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
Overview
- Phase
- Phase 2
- Intervention
- Velmanase Alfa (e.g. Lamazym)
- Conditions
- Alpha-Mannosidosis
- Sponsor
- Chiesi Farmaceutici S.p.A.
- Enrollment
- 5
- Primary Endpoint
- Safety and tolerability of velmanase alfa as per Adverse events
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient's custodial parent(s) must provide signed ICF prior to the involvement of the patient in any trial-related activities
- •The subject's custodial parent(s) must have the ability to comply with the protocol
- •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)
- •The subject must have an age at the time of screening \< 6 years.
Exclusion Criteria
- •The subject's diagnosis cannot be confirmed by alpha-mannosidase activity \< 10% of normal activity
- •Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-mannosidosis
- •History of BMT
- •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
- •Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
- •Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial
- •Participation in other interventional trials testing the IMP within the last 3 months.
Arms & Interventions
Velmanase Alfa
velmanase alfa 1mg/kg body weight infusion
Intervention: Velmanase Alfa (e.g. Lamazym)
Outcomes
Primary Outcomes
Safety and tolerability of velmanase alfa as per Adverse events
Time Frame: From baseline throughout study completion, at least of 2 years
Safety and tolerability assessed as per AEs including infusion-related reactions \[IRRs\]
Safety and tolerability of velmanase alfa as per vital signs
Time Frame: From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology
Time Frame: 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
Time Frame: From baseline throughout study completion, at least of 2 years
Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis
Time Frame: From baseline throughout study completion, at least of 2 years
Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies
Time Frame: From baseline throughout study completion, at least of 2 years
Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained
Secondary Outcomes
- Evaluation of levels of Serum oligosaccharides(From baseline throughout study completion, at least for 2 years)
- Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)(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))