Clinical trial NCT02767531
Conditions: Hyperlipoproteinemia Type I Hypertriglyceridemia
Sponsor: University of Texas Southwestern Medical Center
Start date: 2015-12-01; Completion date: 2022-12-31
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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. arm 2: Standard therapy will be given for three months
Interventions: intervention 1: Orlistat
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
1
 
 
Orlistat for the Treatment of Type I 
Hyperlipoproteinemia 
 
 
 
 
Primary Investigator: Abhimanyu Garg, M.D. 
Sub-Investigator: Nivedita Patni, M.D. 
Funding Sponsor: Local funds, Southwestern Medical Foundation 
Version: 2 
Date: June18, 2018 
IRB number – STU 012013-042       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
2
 
Introduction and Purpose: 
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. 
 
Hypothesis: Inhibiting dietary fat absorption using a lipase inhibitor will lower serum triglyceride 
concentrations in patients with T1HLP.   
 
We expect that Orlistat will markedly reduce serum triglycerides in patients with T1HLP by 
inducing partial fat malabsorption, and we expect that this can be done safely with minimal side 
effects. 
  
Rationale: As there are no therapeutic options in patients with T1HLP, the results of this study 
may help in designing a therapeutic approach to extreme hypertriglyceridemia in these patients.   
 
Primary Endpoint: Fasting serum triglyceride levels 
 
Secondary Endpoints: 
1. Serum chylomicron-TG levels (Fasting and postprandial) 
2. Postprandial serum TG levels during meal tolerance test 
3. 72 hour fecal fat 
4. Fat soluble vitamin levels 
 
Primary Safety Endpoints:  
1. Fat soluble vitamin deficiencies due to fat malabsorption 
2. Gastrointestinal side effects (oily stools, anal leakage, diarrhea, flatus with discharge) 
 
The side effects experienced with Orlistat use are mainly gastrointestinal due to fat malabsorption. 
We intend to reduce these side effects by limiting fat intake in the diet. Additionally, we will provide 
patients with a multivitamin to take daily in order to reduce risk of vitamin deficiencies.  
 
The benefit of taking Orlistat is a reduction in serum triglyceride levels, and thus, a reduction in 
the risk of acute pancreatitis. There is significant morbidity and mortality associated with acute 
pancreatitis, and so we believe a reduction in this risk offers a greater benefit than mild 
gastrointestinal side effects. 
 
 
Background: 
Type I hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive condition characterized by 
recurrent episodes of acute pancreatitis due to extreme hypertriglyceridemia as a result of 
accumulation of chylomicrons (1-2).  In most of the patients, T1HLP is due to lipoprotein lipase 
(LPL) or apolipoprotein CII (APOC2) deficiency, however, recently mutations in lipase maturation 
factor 1 (LMF1), apolipoprotein A-5 (APOA5), and glycosyl-phosphatidylinositol anchored high 
density lipoprotein binding protein 1 (GPIHBP1) have been reported (3-4). In some patients, the 


 
 
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genetic basis of T1HLP remains unknown. Patients present with eruptive or tuberous xanthomas, 
pancreatitis, lipemia retinalis, and hepatosplenomegaly.  Most importantly, acute pancreatitis is 
often a cause for significant morbidity and even mortality in these patients. Treatment of these 
patients poses a significant challenge, as the current medications for hypertriglyceridemia such 
as fibrates, niacin, and omega-3 fatty acids are ineffective (1-2).  Some investigators have tried 
invasive procedures such as plasmapheresis to lower triglycerides (TG), however this is a 
temporary measure (5). Others are exploring gene therapy using intramuscular injection of AAV1-
Lipoprotein lipaseS447X in patients with LPL deficiency. Although this initially lowers triglycerides, 
the effect is transient as patients develop antibodies to the capsid proteins (6). 
 
The only effective therapy is a very low fat diet (<20% of total energy).  Since the basic defect in 
T1HLP is the reduced clearance of chylomicrons due to impaired lipolysis of triglycerides, 
reduction in dietary fat by reducing chylomicron formation can lower serum triglycerides.  
However, some patients continue to have severe triglyceridemia and acute pancreatitis despite 
following a low fat diet (1).  
 
There have been no formal clinical trials conducted in patients with T1HLP so far and most of the 
evidence about efficacy or lack of efficacy of medications or dietary intervention is anecdotal. We 
wish to investigate whether an inhibitor of intestinal lipase (Orlistat) will reduce serum triglyceride 
concentrations in patients with T1HLP. Orlistat is an inhibitor of gastric and pancreatic lipases and 
can reduce dietary fat absorption by 30% (7). Thus, Orlistat may reduce serum TG levels in 
patients with T1HLP by decreasing the substrate available for chylomicron formation. 
 
 
 
 
 
 
 
 
 
 
Concise Summary of Project: 
Fig. 1. The process of dietary lipid digestion and 
absorption. A, The digestion of dietary lipids begins with 
partial digestion by gastric lipase, forming large fat globules 
with a triacylglycerol (TAG) core surrounded by phospholipids 
(PL), free cholesterol (CL), fatty acids (FA), and ionizing 
proteins. In intestine, fat globules are mixed with bile salts 
(BS) and pancreatic lipases. Monoacylglycerol (MAG), 
lysophosphatidic acid (LPA), diacylglycerol (DAG), and FA 
that are released from lipid and PL hydrolysis join bile salts, 
CL, and fat-soluble vitamins to form mixed micelles for dietary 
fat absorption at the brush border of the enterocytes. B, After 
entering the enterocyte, MAG, LPA, and CL are reacylated. 
MAG is sequentially acylated by MGAT and DGAT enzymes 
to form TAG. LPA is acylated by LPA acyltransferase 
(LPAAT) to phosphatidic acid (PA) followed by 
dephosphorylation by PA phosphorylase (PAP) to yield DAG. 
Dietary cholesterol (CL) is acylated by acyl-CoA:cholesterol 
acyltransferase (ACAT) to cholesteryl esters (CE). Facilitated 
by microsomal triglyceride transfer protein (MTP), TAG joins 
CE and apolipoprotein B-48 (ApoB48) to form chylomicrons 
that are secreted in the lymph for delivery to circulation. 
Modified from Shi and Cheng (8). The step that is inhibited by 
Orlistat (an intestinal lipase inhibitor) is shown 
 
Orlistat 


 
 
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A two-treatment condition, four-period, two-sequence cross-over study design will be employed. 
Since T1HLP is a very rare disease, the study design will allow for patients to act as their own 
controls, and thus increase the power of the study. This will be an open-label trial.  
 
Baseline period:   
The baseline period will include a 4-week run-in period during which time dietary counseling will 
be performed. To be included in the study, subjects must have a fasting TG > 1000 mg/dL at the 
end of the baseline period (complete inclusion/exclusion criteria are listed below). All patients will 
be evaluated at the Clinical Research Unit (CRU) at UTSW for three days  at the end of the 
baseline period. During this time, we will instruct them to consume a  diet containing 15% of total 
energy from fat, 70% from carbohydrate and 15% from protein. The same diet will be used during 
subsequent evaluations at CRU. This is to ensure that serum lipid evaluation is made when 
patients are taking a low fat diet to avoid confounding effects of variability in dietary fat content.  
The subjects will also be asked to complete a 3-day food recall before admission to the CTRC to 
assess energy intake as well as dietary composition.  All patients will then be asked to follow a 
low fat diet (< 20% energy from fat) for the remainder of the study period.  The diet counseling 
will be done by a trained research fellow or CTRC dietician immediately after the baseline period 
and at the beginning each new treatment period and at 2 wk duration for the remainder of the 
study. The counseling will be done in person at baseline and at subsequent follow up visits and 
by phone in the intervening intervals.  
 
Fasting blood samples will be obtained for serum lipid profile, chylomicron-TG, serum chemistry, 
and aminotransaminases for the course of three days. Blood will also be drawn once for 
determination of fat soluble vitamin levels (A, D, E, and K).  Patients will collect 72 hour stool for 
determination of fecal fat.  On the last day of the baseline period, a meal tolerance test will be 
performed.  
 
Study phase:  
The patients will then be randomized to receive 3 months of Orlistat or control condition with no 
drug, then will crossover to the opposite condition as shown in Figure 2. This will be repeated 
for a total of 12 months or four periods of study.. Orlistat is approved by the FDA at the higher 
dose of 120 mg three times a day for children over the age of 12 years. There are limited data 
regarding dosing of Orlistat for children, especially normal-weight children. One study used 
Orlistat for the treatment of Crigler-Najjar, which included children over the age of 7. The 
smallest child weighed 29 kg. In this study, the authors used a dose of 66 mg/m2 body surface 
area three times daily, which is roughly equal to the amount for an adult per square meter body 
surface area (Hafkamp et al. Pediatric Research 2007;62(6):725-730). We are unable to 
precisely dose Orlistat since we will be using 60 mg capsules (Alli).  Therefore, for our study, we 
will use a graded system for dosing based on the weight of the child (Table 1).  
 
Table 1: Dosing of Orlistat by weight in pediatric subjects: 
Breakfast 
Lunch 
Dinner 
>50 kg or adult >18 yrs 
120 mg 
120 mg 
120 mg 
40-49.9 kg 
60 mg 
120 mg 
120 mg 
30-39.9 kg 
60 mg 
60 mg 
120 mg 
20-29.9 kg 
60 mg 
60 mg 
60 mg 
 
 
Orlistat has a short half-life of 1 to 2 hours, so no carry-over effects should be observed. Subjects 
will have their triglycerides measured monthly. All laboratory studies enlisted during the baseline 


 
 
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period (vitamin levels, liver function tests, complete blood count, and 72-hour fecal fat, etc.) will 
be repeated during the four study periods at CRU (see figure 2). The patients will also take a daily 
multivitamin supplement containing vitamin A 3,500 IU (71% as retinol and 29% as β-carotene), 
vitamin D 400 IU (as cholecalciferol), vitamin E 30 IU (as dl-α-tocopheryl acetate) and vitamin K 
25 μg (as phytonadione).  Patients will be instructed to take vitamins at least 2 hours apart from 
Orlistat dosing.  
 
 
 
 
 
 
 
 
 
 
Figure 2: Study Flow Diagram 
 
 
 
 
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. At a dose of 120 mg three times 
daily, Orlistat reduces dietary fat absorption by 30% (7). Several studies in the past ten years 
have shown a beneficial effect of Orlistat on postprandial lipids in healthy volunteers and in 
patients with diabetes (9-12). In a 52-week study involving obese type 2 diabetic men, Orlistat 


 
 
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120 mg three times daily reduced triglycerides and apolipoprotein B levels significantly (9). The 
FDA approved dose for obese children 12-18 years is the same as that for adults, i.e., 120 mg 
three times a day.  
 
Most of the patients with T1HLP present with recurrent abdominal pain and even acute 
pancreatitis (a potentially life threatening complication) along with extreme hypertriglyceridemia 
during childhood. Since there is no established therapy for T1HLP, these children are at high risk 
of acute pancreatitis. Therefore, we have included children in this study. We will carefully monitor 
each child during participation in the study for any possible side effects. Since variability in 
glycemic control could be a confounding factor and patients with poorly controlled diabetes 
mellitus can develop secondary hypertriglyceridemia, we have excluded patients with diabetes 
from the study.  
 
Orlistat is currently approved for the treatment of obese children age 12 and older. Our study may 
incorporate younger children since there is currently no therapy available for these patients. A 
Swedish study was done to evaluate the safety of Orlistat in obese children ages 7-12. This study 
found no serious adverse effects (including liver toxicity and vitamin deficiencies). Most subjects 
did experience oily stools and diarrhea on at least one occasion, but this occurred after ingestion 
of a high fat meal, and was not severe enough to cause discontinuation of the study. No negative 
effect on psychological or physical well-being was detected, and no effect on linear growth was 
identified. The adult dose of Orlistat (120 mg three times a day) was used in this study (13). For 
this reason, we will use the adult dose, except for small children weighing less than 30 kg. In 
these children, a dose of 60 mg three times a day will be used. If the adult dose is not tolerated 
in children weighing > 30 kg, it will be reduced to 60 mg three times a day. 
 
Fasting serum TG is chosen as the primary end point variable as this determination is made 
during clinical follow up of patients with T1HLP. Since Orlistat is expected to affect chylomicron 
formation, fasting and postprandial levels of chylomicron TG and serum TG are included as 
secondary endpoint variables. We will also capture any episodes of acute pancreatitis and include 
them as a secondary endpoint variable. Tertiary end point variables include fat soluble vitamin 
levels to assess the potential effects of Orlistat on fat soluble vitamin absorption and fecal fat 
excretion to assess the potency of these drugs in blocking dietary fat absorption.   
 
The majority of Orlistat’s mechanism of action is believed to be exerted in the gastrointestinal 
tract. Pharmacokinetic studies have shown that Orlistat is infrequently detected in plasma in 
subjects taking Orlistat, and when it is detected, very low levels are found (14-15). 
 
For this study, a maximum of 12 patients will be enrolled. The subjects will serve as their own 
controls during their period off of the medication. Conditions which would result in the subject 
exiting the study prior to the expected completion date include safety concerns, intolerable side 
effects, and subject withdrawal of consent. 
 
 
Study Procedures: 
Serum lipoproteins: Serum cholesterol, TG and high density lipoprotein cholesterol will be 
measured by Quest Diagnostics. Serum chylomicron TG will be measured according to the Lipid 
Research Clinics method after ultracentrifugation (16) using enzymatic kits.   
 
Postprandial TG and chylomicron remnant clearance during meal tolerance test:  On the last day 
of evaluation, after obtaining a fasting blood sample, a breakfast meal with a fixed dietary 
composition (600 kcal with 15% fat, 70% carbohydrate and 15% protein) will be given with 50,000 


 
 
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IU of vitamin A (Aquasol).  A low fat meal will be prepared using natural food items and is chosen 
to avoid exacerbation of hypertriglyceridemia and chylomicronemia in these susceptible patients 
with T1HLP. Blood samples will be drawn at hourly intervals for 4 hours after the meal for 
determination of plasma triglyceride and retinyl palmitate concentrations.  .  
 
Plasma retinyl palmitate concentration will be determined as described previously (17). 
Briefly, neutral lipids will be extracted from plasma using methanol and hexane.  All tubes used in 
the extraction will be covered with aluminum foil to protect retinyl esters from light.  Plasma (500 
µL) and retinyl undecanoate as internal standard (300 ng in 100 µL of ethanol) will be added 
dropwise to 5 mL methanol.  After vortexing, 5 mL hexane will be added and the mixture will be 
vortexed again for 30 s.  The samples will be allowed to stand for phase separation, and after 
removal of the upper phase, the lower phase will be washed with 5 mL hexane.  The hexane 
phase will be then dried under nitrogen and the residue will be resuspended in 50 µL benzene.   
 
Retinyl palmitate concentrations in the lipid extracts will be measured using reverse phase 
high performance liquid chromatography (HPLC) using a Waters Model 6000A chromatograph 
(Waters Associates, Milford, MA) and a 3 µM Ultrasphere ODS column 4.6 X 75 mm (Alltech 
Associates, Deerfield, IL).  Column effluent will be monitored at 326 nm and chromatograms will 
be recorded on a Beckman 3390A integrator (Beckman Instruments, Palo Alto, CA) using an 
attenuation setting of three.  Peaks will be quantitated by the area ratio method.  Plasma 
triglyceride and retinyl palmitate data obtained during the oral fat tolerance test will be analyzed 
by calculating incremental area under the curves (normalized to the baseline value) using the 
trapezoidal rule.   
 
 
Serum chemistry, complete blood counts and urinalysis: Complete blood counts will include 
hemoglobin, hematocrit, MCV, MCH, MCHC, WBC count, RBC count, Platelet count and 
differential WBC count. Serum chemistry will include SMA-22 panel with electrolytes (Na, K, Cl, 
carbon dioxide, urea nitrogen, creatinine, Ca, Mg, Phosphate), liver function tests (alanine 
aminotransferase, aspartate aminotransferase, Bilirubin, alkaline phosphatase, gamma glutamyl 
transferase), glucose, hemoglobin A1c, creatine phosphokinase, total protein, albumin, globulin, 
uric acid and lactate dehydrogenase. Urinalysis will include color, appearance, specific gravity, 
pH, glucose, bilirubin, ketones, occult blood, protein, nitrite, leukocyte esterase, WBC, RBC, 
squamous epithelial cells, bacteria and hyaline cast. These tests will be done as indicated in the 
flow diagram. Serum TSH and free T4 will be measured during each CRU visit for those patients 
who are taking thyroid hormone.  
 
72 Hour Fecal Fat:  Stool will be collected for 72 hours during each study period. The 
measurement will be performed by Quest Diagnostics. Oral carmine will be used as a marker to 
ensure 72 hour collection of the stools.  
 
Fat soluble vitamin levels:  Serum retinol, α-tocopherol, 25-OH Vitamin D and vitamin K will be 
measured once at baseline and during each study period. The measurements will be performed 
by Quest Diagnostics.  
 
Three-Day Food Record:  Dietary intake will be assessed by 3-day food record (two weekdays 
and one weekend day), a valid and reliable method. The records will be taken at baseline and at 
two week intervals.  The participants will be instructed on how to record in detail all the food and 
drink consumed in the 3-day food record book provided.  The booklet will be available in English 
and Spanish.  Any questionable input or incomplete food entries recorded will be promptly 
addressed when the subjects return their food records.  The food records will be analyzed for 
nutrient content using the University of Minnesota Nutrient Data System (NDS) for research.   
 


 
 
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Gastrointestinal Symptoms Questionnaire: All patients will complete a gastrointestinal symptoms 
questionnaire (see appendix 1) during visit to the CRU (18). This questionnaire includes questions 
about diarrhea and steatorrhea, the expected side effects of Orlistat.  
 
Subjects will be evaluated every month. They will be evaluated at CRU for evaluation at the 
beginning of the study, and every 3 months thereafter until the end of the study. Each evaluation 
will be 3 days long. In addition, subjects will be seen in the CRU at the 1- and 2-month marks of 
each study period. This evaluation will last 3-4 hours and will not require an overnight stay. If 
patient is unable to come to CRU, they will send blood sample for lipid analysis.The study diagram 
above describes the timing of the procedures in more detail.  
 
Subjects will not be responsible for any research-related costs during this study. 
 
 
Sub-Study Procedures: 
No sub-studies will be involved in this study. 
 
 
Criteria for Inclusion of Subjects: 
1. Type I hyperlipoproteinemia 
2. Fasting serum triglyceride levels of greater than 1000 mg/dL 
3. Age >  8 years 
 
 
Criteria for Exclusion of Subjects: 
1. 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 
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 
 
 
Sources of Research Material: 
Research material obtained in this study will consist of questionnaires, blood and stool specimens, 
physical examination, and 3-day food records obtained from the subjects according to the 
protocol. These will be obtained directly from subjects. Subjects will be asked to provide urine 


 
 
9
and stool, and blood will be collected via venipuncture. New clinical data will be generated from 
these specimens. The specimens will be collected and analyzed solely for research purposes. 
 
 
Recruitment Methods and Consenting Process: 
Investigators will conduct chart review on Children’s EPIC and Parkland EPIC to search for 
patients with above mentioned inclusion and exclusion criteria. The study subjects will be 
recruited from Children’s Medical Center (now called Children’s health), the lipid clinics at the 
Parkland Memorial Hospital, Veterans Affairs North Texas Health Care System, and UT 
Southwestern Aston Ambulatory Center.  In the past, patients have been referred to the P.I. for 
diagnosis, clinical evaluation and management of T1HLP. These patients may be recruited for 
the study as well. Patients will be recruited and consented by the investigators. Investigators will 
obtain informed consent after explaining the study and the subjects having read or been read the 
consent form. For Spanish-speaking subjects, a consent form will be provided in Spanish. For 
other Non-English speaking subjects, an interpreter will be used via phone or in person. All 
information collected will be confidential and kept in a locked room. The subjects will be informed 
that participation is voluntary and will not affect their medical care or their relationship with the 
physician and institution. Minors may be included in this study, and consent for participation will 
be obtained from the subject’s parent or guardian. Consent will be obtained prior to any study 
procedures being performed. A copy of the consent form will be given to the subjects and the 
original consent will be maintained in the subject’s research records, which will be maintained in 
the CRU.   
 
 
 
Potential Risks: 
All subjects will undergo a history and physical examination. Subjects will be asked to collect stool 
and urine samples, for which there is minimal risk of psychological or physical discomfort. They 
will be asked to undergo blood drawing, for which there is an unlikely risk for bruising and infection.  
Phlebotomy volumes for pediatric subjects will be adjusted based on the child’s weight using the 
National Institutes of Health Guidelines for Blood Drawn for Research Purposes in the Clinical 
Center 2003. 
   
The potential risks of Orlistat include gastrointestinal side effects such as: diarrhea, oily stools, 
flatulence with discharge, and anal leakage (9, 19-20). These risks occur commonly but are 
significantly reduced by adherence to a low fat diet. The major risks for Orlistat are: drug-drug 
interactions and the reduction of cyclosporine and thyroid hormone levels in subjects taking 
thyroid supplementation (21), and fat soluble vitamin deficiencies due to malabsorption (9, 19-
22). We will provide vitamin supplementation daily during the study and monitor the fat soluble 
vitamin levels periodically. Vitamins will be taken 2 hours apart from Orlistat dosing. For patients 
taking thyroid supplementation, thyroid hormone levels will be checked during each CRU visit and 
medication adjusted as needed. Patients will be instructed to take levothyroxine 4 hours apart 
from Orlistat dosing. Patients taking cyclosporine are excluded from the study.  
 
Currently the standard care for patients with T1HLP is a very low fat diet. This therapy is ineffective 
and difficult to follow. The risks of Orlistat are mild when compared to the reduction in risk of 
pancreatitis that may be obtained from this medication. No placebo will be used in this study. 
 
 
Subject Safety and Data Monitoring: 
Potential risks will be minimized by utilizing study codes to identify subjects. The physical risks 
will be minimized by the inclusion and exclusion criteria and a complete physical examination 


 
 
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prior to initiating study procedures with careful monitoring throughout. Additionally, pregnant or 
lactating women are excluded from the study. Subjects will have close monitoring of their liver 
enzymes. In the event of adverse effects or events, the study subjects will be referred to an 
appropriate physician for treatment.  A pregnancy test will be performed on all female patients of 
reproductive age at each CRU visit (every 3 months). Study subjects who become pregnant 
during the course of the study will be discontinued from the trial.  Blood tests including 
chemistry, lipids and liver enzymes will be obtained periodically to ensure safety of the subjects. 
All subjects with a BMI <24 who lose >5% body weight from baseline will be required to undergo 
dietary counseling from a dietician or trained research fellow. If weight continues to decrease 
over the next month, subjects will be discontinued from the study. 
 
 
 
We propose the creation of an internal Data and Safety Monitoring Committee composed of 
experts in statistics and lipid metabolism.  Identified for the necessary expertise are individuals 
who are not associated with this trial and not collaborators of the principal investigator. 1. Song 
Zhang, PhD, Assistant Professor, Department of Clinical Sciences.  2.  Scott Grundy, M.D., Ph.D. 
Professor of Internal Medicine 3.  Perrin White, M.D., Professor of Pediatrics 4.  Fredrick Dunn, 
M.D., Associate Professor of Internal Medicine. 
  
 
The Committee will be asked to:  a) Review the research protocol, informed consent documents 
and the plans for data and safety monitoring. b) Evaluate the progress of the study including 
periodic assessments of data quality and timeliness, recruitment, retention, and risk versus 
benefit.  c) Report on the safety and scientific progress of the trial.  d) Make recommendations to 
the PI, and if needed to the IRB, CTRC and FDA concerning continuation, termination or 
modifications of the trial based on the observed beneficial or adverse effects of the interventions 
under study.  e) Conduct or review the interim analysis with regards to safety in accordance with 
stopping rules, which should be defined in advance of the data analysis. f) Ensure data integrity. 
g) Ensure the confidentiality of the data and results of monitoring.  h) Maintain study integrity by 
commenting on any problems with study conduct, enrollment, statistics or data collection. 
      
 
The PI will hold the primary oversight responsibility for this trial and as such he will be responsible 
for surveying the medical literature for scientific or therapeutic developments that may impact the 
safety of participants or the ethics of the study.  He will insure that: subjects are fully informed of 
the study requirements throughout the trial, insure that study subjects receive a study calendar 
upon enrollment, are updated on any new information relevant to their continued participation or 
change in the risk versus benefit ratio of the interventions.  The PI will be responsible for reporting 
adverse events to the IRB, CTRC and FDA in accordance with IRB policies and time frames.  The 
PI is responsible for submitting continuing review reports to the IRB, and FDA.   
 
 
Procedures to Maintain Confidentiality: 
Study codes will be used to identify subjects to maintain confidentiality. All files will be kept locked, 
and all information on computers will be password protected.  Access to research data is restricted 
to key personnel directly involved with the study who have been trained in the protection of human 
subjects and signed statements assuring their compliance with University policies protecting the 
privacy of research subjects. We do not intend to apply for a Certificate of Confidentiality from the 
NIH. 
 
 
Potential Benefits: 


 
 
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The potential benefit of Orlistat therapy is an improvement in serum triglycerides, serum 
chylomicron-TG levels, and postprandial serum triglyceride levels.   
 
If this therapy is effective, it will result in a reduction of the severe hypertriglyceridemia that is 
associated with T1HLP and ultimately decrease the incidence of acute pancreatitis. The 
knowledge to be gained by this study will have important implications in our understanding of how 
to effectively treat this rare condition. 
 
 
Biostatistics: 
Design. Due to the rare disease status of Type I Hyperlipoproteinemia, which will limit 
enrollment, we will implement a dual sequence, four-period crossover design to study the 
Orlistat and control treatment phases.  For a small sample size, this design allows us to better 
estimate treatment and carryover effects that can be aliased in a two period design.  
 
The sample size will be determined by the number of subjects with Type I Hyperlipoproteinemia 
meeting the inclusion criteria. Approximately 6-12 patients are expected to be enrolled.  
Therefore no formal power calculations are performed. 
 
Statistical analysis. Each treatment condition will be summarized with descriptive statistics, 
graphics for each subject, and adverse events will be carefully tabulated.  The treatment effect 
(Orlistat versus control) will be estimated from repeated measures mixed model and 
summarized with the model’s least squares means estimate and corresponding 95% confidence 
interval. 
 
 
 


 
 
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Literature Cited 
 
1. 
Brunzell JD, Deeb SS 2006 Familial Lipoprotein Lipase Deficiency, Apo C-II Deficiency, 
and Hepatic Lipase Deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, 
Antonarakis SE, Ballabio A eds. Online Metabolic and Molecular Bases of Inherited 
Disease: McGraw-Hill; 1-60 
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1 4
A p p e n di x 1: GI S y m pt o m s Q u e sti o n n air e. 
  
G a str oi nt e sti n al S y m pt o m s Q u e sti o n n air e 
 
N a m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
D at e: _ _ _ _ _ _ _ _ _ Vi sit: _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
      N o S y m pt o m s ( 0)    S e v er e S y m pt o m s ( 5) 
S y m pt o m  
 
 
0  
1  
2  
3  
4  
5 
 
1.  A b d o mi n al p ai n s    
 
 
 
 
 
 
 
 
2.  H e art b ur n    
  
 
 
 
 
 
 
 
 
3.  A ci d r e g ur git ati o n    
 
 
 
 
 
 
 
 
 
4.  S u c ki n g s e n s ati o n s   
 
 
 
 
 
 
 
i n t h e di a p hr a g m ar e a  
 
5.  N a u s e a a n d v o miti n g  
 
 
 
 
 
 
 
 
6.  R u m bli n g of st o m a c h  
 
 
 
 
 
 
 
 
7.  A b d o mi n al di st e n si o n  
 
 
 
 
 
 
 
 
8.  B el c hi n g    
  
 
 
 
 
 
 
 
 
9. I n cr e a s e d g a s  
  
 
 
 
 
 
 
 
 
 
1 0.  D e cr e a s e d p a s s a g e   
 
 
 
 
 
 
 
 of st o ol s 
 
1 1.  I n cr e a s e d p a s s a g e   
 
 
 
 
 
 
 
 of st o ol s 
 
1 2.  L o o s e st o ol s  
  
 
 
 
 
 
 
 
 
1 3.  H ar d st o ol s  
  
 
 
 
 
 
 
 
 
1 4.  Ur g e nt n e e d f or    
 
 
 
 
 
 
 
 b o w el m o v e m e nt 
 
1 5.  F e eli n g of i n c o m pl et e  
 
 
 
 
 
 
  
 e v a c u ati o n 
 
1 6.  Oil y st o ol s 
 
 
 
 
 
 
 
  
 
1 7.  St o ol l e a k a g e