## Protocol Section
### Identification Module
**NCT ID:** NCT02998879

**Acronym:** rhLaman-08

**Brief Title:** Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis

**Official Title:** A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated Velmanase Alfa (Recombinant Human Alpha-mannosidase) Treatment in Pediatric Patients Below 6 Years of Age With Alpha-Mannosidosis

#### Organization Study ID Info
**ID:** CCD-LMZYMAA1-08
#### Organization
**Class:** INDUSTRY
**Full Name:** Chiesi Farmaceutici S.p.A.
#### Secondary ID Infos
**ID:** 2016-001988-36
**Type:** EUDRACT_NUMBER
### Status Module
#### Completion Date
**Date:** 2020-07

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2021-10-26

**Type:** ACTUAL

**Last Update Submit Date:** 2021-10-18

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2020-07

**Type:** ACTUAL

#### Start Date
**Date:** 2016-12

**Status Verified Date:** 2021-10

#### Study First Post Date
**Date:** 2016-12-21
**Type:** ESTIMATED
**Study First Submit Date:** 2016-11-25
**Study First Submit QC Date:** 2016-12-16
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Cromsource

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Chiesi Farmaceutici S.p.A.

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The main objectives of the study are to evaluate safety and efficacy of repeated treatment with recombinant human alfa-mannosidase of patients with alfa-mannosidosis aged less than 6 years

**Detailed Description:** The Primary endpoints of the study include:

* Safety and tolerability of velmanase alfa as per Adverse events (AEs, including IRR), vital signs, laboratory parameters (hematology, biochemistry and urinanalysis)
* Detection of anti-velmanase alfa antibodies and neutralizing/inhibitory antibodies

The Secondary endpoints include changes from baseline to 24 months for the following parameters. Efficacy outcomes:

* Serum oligosaccharides
* Functional capacity: Peabody Developmental Motor Scale - 2nd edition (PDMS-2) scores, Mullen's Scale of Early Learning (MSEL) scores, Bruininks-Oseretsky Test Of Motor Proficiency-2nd Edition (BOT-2), when applicable by age (from 4 years) or upon the judgment of the physician
* Endurance: 3-Minute Stair Climb Test (3MSCT) and 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician, 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age, or when applicable according to the judgment of the physician
* Hearing evaluation: Otoacoustic Emissions (OAE) testing, Automatic Auditory Brainstem Response (A-ABR) audiometry
* Immunological profile, when applicable upon the judgment of the physician:
* CSF biomarkers: Tau protein (Tau), Neurofilament Protein Light (NFL), Glial Fibrillary Acidic Protein (GFAp), Oligosaccharides
* Assessment of quality of life via Questionnaire to parents
* Assessment of mannose-rich oligosaccharides in brain tissue, MRI
* Pharmacokinetic parameters

### Conditions Module

**Conditions:**

- Alpha-Mannosidosis

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 5

**Type:** ACTUAL

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** velmanase alfa 1mg/kg body weight infusion

**Intervention Names:**

- Drug: Velmanase Alfa (e.g. Lamazym)

**Label:** Velmanase Alfa

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Velmanase Alfa

**Description:** iv infusion treatment

**Name:** Velmanase Alfa (e.g. Lamazym)

**Other Names:**

- Lamazym

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Safety and tolerability assessed as per AEs including infusion-related reactions \[IRRs\]

**Measure:** Safety and tolerability of velmanase alfa as per Adverse events

**Time Frame:** From baseline throughout study completion, at least of 2 years

**Measure:** Safety and tolerability of velmanase alfa as per vital signs

**Time Frame:** From baseline throughout study completion, at least of 2 years

**Measure:** Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology

**Time Frame:** From baseline throughout study completion, at least of 2 years

**Measure:** Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per blood biochemistry

**Time Frame:** From baseline throughout study completion, at least of 2 years

**Measure:** Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis

**Time Frame:** From baseline throughout study completion, at least of 2 years

**Description:** Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained

**Measure:** Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies

**Time Frame:** From baseline throughout study completion, at least of 2 years

#### Secondary Outcomes

**Description:** Assessment of change from baseline in levels of Serum oligosaccharides

**Measure:** Evaluation of levels of Serum oligosaccharides

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Description:** Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained

**Measure:** Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Functional capacity: Bruininks-Oseretsky test of Motor Proficiency (BOT-2) when applicable by age (from 4 years) or upon the judgment of the physician

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Functional capacity: Mullen Scales of Early Learning (MSEL)

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Endurance: 3-Minute Stair Climb Test (3MSCT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Endurance: 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Hearing evaluation: Otoacoustic Emissions (OAE) testing

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Hearing evaluation: Automatic Auditory Brainstem Response (A-ABR) audiometry

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Immunological profile when applicable upon the judgement of the physician (Serum IgG, IgA, IgM; in vitro synthesis of IgG; in vitro proliferative response and Immunophenotype)

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** CSF biomarkers: Tau protein (Tau) § Neurofilament Protein Light (NFL) § Glial Fibrillary Acidic Protein (GFAp) § Oligosaccharides

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Assessment of quality of life via Questionnaire

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Assessment of mannose-rich oligosaccharides in brain tissue, as measured by Magnetic Resonance Spectroscopy (MRS)

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Magnetic Resonance Imaging (MRI) in white matter, gray matter and in centrum semi ovale, and diffusion-MRI of the brain,

**Time Frame:** From baseline throughout study completion, at least for 2 years

**Measure:** Pharmacokinetic parameters to determine Cmax (Peak Concentration)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine Ctrough (Trough Plasma Concentration)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine Area Under Curve (AUC24)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine AUClast (Area Under Curve After The Last Count)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine AUCinf (Area Under Curve From Time Zero To Infinity)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine tmax (Time To Peak Concentration)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine CL (Clearance)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine t1/2 (Elimination Half-Life)

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

**Measure:** Pharmacokinetic parameters to determine Rac (Obs) Observed Accumulation Ratio

**Time Frame:** At first dose (visit 1) and after 6 months (visit 26)

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Patient's custodial parent(s) must provide signed ICF prior to the involvement of the patient in any trial-related activities
2. The subject's custodial parent(s) must have the ability to comply with the protocol
3. The subject must have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity in leukocytes or fibroblasts \< 10% of normal activity (historical data)
4. The subject must have an age at the time of screening \< 6 years.

Exclusion Criteria:

1. The subject's diagnosis cannot be confirmed by alpha-mannosidase activity \< 10% of normal activity
2. Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-mannosidosis
3. History of BMT
4. 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
5. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
6. Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial
7. Participation in other interventional trials testing the IMP within the last 3 months.

**Maximum Age:** 6 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Wien

**Country:** Austria

**Location 2:**

**City:** Copenhagen

**Country:** Denmark

**Location 3:**

**City:** Lyon

**Country:** France

**Location 4:**

**City:** Hamburg

**Country:** Germany

**Location 5:**

**City:** Mainz

**Country:** Germany

**Location 6:**

**City:** Trieste

**Country:** Italy

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### See Also Links

**Label:** Study Record on EU Clinical Trials Register including results

**URL:** https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001988-36/results

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000002239

- Term: Carbohydrate Metabolism, Inborn Errors

- ID: D000008661

- Term: Metabolism, Inborn Errors

- ID: D000030342

- Term: Genetic Diseases, Inborn

- ID: D000016464

- Term: Lysosomal Storage Diseases

- ID: D000008659

- Term: Metabolic Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M25409

- Name: Mannosidase Deficiency Diseases

- Relevance: HIGH

- As Found: Mannosidosis

- ID: M11352

- Name: alpha-Mannosidosis

- Relevance: HIGH

- As Found: Alpha-Mannosidosis

- ID: M6879

- Name: Deficiency Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11641

- Name: Metabolism, Inborn Errors

- Relevance: LOW

- As Found: Unknown

- ID: M5498

- Name: Carbohydrate Metabolism, Inborn Errors

- Relevance: LOW

- As Found: Unknown

- ID: M23686

- Name: Genetic Diseases, Inborn

- Relevance: LOW

- As Found: Unknown

- ID: M18871

- Name: Lysosomal Storage Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T299

- Name: Alpha-mannosidosis

- Relevance: HIGH

- As Found: Alpha-Mannosidosis

### Condition Browse Module - Meshes

- ID: D000044904

- Term: Mannosidase Deficiency Diseases

- ID: D000008363

- Term: alpha-Mannosidosis

### Misc Info Module

- Version Holder: 2024-05-24
