Clinical Trials Register

Summary
EudraCT Number:	2011-004287-30
Sponsor's Protocol Code Number:	LAL-CL06
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-05-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2011-004287-30

A.3

Full title of the trial

A Multicenter, Open-Label Study of Sebelipase Alfa in Patients with Lysosomal Acid Lipase Deficiency

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

LAL-CL06

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1152-7171

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/112/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Alexion Pharmaceuitcals Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alexion Pharmaceuticals Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Alexion Pharmaceuticals INc
B.5.2	Functional name of contact point	Nicole Spoerri, Associate Manager
B.5.3	Address:
B.5.3.1	Street Address	Giesshübelstrasse 30
B.5.3.2	Town/ city	Zurich
B.5.3.3	Post code	8045
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4144457 4439
B.5.5	Fax number	+4144457 40 01
B.5.6	E-mail	Nicole.Spoerri@alexion.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/827
D.3 Description of the IMP
D.3.1	Product name	Sebelipase Alfa
D.3.2	Product code	SBC-102
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sebelipase alfa
D.3.9.1	CAS number	1276027-63-4
D.3.9.2	Current sponsor code	SBC-102
D.3.9.3	Other descriptive name	lysosomal acid lipase, Esterase, cholesterol (human gene LIPA), Lysosomal acid lipase (human gene LIPA); USAN: sebelipase alpha
D.3.9.4	EV Substance Code	SUB121647
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Lysosomal Acid Lipase Deficiency (LALD)

E.1.1.1

Medical condition in easily understood language

Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body.

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	HLT
E.1.2	Classification code	10024579
E.1.2	Term	Lysosomal storage disorders
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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:
i. Documented small intestinal involvement by small bowel biopsy
performed within 1 year of Screening; AND
ii. Unexplained iron deficiency, osteopenia, weight loss or chronic
diarrhea; OR
iii. Impaired growth in pediatric subjects defined as:
1. WFA or SFA less than the age- and gender-appropriate 5th percentileon a standard CDC WFA chart for at least 6 months prior to study entry;
OR
2. Poor weight gain as evidenced by calculated weight percentile
decreasing across 2 major percentile lines on a standard CDC WFA chart over a period of 6 months prior to study entry;
e. Other clinical manifestation of LAL Deficiency in the opinion of the investigator and in consultation with the Sponsor .
6. Male and female subjects of childbearing potential must agree to use a highly reliable method of birth control from the screening visit through 4 weeks after the last dose of study drug.
7. Women of childbearing potential must have a negative serum
pregnancy test prior to entering the study.
8. Subjects receiving lipid-lowering therapies must be on a stable dose of the medication or stable apheresis regimen for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.
9. Subjects receiving medications for the treatment of nonalcoholic fatty liver disease must be on a stable dose for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.

E.4

Principal 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.

E.5 End points

E.5.1

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.

E.5.1.1

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, an expanded treatment period of a maximum of up to 48 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.

E.5.2

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.

E.5.2.1

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 at least 4 weeks from the last infusion of sebelipase alfa.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belgium

Brazil

Canada

Croatia

Denmark

Germany

Italy

Japan

Mexico

Netherlands

Russian Federation

Spain

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The LVLS will be a follow-up call at least 4 weeks after the last dose of study drug

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Eligible patients starting at 8 months of age will be enrolled into the study. Patient’s parent or legal guardian consents to participation in the study, if the patient is of minor age and deemed unable to do so.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

There is no approved treatment for the condition. The subjects will continue having their disease managed as agreed with their treating physicians or may be eligible for compassionate use or expanded access to the IMP.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-07-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-08-12

P. End of Trial
P.	End of Trial Status	Completed

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