Sphingomyelin Lipidosis
Conditions
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.
Interventions
DRUGplacebo (saline)
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
DRUGOlipudase alfa
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
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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: 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, France, Germany, Italy, Japan, Netherlands, Portugal, Spain, Tunisia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 23 active centers in 17 countries. A total of 62 participants were screened between 18 December 2015 and 22 October 2018, out of which 36 participants were randomized.
Pre-assignment details
A total of 36 participants were randomized in a 1:1 ratio to receive either placebo or olipudase alfa in the primary analysis period (PAP) for 52 weeks. After completing PAP, participants entered an extension treatment period (ETP) where all participants received olipudase alfa up to Year 5.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5. | 18 |
| Olipudase Alfa Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5. | 18 |
| Total Title | 36 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| ETP: From Week 52 up to 5 Years | Adverse Event not Related to COVID-19 | 1 | 0 |
| ETP: From Week 52 up to 5 Years | Not Related to COVID-19 | 0 | 1 |
| ETP: From Week 52 up to 5 Years | Pregnancy | 1 | 0 |
| ETP: From Week 52 up to 5 Years | Related to Coronavirus Disease (COVID-19) | 1 | 0 |
| ETP: From Week 52 up to 5 Years | Withdrawal by Subject | 1 | 1 |
| PAP: Up to 52 Weeks | Poor compliance | 1 | 0 |
Baseline characteristics
| Characteristic | Total Title | Placebo | Olipudase Alfa |
|---|---|---|---|
| Age, Continuous | 34.81 years STANDARD_DEVIATION 14.89 | 33.46 years STANDARD_DEVIATION 17.06 | 36.17 years STANDARD_DEVIATION 12.72 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 32 Participants | 16 Participants | 16 Participants |
| Sex: Female, Male Female | 22 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 14 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 13 / 18 | 17 / 18 | 9 / 17 | 12 / 18 |
| serious Total, serious adverse events | 4 / 18 | 3 / 18 | 6 / 17 | 5 / 18 |
Outcome results
Primary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52 | 0.481 percent change | Standard Error 2.5002 |
| Olipudase Alfa | Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52 | -39.446 percent change | Standard Error 2.4294 |
p-value: <0.000195% CI: [-47.051, -32.803]Mixed model for repeated measures
Primary
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).
Time frame: Baseline (Day 1)
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline | 11.21 multiples of normal (MN) | Standard Deviation 3.84 |
| Olipudase Alfa | Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline | 11.69 multiples of normal (MN) | Standard Deviation 4.92 |
Primary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 | -9.281 score on a scale | Standard Error 2.4165 |
| Olipudase Alfa | Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 | -7.664 score on a scale | Standard Error 2.3481 |
p-value: =0.636495% CI: [-5.302, 8.538]Mixed model for repeated measures
Primary
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.
Time frame: Baseline (Day 1)
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline | 28.05 score on a scale | Standard Deviation 10.56 |
| Olipudase Alfa | Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline | 24.55 score on a scale | Standard Deviation 11.13 |
Primary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 | 2.961 percent change | Standard Error 3.3832 |
| Olipudase Alfa | 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 | 21.968 percent change | Standard Error 3.3362 |
p-value: =0.000495% CI: [9.319, 28.696]Mixed model for repeated measures
Primary
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.
Time frame: Baseline (Day 1)
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline | 48.45 % Predicted DLco | Standard Deviation 10.76 |
| Olipudase Alfa | Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline | 49.44 % Predicted DLco | Standard Deviation 10.99 |
Secondary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52 | -6.769 score on a scale | Standard Error 1.9132 |
| Olipudase Alfa | Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52 | -5.862 score on a scale | Standard Error 1.6918 |
Secondary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52 | -1.806 score on a scale | Standard Error 0.5272 |
| Olipudase Alfa | Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52 | -1.862 score on a scale | Standard Error 0.5129 |
Comparison: A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.p-value: =0.9495% CI: [-1.566, 1.454]Mixed model for repeated measures
Secondary
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.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52 | -2.293 score on a scale | Standard Error 0.5899 |
| Olipudase Alfa | Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52 | -1.404 score on a scale | Standard Error 0.5742 |
Secondary
Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to 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.
Time frame: Baseline (Day 1) and Week 52
Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52 | 1 Participants |
| Olipudase Alfa | Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52 | 4 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52
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.
Time frame: From the first infusion of IMP up to 52 weeks
Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Symptomatic Overdose | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Protocol-defined IARs | 5 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | DLTs | 5 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Algorithm-defined IARs | 13 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Pregnancy | 0 Participants |
| Olipudase Alfa | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Algorithm-defined IARs | 15 Participants |
| Olipudase Alfa | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Pregnancy | 0 Participants |
| Olipudase Alfa | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Symptomatic Overdose | 0 Participants |
| Olipudase Alfa | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | DLTs | 1 Participants |
| Olipudase Alfa | Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 | Protocol-defined IARs | 8 Participants |
Secondary
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52
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.
Time frame: From Baseline (Day 1) up to 52 weeks
Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >3 x ULN | 2 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >5 x ULN | 1 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >10 x ULN | 0 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >20 x ULN | 0 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >3 x ULN | 2 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >5 x ULN | 1 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >10 x ULN | 0 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >20 x ULN | 0 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALP: >1.5 x ULN | 1 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | Total Bilirubin: >1.5 x ULN | 4 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | Total Bilirubin: >2 x ULN | 1 Participants |
| Placebo | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT >3 x ULN and total bilirubin >2 x ULN | 0 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | Total Bilirubin: >2 x ULN | 4 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >3 x ULN | 1 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >10 x ULN | 0 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >5 x ULN | 1 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | Total Bilirubin: >1.5 x ULN | 4 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >10 x ULN | 0 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >20 x ULN | 0 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT: >20 x ULN | 0 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALT >3 x ULN and total bilirubin >2 x ULN | 1 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >3 x ULN | 2 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | ALP: >1.5 x ULN | 1 Participants |
| Olipudase Alfa | Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 | AST: >5 x ULN | 1 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52
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.
Time frame: From the first infusion of investigational medicinal product (IMP) up to 52 weeks
Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 | TEAEs | 18 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 | TESAEs | 4 Participants |
| Olipudase Alfa | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 | TEAEs | 18 Participants |
| Olipudase Alfa | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 | TESAEs | 3 Participants |
Secondary
Percent Change From Baseline in Liver Volume (in MN) at Week 52
Liver volume was assessed by abdominal MRI in MN.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Liver Volume (in MN) at Week 52 | -1.468 percent change | Standard Error 2.5409 |
| Olipudase Alfa | Percent Change From Baseline in Liver Volume (in MN) at Week 52 | -28.064 percent change | Standard Error 2.4899 |
Comparison: A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.p-value: <0.000195% CI: [-33.911, -19.281]Mixed model for repeated measures
Secondary
Percent Change From Baseline in Platelet Counts at Week 52
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Platelet Counts at Week 52 | 2.490 percent change | Standard Error 4.1923 |
| Olipudase Alfa | Percent Change From Baseline in Platelet Counts at Week 52 | 16.822 percent change | Standard Error 3.9596 |
Comparison: A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.p-value: =0.018595% CI: [2.564, 26.099]Mixed model for repeated measures