efficacy, safety, pharmacodynamic, and pharmacokinetics study of olipudase alfa in patients with acid sphingomyelinase deficiency

Conditions: Sphingomyelin Lipidosis

Summary: primary objective: the primary objective of this phase 2/3 study was to evaluate the efficacy of olipudase alfa (recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 52 weeks in adult participants with acid sphingomyelinase deficiency (asmd) by assessing changes in: 1) spleen volume as measured by abdominal magnetic resonance imaging (mri) (and, for the united states \[us\] only, in association with participant perception related to spleen volume as measured by splenomegaly-related score \[srs\]); and 2) infiltrative lung disease as measured by the pulmonary function test, diffusing capacity of the lung for carbon monoxide (dlco). secondary objectives: * to confirm the safety of olipudase alfa administered intravenously once every 2 weeks for 52 weeks. * to characterize the effect of olipudase alfa on the participant perception related to spleen volume as measured by the srs after 52 weeks of study drug administration. (for the us, the effect of olipudase alfa on the srs is part of the primary objective). * to characterize the effect of olipudase alfa after 52 weeks of study drug administration on the following outcome measures assessed sequentially: * the effect of olipudase alfa on liver volume; * the effect of olipudase alfa on platelet count; * the effect of olipudase alfa on fatigue; * the effect of olipudase alfa on pain; * the effect of olipudase alfa on dyspnea.

the planned total duration per participant was for at least 3 years and up to 5 years and 3 months. this included up to approximately two month of screening, 52 weeks of primary analysis period, up to 4 years and 3 months of extension treatment period, an end-of- study visit within 2 weeks of the last treatment, and a safety follow-up 30 to 37 days after the last treatment.

Eligibility criteria:
inclusion criteria : * the participant was willing and able to provide signed written informed consent. * the participant was male or female aged 18 years or older. * the participant had documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes; and a clinical diagnosis consistent with niemann-pick disease type b (npd b). * the participant had diffuse capacity of the lung for carbon monoxide less than or equal to (\<=)70% of the predicted normal value. * the participant had a spleen volume greater than or equal to (\>=)6 multiples of normal (mn) measured by mri; participant who have had partial splenectomy was allowed if the procedure was performed \>=1 year before screening/baseline and the residual spleen volume was \>=6 mn. * the participant had an srs \>=5. * female participants of childbearing potential must have had a negative serum pregnancy test for beta-human chorionic gonadotropin (β-hcg). * female participants of childbearing potential and male participants were willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for up to 15 days following their last dose of study drug. exclusion criteria: * the participant had received an investigational drug within 30 days before study enrollment. * the participant had a medical condition, including significant intercurrent illness; significant cardiac disease (e.g., clinically significant arrhythmia, moderate or severe pulmonary hypertension or clinically significant valve dysfunction, or less than or equal to (\<=)40% left ventricular ejection fraction by echocardiogram); active hepatitis b or hepatitis c, or infection with human immunodeficiency virus (hiv); malignancy diagnosed within the past 5 years (other than non-melanoma skin cancer), or any other serious medical condition that might have precluded participation in the study. * the participant had a platelet count less than (\<)60,000/microliters based on the average of 2 samples. * the participant had an international normalized ratio (inr) greater than (\>)1.5. * the participant had alanine aminotransferase (alt) or aspartate aminotransferase (ast) \>250 iu/l or total bilirubin \>1.5 mg/dl (except for participant with gilbert's syndrome). * the participant had a major organ transplant (eg, bone marrow or liver). * the participant was scheduled during the study for in-patient hospitalization including elective surgery and excluding the liver biopsies required per protocol. * the participant, in the opinion of the investigator, was unable to adhere to the requirements of the study. * the participant was unwilling or unable to abstain from the use of alcohol for 1 day before and 3 days after each study drug infusion. testing for blood alcohol levels was not required. * the participant was unwilling or unable to avoid 10 days before and 3 days after the protocol scheduled liver biopsies the use of medications or herbal supplements that were potentially hepatotoxic (e.g., 3-hydroxy-3-methyl glutaryl coenzyme a reductase inhibitors, erythromycin, valproic acid, anti-depressants, kava, echinacea) and/or might have caused or prolonged bleeding (e.g., anti-coagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng). * the participant required medications that might have decreased olipudase alfa activity (e.g., fluoxetine, chlorpromazine, tricyclic antidepressants \[e.g., imipramine, or desipramine\]). * the participant required use of invasive ventilatory support. * the participant required use of noninvasive ventilator support while awake for longer than 12 hours daily. * 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.