Phase 2
N=20
Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of Olipudase Alfa in Pediatric Patients <18 Years of Age With Acid Sphingomyelinase Deficiency
Sphingomyelin Lipidosis
Bottom Line
View on ClinicalTrials.gov: NCT02292654 ↗Enrolled (actual)
20
Serious AEs
25.0%
Results posted
Feb 2021
Primary outcome: Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) — 4; 9; 7; 20 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Olipudase alfa (Drug)
- Age
- Pediatric
- Sex
- All
- Sponsor
- Genzyme, a Sanofi Company
- Primary completion
- Dec 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |
4; 9; 7; 20; 0; 0 | — |
| PRIMARY Number of Participants With Infusion-Associated Reactions (IARs) |
0; 6; 5; 11 | — |
| PRIMARY Number of Participants With Change in Physical Examination |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Change in Neurological Examination |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study |
0; 1; 1; 2; 0; 1 | — |
| PRIMARY Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities |
0; 5; 3; 8; 1; 0 | — |
| PRIMARY Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities |
2; 2; 2; 6; 0; 0 | — |
| PRIMARY Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 |
-1.603; -0.168; -0.206; -0.497 | — |
| PRIMARY Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 |
-3.90; -3.23; -5.93; -4.31 | — |
| PRIMARY Change From Baseline in Safety Biomarker: Iron at Week 64 |
1.40; -0.41; 1.52; 0.58 | — |
| PRIMARY Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 |
0.000; 0.000; 0.000; 0.000; -38.325; -45.611 | — |
| PRIMARY Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 |
0.47; 0.89; 0.77; -7.25; -18.22; -14.85 | — |
| PRIMARY Change From Baseline in Safety Biomarker: Calcitonin at Week 64 |
3.612; -5.337; -8.609; -4.710 | — |
| PRIMARY Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 |
0.33; -1.00; 1.17; 0.06 | — |
| PRIMARY Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) |
2; 7; 3; 12; 0; 1 | — |
| PRIMARY Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 |
0; 0; 0; 0 | — |
| SECONDARY Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) |
28.0; 23.0; 22.1; 22.4; 24.4; 22.4 | — |
| SECONDARY Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa |
28.0; 23.0; 22.1; 22.4; 24.4; 22.4 | — |
| SECONDARY Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa |
452; 441; 412; 461; 482; 429 | — |
| SECONDARY Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa |
17.1; 23.1; 22.6; 24.3; 23.3; 23.6 | — |
| SECONDARY Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa |
6.34; 6.75; 7.20; 6.16; 6.16; 6.79 | — |
| SECONDARY Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa |
133; 166; 165; 172; 153; 161 | — |
| SECONDARY Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa |
3.94; 4.00; 4.13; 3.81; 4.25; 4.42 | — |
| SECONDARY Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 |
-46.936; -46.038; -54.590; -49.211; -41.726; -36.741 | — |
| SECONDARY Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs |
-0.2188; -0.5833; -0.8958; -0.6053 | — |
| SECONDARY Change From Baseline in Height Z-Scores at Week 52 |
0.606; 0.371; 0.736; 0.555 | — |
| SECONDARY Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52 |
28.01; 35.41 | — |
| SECONDARY Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 |
1.595; 2.876; -0.702; 1.368 | — |
| SECONDARY Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 |
38.3; 20.5 | — |
| SECONDARY Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 |
1.3; 2.4; 2.7; 2.3 | — |
| SECONDARY Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 |
-55.8; -44.7; -74.6; -58.0; -55.25; -66.20 | — |
| SECONDARY Percent Change From Baseline in Lipid Profile at Week 52 |
-38.31; -35.82; -34.04; -35.78; 118.63; 87.49 | — |
| SECONDARY Percent Change From Baseline in Bone Biomarkers at Week 52 |
-9.154; 44.768; 35.040; 32.391; 69.0; 92.5 | — |
| SECONDARY Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 |
9.4; 14.6; 4.2; 2.1; 6.8; 7.6 | — |
| SECONDARY Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 |
-4.4; -37.1; -18.6; -24.1; -84.050; -88.029 | — |
Summary
Primary Objective:
To evaluate the safety and tolerability of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.
Secondary Objective:
To characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.
Eligibility Criteria
Inclusion criteria
- The participant and/or participant's parent(s)/legal guardian(s) must provide written informed assent/consent prior to any protocol-related procedures being performed.
- The participant was =) 5 multiples of normal (MN) measured by magnetic resonance imaging (MRI); participants who had partial splenectomy were allowed if the procedure was performed >=1 year before screening and the residual spleen volume was >=5 MN.
- The participant's height was -1 Z-score or lower.
- A negative serum pregnancy test in female participants of childbearing potential.
- Female participants of childbearing potential and male participants must be willing to practice true abstinence in line with their preferred and usual lifestyle or use 2 acceptable effective methods of contraception.
Exclusion criteria
- The participant had received an investigational drug within 30 days before study enrollment.
- The participant had any of the following medical conditions:
- An active, serious, intercurrent illness.
- Active hepatitis B or hepatitis C infection.
- Infection with human immunodeficiency virus (HIV).
- Cirrhosis (determined by clinical evaluation).
- Significant cardiac disease (eg, clinically significant arrhythmia, moderate or severe pulmonary hypertension or valvular dysfunction, or )12 hours a day.
- The participant in the investigator's opinion, was unable to adhere to the requirements of the study.
- The participant had a platelet count 250 IU/L or total bilirubin >1.5 mg/dL.
- The participant had an international normalized ratio (INR) >1.5.
- The participant was unwilling or unable to abstain from ingesting alcohol the day before through 3 days after each infusion of olipudase alfa during the treatment period. Measuring alcohol concentration in blood was not required.
- The participant was scheduled during the study for in-patient hospitalization including elective surgery.
- The participant required medication(s) that may can decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants [eg, imipramine, or desipramine]).
- The participant was breast-feeding.
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Data sourced from ClinicalTrials.gov (NCT02292654). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.