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Safety and Dose Ranging Study of Human Insulin Receptor MAb-IDUA Fusion Protein in Adults and Children With MPS I

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ClinicalTrials.gov Identifier: NCT03053089
Recruitment Status : Completed
First Posted : February 14, 2017
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
ArmaGen, Inc

Brief Summary:

AGT-181 is a fusion protein containing alpha-L-iduronidase that is intended to deliver the enzyme peripherally and to the brain, when administered intravenously. This is a safety and tolerability study to obtain safety and exposure data as well as information on the biological activity of the investigational drug.

This is a two-stage, sequential, single and multi-dose study of AGT-181 in patients with MPS I. The first stage will be an open-label, single-dose, dose-escalation cohort study and the second stage will be an open-label, multi dose, adaptive dose escalation cohort study.


Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis I Drug: AGT-181 Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Stage 1: 6 adults will be given a single dose, assigned to 0.3, 1.0 or 3.0 mg/kg (with cohort assignment based on order of study entry)

Stage 2: up to 15 children will be given repeat weekly doses for 26 weeks, assigned to 1.0, 3.0 and 6.0 or 9.0 mg/kg (with cohort assignment based on order of study entry). Early term

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two-Stage, Phase 1/2, Open-Label Study of the Human Insulin Receptor Monoclonal Antibody-Human Alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein, AGT-181 in Patients With Mucopolysaccharidosis I (MPS I, Hurler Syndrome)
Actual Study Start Date : October 2015
Actual Primary Completion Date : February 1, 2018
Actual Study Completion Date : February 1, 2018


Arm Intervention/treatment
Experimental: Stage 1 (adult)
AGT-181
Drug: AGT-181
Human Insulin Receptor Monoclonal Antibody-Human alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein

Experimental: Stage 2 (children)
AGT-181
Drug: AGT-181
Human Insulin Receptor Monoclonal Antibody-Human alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein




Primary Outcome Measures :
  1. Stage 1: number of patients with adverse events as a measure of safety and tolerability of a single dose [ Time Frame: 4 weeks ]
  2. Stage 2: number of patients with adverse events as a measure of safety and tolerability of repeat weekly doses [ Time Frame: 26 weeks ]

Secondary Outcome Measures :
  1. PK parameters (maximal concentration, half-life, AUC, distribution and clearance) of AGT-181 [ Time Frame: 26 weeks ]
  2. change in total urinary glycosaminoglycans (GAGs) [ Time Frame: 26 weeks ]
  3. change in functional capacity (6-minute walk test) or lung function (forced vital capacity) [ Time Frame: 26 weeks ]
  4. change in shoulder range of motion (ROM) [ Time Frame: 26 weeks ]
  5. change in liver and/or spleen volume (measured by MRI) [ Time Frame: 26 weeks ]

Other Outcome Measures:
  1. change in levels of heparan sulfate and/or dermatan sulfate in cerebrospinal fluid (CSF) [ Time Frame: 26 weeks ]
  2. change in levels of heparan sulfate and/or dermatan sulfate in plasma [ Time Frame: 26 weeks ]
  3. change in neurocognition (measured by VABS-II and BSID-III or KABC-II) [ Time Frame: 26 weeks ]
  4. change in CNS neuroimaging (brain volumetric MRI and diffusion tensor imaging, DTI) [ Time Frame: 26 weeks ]


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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written consent and assent as required
  • Diagnosis of MPS 1 confirmed by clinical signs and symptoms, documented fibroblast or leukocyte IDUA enzyme activity of less than 10% the lower limit of normal
  • Female patients must not be pregnant, willing to utilize appropriate birth control methods and undergo pregnancy testing during the study
  • if taking standard ERT, must be willing to discontinue for 1 week prior to dosing and for the study duration

Additional Inclusion Criteria, Stage 1:

  • 18 years of age or older
  • must have a diagnosis of Hurler-Scheie or Scheie syndrome

Additional Inclusion Criteria, Stage 2:

  • 2 years of age or older (and less than 18)
  • must be willing to undergo CNS testing, including assessment of CSF via lumbar puncture, MRI scans and neurocognitive testing
  • must have evidence of Hurler-Scheie or Scheie with CNS involvement, as evidence by:
  • score of 1 to 3 standard deviations below mean on IQ testing (i.e. IQ=55 or more) or in one domain of neuropsychological function (language, memory, non-verbal ability) OR
  • documented historical evidence of a decline greater than 1 standard deviation on sequential testing, OR
  • score between 0.75 and 1 standard deviation below the mean, AND cognitive deficit affects daily performance

Exclusion Criteria:

  • Refusal to complete all assessments
  • Pregnant or Lactating
  • Received investigational drug within 1 year prior to study enrollment
  • Medical condition or extenuating circumstance that, in the opinion of the investigator, may interfere with study compliance
  • CSF pressure greater than 25 cm H20 (18 mm Hg)
  • Known hypersensitivity to alpha-L-iduronidase (IDUA/Aldurazyme) or any components/excipients found in AGT-181
  • Previous successful (engrafted) hematopoietic stem cell transplantation which has resulted in normalization of urinary glycosaminoglycans (GAGs); or major organ transplantation
  • Clinically significant spinal cord compression or evidence of cervical instability (i.e. expected to require intervention during study participation)
  • History of diabetes mellitus or hypoglycemia

Additional Exclusion Criteria, Stage 2:

  • Has ventriculoperitoneal shunt
  • IQ below 55
  • Previously received AGT-181 in Stage 1 of the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03053089


Locations
Brazil
HCPA - Hospital das Clinicas de Porto Alegre
Porto Alegre, RS, Brazil, 90035-903
Sponsors and Collaborators
ArmaGen, Inc
Investigators
Study Director: Patrice P Rioux, MD PhD ArmaGen, Inc

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: ArmaGen, Inc
ClinicalTrials.gov Identifier: NCT03053089     History of Changes
Other Study ID Numbers: AGT-181-101
First Posted: February 14, 2017    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ArmaGen, Inc:
MPS I; Hurler Syndrome

Additional relevant MeSH terms:
Mucopolysaccharidoses
Mucopolysaccharidosis I
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Insulin, Globin Zinc
Insulin
Antibodies, Monoclonal
Hypoglycemic Agents
Physiological Effects of Drugs
Immunologic Factors