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

Primary Purpose

Alpha-Mannosidosis

Status
Completed
Phase
Phase 3
Locations
Denmark
Study Type
Interventional
Intervention
Lamazym
Sponsored by
Zymenex A/S
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alpha-Mannosidosis

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lamazym

Arm Description

1 mg Lamazym/kg Body weight

Outcomes

Primary Outcome Measures

Change from baseline in reduction of oligosaccharides in serum
Primary Endpoint evaluation as change
Change from baseline in 3 Minutes Stair Climb Test (3MSCT)
Primary Endpoint evaluation as change

Secondary Outcome Measures

6 Minute Walk Test (6MWT)
Endpoint evaluation as change
Pulmonary function: Forced Vital Capacity (FVC)
Endpoint evaluation as change
Pulmonary function: Forced Expiratory Volume during first second (FEV1)
Endpoint evaluation as change
Pulmonary function: Peak Expiratory Flow Rate (PEF)
Endpoint evaluation as change
Functional capacity according to Bruininks-Oseretsky test of Motor Proficiency (BOT-2)
Endpoint evaluation as change
Pure Tone Audiometry (PTA)
Endpoint evaluation as change
Equivalence age measured by Leiter International Performance Scale-Revised (Leiter-R)
Endpoint evaluation as change
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
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
Cerebrospinal fluid biomarkers: Oligosaccharides in Cerebrospinal Fluid (CSF)
Endpoint evaluation as change
Cerebrospinal fluid neuro-degeneration biomarkers: Tau Protein (Tau) in Cerebrospinal Fluid (CSF)
Endpoint evaluation as change
Cerebrospinal fluid neuro-degeneration biomarkers: Neurofilament Protein Light (NFL) in Cerebrospinal Fluid (CSF)
Endpoint evaluation as change
Cerebrospinal fluid neuro-degeneration biomarkers: Glial Fibrillary Acidic protein (GFAp) in Cerebrospinal Fluid (CSF)
Endpoint evaluation as change
Drug exposure by Pharmaco Kinetic (PK) sampling profile on plasma
Evaluation of steady state Pharmaco Kinetics
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
Oligosaccharides in urine
Evaluation of steady state

Full Information

First Posted
February 9, 2015
Last Updated
November 18, 2020
Sponsor
Zymenex A/S
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1. Study Identification

Unique Protocol Identification Number
NCT02478840
Brief Title
Evaluation of Long-term Efficacy of Treatment With Lamazym
Acronym
rhLAMAN-10
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
February 2015 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
June 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Zymenex A/S

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alpha-Mannosidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lamazym
Arm Type
Experimental
Arm Description
1 mg Lamazym/kg Body weight
Intervention Type
Drug
Intervention Name(s)
Lamazym
Other Intervention Name(s)
rhLAMAN
Intervention Description
recombinant human alpha-mannosidase
Primary Outcome Measure Information:
Title
Change from baseline in reduction of oligosaccharides in serum
Description
Primary Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Change from baseline in 3 Minutes Stair Climb Test (3MSCT)
Description
Primary Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Secondary Outcome Measure Information:
Title
6 Minute Walk Test (6MWT)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Pulmonary function: Forced Vital Capacity (FVC)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Pulmonary function: Forced Expiratory Volume during first second (FEV1)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Pulmonary function: Peak Expiratory Flow Rate (PEF)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Functional capacity according to Bruininks-Oseretsky test of Motor Proficiency (BOT-2)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Pure Tone Audiometry (PTA)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Equivalence age measured by Leiter International Performance Scale-Revised (Leiter-R)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
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)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
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)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Cerebrospinal fluid biomarkers: Oligosaccharides in Cerebrospinal Fluid (CSF)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Cerebrospinal fluid neuro-degeneration biomarkers: Tau Protein (Tau) in Cerebrospinal Fluid (CSF)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Cerebrospinal fluid neuro-degeneration biomarkers: Neurofilament Protein Light (NFL) in Cerebrospinal Fluid (CSF)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Cerebrospinal fluid neuro-degeneration biomarkers: Glial Fibrillary Acidic protein (GFAp) in Cerebrospinal Fluid (CSF)
Description
Endpoint evaluation as change
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Drug exposure by Pharmaco Kinetic (PK) sampling profile on plasma
Description
Evaluation of steady state Pharmaco Kinetics
Time Frame
1 week
Title
Measurement of in vivo biological activity of Lamazym in blood before and after Infusion of Lamazym
Description
Comparing with Anti Body (AB) and PK measurements. Measuring unit is mU/mL
Time Frame
1 week
Title
Oligosaccharides in urine
Description
Evaluation of steady state
Time Frame
1 week
Other Pre-specified Outcome Measures:
Title
Quality of life based on questionnaires
Description
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
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Quality of life based on questionnaires
Description
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
Time Frame
Baseline evaluation prior to first dose compared to evaluation after one, two or four years of treatment
Title
Development of adverse events
Description
Safety endpoint assessed from signing of the Informed Consent Form (ICF)
Time Frame
1 week
Title
Development of clinically significant changes in vital signs and change in physical examination
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week
Title
Development of clinically significant changes in the clinical laboratory Parameters: Hematology
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week
Title
Development of clinically significant changes in the clinical laboratory Parameters: Biochemistry
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week
Title
Development of clinically significant changes in the clinical laboratory Parameters: Urinalysis
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week
Title
Development of rhLAMAN antibodies
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week
Title
Development of rhLAMAN neutralizing/inhibitory antibodies
Description
Safety endpoint assessed throughout the trial
Time Frame
1 week

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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) The subject must still be receiving weekly intravenous infusions of Lamazym according to the AfterCare Program The 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 Exclusion Criteria: History of bone marrow transplantation 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 Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the investigator, would preclude participation in the trial 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. 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 Pause of the IMP for 2 consecutive weeks during the last month. Subjects are allowed to be re-screened
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Allan M Lund, MD
Organizational Affiliation
Copenhagen University Hospital, Center for Metabolic Diseases, Department of Clinical Genetics
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jens M Fogh, DVM
Organizational Affiliation
Zymenex A/S
Official's Role
Study Chair
Facility Information:
Facility Name
Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9
City
Copenhagen
ZIP/Postal Code
DK-2100
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
32292699
Citation
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.
Results Reference
background
Citation
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
Results Reference
background
PubMed Identifier
29725868
Citation
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.
Results Reference
result
PubMed Identifier
29716835
Citation
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.
Results Reference
result
Links:
URL
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003950-15
Description
Study Record on EU Clinical Trials Register including results

Learn more about this trial

Evaluation of Long-term Efficacy of Treatment With Lamazym

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