Clinical trial NCT02292654: Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of Olipudase Alfa in Pediatric Patients <18 Years of Age With Acid Sphingomyelinase Deficiency
Official title: 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 Patients Aged <18 Years With Acid Sphingomyelinase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Sphingomyelin Lipidosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2014-11-17
Enrollment: 20
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: The maximum study duration per participant was approximately 18 months (screening period: up to 60 days; treatment period: 64 weeks; post-treatment period: up to 37 days, not applicable if participants enrolled in a long-term extension treatment trial).

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 \<18 years of age on the date of informed assent/consent.
* The participant had documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes.
* The participant had a spleen volume greater than or equal to (\>=) 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 \<40 percent (%) left ventricular ejection fraction by echocardiogram).
* Malignancy diagnosed within the previous 5 years (except basal cell carcinoma).
* Any other extenuating circumstance that can significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
* The participant had acute or rapidly progressive neurological abnormalities.
* The participant was homozygous for SMPD1 gene mutations R496L, L302P, and fs330 or any combination of these 3 mutations.
* The participant had a delay of gross motor skills.
* The participant had a major organ transplant (eg, bone marrow, liver).
* The participant required use of invasive ventilatory support.
* The participant required use of noninvasive ventilatory support while awake and for greater than (\>)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 \<60 × 10\^3/µL (based on the average of 2 screening samples obtained up to 24 hours apart).
* The participant had alanine aminotransferase or aspartate aminotransferase \>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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From Baseline up to End of study (64 weeks)
measure: Number of Participants With Infusion-Associated Reactions (IARs)
timeFrame: Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks)
measure: Number of Participants With Change in Physical Examination
timeFrame: Baseline, Week 52 (last complete assessment)
measure: Number of Participants With Change in Neurological Examination
timeFrame: Baseline, Week 52 (last assessment)
measure: Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study
timeFrame: At End of Study (Week 64)
measure: Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities
timeFrame: From Baseline up to End of Study (64 weeks)
measure: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: From Baseline up to End of Study (64 weeks)
measure: Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64
timeFrame: Baseline, Week 64 (pre-infusion)
measure: Change From Baseline in Safety Biomarker: Ceramide Level at Week 64
timeFrame: Baseline, Week 64 (pre-infusion)
measure: Change From Baseline in Safety Biomarker: Iron at Week 64
timeFrame: Baseline, Week 64 (pre-infusion)
measure: Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64
timeFrame: Baseline, Week 64 (pre-infusion)
measure: Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24
timeFrame: Baseline, Week 24 (pre-infusion, last assessment)
measure: Change From Baseline in Safety Biomarker: Calcitonin at Week 64
timeFrame: Baseline, Week 64 (pre-infusion)
measure: Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb)
timeFrame: From Baseline up to Week 64
measure: Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52
timeFrame: Week 52 (last assessment)
Secondary outcomes:
measure: Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi)
timeFrame: At the end of infusion of the first 3.0 mg/kg dose and at Week 52
measure: Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa
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
measure: Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa
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
measure: Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa
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
measure: Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa
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
measure: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa
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
measure: Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa
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
measure: Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs
timeFrame: Baseline, Week 52 (last assessment)
measure: Change From Baseline in Height Z-Scores at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52
timeFrame: Week 52 (last assessment)
measure: Percent Change From Baseline in Efficacy Biomarkers Level at Week 52
timeFrame: Baseline, Week 52
measure: Percent Change From Baseline in Lipid Profile at Week 52
timeFrame: Baseline, Week 52
measure: Percent Change From Baseline in Bone Biomarkers at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52
timeFrame: Baseline, Week 52 (last assessment)
measure: Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52
timeFrame: Baseline, Week 52 (Pre- infusion)
Other outcomes:
Locations:
city: New York
country: United States
facility: Investigational Site Number 840001
state: New York
city: Porto Alegre
country: Brazil
facility: Investigational Site Number 076001
city: Bron Cedex
country: France
facility: Investigational Site Number 250002
city: Mainz
country: Germany
facility: Investigational Site Number 276001
city: Udine
country: Italy
facility: Investigational Site Number 380001
city: Manchester
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Diaz GA, Jones SA, Scarpa M, Mengel KE, Giugliani R, Guffon N, Batsu I, Fraser PA, Li J, Zhang Q, Ortemann-Renon C. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021 Aug;23(8):1543-1550. doi: 10.1038/s41436-021-01156-3. Epub 2021 Apr 19.