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

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

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

Study Overview

• Status: Withdrawn
• Conditions: Alpha-Mannosidosis
• Intervention / Treatment: Drug: Velmanase Alfa; Drug: Placebo

Detailed Description

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).

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: Placebo; infusion i.v. treatment
Experimental: Velmanase alfa	Drug: Velmanase Alfa; infusion i.v. treatment

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	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	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)

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Paul Harmatz, MD, UCSF Benioff Children's Hospital Oakland

Study record dates

Study Major Dates

• Study Start (Anticipated): January 11, 2021
• Primary Completion (Anticipated): October 27, 2021
• Study Completion (Anticipated): December 29, 2021

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 22, 2019
• First Posted (Actual): July 24, 2019

Study Record Updates

• Last Update Posted (Actual): December 8, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Alpha-Mannosidosis; velmanase alfa; alpha-mann; shaman; mannosidosis; alpha-mannosidasis
• 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: CLI-LMZYMAA2-01

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: Yes
• Studies a U.S. FDA-regulated device product: No