Evaluation of Long-term Efficacy of Treatment With Lamazym (rhLAMAN-10)

A Single Center, Open Label Clinical Trial Investigating the Long-term Efficacy of rhLAMAN (Recombinant Human Alpha-mannosidase or Lamazym) Treatment in Subjects With Alpha-Mannosidosis Who Previously Participated in Lamazym Trials

The overall objective is to evaluate the long-term efficacy of Lamazym i.v. treatment in patients with alpha-Mannosidosis previously enrolled in Lamazym trials and currently receiving the treatment according to the AfterCare Program.

Study Overview

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

Detailed Description

The primary objective of the trial is to evaluate the impact of the long-term treatment with Lamazym upon the level of biomarker oligosaccharides in serum and upon the endurance as measured by the change from baseline in the number of steps climbed in 3 minutes (3MSCT).

As secondary objectives, the long term efficacy of Lamazym will be investigated upon endurance as measured by the change from baseline in the number of meters walked in six minutes (6MWT), upon pulmonary function, motor proficiency by BOT-2 and hearing capability by audiometry. In addition, cognitive development will be assessed by Leiter-R test. CNS involvement will be evaluated with MRI/MRS (for patients who previously participated in rhLAMAN-02 trial), CSF biomarkers (Tau, NFL, GFAp) and CSF biomarkers oligosaccharides. Clearance of oligosaccharides in urine will be measured.

Long-term safety and Pharmaco-Kinetic (PK) profile after long-term treatment as measured by rhLAMAN levels in plasma will be assessed as well.

Quality of life will be assessed by questionnaires (CHAQ and EQ-5D-5L).

• Study Type: Interventional
• Enrollment (Actual): 18
• 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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject must have participated in the phase 1 trial (EudraCT number: 2010-022084-36), phase 2a trial (EudraCT number: 2010-022085-26), phase 2b trial (EudraCT number: 2011-004355-40) or phase 3 trial (EudraCT number: 2012-000979-17)
2. The subject must still be receiving weekly intravenous infusions of Lamazym according to the AfterCare Program
3. The Subject or subjects legally authorized guardian(s) must provide signed, informed consent prior to performing any trial-related activities
4. The subject and his/her guardian(s) must have the ability to comply with the protocol

Exclusion Criteria:

1. History of bone marrow transplantation
2. 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. Subjects unable to perform the motor tests independently from support are permitted to participate in the trial and will be evaluated for the remnant non motor endpoints
3. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the investigator, would preclude participation in the trial
4. Pregnant and/or lactating women cannot participate in the trial. Concerning women of child bearing potential (WOCBP), the investigators will decide whether or not there is a need for contraception. This assessment will be done through interviews with the patient and parents.
5. Participation in other interventional trials testing IMP, including rhLAMAN-07 (EudraCT number: 2013-000336-97) and rhLAMAN-09 (EudraCT number: 2013-000321-31) trials with Lamazym
6. Pause of the IMP for 2 consecutive weeks during the last month. Subjects are allowed to be re-screened

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Lamazym; 1 mg Lamazym/kg Body weight	Drug: Lamazym; recombinant human alpha-mannosidase; Other Names: rhLAMAN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in reduction of oligosaccharides in serum	Primary Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Change from baseline in 3 Minutes Stair Climb Test (3MSCT)	Primary Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Minute Walk Test (6MWT)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Pulmonary function: Forced Vital Capacity (FVC)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Pulmonary function: Forced Expiratory Volume during first second (FEV1)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Pulmonary function: Peak Expiratory Flow Rate (PEF)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Functional capacity according to Bruininks-Oseretsky test of Motor Proficiency (BOT-2)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Pure Tone Audiometry (PTA)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Equivalence age measured by Leiter International Performance Scale-Revised (Leiter-R)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Assessment of mannose-rich oligosaccharides in brain tissue as measured by Magnetic Resonance Spectroscopy (MRS) visual score (for patients who previously participated in rhLAMAN-02)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Assessment of mannose-rich oligosaccharides in brain tissue as measured by Magnetic Resonance Imaging (MRI) diffusion coefficient (for patients who previously participated in rhLAMAN-02)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Cerebrospinal fluid biomarkers: Oligosaccharides in Cerebrospinal Fluid (CSF)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Cerebrospinal fluid neuro-degeneration biomarkers: Tau Protein (Tau) in Cerebrospinal Fluid (CSF)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Cerebrospinal fluid neuro-degeneration biomarkers: Neurofilament Protein Light (NFL) in Cerebrospinal Fluid (CSF)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Cerebrospinal fluid neuro-degeneration biomarkers: Glial Fibrillary Acidic protein (GFAp) in Cerebrospinal Fluid (CSF)	Endpoint evaluation as change	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Drug exposure by Pharmaco Kinetic (PK) sampling profile on plasma	Evaluation of steady state Pharmaco Kinetics	1 week
Measurement of in vivo biological activity of Lamazym in blood before and after Infusion of Lamazym	Comparing with Anti Body (AB) and PK measurements. Measuring unit is mU/mL	1 week
Oligosaccharides in urine	Evaluation of steady state	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life based on questionnaires	filled by the subject's guardian, will be evaluated by Childhood Health Assessment Questionnaire (CHAQ) questionnaires filled in by the subject's guardian, will be evaluated by CHAQ and EQ-5D-5L	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Quality of life based on questionnaires	filled by the subject's guardian, will be evaluated by Health Questionnaire (EQ-5D-5L) questionnaires filled in by the subject's guardian, will be evaluated by CHAQ and EQ-5D-5L	Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Development of adverse events	Safety endpoint assessed from signing of the Informed Consent Form (ICF)	1 week
Development of clinically significant changes in vital signs and change in physical examination	Safety endpoint assessed throughout the trial	1 week
Development of clinically significant changes in the clinical laboratory Parameters: Hematology	Safety endpoint assessed throughout the trial	1 week
Development of clinically significant changes in the clinical laboratory Parameters: Biochemistry	Safety endpoint assessed throughout the trial	1 week
Development of clinically significant changes in the clinical laboratory Parameters: Urinalysis	Safety endpoint assessed throughout the trial	1 week
Development of rhLAMAN antibodies	Safety endpoint assessed throughout the trial	1 week
Development of rhLAMAN neutralizing/inhibitory antibodies	Safety endpoint assessed throughout the trial	1 week

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Phillips D, Hennermann JB, Tylki-Szymanska A, Borgwardt L, Gil-Campos M, Guffon N, Amraoui Y, Geraci S, Ardigo D, Cattaneo F, Lund AM. Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis. Mol Genet Metab Rep. 2020 Apr 8;23:100586. doi: 10.1016/j.ymgmr.2020.100586. eCollection 2020 Jun.
• Borgwardt L, Guffon N, Amraoui Y, Jones SA, De Meirleir L, Lund AM, Gil-Campos M, Van den Hout JMP, Tylki-Szymanska A, Geraci S, Ardigò D, Cattaneo F, Harmatz P, Phillips D. Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase). Journal of Inborn Errors of Metabolism & Screening 2018, Volume 6: 1-12
• Lund AM, Borgwardt L, Cattaneo F, Ardigo D, Geraci S, Gil-Campos M, De Meirleir L, Laroche C, Dolhem P, Cole D, Tylki-Szymanska A, Lopez-Rodriguez M, Guillen-Navarro E, Dali CI, Heron B, Fogh J, Muschol N, Phillips D, Van den Hout JMH, Jones SA, Amraoui Y, Harmatz P, Guffon N. Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis. J Inherit Metab Dis. 2018 Nov;41(6):1225-1233. doi: 10.1007/s10545-018-0175-2. Epub 2018 May 3.
• 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.

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: February 9, 2015
• First Submitted That Met QC Criteria: June 22, 2015
• First Posted (ESTIMATE): June 23, 2015

Study Record Updates

• Last Update Posted (ACTUAL): November 20, 2020
• Last Update Submitted That Met QC Criteria: November 18, 2020
• Last Verified: November 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-10