Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency

Study Overview
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Brief Summary
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Primary Objective: The primary objective of this phase 2/3 study is 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.

Detailed Description
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The total duration per participant will be at least 3 years and up to 5 years and 3 months. This includes 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.

Official Title
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A Phase 2/3, Multicenter, Randomized, Double-blinded, Placebo-controlled, Repeat-dose Study to Evaluate the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency

Conditions
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Sphingomyelin Lipidosis

Intervention / Treatment
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* Drug: placebo (saline)
* Drug: GZ402665


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : The participant is willing and able to provide signed written informed consent. The participant is male or female aged 18 years or older. The participant has 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 has diffuse capacity of the lung for carbon monoxide less than or equal to (<=)70% of the predicted normal value. The participant has a spleen volume greater than or equal to (>=)6 multiples of normal (MN) measured by MRI; participant who have had partial splenectomy will be allowed if the procedure was performed >=1 year before screening/baseline and the residual spleen volume is >=6 MN. The participant has an SRS >=5. Female participants of childbearing potential must have a negative serum pregnancy test for beta-human chorionic gonadotropin (β-HCG). 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 for up to 15 days following their last dose of study drug. Exclusion criteria: The participant has received an investigational drug within 30 days before study enrollment. The participant has 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 may preclude participation in the study. The participant has a platelet count less than (<)60,000/microliters based on the average of 2 samples. The participant has an international normalized ratio (INR) greater than (>)1.5. The participant has 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 has had a major organ transplant (eg, bone marrow or liver). The participant is 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, is unable to adhere to the requirements of the study. The participant is 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 will not be required. The participant is 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 are potentially hepatotoxic (e.g., 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, erythromycin, valproic acid, anti-depressants, kava, echinacea) and/or may cause or prolong bleeding (e.g., anti-coagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng). The participant requires medications that may decrease olipudase alfa activity (e.g., fluoxetine, chlorpromazine, tricyclic antidepressants [e.g., imipramine, or desipramine]). The participant requires use of invasive ventilatory support. The participant requires use of noninvasive ventilator support while awake for longer than 12 hours daily. The participant is breast-feeding. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (saline) administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to placebo. | Drug: placebo (saline)<br>* Pharmaceutical form: solution administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to placebo. Route of administration: intravenous infusion<br>|
| Experimental: GZ402665<br>Olipudase alfa dose (3 mg/kg body weight) in saline administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to olipudase alfa, and during the extension treatment period for all patients. | Drug: GZ402665<br>* Pharmaceutical form: Powder for concentrate for solution for infusion administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to olipudase alfa, and during the extension treatment period for all participants. Route of administration: intravenous infusion<br>* Other names: olipudase alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline | Percent predicted Hb and Altitude-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) times Hemoglobin-adjusted factor times Altitude-adjustment factor. | Baseline (Day 1) | 
| Percent Change From Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52 | Percent predicted Hb and Altitude-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) times Hemoglobin-adjusted factor times Altitude-adjustment factor. | Baseline, Week 52 | 
| Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline | Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN). | Baseline (Day 1) | 
| Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52 | Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN. | Baseline, Week 52 | 
| Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline | The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. It was pre-specified as secondary endpoint for countries outside of US. | Baseline (Day 1) | 
| Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 | The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. It was pre-specified as secondary endpoint for countries outside of US. | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Liver Volume (in MN) at Week 52 | Liver volume was assessed by abdominal MRI in MN. | Baseline, Week 52 | 
| Percent Change From Baseline in Platelet Counts at Week 52 |  | Baseline, Week 52 | 
| Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52 | The BFI is a 9-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 9-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. Numerical rating scale ranges from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. | Baseline, Week 52 | 
| Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52 | The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale to assess pain severity and pain interference in the past 24 hours and the past week. For BPI-SF Item 3 asks participants to Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours. The numeric rating scale ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain. | Baseline, Week 52 | 
| Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52 | FACIT-Dyspnea is a 20 Item assessment that is split into two 10-item sections. The first 10-item section asks participants about the severity of their shortness of breath during various activities. The second 10-item section asks participants to rate the difficulty due to shortness of breath associated with the same activities that were referenced in the first section. For the dyspnea severity items, score range from 0=no shortness of breath; 1=mildly short of breath; 2=moderately short of breath; 3=severely short of breath. For the functional limitation items, score range from no difficult = 0, A little difficult = 1, some difficult = 2, and much difficulty =3. A raw score was calculated as: sum of individual item scores * 10/number of items answered. Raw scores were then converted to scale scores using the table included in the FACIT Dyspnea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranged between 27.7 to 75.9. Higher score represented high levels of dyspnea. | Baseline, Week 52 |