Study of sebelipase alfa in a broad population of patients with Lysosomal Acid Lipase Deficiency (LALD).

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2011-004287-30-GB
• Date of registration: 11/04/2014
• Prospective Registration: Yes
• Primary sponsor: Alexion Pharmaceuticals Inc
• Public title: Study of sebelipase alfa in a broad population of patients with Lysosomal Acid Lipase Deficiency (LALD).
• Scientific title: A Multicenter, Open-Label Study of Sebelipase Alfa in Patients with Lysosomal Acid Lipase Deficiency
• Date of first enrolment: 19/01/2015
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004287-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Brazil, Canada, Croatia, Denmark, Germany, Italy, Japan, Mexico, Netherlands, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Harold Pestana, Assoc Dir Clin Ops
• Affiliation: Alexion Pharmaceuticals Inc

• Name: Harold Pestana, Assoc Dir Clin Ops
• Affiliation: Alexion Pharmaceuticals Inc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subject will be > 8 months of age at the time of dosing.
2. Subject or subject's parent or legal guardian consents to participation in the study. If the subject is of minor age, he/she is willing to provide assent where required per local regulations, and if deemed able to do so.
3. Confirmation of LALD diagnosis as determined by the central lab; a subject who received a liver or hematopoietic stem cell transplant who does not show evidence of LAL enzyme deficiency by DBS due to the effects of transplantation must have either:
a. Molecular genetic testing which confirms mutations in both alleles of the LIPA gene; OR
b. Appropriately documented historical result of an enzyme test prior to hematopoietic or liver transplantation.
4. Subjects > 8 months but < 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LALD:
a. Dyslipidemia (defined as Screening LDL-C > 130 mg/dL; TG > 200 mg/dL);
b. Elevated transaminases (ALT =1.5x ULN);
c. Impaired growth as defined as:
i. WFA or SFA less than the age- and gender-appropriate 5th percentile on a standard WHO (subjects = 24 months of age) or CDC (subjects > 24 months and < 4 years of age) WFA or SFA chart for at least 3 months prior to study entry; OR
ii. Poor weight gain as evidenced by calculated weight percentile decreasing across 2 major percentile (99th, 97th, 95th, 90th, 75th, 50th, 25th, 10th, 5th, 3rd, and 1st) lines on a standard WHO (subjects =24 months of age) or CDC subjects > 24 months and <4 years of age) WFA chart over a period of 6 months prior to study entry;
d. Suspected malabsorption with:
i. Persistent unexplained gastrointestinal symptoms such as nausea, diarrhea, abdominal pain, and bloating; OR
ii. Unexplained anemia, or other abnormalities suggestive of malabsorption; AND
iii. Documented small intestinal disease involvement on a small bowel biopsy performed within 1 year of Screening
e. Other clinical manifestation of LALD in the opinion of the investigator and in consultation with the Sponsor.
5. Subjects = 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LALD:
a. Evidence of advanced liver disease at Screening accompanied by:
i. Clinically significant portal hypertension as defined by a hepatic venous pressure gradient (HVPG) greater than or equal to 10 mmHg; OR
ii. Documented esophageal varices at Screening.
b. Disease recurrence in subjects with past liver or hematopoietic transplants;
c. Persistent dyslipidemia (defined as LDL-C > 130mg/dL, triglycerides > 200mg/dL, or HDL-C <40mg/dL in males, and < 50mg/dL in females) that has persisted despite 3 or more months of treatment with one or more lipid-lowering therapies such as statins, cholesterol absorption inhibitors (ezetimibe), combination therapies (single-pill; ezetimibe/simvastatin, niacin/simvastatin), fibrates (fenofibrate, gemfibrozil, fenofibric acid), niacin or bile acid
sequestrants (cholestyramine, colestipol, colesevelam);
d. Suspected malabsorption based on the following manifestations:

Exclusion criteria:
1. Subject meets eligibility criteria for another interventional study of sebelipase alfa in LALD that is open for enrollment in the region where the subject will receive treatment.
2. Subject has known causes of active liver disease other than LALD which have not been adequately treated
3. Subject is unable or unwilling to comply with study procedures.
4. Subject received a hematopoietic stem cell or liver transplant < 2 years from the time of dosing.
5. Females who are nursing or pregnant.
6. Subject with co-morbidities other than complications due to LALD which, in the opinion of the Investigator and in consultation with the Sponsor, are irreversible or associated with a high mortality risk within 6 months, or would interfere with study compliance or data interpretation.
7. Exposure to any investigational product within 30 days of Screening for a small molecule and 60 days of Screening for a biologic.
8. Known hypersensitivity to eggs.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Lysosomal Acid Lipase Deficiency (LALD)
MedDRA version: 18.1 Level: HLT Classification code 10024579 Term: Lysosomal storage disorders System Organ Class: 100000004850

Intervention(s)

Product Name: Sebelipase Alfa
Product Code: SBC-102
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: sebelipase alfa
CAS Number: 1276027-63-4
Current Sponsor code: SBC-102
Other descriptive name: lysosomal acid lipase, Esterase, cholesterol (human gene LIPA), Lysosomal acid lipase (human gene LIPA); USAN: sebelipase alpha
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Secondary Objective: The secondary objectives of this study are (1) to evaluate effects of sebelipase alfa relative to Baseline assessment of lipid metabolism and liver function (including histopathology); (2) to evaluate the effects of sebelipase alfa on additional clinical parameters of LALD including those not previously well characterized in the literature, and (3) to evaluate the effects of sebelipase alfa on growth parameters in pediatric patients presenting with evidence of growth delay.

Primary end point(s): Safety endpoints will include the incidence of adverse events (AEs), SAEs, and infusion-associated reactions (IARs); changes from Baseline in 12-lead electrocardiograms (ECGs) and clinical laboratory tests (hematology, serum chemistry [including lipid panel], and urinalysis); changes in vital signs during and after infusion, relative to pre-infusion
values; physical examination findings; use of concomitant medications/therapies; characterization of anti-drug antibodies (ADAs) including ADA titer by time point, peak ADA titer, and time to peak ADA titer. The effect of ADAs on the safety of sebelipase alfa will also be explored, in particular, the relationship between ADA-positive subjects and the incidence of IARs. Functional and overall development in subjects = 6 years of age will be assessed, as determined by Denver II scores.

Timepoint(s) of evaluation of this end point: Screening will occur within 45 days.Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks. All patients will receive a starting dose of 1 mg·kg-1 qow. Dose increases (up to 3 mg·kg-1 qw) will be permitted during the treatment period. The follow-up period will be 4 weeks from the last infusion of sebelipase alfa.

Main Objective: The primary objective of this study is to evaluate the safety of sebelipase alfa in a broad population of patients with LALD than previously studied.

Secondary Outcome(s)

Secondary end point(s): Secondary outcome measures include the following changes or percent change from Baseline to the end of the treatment period: (1) decrease in Alanine Aminotransferase (ALT); (2) decrease in Aspartate Aminotransferase (AST); (3) decrease in LDL-C; (4) decrease in non-HDL-C; (5) increase in HDL-C; (6) decrease in triglyceride, (7) decrease in Child-Pugh status, (8) decrease in United Kingdom Model for End-Stage Liver Disease (UKELD)
score. In the subset of subjects for whom these assessments are performed: (9) improvement in hepatic histology; (10) decrease in liver and spleen volume by MRI; and (11) decrease in liver fat fraction by MRI. The effect of sebelipase alfa on growth parameters in pediatric subjects with manifestations of impaired growth will be measured. Additional clinical, biochemical and hematological abnormalities will also be evaluated, including (1) total and conjugated bilirubin, (2) gamma glutamyltransferase (GGT), (3) markers of macrophage activation, (4) high-sensitivity C-reactive protein, (4) hemoglobin level, and (5) platelet count. Exploratory measures of additional clinical manifestations of LALD not
previously well characterized in the literature will include changes in functional assessments outcomes. Pharmacokinetics PK parameters (in subjects for whom these assessments are performed) will be reported, as the data permit, and may include serum clearance
and apparent volume of distribution estimates along with secondary parameters of area under the concentration-time curve, maximum observed concentration, time to maximum observed concentration, and terminal elimination half-life (t1/2). The effect of ADAs on sebelipase alfa PK will also be explored. PK analysis will be discussed in the statistical analysis plan (SAP). Health-Related Quality of Life Exploratory HRQOL measures will include
changes from Baseline in scores for the Functional Assessment of Chronic Illness Therapy-Fatigue scale, Chronic Liver Disease Questionnaire, or Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales, as appropriate to the age of the subject. Pharmacodynamics Exploratory disease-related biomarkers, which may be identified based on emerging information from the sebelipase alfa development program and scientific literature, will be analyzed by changes or percent changes over time.

Timepoint(s) of evaluation of this end point: Screening will occur within 45 days. Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks. All patients will receive a starting dose of 1 mg·kg-1 qow. Dose increases (up to 3 mg·kg-1 qw) will be permitted during the treatment period. The followup period will be at least 4 weeks from the last infusion of sebelipase alfa.

Secondary ID(s)

2011-004287-30-DK

LAL-CL06

Source(s) of Monetary Support

Alexion Pharmaceuticals Inc

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 21/07/2018
• Date Completed: 28/12/2017
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-004287-30/results