Phase 2 Study of Orlistat and SLx-4090 for the Treatment of Type 1 Hyperlipoproteinemia

Study Overview
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Brief Summary
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Funding Source - FDA OOPD This study is being done to find out whether an investigational (not approved by FDA ) drug called SLx-4090 or Orlistat (FDA approved medication for weight loss) when given alone or in combination can treat the high blood fat (elevated triglycerides)levels found in the condition Type 1 Hyperlipoproteinemia (T1HLP) better or more safely than low fat diet alone, the current standard medical care. It is also not clear whether Orlistat, that is FDA approved for weight loss, is effective in lowering blood fat levels in patients with Type 1 hyperlipoproteinemia (T1HLP). The researchers are interested in learning whether any one of these drugs when given alone or in combination is more effective and safe in treating T1HLP.

Detailed Description
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Type I hyperlipoproteinemia is a rare, autosomal recessive metabolic disorder characterized by extreme hypertriglyceridemia due to a deficiency in lipoprotein lipase or related proteins. Treatment of these patients is challenging as triglyceride-lowering medications are ineffective. A low fat diet is helpful, however, despite good dietary compliance, some patients continue to have severe hypertriglyceridemia and recurrent pancreatitis which can be life threatening. Therefore, we wish to investigate whether inducing dietary fat malabsorption or inhibiting chylomicron formation will cause further lowering of serum triglycerides (TG) beyond the effect of limiting dietary fat intake. We will study the efficacy and safety of an inhibitor of intestinal lipase (Orlistat) and an intestinal-specific inhibitor of microsomal triglyceride transport protein (MTP) involved in the assembly and secretion of chylomicrons (SLx-4090), alone and in combination, for reducing serum triglyceride levels in patients with Type I hyperlipoproteinemia. We plan to enroll 20 patients with Type I hyperlipoproteinemia in a randomized, double-blind, placebo-controlled, cross-over trial. After a baseline evaluation, the subjects will be randomly assigned to placebo/placebo, Orlistat/placebo, SLx-4090/placebo or Orlistat/SLx-4090 for the duration of four weeks followed by a one week wash out period. During the last week of each study period, fasting blood samples will be drawn for three consecutive days for serum lipids and chemistry panel. The primary endpoint will be serum triglycerides; the secondary endpoint variables will be fasting and postprandial serum chylomicron-TG levels, postprandial serum TG levels during a meal tolerance test and retinyl palmitate levels during a meal tolerance test. Repeated measures analysis of variance will be used for statistical comparisons. Our results may help in designing novel therapeutic approaches for patients with Type 1 hyperlipoproteinemia.

Official Title
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Phase 2 Study of Orlistat and SLx-4090 for the Treatment of Type 1 Hyperlipoproteinemia

Conditions
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Type 1 Hyperlipoproteinemia

Intervention / Treatment
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* Drug: SLx-4090 placebo
* Drug: Orlistat Placebo
* Drug: Orlistat
* Drug: Slx-4090


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type I hyperlipoproteinemia. Fasting serum triglyceride levels of greater than 1000 mg/dL. Age > 12 years Exclusion Criteria: Secondary hypertriglyceridemias due to diabetes, renal disease, hypothyroidism, alcoholism and drug therapy such as estrogens and estrogen analogues, steroids, HIV-protease inhibitors, retinoic acid derivatives and interferons. Pregnant or lactating women Significant liver disease (elevated transaminases > 2 times upper limit of normal) Alcohol abuse (> 7 drinks or 84 g per week for women and > 14 drinks for men or 168 g per week for men) Drug use (cocaine, marijuana, LSD, etc.) Major surgery in the past three months Congestive heart failure Serum creatinine greater than 2.5 mg/dL Cancer within the past five years Gastrointestinal surgery in the past Current therapy with anti-coagulants, digoxin and anti-arrhythmics Chronic malabsorption syndromes Cholestasis Acute illnesses such as acute pancreatitis in the last 8 weeks

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 100 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This trial is adaptive design/flexible design. The participants were randomized from the start of the study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SLx-4090 placebo/Orlistat Placebo<br>Slx-4090(placebo) is dosed as 4 tablets of 50 mg, three times per day with meals. Orlistat (placebo) is dosed as 2 capsules of 60 mg, three times per day with meals. This trial is adaptive design/flexible design. The participants were either randomized from the start of the study or after the completion of each treatment. | Drug: SLx-4090 placebo<br>* Given for 4 weeks<br>Drug: Orlistat Placebo<br>* Given for 4 weeks<br>|
| Experimental: Orlistat/placebo<br>Orlistat two capsules 60mg each, three times per day with meals. Placebo for SLx-4090, 4 tablets 50mg each, three times per day with meals. This trial is adaptive design/flexible design. The participants were either randomized from the start of the study or after the completion of each treatment. | Drug: SLx-4090 placebo<br>* Given for 4 weeks<br>Drug: Orlistat<br>* Given for 4 weeks<br>|
| Experimental: Orlistat placebo /SLx-4090<br>Orlistat placebo 2 capsules, 60mg each three times per day with meals. Slx-4090 4 tablets, 50mg each. three times per day with meals. This trial is adaptive design/flexible design. The participants were either randomized from the start of the study or after the completion of each treatment. | Drug: Orlistat Placebo<br>* Given for 4 weeks<br>Drug: Slx-4090<br>* Given for 4 weeks<br>|
| Experimental: Orlistat/SLx-4090<br>Orlistat, 2 capsules 60 mg each, three times per day with meals. SLx-4090 4 tablets 50mg each, three times per day with meals. This trial is adaptive design/flexible design. The participants were either randomized from the start of the study or after the completion of each treatment. | Drug: Orlistat<br>* Given for 4 weeks<br>Drug: Slx-4090<br>* Given for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Triglycerides at First Intervention Period | Serum triglyceride level will be measured after taking each assigned intervention at first intervention period. | 4 weeks after the assigned treatment (first intervention period) | 
| Serum Triglycerides at Second Intervention Period | Serum triglyceride level will be measured after taking each assigned intervention at second intervention period | 4 weeks after the assigned treatment (Second Intervention Period) | 
| Serum Triglycerides at Third Intervention Period | Serum triglyceride level will be measured after taking each assigned intervention at intervention period | 4 weeks after the assigned treatment (Third Intervention Period) | 
| Serum Triglycerides at Fourth Intervention Period | Serum triglyceride level will be measured after taking each assigned intervention at fourth intervention period | 4 weeks after the assigned treatment (Fourth Intervention Period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypertriglyceridemia