Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency
- Conditions
- Sphingomyelin Lipidosis
- Interventions
- Drug: Olipudase alfaDrug: placebo (saline)
- Registration Number
- NCT02004691
- Lead Sponsor
- Genzyme, a Sanofi Company
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 36
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Olipudase alfa Olipudase alfa 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. Placebo placebo (saline) Placebo (saline) administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to placebo.
- Primary Outcome Measures
Name Time Method Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline Baseline (Day 1) Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN).
Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52 Baseline, Week 52 Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN.
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 Baseline, 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.
Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline Baseline (Day 1) 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.
Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline Baseline (Day 1) 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.
Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 Baseline, 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 From the first infusion of investigational medicinal product (IMP) up to 52 weeks An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Reported AEs are treatment-emergent AEs that developed, worsened or became serious during the treatment period.
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 From the first infusion of IMP up to 52 weeks An AESI was defined as an AE (serious or nonserious) of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor was appropriate. AESIs included any pregnancy, symptomatic overdose, dose-limiting toxicities (DLTs) as defined in protocol and infusion associated reactions (IARs). Protocol-defined IARs were 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. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might have been judged an IAR at the discretion of the investigator or sponsor. Algorithm-defined IARs were all AEs that started between the start of infusion and the end of infusion plus 24 hours, irrespective of the perceived relation with study treatment.
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 From Baseline (Day 1) up to 52 weeks PCSA criteria: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \>3 x upper limit of normal (ULN), \>5 x ULN, \>10 x ULN and \>20 x ULN. Alkaline phosphatase (ALP) \> 1.5 x ULN. Total bilirubin \>1.5 x ULN and \>2 x ULN. ALT and total bilirubin: ALT \> 3 x ULN and total bilirubin \> 2 x ULN. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.
Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52 Baseline (Day 1) and Week 52 Number of participants with treatment-emergent ADA are presented. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.
Percent Change From Baseline in Liver Volume (in MN) at Week 52 Baseline, Week 52 Liver volume was assessed by abdominal MRI in MN.
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 Baseline, 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.
Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52 Baseline, 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.
Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52 Baseline, 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.
Trial Locations
- Locations (24)
Montefiore Medical Center Site Number : 840006
🇺🇸Bronx, New York, United States
Investigational Site Number : 380002
🇮🇹Napoli, Italy
Investigational Site Number : 380001
🇮🇹Udine, Italy
Investigational Site Number : 250001
🇫🇷Paris, France
Investigational Site Number : 276001
🇩🇪Mainz, Germany
Hospital De Clinicas De Porto Alegre Site Number : 076001
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Investigational Site Number : 392001
🇯🇵Fukushima-shi, Fukushima, Japan
Investigational Site Number : 792002
🇹🇷Ankara, Turkey
Investigational Site Number : 792003
🇹🇷Istanbul, Turkey
Investigational Site Number : 792001
🇹🇷Izmir, Turkey
Investigational Site Number : 528001
🇳🇱Amsterdam, Netherlands
Investigational Site Number : 056001
🇧🇪Leuven, Belgium
Investigational Site Number : 032001
🇦🇷Córdoba, Argentina
Investigational Site Number : 620002
🇵🇹Porto, Portugal
Investigational Site Number : 152001
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 788001
🇹🇳Tunis, Tunisia
UCSF Medical Center Site Number : 840005
🇺🇸San Francisco, California, United States
Emory University Site Number : 840003
🇺🇸Decatur, Georgia, United States
Investigational Site Number : 036001
🇦🇺Westmead, New South Wales, Australia
Investigational Site Number : 100001
🇧🇬Sofia, Bulgaria
Investigational Site Number : 792004
🇹🇷Istanbul, Turkey
Investigational Site Number : 826001
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number : 826002
🇬🇧Birmingham, United Kingdom
Investigational Site Number : 724001
🇪🇸Madrid, Spain