Interventional Study to Assess Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis

Study Overview
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Brief Summary
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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

Detailed Description
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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).

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis

Conditions
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Alpha-Mannosidosis

Intervention / Treatment
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* Drug: Velmanase Alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of alpha-mannosidosis based on alpha mannosidase activity <10% of normal in leukocytes or fibroblasts or through genetic testing; Capability to comply with the protocol; Evidence of informed consent provided by subject or legally authorized guardian(s) prior to performance of any trial-related activities. Exclusion Criteria: Previous hematopoietic stem cells transplantation (HSCT) with positive outcome; Major surgery planned within 3 months prior to study entry or planned during the study that, in the opinion of the Investigator, would preclude participation in the trial; Known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition that would preclude participation in the study in the Investigator's judgment; Pregnant (as evident by a positive urine hCG or serum-hCG test) or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential [WOCBP]) UNLESS they are willing to use highly effective birth control methods; Participation in other interventional trials testing investigational medicinal products (IMPs) within the last 6 months; Total IgE >800 IU/ml; Any hypersensitivity to velmanase alfa or its excipients that, in the judgment of the Investigator, places the subject at an increased risk for adverse reactions Clinically active infection and recent vaccinations (within the last month before screening).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind, randomized 2:1 to either velmanase alfa:placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Velmanase alfa<br> | Drug: Velmanase Alfa<br>* infusion i.v. treatment<br>|
| Placebo Comparator: placebo<br> | Drug: Placebo<br>* infusion i.v. treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alpha-Mannosidosis, velmanase alfa, alpha-mann, shaman, mannosidosis, alpha-mannosidasis