Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis (rhLaman-08)

A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated Velmanase Alfa (Recombinant Human Alpha-mannosidase) Treatment in Pediatric Patients Below 6 Years of Age With Alpha-Mannosidosis

The main objectives of the study are to evaluate safety and efficacy of repeated treatment with recombinant human alfa-mannosidase of patients with alfa-mannosidosis aged less than 6 years

Study Overview

• Status: Completed
• Conditions: Alpha-Mannosidosis
• Intervention / Treatment: Drug: Velmanase Alfa (e.g. Lamazym)

Detailed Description

The Primary endpoints of the study include:

• Safety and tolerability of velmanase alfa as per Adverse events (AEs, including IRR), vital signs, laboratory parameters (hematology, biochemistry and urinanalysis)
• Detection of anti-velmanase alfa antibodies and neutralizing/inhibitory antibodies

The Secondary endpoints include changes from baseline to 24 months for the following parameters. Efficacy outcomes:

• Serum oligosaccharides
• Functional capacity: Peabody Developmental Motor Scale - 2nd edition (PDMS-2) scores, Mullen's Scale of Early Learning (MSEL) scores, Bruininks-Oseretsky Test Of Motor Proficiency-2nd Edition (BOT-2), when applicable by age (from 4 years) or upon the judgment of the physician
• Endurance: 3-Minute Stair Climb Test (3MSCT) and 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician, 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age, or when applicable according to the judgment of the physician
• Hearing evaluation: Otoacoustic Emissions (OAE) testing, Automatic Auditory Brainstem Response (A-ABR) audiometry
• Immunological profile, when applicable upon the judgment of the physician:
• CSF biomarkers: Tau protein (Tau), Neurofilament Protein Light (NFL), Glial Fibrillary Acidic Protein (GFAp), Oligosaccharides
• Assessment of quality of life via Questionnaire to parents
• Assessment of mannose-rich oligosaccharides in brain tissue, MRI
• Pharmacokinetic parameters

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria
• Denmark
  • Copenhagen, Denmark
• France
  • Lyon, France
• Germany
  • Hamburg, Germany
  • Mainz, Germany
• Italy
  • Trieste, Italy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient's custodial parent(s) must provide signed ICF prior to the involvement of the patient in any trial-related activities
2. The subject's custodial parent(s) must have the ability to comply with the protocol
3. The subject must have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity in leukocytes or fibroblasts < 10% of normal activity (historical data)
4. The subject must have an age at the time of screening < 6 years.

Exclusion Criteria:

1. The subject's diagnosis cannot be confirmed by alpha-mannosidase activity < 10% of normal activity
2. Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-mannosidosis
3. History of BMT
4. Presence of known clinically significant cardiovascular, hepatic, pulmonary, or renal disease or other medical conditions that, in the opinion of the Investigator, would preclude participation in the trial
5. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
6. Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial
7. Participation in other interventional trials testing the IMP within the last 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Velmanase Alfa; velmanase alfa 1mg/kg body weight infusion	Drug: Velmanase Alfa (e.g. Lamazym); iv infusion treatment; Other Names: Lamazym

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of velmanase alfa as per Adverse events	Safety and tolerability assessed as per AEs including infusion-related reactions [IRRs]	From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per vital signs		From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology		From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per blood biochemistry		From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis		From baseline throughout study completion, at least of 2 years
Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies	Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained	From baseline throughout study completion, at least of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of levels of Serum oligosaccharides	Assessment of change from baseline in levels of Serum oligosaccharides	From baseline throughout study completion, at least for 2 years
Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)	Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained	From baseline throughout study completion, at least for 2 years
Functional capacity: Bruininks-Oseretsky test of Motor Proficiency (BOT-2) when applicable by age (from 4 years) or upon the judgment of the physician		From baseline throughout study completion, at least for 2 years
Functional capacity: Mullen Scales of Early Learning (MSEL)		From baseline throughout study completion, at least for 2 years
Endurance: 3-Minute Stair Climb Test (3MSCT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician		From baseline throughout study completion, at least for 2 years
Endurance: 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age		From baseline throughout study completion, at least for 2 years
Hearing evaluation: Otoacoustic Emissions (OAE) testing		From baseline throughout study completion, at least for 2 years
Hearing evaluation: Automatic Auditory Brainstem Response (A-ABR) audiometry		From baseline throughout study completion, at least for 2 years
Immunological profile when applicable upon the judgement of the physician (Serum IgG, IgA, IgM; in vitro synthesis of IgG; in vitro proliferative response and Immunophenotype)		From baseline throughout study completion, at least for 2 years
CSF biomarkers: Tau protein (Tau) § Neurofilament Protein Light (NFL) § Glial Fibrillary Acidic Protein (GFAp) § Oligosaccharides		From baseline throughout study completion, at least for 2 years
Assessment of quality of life via Questionnaire		From baseline throughout study completion, at least for 2 years
Assessment of mannose-rich oligosaccharides in brain tissue, as measured by Magnetic Resonance Spectroscopy (MRS)		From baseline throughout study completion, at least for 2 years
Magnetic Resonance Imaging (MRI) in white matter, gray matter and in centrum semi ovale, and diffusion-MRI of the brain,		From baseline throughout study completion, at least for 2 years
Pharmacokinetic parameters to determine Cmax (Peak Concentration)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine Ctrough (Trough Plasma Concentration)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine Area Under Curve (AUC24)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine AUClast (Area Under Curve After The Last Count)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine AUCinf (Area Under Curve From Time Zero To Infinity)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine tmax (Time To Peak Concentration)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine CL (Clearance)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine t1/2 (Elimination Half-Life)		At first dose (visit 1) and after 6 months (visit 26)
Pharmacokinetic parameters to determine Rac (Obs) Observed Accumulation Ratio		At first dose (visit 1) and after 6 months (visit 26)

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Collaborators: Cromsource

Publications and helpful links

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): July 1, 2020
• Study Completion (Actual): July 1, 2020

Study Registration Dates

• First Submitted: November 25, 2016
• First Submitted That Met QC Criteria: December 16, 2016
• First Posted (Estimate): December 21, 2016

Study Record Updates

• Last Update Posted (Actual): October 26, 2021
• Last Update Submitted That Met QC Criteria: October 18, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mannosidase Deficiency Diseases; alpha-Mannosidosis
• Other Study ID Numbers: CCD-LMZYMAA1-08; 2016-001988-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No