Clinical trial NCT01681953: A Placebo-Controlled Phase 3 Trial of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alpha-Mannosidosis
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
Collaborators: name: European Commission
First posted: 2012-09-10
Enrollment: 25
Sex: ALL
Minimum age (years): 5
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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)

Primary outcomes:
measure: Reduction of oligosaccharides in serum
timeFrame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
measure: The number of steps climbed in 3 minutes (3-minute stair climb test)
timeFrame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
Secondary outcomes:
measure: Forced Vital Capacity
timeFrame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
measure: The distance walked in 6 minutes (6-minute walk test)
timeFrame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
measure: Adverse Events
timeFrame: 1 week
measure: Development of clinically significant changes in vital signs and change in physical examination
timeFrame: 1 week
measure: Clinical laboratory parameters (hematology, biochemistry and urinalysis)
timeFrame: 1 week
measure: Development of Lamazym antibodies and neutralizing/inhibitory antibodies
timeFrame: 1 week
Other outcomes:
measure: Quantitative determination of rhLAMAN in plasma
timeFrame: 10 min, 60 min, 2 hours, 24 hours, 3 days, 7 days
Locations:
city: Copenhagen
country: Denmark
facility: Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9
city: Bron
country: France
facility: Hôpital Femme Mère Enfant, Lyon, 59 boulevard Pinel
city: PARIS Cedex 12
country: France
facility: Hôpital Trousseau, Service de neuropédiatrie, Centre Référence des Maladies Lysosomales, 26 avenue du Docteur Arnold Netter
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz, Zentrum für Kinder- und Jugendmedizin, Langenbeckstrasse 1
city: Warszawa
country: Poland
facility: The Children's Memorial Health Institute Warsaw, Department of Metabolic Diseases, Al Dzieci Polskich 20
city: Manchester
country: United Kingdom
facility: Genetic Medicine, 6th floor, St Mary's Hospital, Oxford Road,
Study officials:
affiliation: Copenhagen University Hospital, Center for Metabolic Diseases, Department for Clinical Genetics
name: Allan M Lund, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Zymenex A/S
name: Jens Fogh
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
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.
citation: 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.