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Big delay on study activation (approval procedures by IRBs, hospitals contract negotiation) and on enrolment deadline due to CoViD-19; Placebo stock expires November 2021 and new batch not be available for at least one year
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Randomized, double-blind, placebo-controlled, parallel group study where subjects will receive velmanase alfa or placebo for 24 weeks.
Each subject undergoes to 8 complete visits at the clinic for clinical, laboratory and functional assessments. Study treatment is administered weekly through i.v. infusions
A Screening visit (V1) will take place 7±3 days prior to randomization in order to give the subject enough time to consider their participation in the study, to plan the next visits including the long-stay visits at V2, V5 and V8 (long-stay visits as PK and certain tests are performed over more than one day), and to allow the clinic center to complete the evaluation of the eligibility criteria.
Upon confirmation of eligibility, subjects will be randomized to receive weekly i.v. administration of either velmanase alfa 1 mg/kg or placebo.
Thereafter, subjects will undergo weekly visits for administration of study treatment and safety data collection. Clinical, laboratory and functional assessments will be performed at the 4-weekly assessment visits with each subject undergoing a minimum of 8 assessment visits (V1 to V8).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Velmanase alfa | Experimental |
| |
| placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Velmanase Alfa | Drug | infusion i.v. treatment |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Change in concentration of serum oligosaccharides | To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Level of serum oligosaccharides; | 24 weeks (end of study) |
| Change in serum level of total immunoglobulin (Ig)G level | Efficacy of velmanase alfa compared with placebo in alpha mannosidosis subjects based on serum levels of total immunoglobulin (Ig)G after 24 weeks of velmanase alfa treatment | 24 weeks (end of study) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Intracellular level of oligosaccharides in peripheral blood leukocytes | To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Intracellular level of oligosaccharides accumulated in peripheral blood leukocytes. | 24 weeks (end of study) |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events (AEs) | Number of AEs will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Infusion Related Reactions (IRRs) | Number of IRRs will be described for each patient and cumulatively in the safety population |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Paul Harmatz, MD | UCSF Benioff Children's Hospital Oakland | Principal Investigator |
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| ID | Term |
|---|---|
| D008363 | alpha-Mannosidosis |
| D044904 | Mannosidase Deficiency Diseases |
| ID | Term |
|---|---|
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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double-blind, randomized 2:1 to either velmanase alfa:placebo
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Randomized using IRT system
| Drug |
infusion i.v. treatment |
|
| Change in serum IgG Subclasses |
To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Subclasses of IgG; |
| 24 weeks (end of study) |
| Incidence of Infections | Change in number of infections requiring antibiotics and/or hospitalization and/or loss of school/working days | 24 weeks (end of study) |
| Assessment of PK parameter Maximum plasma Concentration [Cmax] | To collect additional data on Cmax profile following velmanase alfa treatment | 12 weeks |
| Assessment of PK parameter Maximum plasma Concentration [Cmax] | To collect additional data on Cmax profile following velmanase alfa treatment | 24 weeks (end of study) |
| Assessment of PK parameter Area Under the Curve [AUC] | To collect additional data on AUC profile following velmanase alfa treatment | 24 weeks (end of study) |
| Assessment of PK parameter Area Under the Curve [AUC] | To collect additional data on AUC profile following velmanase alfa treatment | 12 weeks |
| Assessment of PK parameter Elimination half-life [t1/2] | To collect additional data on t1/2 profile following velmanase alfa treatment | 12 weeks |
| Assessment of PK parameter Elimination half-life [t1/2] | To collect additional data on t1/2 profile following velmanase alfa treatment | 24 weeks (end of study) |
| Assessment of PK parameter trough concentration (Ctrough) | To collect additional data on Ctrough profile following velmanase alfa treatment | 12 weeks |
| Assessment of PK parameter trough concentration (Ctrough) | To collect additional data on Ctrough profile following velmanase alfa treatment | 24 weeks (end of study) |
| 24 weeks (end of study) |
| Incidence of Adverse Drug Reactions (ADRs) | Number of ADRs will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Anty-Drug Antibody (ADA) level | Change in ADA will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Neutralizing Antibody (NAb) level | Change in NAb levels will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Change on Immunoglobuline Type A (IgA) values | Change in IgA levels will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Change on Immunoglobuline Type M (IgM) values | Change in IgM levels will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| Change on B-cell immunophenotype level | Change in B-cell immunophenotype levels will be described for each patient and cumulatively in the safety population | 24 weeks (end of study) |
| 3MSCT (3-Minute Stair Climb Test) | Change from baseline in motricity tests (climbing test) will be described for each patient | 24 weeks (end of study) |
| 6MWT (2MWT for children) (6- or 2-Minute Walk Test) | Change from baseline in motricity tests (walking test) will be described for each patient | 24 weeks (end of study) |
| FVC, FEV1 and PEF | Change from baseline in respiratory tests (Spirometry) will be described for each patient | 24 weeks (end of study) |
| Psychotic events | Change from baseline in number of psychotic events will be described for each patient | 24 weeks (end of study) |
| Shoulder mobility | Change from baseline in shoulder mobility will be described for each patient | 24 weeks (end of study) |
| ECG PR interval | Change from baseline in electrocardiogram (ECG) PR interval will be described for each patient | 24 weeks (end of study) |
| ECG QT interval | Change from baseline in electrocardiogram (ECG) QT interval will be described for each patient | 24 weeks (end of study) |
| ECG QRS duration | Change from baseline in electrocardiogram (ECG) QRS duration will be described for each patient | 24 weeks (end of study) |
| Heart diseases | Change from baseline in Echocardiogram will be described for each patient | 24 weeks (end of study) |
| Hearing testing | Change from baseline in hearing testing through PTA will be described for each patient | 24 weeks (end of study) |
| Kaufman-II (Kaurfman Assessment Battery for Children - 2nd Edition) | Change in score from baseline in cognitive testing Kaufman-II will be described for each patient | 24 weeks (end of study) |
| Bayley-III (Bayley Scales of Infant and Toddler Development - 3rd Edition) | Change in score from baseline in cognitive testing Bayley-III will be described for each patient | 24 weeks (end of study) |
| VABS-3 scores (Vineland Adaptive Behavior Scales - 3rd Edition) | Change in score from baseline in cognitive testing VABS-3 will be described for each patient | 24 weeks (end of study) |
| Development Motor scale | Change from baseline in Peabody Delelopment Motor scale (PMDS-2) scores will be described for each patient | 24 weeks (end of study) |
| EQ-5D-5L (European Quality of Life Five Dimension Five Level) Questionnaire | Change in score from baseline for questionnaire EQ-5D-5L will be described for each patient | 24 weeks (end of study) |
| CHAQ (Childhood Health Assessment Questionnaire) | Change in score from baseline for CHAQ will be described for each patient | 24 weeks (end of study) |
| MPS Health Assessment Questionnaire | Change in score from baseline for questionnaire MPS Health Assessment Questionnaire will be described for each patient | 24 weeks (end of study) |
| Zarit Burden Interview | Change in score from baseline for questionnaire Zarit Burden Interview will be described for each patient | 24 weeks (end of study) |
| CBCL (Child Behavioral Checklist) or ABCL (Adult Behavioral Checklist) according to age | Change in score from baseline for CBCL or ABCL will be described for each patient | 24 weeks (end of study) |
| PEDI (Pediatric Evaluation of Disability Inventory) | Change in score from baseline for PEDI will be described for each patient | 24 weeks (end of study) |
| PROMIS-SF (Patient-reported Outcomes Measurement Information System Short Forms) | Change in score from baseline for PROMIS-SF will be described for each patient | 24 weeks (end of study) |
| Service-use and cost questionnaire to patient and families | Change in score from baseline will be described for each patient | 24 weeks (end of study) |
| Physician's Judgement of Overall Response | Change from baseline based on a Likert scale (0 to 5) | 24 weeks (end of study) |
| Caregiver's Judgement of Overall Response | Change from baseline based on a Likert scale (0 to 5) | 24 weeks (end of study) |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |