Atorvastatin Therapy on Xanthoma in Alagille Syndrome

Study Overview
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Brief Summary
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To observe the efficacy and safety of atorvastatin on xanthoma in Alagille syndrome through a prospective study.

Detailed Description
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Alagille syndrome (ALGS, OMIM 118450) is an important cause of chronic cholestasis in children, and the incidence rate is about 1:30000 1:50000. Most patients with ALGS have hypercholesterolemia. In severe cases, multiple xanthomas can be seen, and some patients are accompanied by severe itching and pain. Disfigured xanthomas affect the normal social interaction of patients, thereby causing physical and mental damage to children. At present, xanthoma caused by hypercholesterolemia can be cured by treating the primary disease, taking lipid-lowering drugs (such as bile acid chelators, ezetimibe, statins, etc.), or lipoprotein apheresis. If it affects the beauty or function, local treatment such as 33% trichloroacetic acid dot coating, carbon dioxide laser, liquid nitrogen freezing or surgical resection is feasible, and even surgical operation( such as portal vena cava anastomosis, liver transplantation). Compared with expensive lipoprotein apheresis and other invasive therapies, taking lipid-lowering drug has the advantages of higher acceptance, lower cost and higher safety. However, at present, there are no guidelines for application of oral lipid-lowering drugs in children under 6 years old with hypercholesterolemia. Therefore, the purpose of this study is to clarify the safety and efficacy of atorvastatin on xanthoma in ALGS , so as to provide reference for the treatment of ALGS patients' xanthomas. Risk prevention and treatment: The patients began to take atorvastatin from a small dose, followed up closely in the early stage (2-4 weeks) to see if the patients had obvious discomfort such as myalgia, and monitored the changes of Biochemistry (CK, ALT, AST, etc.). If moderate or more serious adverse reactions occurred during the trial or the following laboratory abnormalities occurred (CK exceeded 10 times the upper limit of normal; ALT or AST had been continued to rise, exceeding 2 times the baseline value), atorvastatin was temporarily stopped, and patients should be rechecked within 2 weeks. It is necessary to reevaluate and decide whether to restart atorvastatin treatment.

Official Title
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The Safety and Efficacy of Atorvastatin on Xanthoma in Alagille Syndrome

Conditions
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Alagille Syndrome, Atorvastatin, Xanthoma

Intervention / Treatment
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* Drug: atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the ALGS diagnostic criteria; Xanthoma of skin; Before treatment with atorvastatin,non-HDL-C≥5.76mmol/L（223 mg/dL）; Informed consent; Age 0-17 years old, male or female; Taking bile acid chelator (colenemide) has no obvious effect or intolerance. Exclusion Criteria: Liver transplantation has been performed; In the recovery period of cholestasis, xanthoma is obviously subsiding; Patients with serious systemic diseases and unstable vital signs; Progressive active liver injury, such as continuous increase of transaminase; Serious myopathy; Known to be allergic to any component of atorvastatin; The weight is less than 5kg.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atorvastatin+ALGS-Xanthoma<br>Drug: atorvastatin Dosage form: tablet Route of administration: oral Duration: 6 months （After 6 months of medication, according to the actual situation of the patient, choose to maintain the original dosage, gradually reduce the dosage or stop the medication） Administration method: Initial dose: ① < 1 year old: 1.25mg/d, qd; ② 1-5 years old: 2.5mg/d, qd; ③ 6-9 years old: 5mg/d, qd; ④ ≥ 10 years old: 10mg/d, qd. The maximum dose is 40mg/d and not more than 1mg/kg/d. During the follow-up, the medication was adjusted according to the laboratory results until non-HDL-C≤4.2mmol/L（162 mg/dL）, xanthoma disappear, or the patient had moderate or more serious adverse reactions. | Drug: atorvastatin<br>* Oral atorvastatin treatment for ALGS children with xanthoma<br>* Other names: Lipitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade change of xanthoma | The grade change of xanthoma would be assessed at the 3th/6th month after enrollment 【Explanation：Xanthomas were graded as 0 = none, 1 = minimal, 2 =moderate, 3 = disfiguring, and 4 = disabling. Minimal xanthomas signified fewer than 20 scattered individual lesions, moderate represented more than 20 lesions that did not interfere with or limit activities, disfiguring represented large numbers of lesions that by their large numbers or size caused distortion of the face or xtremities, and disabling signified that the xanthomas interfered with function (such as hand use or ability to walk) because of excess size or number.】 | from enrollment to the 3th/6th month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| non-HDL-C change | The non-HDL-C change would be measured at the 3th/6th month after enrollment 【Explanation: non-HDL-C is defined as the difference between total cholesterol and HDL-C】 | from enrollment to the 3th/6th month | 
| Incidence of adverse events | It is a binary variable. Incidence Rates for adverse event（including：rhabdomyolysis and myopathy，liver enzymes exceeded twice the baseline value，nasopharyngitis, muscle pain，diarrhea，nausea, fever，urinary tract infection, joint swelling，epistaxis，urticaria，etc.）would be calculated. | from enrollment to the 3th/6th month |