|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Patients with acid sphingomyelinase deficiency (Niemann-Pick Type B disease)
|Medical condition in easily understood language
|Patients with Niemann-Pick Type B disease
|Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|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 patients 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 patient 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 of the trial
|-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 patient 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 splenomegaly related score is part of the primary objective).
-To characterize the effect of olipudase alfa after 52 weeks of study drug administration on the following endpoints 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.
|Trial contains a sub-study
|Principal inclusion criteria
|-The patient is willing and able to provide signed written informed consent.
-The patient is male or female aged 18 years or older.
-The patient 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 patient has diffuse capacity of the lung for carbon monoxide ≤70% of the predicted normal value.
-The patient has a spleen volume ≥6 multiples of normal (MN) measured by MRI; patients 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 patient has an SRS ≥5..
-Female patients of childbearing potential must have a negative serum pregnancy test for beta-human chorionic gonadotropin (β-HCG).
-Female patients of childbearing potential and male patients 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.
|Principal exclusion criteria
|-The patient has received an investigational drug within 30 days before study enrollment.
-The patient 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 <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 patient has a platelet count <60,000/μL based on the average of 2 samples.
-The patient has an international normalized ratio (INR) >1.5.
-The patient has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >250 IU/L or total bilirubin >1.5 mg/dL (except for patients with Gilbert's syndrome).
-The patient has had a major organ transplant (eg, bone marrow or liver).
-The patient is scheduled during the study for in-patient hospitalization including elective surgery and excluding the liver biopsies required per protocol.
-The patient, in the opinion of the investigator, is unable to adhere to the requirements of the study.
-The patient 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 patient 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 (eg, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, erythromycin, valproic acid, anti-depressants, kava, echinacea) and/or may cause or prolong bleeding (eg, anti-coagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng).
-The patient requires medications that may decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine, tricyclic antidepressants [eg, imipramine, or desipramine]).
-The patient requires use of invasive ventilatory support.
-The patient requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
-The patient is breast-feeding.
|E.5 End points
|Primary end point(s)
|- Percentage change in spleen volume (combined with change in SRS in the US only, and referred to as "combination spleen endpoint").
- Percentage change in diffusing capacity of the lung for carbon monoxide.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|1 - Percentage change in liver volume
2 - Percentage change in platelet count
3 - Change in fatigue severity as measured by item 3 of the Brief Fatigue Inventory scale
4 - Change in pain severity as measured by item 3 of the Brief Pain Inventory scale
5 - Change in dyspnea severity as measured by the Fonctional Assessment of Chronic Illness Therapy dyspnea tool
6 - Number of adverse events
7 - Change in SRS (except US, where it is part of the primary "combination spleen endpoint")
|Timepoint(s) of evaluation of this end point
|1-2-3-4-5 : Baseline to Week 52
6 : Baseline to approximately 5 years
7 : Baseline to Week 52
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|Last visit of the last subject
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years