A Placebo-Controlled Phase 3 Trial of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis

A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Group Trial, Investigating the Efficacy and Safety of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis.

The overall objective of this trial is to evaluate the efficacy and safety of repeated Lamazym i.v. treatment, compared with placebo, in subjects 5-35 years of age with alpha-Mannosidosis

Study Overview

• Status: Completed
• Conditions: Alpha-Mannosidosis
• Intervention / Treatment: Drug: Lamazym; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9
• France
  • Bron, France, 69677
    • Hôpital Femme Mère Enfant, Lyon, 59 boulevard Pinel
  • PARIS Cedex 12, France, 75 571
    • Hôpital Trousseau, Service de neuropédiatrie, Centre Référence des Maladies Lysosomales, 26 avenue du Docteur Arnold Netter
• Germany
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz, Zentrum für Kinder- und Jugendmedizin, Langenbeckstrasse 1
• Poland
  • Warszawa, Poland, 04 730
    • The Children's Memorial Health Institute Warsaw, Department of Metabolic Diseases, Al Dzieci Polskich 20
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Genetic Medicine, 6th floor, St Mary's Hospital, Oxford Road,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject or subjects legally authorized guardian(s) must provide signed, informed consent prior to performing any trial-related activities
• The subject and his/her guardian(s) must have the ability to comply with the protocol
• The subject must have a confirmed diagnosis of alpha-Mannosidosis as defined by alpha-Mannosidase activity < 10% of normal activity (historical data)
• The subject must have an age at the time of screening ≥ 5 years and ≤ 35 years
• The subject must have the ability to physically and mentally cooperate in the tests
• The subject must have an ECHO without abnormalities that, in the opinion of the Investigator, would preclude participation in the trial

Exclusion Criteria:

• The subjects diagnosis cannot be confirmed by alpha-Mannosidase activity < 10% of normal activity
• The subject cannot walk without support
• Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-Mannosidosis
• History of BMT
• 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
• Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
• Pregnancy: Pregnant woman is excluded. Before start of the treatment the investigators will for women of childbearing potential perform a pregnancy test and decide whether or not there is a need for contraception
• Psychosis; any psychotic disease, also in remission, is an exclusion criteria
• Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial
• Participation in other interventional trials testing IMP (including Lamazym) within the last 3 months
• Adult patients who, in the opinion of the Investigator, would be unable to give consent, and who does not have any legal protection or guardianship
• Total IgE >800 IU/ml
• Known allergy to the IMP or any excipients (Sodium-Phosphate, Glycine, Mannitol)

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
Active Comparator: Lamazym; 1 mg Lamazym/kg body weight	Drug: Lamazym; ERT, i.v. infusions weekly; Other Names: rhLAMAN; recombinant human alpha-mannosidase
Placebo Comparator: Placebo; Placebo is formulated as an isotonic phosphate buffer with glycine and mannitol	Drug: Placebo; Infusions weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of oligosaccharides in serum	Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group	Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
The number of steps climbed in 3 minutes (3-minute stair climb test)	Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group	Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Vital Capacity	Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group	Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
The distance walked in 6 minutes (6-minute walk test)	Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group	Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
Adverse Events	Safety endpoint assessed weekly throughout the trial	1 week
Development of clinically significant changes in vital signs and change in physical examination	Safety endpoints assessed weekly throughout the trial	1 week
Clinical laboratory parameters (hematology, biochemistry and urinalysis)	Safety endpoints assessed weekly throughout the trial	1 week
Development of Lamazym antibodies and neutralizing/inhibitory antibodies	Safety endpoints assessed weekly throughout the trial	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative determination of rhLAMAN in plasma	Pharmacokinetic (PK) assessments. Blood samples are drawn pre-treatment and at various times post-treatment (see time frame above)	10 min, 60 min, 2 hours, 24 hours, 3 days, 7 days

Collaborators and Investigators

• Sponsor: Zymenex A/S
• Collaborators: European Commission
• Investigators: Principal Investigator: Allan M Lund, MD, Copenhagen University Hospital, Center for Metabolic Diseases, Department for Clinical Genetics; Study Chair: Jens Fogh, Zymenex A/S

Publications and helpful links

General Publications

• Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, Amraoui Y, Arash L, Fogh J, Nilssen O, Dali CI, Lund AM. Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. Orphanet J Rare Dis. 2015 Jun 6;10:70. doi: 10.1186/s13023-015-0286-x.
• Borgwardt L, Thuesen AM, Olsen KJ, Fogh J, Dali CI, Lund AM. Cognitive profile and activities of daily living: 35 patients with alpha-mannosidosis. J Inherit Metab Dis. 2015 Nov;38(6):1119-27. doi: 10.1007/s10545-015-9862-4. Epub 2015 May 28.
• Harmatz P, Cattaneo F, Ardigo D, Geraci S, Hennermann JB, Guffon N, Lund A, Hendriksz CJ, Borgwardt L. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018 Jun;124(2):152-160. doi: 10.1016/j.ymgme.2018.04.003. Epub 2018 Apr 18.
• Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, Heron B, Geraci S, Ardigo D, Cattaneo F, Fogh J, Van den Hout JMH, Beck M, Jones SA, Tylki-Szymanska A, Haugsted U, Lund AM. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018 Nov;41(6):1215-1223. doi: 10.1007/s10545-018-0185-0. Epub 2018 May 30.

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: August 22, 2012
• First Submitted That Met QC Criteria: September 5, 2012
• First Posted (Estimate): September 10, 2012

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• 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: rhLAMAN-05; 2012-000979-17 (EudraCT Number)