Safety Study of rhASM Enzyme Replacement Therapy in Adults With Acid Sphingomyelinase Deficiency (Niemann-Pick Disease)

A Phase I, Single-Center, Single Dose, Dose Escalation Study of Recombinant Human Acid Sphingomyelinase (rhASM) in Adults With Acid Sphingomyelinase Deficiency (ASMD)

The purpose of this study is to determine the safe range of single doses of rhASM administered to adults with ASM deficiency.

Study Overview

• Status: Terminated
• Conditions: Niemann-Pick Disease; Acid Sphingomyelinase Deficiency
• Intervention / Treatment: Drug: rhASM; Drug: rhASM; Drug: rhASM; Drug: rhASM; Drug: rhASM

Detailed Description

ASM deficiency (ASMD), also known as Niemann-Pick A and B disease, is a rare genetic disorder in which reduced activity of the lysosomal enzyme, ASM, leads to the accumulation of sphingomyelin primarily in macrophages throughout the body. This deficiency results in characteristic features such as hepatosplenomegaly, thrombocytopenia, interstitial lung disease, growth retardation, coronary artery disease, fatigue, and in severe cases, neurodegeneration with death in early childhood. There is no specific treatment for this disease. This Phase 1 safety study will seek to enroll a minimum of 12 and a maximum of 30 eligible adults patients with ASMD with each patient participating for approximately 7 weeks.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed, informed consent by the patient or legal guardian prior to performing any study-related procedures;
• Have ≤ 0.2 nmol/hr/mg protein ASM activity in peripheral leukocytes, as measured by the reference laboratory;
• Have a diffusing capacity (DLco) > 30% of the predicted normal value;
• Have a spleen volume ≥ 2x normal
• Female patients of childbearing potential must have a serum pregnancy test negative for β-hCG and agree to use a reliable birth control method for the duration of the study.

Exclusion Criteria:

• Is pregnant or lactating;
• Has received an investigational drug within 30 days prior to study enrollment;
• Has a medical condition, including serious intercurrent illness, active hepatitis B or C or human immunodeficiency virus (HIV) infection, cirrhosis, > stage 3 liver fibrosis, INR >1.5, platelet count < 60.0x10^3/µL, significant cardiac disease (e.g. pulmonary artery pressure > 40 mm Hg, moderate or severe valvular dysfunction, or < 40% left ventricular ejection fraction by echocardiography (ECHO)), or any other extenuating circumstances that may significantly interfere with study compliance including all prescribed evaluations and follow-up activities;
• Has had a major organ transplant (e.g. bone marrow or liver);
• Has had a total splenectomy;
• Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >250 IU/L or a total bilirubin >3.6 mg/dL;
• Is unwilling or unable to avoid the use of alcohol, medications that may decrease rhASM activity, medications or herbal supplements that may cause or prolong bleeding, and the use of medications or herbal supplements with potential hepatoxicity within 14 days prior to and 28 days afte the rhASM infusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: rhASM; Single dose of 0.03mg/kg body weight IV; Drug: rhASM; Single dose of 0.1mg/kg body weight IV; Drug: rhASM; Single dose of 0.3mg/kg body weight IV; Drug: rhASM; Single dose of 0.6mg/kg body weight IV; Drug: rhASM; Single dose of 1.0mg/kg body weight IV
Experimental: 2	Drug: rhASM; Single dose of 0.03mg/kg body weight IV; Drug: rhASM; Single dose of 0.1mg/kg body weight IV; Drug: rhASM; Single dose of 0.3mg/kg body weight IV; Drug: rhASM; Single dose of 0.6mg/kg body weight IV; Drug: rhASM; Single dose of 1.0mg/kg body weight IV
Experimental: 3	Drug: rhASM; Single dose of 0.03mg/kg body weight IV; Drug: rhASM; Single dose of 0.1mg/kg body weight IV; Drug: rhASM; Single dose of 0.3mg/kg body weight IV; Drug: rhASM; Single dose of 0.6mg/kg body weight IV; Drug: rhASM; Single dose of 1.0mg/kg body weight IV
Experimental: 4	Drug: rhASM; Single dose of 0.03mg/kg body weight IV; Drug: rhASM; Single dose of 0.1mg/kg body weight IV; Drug: rhASM; Single dose of 0.3mg/kg body weight IV; Drug: rhASM; Single dose of 0.6mg/kg body weight IV; Drug: rhASM; Single dose of 1.0mg/kg body weight IV
Experimental: 5	Drug: rhASM; Single dose of 0.03mg/kg body weight IV; Drug: rhASM; Single dose of 0.1mg/kg body weight IV; Drug: rhASM; Single dose of 0.3mg/kg body weight IV; Drug: rhASM; Single dose of 0.6mg/kg body weight IV; Drug: rhASM; Single dose of 1.0mg/kg body weight IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety assessments via physical exam,AE reporting,telemetry heartrate monitoring,ECG,ECHO,clinical lab evaluations,liver and adrenal function tests,cytokine testing,adrenal hormone levels,lipid profile,chest Xrays,liver biopsies,MRI of internal	Pre-, During-, and Post-infusion (up to 72 hrs); 14 day and 28 day follow-up visit
Immune Response Measure	Pre-infusion and final visit (Day 28)

Secondary Outcome Measures

Outcome Measure	Time Frame
PK measurements	Pre- and Post-infusion up to 72 hrs.

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: December 11, 2006
• First Submitted That Met QC Criteria: December 11, 2006
• First Posted (Estimate): December 13, 2006

Study Record Updates

• Last Update Posted (Estimate): March 19, 2015
• Last Update Submitted That Met QC Criteria: March 17, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Treatment; Enzyme replacement therapy; Lysosomal storage disorder; Acid sphingomyelinase deficiency; Niemann-Pick disease
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Genetic Diseases, Inborn; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Language Disorders; Communication Disorders; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C
• Other Study ID Numbers: SPHINGO00605