The primary objective of this study is to evaluate the safety of sebelipase alfa in a more broad population of subjects with LAL Deficiency than have been previously studied.The secondary objectives of this study are (1) to evaluate effects of…
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Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
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 IARRs.
Functional and overall development in subjects <= 6 years of age will be
assessed, as determined by Denver II scores.
Secondary outcome
Efficacy:
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 (UK-ELD) 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 LAL Deficiency
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.
Background summary
Lysosomal Acid Lipase Deficiency (LALD) is a disease that causes build-up of
fat (lipids) in the liver and other parts of the body. This is due to lack of
the enzyme called lysosomal acid lipase, a substance that normally breaks down
fat. The build-up causes health problems, including swelling and damage
(scarring) of the liver and high cholesterol in the blood. High cholesterol in
the blood may increase the risk of heart disease. It can also cause problems
due to blocking of these arteries. There are no approved treatments for LALD.
The purpose of this study, which involves research, is to see if an
investigational drug (called sebelipase alfa) is a safe and effective treatment
of this disease. In studies with animals that also lack this enzyme, the
investigational drug has been shown to make the liver better. One clinical
study with the investigational drug in adults with LALD has been completed.
Three studies are now ongoing in infants, children or adults with LALD.
Study objective
The primary objective of this study is to evaluate the safety of sebelipase
alfa in a more broad population of subjects with LAL Deficiency than have been
previously studied.
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 LAL Deficiency including those not
previously well characterized in the literature, and (3) to evaluate the
effects of sebelipase alfa on growth parameters in pediatric subjects
presenting with evidence of growth delay, (4) to evaluate the immunogenicity of
sebelipase alfa.
The exploratory objectives of this study are (1) to further characterize the PK
of sebelipase alfa in pediatric subjects, subjects with severe hepatic
dysfunction, and those who have had a previous liver or hematopoietic stem cell
transplants; and (2) to evaluate the effect of sebelipase alfa on HRQOL
assessments.
Study design
This is an open-label, multicenter study. The study will consist of a screening
period of up to 45 days, a treatment period for up to 96 weeks (an expanded
treatment period of a maximum of up to 48 weeks), and a follow-up phone call at
least 4 weeks after the last dose of sebelipase alfa.
Safety and efficacy assessments will be performed at regular intervals
throughout the study. Exploratory safety and efficacy assessments may be
performed for subjects who exhibit specific atypical manifestations of LAL
Deficiency at the discretion of the Investigator in consultation with the
Sponsor (e.g., pulmonary function tests for an individual presenting with
significant pulmonary involvement, etc). In addition, the PK of sebelipase alfa
will be assessed for the pediatric population (where local regulations permit),
those with severe hepatic dysfunction, and those who have had a previous liver
or hematopoietic stem cell transplant.
Effects on health-related quality of life (HRQOL) will be characterized for all
subjects at selected time points. Blood samples will also be collected for an
additional analysis of potential disease-related biomarkers in this population.
An independent program-level safety committee appointed by the Sponsor
will provide additional oversight of subject
Intervention
All subjects will initiate treatment with sebelipase alfa at a dose of 1
mg·kg-1 through intravenous administration every other week (qow). Dose
escalations up to 3 mg·kg-1 once weekly (qw) will be allowed if the subject
meets dose escalation criteria (e.g., significant clinical progression) after a
minimum time on the previous dose. All infusions will initially be administered
at a study center. After Week 48, home infusions may be permitted for subjects
who have had no moderate-tosevere hypersensitivity reactions requiring medical
intervention/management and no serious adverse events (SAEs) related to study
drug within the prior 24 weeks, contingent on Sponsor approval, local
regulations, and the availability of established regional infrastructure and
resources for home infusions.
Study burden and risks
Potential disadvantages of participations include the risk of experiencing side
effects from treatment with sebelipase alfa, or from study-related procedures.
Sebelipase alfa is an investigational enzyme replacement therapy. Larger
numbers of patients with other lysosomal storage diseases (like LALD) have been
treated with enzyme replacement therapies. It is possible that the risks and
discomforts for sebelipase alfa maybe similar to these drugs.
• Mild side effects include: flushing, rash, fast heart rate, fast breathing
rate, headache, and a slight fever.
• Severe infusion reactions and serious side effects related to enzyme
replacement therapy administration are rare. These side effects include
shortness of breath or difficulty breathing, very low or very high blood
pressure, and very fast or very slow heart rate.
Other disadvantages of participation are that they have to make additional
visits to the clinic and follow the instructions for participation in the
trial.
Hayden Avenue 33
Lexington 02421
US
Hayden Avenue 33
Lexington 02421
US
Listed location countries
Age
Inclusion criteria
1. Subject will be > 8 months of age at the time of dosing.
2. Subject or subject*s parent or legal guardian (if applicable) 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 LAL Deficiency 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 (Note: in a highly suggestive case of LAL Deficiency where only 1 mutation is identified, subjects
may be included based on a fibroblast enzyme activity assay); OR
b. Appropriately documented (based on consultation with the Sponsor) historical result of an enzyme test prior to
hematopoietic or liver transplantation (performed in dry blood spots, leukocytes or fibroblasts).
4. Subjects > 8 months but < 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LAL Deficiency:
a. Dyslipidemia (defined as Screening LDL-C > 130 mg/dL; TG > 200 mg/dL);
b. Elevated transaminases (ALT >=1.5x ULN (based on the age-
and gender-specific normal ranges of the central laboratory performing the assay)
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 (e.g., osteomalacia, hypoalbuminaemia, prolonged bleeding time due to vitamin K deficiency); AND
iii. Documented small intestinal disease involvement on
a small bowel biopsy performed within 1 year of Screening
e. Other clinical manifestation of LAL Deficiency in the opinion
of the investigator and in consultation with the Sponsor (e.g., abnormal cardiac or pulmonary functions, or presence
of lymphadenopathy by imaging or palpation).
5. Subjects >= 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LAL Deficiency:
a. Evidence of advanced liver disease (e.g., cirrhosis confirmed
by imaging or biopsy) 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 (historical or by esophagogastroduodenoscopy (EGD) at Screening
(unless medically contraindicated due to high risk of endoscopy-related bleeding based on presence of esophageal varices on endoscopy carried out within
3 months of assessment).
b. Disease recurrence in subjects with past liver or hematopoietic transplants (e.g., re-accumulation of lipid
containing Kupffer cells, recurrence of fibrosis);
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 percentile on 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 (99th, 97th, 95th, 90th, 75th, 50th, 25th,
10th, 5th, 3rd, and 1st) 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 (e.g., abnormal cardiac or pulmonary functions, or presence
of lymphadenopathy by imaging or palpation).
6. Male and female subjects of childbearing potential must agree to use
a highly reliable method of birth control (expected failure rate less than 5% per year) 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 (e.g., glitazones, high-dose vitamin E, metformin, ursodeoxycholic acid [UDCA]) 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.
Exclusion criteria
1. Subject meets eligibility criteria for another interventional study of sebelipase alfa in LAL Deficiency 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 LAL Deficiency which have not been adequately treated (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease).
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 LAL Deficiency 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 (e.g. excessive alcohol consumption).
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-00428730-NL |
| ClinicalTrials.gov | NCT02112994 |
| CCMO | NL52764.018.15 |