Hyperlipoproteinemia Type I, Hypertriglyceridemia
Conditions
Brief summary
Patients with Type I Hyperlipoproteinemia (T1HLP) have a rare form of hypertriglyceridemia marked by significant chylomicronemia and recurrent episodes of acute pancreatitis. T1HLP is caused by a deficiency of lipoprotein lipase or one of its cofactors. Many patients are a challenge to treat, as the only effective therapy available is an extremely low fat diet. This diet is exceedingly difficult to follow, and despite adherence, many patients still have chylomicronemia and develop acute pancreatitis. Specific Aim: To determine the efficacy of a gastric and pancreatic lipase inhibitor, Orlistat, in reducing serum triglyceride levels in patients with T1HLP.
Detailed description
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, Investigator 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. Investigator will study the efficacy and safety of an inhibitor of intestinal lipase (Orlistat) for reducing serum triglyceride levels in patients with Type I hyperlipoproteinemia. Investigator plan to enroll 20 patients with Type I hyperlipoproteinemia in a randomized, double-blind, placebo-controlled, cross-over trial. 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. These results may help in designing novel therapeutic approaches for patients with Type 1 hyperlipoproteinemia.
Interventions
DRUGOrlistat
Orlistat is a gastric and pancreatic lipase inhibitor that is approved by the FDA for weight loss. It is available over-the-counter as 60 mg tablets under the trade name Alli, and available by prescription as 120 mg capsules under the trade name Xenical.
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Type I hyperlipoproteinemia 2. Fasting serum triglyceride levels of greater than 1000 mg/dL 3. Age \> 8 years
Exclusion criteria
1. Secondary hypertriglyceridemias due to diabetes, renal disease, hypothyroidism, alcoholism and drug therapy such as estrogens and estrogen analogues, steroids, HIVprotease inhibitors, retinoic acid derivatives and interferons 2. Pregnant or lactating women 3. 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 or 168 g per week for men) 4. Severe anemia (hematocrit \< 24%) 5. Drug use (cocaine, marijuana, LSD, etc.) 6. Major surgery in the past three months 7. Congestive heart failure 8. Serum creatinine greater than 2.5 mg/dL 9. Cancer within the past five years 10. Gastrointestinal surgery in the past 11. Current therapy with anti-coagulants, digoxin, and anti-arrhythmics 12. Current therapy with cyclosporine 13. Chronic malabsorption syndromes 14. Cholestasis 15. Acute illnesses such as acute pancreatitis in the last 8 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Serum Triglycerides | 3 days | Fasting blood samples were collected on three consequetive days at the end of each three month period. Mean values of the three days were calculated. |
Countries
United States
Participant flow
Recruitment details
A randomized,open-label, crossover trial with four periods and two sequences (orlistat and off for 3 months each) was conducted.
Participants by arm
| Arm | Count |
|---|---|
| Baseline Features of Patients Enrolled 120 mg of Orlistat will be given 3 times to patients weighing greater than 50 kg and patients weighing less than 40 kg will be given 60 mg of Orlistat 3 times a day for 3 months.
The patients were randomized to receive 3 months of orlistat or no therapy (off), then crossed over to the other arm, and this sequence was then repeated for an additional 6 months | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Baseline Features of Patients Enrolled |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
| Triglyceride | 1674 mg/dL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Fasting Serum Triglycerides
Fasting blood samples were collected on three consequetive days at the end of each three month period. Mean values of the three days were calculated.
Time frame: 3 days
Population: The patients were randomized to receive 3 months of orlistat or no therapy (off), then crossed over to the other arm, and this sequence was then repeated. Because only 2 patients participated, the results are provided per sequence and not per intervention.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Orlistat and Then Off Therapy | Fasting Serum Triglycerides | Period 3 | 758 mg/dL |
| Orlistat and Then Off Therapy | Fasting Serum Triglycerides | Period 1 | 705 mg/dL |
| Orlistat and Then Off Therapy | Fasting Serum Triglycerides | Period 4 | 1614 mg/dL |
| Orlistat and Then Off Therapy | Fasting Serum Triglycerides | Period 2 | 1511 mg/dL |
| Off Therapy and Then Orlistat | Fasting Serum Triglycerides | Period 4 | 1181 mg/dL |
| Off Therapy and Then Orlistat | Fasting Serum Triglycerides | Period 3 | 3121 mg/dL |
| Off Therapy and Then Orlistat | Fasting Serum Triglycerides | Period 2 | 1007 mg/dL |
| Off Therapy and Then Orlistat | Fasting Serum Triglycerides | Period 1 | 1827 mg/dL |