E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lysosomal Acid Lipase Deficiency (LALD) |
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E.1.1.1 | Medical condition in easily understood language |
Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body. |
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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 | 16.1 |
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 |
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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. |
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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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient will be > 8 months of age at the time of dosing.
2. Confirmation of LALD diagnosis as determined by the central lab; a patient 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 (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).
3. Patients > 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 (based on the ageand
gender-specific normal ranges of the central laboratory performing the assay);
c. Impaired growth as defined as:
i. WFA or SFA less than the age- and gender appropriate 5th percentile on a standard WHO or CDC 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 lines on a standard WHO (patients < 24 months of age) or CDC (patients ≥ 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 LALD 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).
4. Patients ≥ 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 (e.g., cirrhosis confirmed
by imaging or biopsy, and Child-Pugh C) 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. Histologically confirmed disease recurrence in patients 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 patients defined as:
1. WFA or SFA less than the age- and genderappropriate
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 lines on a standard CDC
WFA chart over a period of 6 months prior to
study entry;
e. Other clinical manifestation of LALD 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. Male and female patients of childbearing potential must agree to use birth control
6. Women of childbearing potential must have a negative serum
pregnancy test prior to entering the study.
7. Patients 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 for first 12 weeks of the study.
8. Patients receiving medications for the treatment of nonalcoholic fatty liver disease must be on a stable dose for at least 4 weeks prior and for first 12 weeks of study. |
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E.4 | Principal exclusion criteria |
A patient who meets any of the following exclusion criteria will be ineligible for this study:
1. Patient meets eligibility criteria for another interventional study of sebelipase alfa in LALD that is open for enrollment in the region where the patient will receive treatment.
2. Patient has known causes of active liver disease other than LALD which have not been adequately treated (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease).
3. Patient is unable or unwilling to comply with study procedures.
4. Patient received a hematopoietic stem cell or liver transplant <2 years from the time of dosing.
5. Females who are nursing or pregnant.
6. Patient 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 (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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety endpoints will include the incidence of adverse events (AEs), SAEs, and infusion-related reactions (IRRs); 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 antidrug antibodies (ADAs) including seroconversion rate, time to seroconversion, ADA titer by time point, peak ADA titer, time to peak ADA titer, and tolerization. The effect of ADAs on the safety of sebelipase alfa will also be explored, in particular, the relationship between ADA-positive patients and the incidence of IRRs. Functional and overall development in patients ≤ 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. 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 for efficacy 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 patients 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 patients 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) highsensitivity 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 patients 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 patient.
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. |
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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 4 weeks from the last infusion of sebelipase alfa. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | No |
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 |
Canada |
Denmark |
Italy |
Japan |
Croatia |
Australia |
Brazil |
Germany |
Spain |
Mexico |
Poland |
Russian Federation |
Turkey |
United Kingdom |
United States |
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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
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The LVLS will be a follow-up call at least 4 weeks after the last dose of study drug |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |