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出境医 / 临床实验 / Interventional Study to Assess Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis (SHAMAN)

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

Study Description
Brief Summary:

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


Condition or disease Intervention/treatment Phase
Alpha-Mannosidosis Drug: Velmanase Alfa Drug: Placebo Phase 3

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 Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: double-blind, randomized 2:1 to either velmanase alfa:placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomized using IRT system
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : January 11, 2021
Estimated Primary Completion Date : October 27, 2021
Estimated Study Completion Date : December 29, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Velmanase alfa Drug: Velmanase Alfa
infusion i.v. treatment
Placebo Comparator: placebo Drug: Placebo
infusion i.v. treatment
Outcome Measures
Primary Outcome Measures :
  1. Change in concentration of serum oligosaccharides [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Level of serum oligosaccharides;

  2. Change in serum level of total immunoglobulin (Ig)G level [ Time Frame: 24 weeks (end of study) ]
    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


Secondary Outcome Measures :
  1. Change in Intracellular level of oligosaccharides in peripheral blood leukocytes [ Time Frame: 24 weeks (end of study) ]
    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.

  2. Change in serum IgG Subclasses [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Subclasses of IgG;

  3. Incidence of Infections [ Time Frame: 24 weeks (end of study) ]
    Change in number of infections requiring antibiotics and/or hospitalization and/or loss of school/working days

  4. Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 12 weeks ]
    To collect additional data on Cmax profile following velmanase alfa treatment

  5. Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Cmax profile following velmanase alfa treatment

  6. Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on AUC profile following velmanase alfa treatment

  7. Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 12 weeks ]
    To collect additional data on AUC profile following velmanase alfa treatment

  8. Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 12 weeks ]
    To collect additional data on t1/2 profile following velmanase alfa treatment

  9. Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on t1/2 profile following velmanase alfa treatment

  10. Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 12 weeks ]
    To collect additional data on Ctrough profile following velmanase alfa treatment

  11. Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Ctrough profile following velmanase alfa treatment


Other Outcome Measures:
  1. Adverse Events (AEs) [ Time Frame: 24 weeks (end of study) ]
    Number of AEs will be described for each patient and cumulatively in the safety population

  2. Infusion Related Reactions (IRRs) [ Time Frame: 24 weeks (end of study) ]
    Number of IRRs will be described for each patient and cumulatively in the safety population

  3. Incidence of Adverse Drug Reactions (ADRs) [ Time Frame: 24 weeks (end of study) ]
    Number of ADRs will be described for each patient and cumulatively in the safety population

  4. Anty-Drug Antibody (ADA) level [ Time Frame: 24 weeks (end of study) ]
    Change in ADA will be described for each patient and cumulatively in the safety population

  5. Neutralizing Antibody (NAb) level [ Time Frame: 24 weeks (end of study) ]
    Change in NAb levels will be described for each patient and cumulatively in the safety population

  6. Change on Immunoglobuline Type A (IgA) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgA levels will be described for each patient and cumulatively in the safety population

  7. Change on Immunoglobuline Type M (IgM) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgM levels will be described for each patient and cumulatively in the safety population

  8. Change on B-cell immunophenotype level [ Time Frame: 24 weeks (end of study) ]
    Change in B-cell immunophenotype levels will be described for each patient and cumulatively in the safety population

  9. 3MSCT (3-Minute Stair Climb Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (climbing test) will be described for each patient

  10. 6MWT (2MWT for children) (6- or 2-Minute Walk Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (walking test) will be described for each patient

  11. FVC, FEV1 and PEF [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in respiratory tests (Spirometry) will be described for each patient

  12. Psychotic events [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in number of psychotic events will be described for each patient

  13. Shoulder mobility [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in shoulder mobility will be described for each patient

  14. ECG PR interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) PR interval will be described for each patient

  15. ECG QT interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QT interval will be described for each patient

  16. ECG QRS duration [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QRS duration will be described for each patient

  17. Heart diseases [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Echocardiogram will be described for each patient

  18. Hearing testing [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in hearing testing through PTA will be described for each patient

  19. Kaufman-II (Kaurfman Assessment Battery for Children - 2nd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Kaufman-II will be described for each patient

  20. Bayley-III (Bayley Scales of Infant and Toddler Development - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Bayley-III will be described for each patient

  21. VABS-3 scores (Vineland Adaptive Behavior Scales - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing VABS-3 will be described for each patient

  22. Development Motor scale [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Peabody Delelopment Motor scale (PMDS-2) scores will be described for each patient

  23. EQ-5D-5L (European Quality of Life Five Dimension Five Level) Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire EQ-5D-5L will be described for each patient

  24. CHAQ (Childhood Health Assessment Questionnaire) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CHAQ will be described for each patient

  25. MPS Health Assessment Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire MPS Health Assessment Questionnaire will be described for each patient

  26. Zarit Burden Interview [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire Zarit Burden Interview will be described for each patient

  27. CBCL (Child Behavioral Checklist) or ABCL (Adult Behavioral Checklist) according to age [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CBCL or ABCL will be described for each patient

  28. PEDI (Pediatric Evaluation of Disability Inventory) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PEDI will be described for each patient

  29. PROMIS-SF (Patient-reported Outcomes Measurement Information System Short Forms) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PROMIS-SF will be described for each patient

  30. Service-use and cost questionnaire to patient and families [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline will be described for each patient

  31. Physician's Judgement of Overall Response [ Time Frame: 24 weeks (end of study) ]
    Change from baseline based on a Likert scale (0 to 5)

  32. Caregiver's Judgement of Overall Response [ Time Frame: 24 weeks (end of study) ]
    Change from baseline based on a Likert scale (0 to 5)


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).
Contacts and Locations

Sponsors and Collaborators
Chiesi Farmaceutici S.p.A.
Investigators
Layout table for investigator information
Principal Investigator: Paul Harmatz, MD UCSF Benioff Children's Hospital Oakland
Tracking Information
First Submitted Date  ICMJE July 17, 2019
First Posted Date  ICMJE July 24, 2019
Last Update Posted Date December 8, 2020
Estimated Study Start Date  ICMJE January 11, 2021
Estimated Primary Completion Date October 27, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2020)
  • Change in concentration of serum oligosaccharides [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Level of serum oligosaccharides;
  • Change in serum level of total immunoglobulin (Ig)G level [ Time Frame: 24 weeks (end of study) ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: July 22, 2019) 		Change in serum level of total immunoglobulin (Ig)G level [ Time Frame: 24 weeks (end of study) ]
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2020)
  • Change in Intracellular level of oligosaccharides in peripheral blood leukocytes [ Time Frame: 24 weeks (end of study) ]
    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.
  • Change in serum IgG Subclasses [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Subclasses of IgG;
  • Incidence of Infections [ Time Frame: 24 weeks (end of study) ]
    Change in number of infections requiring antibiotics and/or hospitalization and/or loss of school/working days
  • Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 12 weeks ]
    To collect additional data on Cmax profile following velmanase alfa treatment
  • Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Cmax profile following velmanase alfa treatment
  • Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on AUC profile following velmanase alfa treatment
  • Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 12 weeks ]
    To collect additional data on AUC profile following velmanase alfa treatment
  • Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 12 weeks ]
    To collect additional data on t1/2 profile following velmanase alfa treatment
  • Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on t1/2 profile following velmanase alfa treatment
  • Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 12 weeks ]
    To collect additional data on Ctrough profile following velmanase alfa treatment
  • Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Ctrough profile following velmanase alfa treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
  • Change in concentration of serum oligosaccharides [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Level of serum oligosaccharides;
  • Change in Intracellular level of oligosaccharides in peripheral blood leukocytes [ Time Frame: 24 weeks (end of study) ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: January 14, 2020)
  • Adverse Events (AEs) [ Time Frame: 24 weeks (end of study) ]
    Number of AEs will be described for each patient and cumulatively in the safety population
  • Infusion Related Reactions (IRRs) [ Time Frame: 24 weeks (end of study) ]
    Number of IRRs will be described for each patient and cumulatively in the safety population
  • Incidence of Adverse Drug Reactions (ADRs) [ Time Frame: 24 weeks (end of study) ]
    Number of ADRs will be described for each patient and cumulatively in the safety population
  • Anty-Drug Antibody (ADA) level [ Time Frame: 24 weeks (end of study) ]
    Change in ADA will be described for each patient and cumulatively in the safety population
  • Neutralizing Antibody (NAb) level [ Time Frame: 24 weeks (end of study) ]
    Change in NAb levels will be described for each patient and cumulatively in the safety population
  • Change on Immunoglobuline Type A (IgA) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgA levels will be described for each patient and cumulatively in the safety population
  • Change on Immunoglobuline Type M (IgM) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgM levels will be described for each patient and cumulatively in the safety population
  • Change on B-cell immunophenotype level [ Time Frame: 24 weeks (end of study) ]
    Change in B-cell immunophenotype levels will be described for each patient and cumulatively in the safety population
  • 3MSCT (3-Minute Stair Climb Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (climbing test) will be described for each patient
  • 6MWT (2MWT for children) (6- or 2-Minute Walk Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (walking test) will be described for each patient
  • FVC, FEV1 and PEF [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in respiratory tests (Spirometry) will be described for each patient
  • Psychotic events [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in number of psychotic events will be described for each patient
  • Shoulder mobility [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in shoulder mobility will be described for each patient
  • ECG PR interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) PR interval will be described for each patient
  • ECG QT interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QT interval will be described for each patient
  • ECG QRS duration [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QRS duration will be described for each patient
  • Heart diseases [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Echocardiogram will be described for each patient
  • Hearing testing [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in hearing testing through PTA will be described for each patient
  • Kaufman-II (Kaurfman Assessment Battery for Children - 2nd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Kaufman-II will be described for each patient
  • Bayley-III (Bayley Scales of Infant and Toddler Development - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Bayley-III will be described for each patient
  • VABS-3 scores (Vineland Adaptive Behavior Scales - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing VABS-3 will be described for each patient
  • Development Motor scale [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Peabody Delelopment Motor scale (PMDS-2) scores will be described for each patient
  • EQ-5D-5L (European Quality of Life Five Dimension Five Level) Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire EQ-5D-5L will be described for each patient
  • CHAQ (Childhood Health Assessment Questionnaire) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CHAQ will be described for each patient
  • MPS Health Assessment Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire MPS Health Assessment Questionnaire will be described for each patient
  • Zarit Burden Interview [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire Zarit Burden Interview will be described for each patient
  • CBCL (Child Behavioral Checklist) or ABCL (Adult Behavioral Checklist) according to age [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CBCL or ABCL will be described for each patient
  • PEDI (Pediatric Evaluation of Disability Inventory) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PEDI will be described for each patient
  • PROMIS-SF (Patient-reported Outcomes Measurement Information System Short Forms) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PROMIS-SF will be described for each patient
  • Service-use and cost questionnaire to patient and families [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline will be described for each patient
  • Physician's Judgement of Overall Response [ Time Frame: 24 weeks (end of study) ]
    Change from baseline based on a Likert scale (0 to 5)
  • Caregiver's Judgement of Overall Response [ Time Frame: 24 weeks (end of study) ]
    Change from baseline based on a Likert scale (0 to 5)
Original Other Pre-specified Outcome Measures
 (submitted: July 22, 2019)
  • Change in serum IgG Subclasses [ Time Frame: 24 weeks (end of study) ]
    To evaluate the efficacy of velmanase alfa compared with placebo after 24 weeks of velmanase alfa treatment as measured by Subclasses of IgG;
  • Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 12 weeks ]
    To collect additional data on Cmax profile following velmanase alfa treatment
  • Assessment of PK parameter Maximum plasma Concentration [Cmax] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Cmax profile following velmanase alfa treatment
  • Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on AUC profile following velmanase alfa treatment
  • Assessment of PK parameter Area Under the Curve [AUC] [ Time Frame: 12 weeks ]
    To collect additional data on AUC profile following velmanase alfa treatment
  • Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 12 weeks ]
    To collect additional data on t1/2 profile following velmanase alfa treatment
  • Assessment of PK parameter Elimination half-life [t1/2] [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on t1/2 profile following velmanase alfa treatment
  • Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 12 weeks ]
    To collect additional data on Ctrough profile following velmanase alfa treatment
  • Assessment of PK parameter trough concentration (Ctrough) [ Time Frame: 24 weeks (end of study) ]
    To collect additional data on Ctrough profile following velmanase alfa treatment
  • Adverse Events (AEs) [ Time Frame: 24 weeks (end of study) ]
    Number of AEs will be described for each patient and cumulatively in the safety population
  • Infusion Related Reactions (IRRs) [ Time Frame: 24 weeks (end of study) ]
    Number of IRRs will be described for each patient and cumulatively in the safety population
  • Incidence of Adverse Drug Reactions (ADRs) [ Time Frame: 24 weeks (end of study) ]
    Number of ADRs will be described for each patient and cumulatively in the safety population
  • Anty-Drug Antibody (ADA) level [ Time Frame: 24 weeks (end of study) ]
    Change in ADA will be described for each patient and cumulatively in the safety population
  • Neutralizing Antibody (NAb) level [ Time Frame: 24 weeks (end of study) ]
    Change in NAb levels will be described for each patient and cumulatively in the safety population
  • Immunoglobuline Type A (IgA) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgA levels will be described for each patient and cumulatively in the safety population
  • Change on Immunoglobuline Type G (IgG) values [ Time Frame: 24 weeks (end of study) ]
    Change in IgG levels will be described for each patient and cumulatively in the safety population
  • Change on B-cell immunophenotype level [ Time Frame: 24 weeks (end of study) ]
    Change in B-cell immunophenotype levels will be described for each patient and cumulatively in the safety population
  • 3MSCT (3-Minute Stair Climb Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (climbing test) will be described for each patient
  • 6MWT (2MWT for children) (6- or 2-Minute Walk Test) [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in motricity tests (walking test) will be described for each patient
  • FVC, FEV1 and PEF [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in respiratory tests (Spirometry) will be described for each patient
  • Psychotic events [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in number of psychotic events will be described for each patient
  • Shoulder mobility [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in shoulder mobility will be described for each patient
  • ECG PR interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) PR interval will be described for each patient
  • ECG QT interval [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QT interval will be described for each patient
  • ECG QRS duration [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in electrocardiogram (ECG) QRS duration will be described for each patient
  • Heart diseases [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Echocardiogram will be described for each patient
  • Hearing testing [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in hearing testing through PTA will be described for each patient
  • Kaufman-II (Kaurfman Assessment Battery for Children - 2nd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Kaufman-II will be described for each patient
  • Bayley-III (Bayley Scales of Infant and Toddler Development - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing Bayley-III will be described for each patient
  • VABS-3 scores (Vineland Adaptive Behavior Scales - 3rd Edition) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline in cognitive testing VABS-3 will be described for each patient
  • Development Motor scale [ Time Frame: 24 weeks (end of study) ]
    Change from baseline in Peabody Delelopment Motor scale (PMDS-2) scores will be described for each patient
  • EQ-5D-5L (European Quality of Life Five Dimension Five Level) Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire EQ-5D-5L will be described for each patient
  • CHAQ (Childhood Health Assessment Questionnaire) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CHAQ will be described for each patient
  • MPS Health Assessment Questionnaire [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire MPS Health Assessment Questionnaire will be described for each patient
  • Zarit Burden Interview [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for questionnaire Zarit Burden Interview will be described for each patient
  • CBCL (Child Behavioral Checklist) or ABCL (Adult Behavioral Checklist) according to age [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for CBCL or ABCL will be described for each patient
  • PEDI (Pediatric Evaluation of Disability Inventory) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PEDI will be described for each patient
  • PROMIS-SF (Patient-reported Outcomes Measurement Information System Short Forms) [ Time Frame: 24 weeks (end of study) ]
    Change in score from baseline for PROMIS-SF will be described for each patient
  • Change on quality of life [ Time Frame: 24 weeks (end of study) ]
    Incidence of infections requiring antibiotics and/or hospitalization and/or loss of school/working days
 
Descriptive Information
Brief Title  ICMJE Interventional Study to Assess Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis
Official Title  ICMJE 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
Brief Summary

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

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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
double-blind, randomized 2:1 to either velmanase alfa:placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Randomized using IRT system
Primary Purpose: Treatment
Condition  ICMJE Alpha-Mannosidosis
Intervention  ICMJE
  • Drug: Velmanase Alfa
    infusion i.v. treatment
  • Drug: Placebo
    infusion i.v. treatment
Study Arms  ICMJE
  • Experimental: Velmanase alfa
    Intervention: Drug: Velmanase Alfa
  • Placebo Comparator: placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: December 4, 2020) 		0
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2019) 		12
Estimated Study Completion Date  ICMJE December 29, 2021
Estimated Primary Completion Date October 27, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04031066
Other Study ID Numbers  ICMJE CLI-LMZYMAA2-01
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Chiesi Farmaceutici S.p.A.
Study Sponsor  ICMJE Chiesi Farmaceutici S.p.A.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul Harmatz, MD UCSF Benioff Children's Hospital Oakland
PRS Account Chiesi Farmaceutici S.p.A.
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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