Clinical trial NCT02998879: Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alpha-Mannosidosis
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
Collaborators: name: Cromsource
First posted: 2016-12-21
Enrollment: 5
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and tolerability of velmanase alfa as per Adverse events
timeFrame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per vital signs
timeFrame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology
timeFrame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per blood biochemistry
timeFrame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis
timeFrame: From baseline throughout study completion, at least of 2 years
measure: Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies
timeFrame: From baseline throughout study completion, at least of 2 years
Secondary outcomes:
measure: Evaluation of levels of Serum oligosaccharides
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Functional capacity: Bruininks-Oseretsky test of Motor Proficiency (BOT-2) when applicable by age (from 4 years) or upon the judgment of the physician
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Functional capacity: Mullen Scales of Early Learning (MSEL)
timeFrame: From baseline throughout study completion, at least for 2 years
measure: 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
timeFrame: From baseline throughout study completion, at least for 2 years
measure: 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
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Hearing evaluation: Otoacoustic Emissions (OAE) testing
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Hearing evaluation: Automatic Auditory Brainstem Response (A-ABR) audiometry
timeFrame: From baseline throughout study completion, at least for 2 years
measure: 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)
timeFrame: From baseline throughout study completion, at least for 2 years
measure: CSF biomarkers: Tau protein (Tau) § Neurofilament Protein Light (NFL) § Glial Fibrillary Acidic Protein (GFAp) § Oligosaccharides
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Assessment of quality of life via Questionnaire
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Assessment of mannose-rich oligosaccharides in brain tissue, as measured by Magnetic Resonance Spectroscopy (MRS)
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Magnetic Resonance Imaging (MRI) in white matter, gray matter and in centrum semi ovale, and diffusion-MRI of the brain,
timeFrame: From baseline throughout study completion, at least for 2 years
measure: Pharmacokinetic parameters to determine Cmax (Peak Concentration)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Ctrough (Trough Plasma Concentration)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Area Under Curve (AUC24)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine AUClast (Area Under Curve After The Last Count)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine AUCinf (Area Under Curve From Time Zero To Infinity)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine tmax (Time To Peak Concentration)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine CL (Clearance)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine t1/2 (Elimination Half-Life)
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Rac (Obs) Observed Accumulation Ratio
timeFrame: At first dose (visit 1) and after 6 months (visit 26)
Other outcomes:
Locations:
city: Wien
country: Austria
city: Copenhagen
country: Denmark
city: Lyon
country: France
city: Hamburg
country: Germany
city: Mainz
country: Germany
city: Trieste
country: Italy
Study officials:
References: