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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lamazym | Experimental | 1 mg Lamazym/kg Body weight |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lamazym | Drug | recombinant human alpha-mannosidase |
|
|
| 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 |
| 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) |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Allan M Lund, MD | Copenhagen University Hospital, Center for Metabolic Diseases, Department of Clinical Genetics | Principal Investigator |
| Jens M Fogh, DVM | Zymenex A/S | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9 | Copenhagen | DK-2100 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32292699 | Background | 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. | |
| Background | 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 | ||
| 29725868 |
| Label | URL |
|---|---|
| Study Record on EU Clinical Trials Register including results | View source |
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| ID | Term |
|---|---|
| D008363 | alpha-Mannosidosis |
| ID | Term |
|---|---|
| D044904 | Mannosidase Deficiency Diseases |
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
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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 |
| 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 |
| Result |
| 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. |
| 29716835 | Result | 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. |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |