to quantitate the degree of possible infiltrative lung disease. Lung fields were assessed by a central reader & scored subjectively for the degree of interstitial lung disease on a scale ranges from 0 =normal, 1 =mild, 2=moderate and 3 =severe, where higher scores indicate more severity. Analysis was performed on mITT population. Here, number of subjects analysed=subjects with available data for this endpoint.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Height Z-Scores at Week 52 | ||||||||||||||||||||
End point description |
Z-score for height of subjects was evaluated. Analysis was performed on mITT population.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Lung Diffusing Capacity for Carbon Monoxide (DLco) at Week 52 [18] | ||||||||||||
End point description |
Percent predicted Hemoglobin-adjusted DLco was calculated as:
100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) divided by Hemoglobin-adjusted factor. Per planned analysis, pulmonary function testing (PFT) was to be performed only on subjects >=5 years of age and who could perform the test, therefore, for subjects in "age cohort: infant/early child" data was not collected. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||
| Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PFT was to be performed only on subjects >=5 years of age and who could perform the test, therefore, for subjects in "age cohort: infant/early child" data was not collected. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||
End point title |
Change From Baseline in Difference Between Actual Age and Bone age of Subjects at Week 52 | ||||||||||||||||||||
End point description |
Hand X-ray was performed on subject's left hand, fingers and wrist to assess bone age of subjects. At each visit (baseline and Week 52), difference between the bone age and actual age at that visit was calculated. Difference in age in months was calculated as bone age in months minus real age at time of assessment (in months) at specified time points. In this endpoint change from baseline at Week 52 in the difference between actual age and bone age (in months) is reported. Analysis was performed on mITT population.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 [19] | ||||||||||||
End point description |
Cardiopulmonary status was assessed using a stationary one-wheeled cycle used as an ergometer to measure a person's work output under controlled conditions. Subjects were asked to ride the cycle at increasing workload levels until they could no longer proceed. The workload at which subject stopped and cannot proceed was considered as maximum workload (in watt). As per the planned analysis, this assessment was not to be performed on subjects that were <=6 years of age or <120 cm in height on day 1/week 0, therefore data was not collected for the infant/early child cohort. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 52 (last assessment)
|
||||||||||||
| Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data not collected in subjects <6 years old, per protocol. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||
End point title |
Physician’s Global Assessment of Subject’s Progress: Observed Scores | ||||||||||||||||||||
End point description |
Physician assessed subject’s current clinical status (refers to clinical status at Weeks 52 in comparison to Baseline) was evaluated by marking 1 of the following 7 categories: • marked improvement, • moderate improvement, • mild improvement, • no change, • mild worsening, • moderate worsening, or • marked worsening. These 7 categories were converted to scores as follows: 3 = marked improvement of daily activities, 2 = moderate improvement of daily activities, 1 = mild improvement of daily activities, 0 = no change, -1 = mild worsening of daily activities, -2 = moderate worsening of daily activities, -3 = marked worsening of daily activities where higher score indicated improvement in daily activities as compared to baseline. In this endpoint, observed scores of subject’s clinical status at Week 52 are reported. Analysis was performed on mITT population.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Week 52 (last assessment)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | |||||||||||||||||||||||||||||||||||
End point description |
Efficacy biomarkers included chitotriosidase, chemokine ligand 18 (CCL18), angiotensin-converting enzyme (ACE). Analysis was performed on mITT population. Here 'n' = number of subjects with available data for specified category.
|
|||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 52
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Lipid Profile at Week 52 | |||||||||||||||||||||||||||||||||||
End point description |
Lipid profile parameters included low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. Analysis was performed on mITT population. Here 'n'=number of subjects with available data for specified category.
|
|||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 52
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Bone Biomarkers at Week 52 | ||||||||||||||||||||||||||||||
End point description |
Bone biomarkers included bone specific alkaline phosphatase, C-Telopeptide. Analysis was performed on mITT population. Here 'n'= number of subjects with available data for specified category.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Health Outcome Questionnaires: Pediatric Quality of Life (PedsQL) Generic Core Scale Scores at Week 52 | ||||||||||||||||||||||||||||||||
End point description |
PedsQL included 23 items which covered 4 sub scales:physical, emotional, social & school functioning. Each item in every scale used 4-point rating scale(0=never to 4=almost always). Scale items were reversely scored & linearly transformed from 0-4 to 0-100 scale where 0=100, 1=75, 2=50, 3=25 & 4=0,higher scores=better health related quality of life(QoL). Psychosocial health summary score:mean was computed as sum of items scored over number of items answered in emotional, social & school functioning scale. Total score:mean was computed as sum of all items scored over number of items answered on all scales & was calculated based on 0(almost always)-100(never) scale scores,higher scores=better health related QoL. Scale assessed subject’s & parent’s perceptions of health related QoL in pediatric subjects with chronic health condition.mITT population.Number of subjects analysed=subjects with available data for this endpoint.'n'=number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52 (last assessment)
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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 |
All Adverse Events (AEs) were collected from first IMP administration up to 64 weeks regardless of seriousness or relationship to investigational product.
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Adverse event reporting additional description |
Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period'. Occurrences related to treatment” only include events assessed as “related” by the investigator, and it does not include events assessed as “possibly related” by investigator. Analysis was performed on safety population.
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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 |
22.0
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Reporting groups
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Reporting group title |
Olipudase alfa: Adolescent cohort
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Reporting group description |
Subjects aged 12 to <18 years received IV infusion of olipudase alfa once in Q2W for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Olipudase alfa: Child cohort
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Reporting group description |
Subjects aged 6 to <12 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Olipudase alfa: Infant/Early Child cohort
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Reporting group description |
Subjects aged <6 years received IV infusion of olipudase alfa Q2W for 64 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Total Subjects
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Reporting group description |
All subjects received IV infusion of olipudase alfa Q2W for 64 weeks. Each subject underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. The target maintenance dose was 3.0 mg/kg, which was maintained for the remaining duration of the 64 treatment weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 May 2015 |
Following changes were made:
• The International Nonproprietary Name (INN) olipudase alfa was recommended for recombinant human acid sphingomyelinas: Refinement of clinical laboratory assessments and safety biomarker assessments in the child and early child/infant age cohorts;
• Correction of typographical error in exclusion criteria: The SMPD1 gene mutation was corrected to R496L;
• Replacement of cognitive and adaptive function assessment tools: Modification to pregnancy reporting requirements: Pregnancy was reported as an adverse event per updates to the sponsor’s standard operating procedures.
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13 Nov 2015 |
Following changes were made:
• Pharmacokinetic sample collection schedule was modified: The Food and Drug Administration recommended the inclusion of a 96 hour pharmacokinetic sample. In order to avoid increased subject burden and increased blood collection volumes in pediatric subjects, the 72 hour pharmacokinetic sample in the adolescent cohort was to be replaced by a 96 hour sample. As a result of this change the 60-72 hour sample window in the child and infant/early child cohorts was to be replaced by an 84-96 hour sample window.
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18 Feb 2016 |
Following changes were made • Extension of the olipudase alfa treatment period to 64 weeks.
• subjects stopping criteria was clarified.
• Removal of a desensitization regimen with acute or recurrent adverse events suggestive of a hypersensitivity reaction with a positive immunoglobulin E titer.
• Removal of consolidation as a qualitative high resolution computed tomography (HRCT) assessment.
• overdose definition was updated.
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21 Aug 2017 |
Following changes were made • Included enrolment of at least 8 additional ASMD subjects < 12 years of age: additional acid sphingomyelinase deficiency (ASMD) subjects <12 years were enrolled to evaluate the safety, tolerability, PK, Pharmacodynamic, and exploratory efficacy of olipudase alfa manufactured using the intended commercial process and scale.
• Guidelines for Serious Adverse Event and adverse event of special interest (AESIs) were modified to be consistent with other ongoing studies and take into account the underlying disease.
• Updated dose limiting toxicity (DLT) subject stopping criteria to be consistent with other ongoing studies and as agreed upon by the data monitoring committee (DMC).
• Updated addition of recommendation on usage of cationic amphiphilic antihistamines in rules on concomitant medications.
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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 | |||
