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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Sanofi
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT02004691
First received: November 26, 2013
Last updated: March 9, 2017
Last verified: March 2017
  Purpose

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 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:

  • 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.

Condition Intervention Phase
Sphingomyelin Lipidosis
Drug: placebo (saline)
Drug: GZ402665
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Percentage change in spleen volume (combined with change in SRS in the US only, and referred to as "combination spleen endpoint") [ Time Frame: Baseline to Week 52 ]
  • Percentage change in diffusing capacity of the lung for carbon monoxide [ Time Frame: Baseline to Week 52 ]

Secondary Outcome Measures:
  • Change in splenomegaly-related symptom score (except US, where it is part of the primary "combination spleen endpoint") [ Time Frame: Baseline to Week 52 ]
  • Percentage change in liver volume [ Time Frame: Baseline to Week 52 ]
  • Percentage change in platelet count [ Time Frame: Baseline to Week 52 ]
  • Change in fatigue severity as measured by item 3 of the Brief Fatigue Inventory scale [ Time Frame: Baseline to Week 52 ]
  • Change in pain severity as measured by item 3 of the Brief Pain Inventory scale [ Time Frame: Baseline to Week 52 ]
  • Change in dyspnea severity as measured by the Functional Assessment of Chronic Illness Therapy dyspnea tool [ Time Frame: Baseline to Week 52 ]
  • Number of adverse events [ Time Frame: Baseline to approximately 5 years ]

Estimated Enrollment: 36
Study Start Date: December 2015
Estimated Study Completion Date: July 2023
Estimated Primary Completion Date: July 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GZ402665
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

Pharmaceutical form: Powder for concentrate for solution for infusion administered once every two 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.

Route of administration: intravenous infusion

Other Name: olipudase alfa
Placebo Comparator: Placebo
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)

Pharmaceutical form: solution administered once every two weeks during the 52 weeks of the primary analysis period for patients randomized to placebo.

Route of administration: intravenous infusion


Detailed Description:

The total duration per patient is 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 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.

The study will be divided into 2 consecutive major periods: 1) a randomized placebo-controlled, double-blinded primary analysis period (PAP) from day -60 to week 52, which will be followed by 2) an extension treatment period (ETP) that will last up to 4 years and 1 month and during which all patients will receive olipudase alfa.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 a mean SRS of at least 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.

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 valvular dysfunction, or <40% left ventricular ejection fraction by echocardiogram); active hepatitis B or hepatitis C, or infection with human immunodeficiency virus (HIV); cirrhosis (as determined by clinical evaluation or liver biopsy); malignancy diagnosed within the past 5 years (other than basal cell carcinoma), or any other extenuating circumstance that may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
  • The patient has a platelet count <60,000/μL.
  • 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 (e.g., 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 (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 patient requires medications that may decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine, tricyclic antidepressants [e.g., 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.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02004691

Contacts
Contact: For site information, send an email with site number to Contact-Us@sanofi.com

Locations
United States, California
Investigational Site Number 840005 Recruiting
San Francisco, California, United States, 94143
United States, Georgia
Investigational Site Number 840003 Recruiting
Decatur, Georgia, United States, 30033
Australia
Investigational Site Number 036001 Recruiting
Westmead, Australia, 2145
Brazil
Investigational Site Number 076001 Recruiting
Porto Alegre, Brazil, 90035 003
Chile
Investigational Site Number 152001 Recruiting
Santiago, Chile, 753-0204
France
Investigational Site Number 250001 Recruiting
Paris, France, 75020
Germany
Investigational Site Number 276001 Recruiting
Mainz, Germany, 55131
Italy
Investigational Site Number 380002 Recruiting
Napoli, Italy, 80131
Investigational Site Number 380001 Recruiting
Udine, Italy, 33100
Japan
Investigational Site Number 392001 Recruiting
Fukushima-Shi, Japan
Netherlands
Investigational Site Number 528001 Recruiting
Amsterdam, Netherlands, 1105 AZ
Portugal
Investigational Site Number 620001 Recruiting
Coimbra, Portugal, 3041-801
Investigational Site Number 620002 Recruiting
Porto, Portugal, 4099-001
Spain
Investigational Site Number 724001 Recruiting
Madrid, Spain, 28034
Turkey
Investigational Site Number 792002 Recruiting
Ankara, Turkey, 06500
Investigational Site Number 792001 Recruiting
Izmir, Turkey, 35040
United Kingdom
Investigational Site Number 826002 Recruiting
Birmingham, United Kingdom, B15 2TH
Investigational Site Number 826001 Recruiting
London, United Kingdom, WC1N 3JZ
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT02004691     History of Changes
Other Study ID Numbers: DFI12712
2015‐000371‐26 ( EudraCT Number )
U1111-1142-5963 ( Other Identifier: UTN )
Study First Received: November 26, 2013
Last Updated: March 9, 2017

Additional relevant MeSH terms:
Niemann-Pick Disease, Type A
Niemann-Pick Diseases
Niemann-Pick Disease, Type C
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lymphatic Diseases
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Lipidoses
Sphingolipidoses
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Metabolism, Inborn Errors
Lipid Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on March 24, 2017