Type 1 Hyperlipoproteinemia
Conditions
Keywords
hypertriglyceridemia
Brief summary
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
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.
Interventions
DRUGSlx-4090
Given for 4 weeks
DRUGSLx-4090 placebo
Given for 4 weeks
DRUGOrlistat Placebo
Given for 4 weeks
DRUGOrlistat
Given for 4 weeks
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This trial is adaptive design/flexible design. The participants were randomized from the start of the study
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Triglycerides at First Intervention Period | 4 weeks after the assigned treatment (first intervention period) | Serum triglyceride level will be measured after taking each assigned intervention at first intervention period. |
| Serum Triglycerides at Second Intervention Period | 4 weeks after the assigned treatment (Second Intervention Period) | Serum triglyceride level will be measured after taking each assigned intervention at second intervention period |
| Serum Triglycerides at Third Intervention Period | 4 weeks after the assigned treatment (Third Intervention Period) | Serum triglyceride level will be measured after taking each assigned intervention at intervention period |
| Serum Triglycerides at Fourth Intervention Period | 4 weeks after the assigned treatment (Fourth Intervention Period) | Serum triglyceride level will be measured after taking each assigned intervention at fourth intervention period |
Countries
United States
Participant flow
Recruitment details
This trial is adaptive design/flexible design. The participants were randomized from the start of the study
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Placebo at First Intervention Period 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. | 2 |
| Orlistat/Placebo at First Intervention Period 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 were administered. | 1 |
| Orlistat Placebo /Slx-4090 at First Intervention Period Orlistat placebo 2 capsules, 60mg each three times per day with meals. Slx-4090 4 tablets, 50mg each. three times per day with meals were administered | 1 |
| Orlistat/SLx-4090 at First Intervention Period Orlistat, 2 capsules 60 mg each, three times per day with meals. SLx-4090 4 tablets 50mg each, three times per day with meals were administered. | 1 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Third Intervention Period (4 Weeks) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo/Placebo at First Intervention Period | Orlistat/Placebo at First Intervention Period | Orlistat Placebo /Slx-4090 at First Intervention Period | Orlistat/SLx-4090 at First Intervention Period | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| BMI <18.5 kg/m^2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| BMI 18.5 kg/m^2-24.9 kg/m^2 | 1 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| BMI 25 kg/m^2-29.9 kg/m^2 | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| BMI 30 kg/m^2-34.9 kg/m^2 | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| BMI 35 kg/m^2-39.9 kg/m^2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| BMI >=40 kg/m^2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Triglycerides | 1969 mg/dL STANDARD_DEVIATION 419 | 4840 mg/dL STANDARD_DEVIATION 0 | 814 mg/dL STANDARD_DEVIATION 0 | 2061 mg/dL STANDARD_DEVIATION 0 | 2421 mg/dL STANDARD_DEVIATION 1480 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 |
| other Total, other adverse events | 0 / 2 | 1 / 1 | 1 / 1 | 1 / 1 | 0 / 1 | 0 / 1 | 1 / 1 | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 1 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 1 | 0 / 0 |
Outcome results
Primary
Serum Triglycerides at First Intervention Period
Serum triglyceride level will be measured after taking each assigned intervention at first intervention period.
Time frame: 4 weeks after the assigned treatment (first intervention period)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLx-4090 Placebo/Orlistat Placebo | Serum Triglycerides at First Intervention Period | 2086 mg/dL | Standard Deviation 481.54 |
| Orlistat/Placebo | Serum Triglycerides at First Intervention Period | 3320 mg/dL | — |
| Orlistat Placebo /Slx-4090 | Serum Triglycerides at First Intervention Period | 1576 mg/dL | — |
| Orlistat/SLx-4090 | Serum Triglycerides at First Intervention Period | 1280 mg/dL | — |
Primary
Serum Triglycerides at Fourth Intervention Period
Serum triglyceride level will be measured after taking each assigned intervention at fourth intervention period
Time frame: 4 weeks after the assigned treatment (Fourth Intervention Period)
Population: Patient assigned to Orlistat/SLX-4090 group did not start the assigned treatment due to lack of drugs.~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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SLx-4090 Placebo/Orlistat Placebo | Serum Triglycerides at Fourth Intervention Period | 1156 mg/dL |
| Orlistat Placebo /Slx-4090 | Serum Triglycerides at Fourth Intervention Period | 2946 mg/dL |
Primary
Serum Triglycerides at Second Intervention Period
Serum triglyceride level will be measured after taking each assigned intervention at second intervention period
Time frame: 4 weeks after the assigned treatment (Second Intervention Period)
Population: Patient assigned to SLX-4090 placebo/Orlistat placebo group withdrew from the study in this phase.~One more subject was assigned to the Orlistat/SLx-4090 but could not start the study as the drug SLx-4090 was not available.~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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Orlistat/Placebo | Serum Triglycerides at Second Intervention Period | 1419 mg/dL |
| Orlistat Placebo /Slx-4090 | Serum Triglycerides at Second Intervention Period | 2040 mg/dL |
| Orlistat/SLx-4090 | Serum Triglycerides at Second Intervention Period | 3478 mg/dL |
Primary
Serum Triglycerides at Third Intervention Period
Serum triglyceride level will be measured after taking each assigned intervention at intervention period
Time frame: 4 weeks after the assigned treatment (Third Intervention Period)
Population: Patient assigned to Orlistat/SLX-4090 placebo group did not start the assigned treatment due to lack of drugs.~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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SLx-4090 Placebo/Orlistat Placebo | Serum Triglycerides at Third Intervention Period | 6220 mg/dL |
| Orlistat Placebo /Slx-4090 | Serum Triglycerides at Third Intervention Period | 1320 mg/dL |