mixed dyslipidaemia

This study is designed as a proof of concept of TAP311 in mixed dyslipidemic patients with fasting plasma triglyceride level more than 400 mg/dL. The purpose of the present study is to assess safety, tolerability, pharmacokinetics (PK) and explore pharmacodynamics (PD) properties of TAP311 following multiple dose administration for 14 days.

TAP311

TAP311

10mg/ cap

Exploratory pharmacodynamic assessments: Blood samples will be collected for CETP activity,
HDL, LDL, triglycerides and apoA-I assessments at specific time points on the days specified in the
assessment schedules.
Safety assessments: As part of the safety assessment, following assessments will be performed -
physical examination, vital signs (ABPM), height and weight, laboratory evaluations (hematology,
clinical chemistry and urinalysis), electrocardiogram (ECG).

Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any study related assessment is
performed.
2. Patients must have fasting LDL-C between 80-180 mg/dL inclusive, HDL-C ≤50 mg/dL,
and triglycerides ≥400 mg/dL at screening.
3. Patients are not treated for dyslipidemia with medications other than HMG-CoA reductase
inhibitors (statins) for at least 4 weeks prior to Day 1. Patients should be on stable doses of
current medications, if any, for at least 3 months to be eligible. When in doubt about
current medications, the PI should discuss and confirm eligibility of the patient with the
sponsor.
4. Male and female patients 18 to 80 years (inclusive) of age. Other than dyslipidemia,
patients should be in stable health as determined by past medical history, physical
examination, electrocardiogram, and laboratory tests at screening and baseline.
5. At screening, and baseline, vital signs (systolic and diastolic blood pressure and pulse rate)
will be assessed in the sitting position after the patient has rested for at least three (3)
minutes and again when required after three (3) minutes in the standing position.
Investigators can be guided by the following ranges (judged by the mean for the blood
pressure measurements):
Oral body temperature between 35.0-37.5 °C
Sitting systolic blood pressure, 80-150 mm Hg
Sitting diastolic blood pressure, 50-95 mm Hg
Sitting pulse rate, 50-100 bpm
When blood pressure and pulse are taken after at least 3 minutes standing, there should be no
more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and
increase in heart rate (>20 bpm) (compared to the sitting results) associated with clinical
manifestations of postural hypotension. Any patient exhibiting clinical manifestations of
postural hypotension should be excluded.
6. Patients must weigh at least 50 kg to participate in the study, and must have a body mass
index (BMI) within the range of 18 - 40 kg/m2.
7. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.

Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives of enrollment, whichever is longer; or longer if required by local regulations, and for
any other limitation of participation in an investigational trial based on local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.
3. HbA1c >8.5 at screening. Diabetic patients whose plasma glucose is well controlled by
stable diabetic treatment for at least 3 months can be included in the study.
4. History or active diseases of the liver, including but not limited to liver cirrhosis, and
hemochromatosis.
5. A past medical history of clinically significant ECG abnormalities, documented cardiac
arrhythmias, or a family history (parents, siblings and children) of a prolonged QTinterval syndrome. Any parameter above the values defined below at screening and
baseline should be repeated right away and/or manually calculated.
• PR > 220 msec
• QRS complex > 120 msec
• QTcF > 450 msec (males)
• QTcF > 470 msec (females)
6. Acute coronary syndrome (ACS)/ acute myocardial infarction, unstable angina, onset of
class II congestive heart failure (CHF), or onset of clinically significant valvular diseases
in the past 12 months; or NYHA class III and IV CHF.
7. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether there is
evidence of local recurrence or metastases.
8. Pregnant or nursing (lactating) women.
9. Women of child-bearing potential (WOCBP) can be included but must use highly
effective contraception during the study and for at least 14 days after drug dosing stopped.
Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure
rate <1%), for example hormone vaginal ring or transdermal hormone
contraception. Oral or injected contraceptive agents that are predominantly metabolized by CYP3A4 enzyme such as ethinyl estradiol, drospirenone,
norgestimate, 17-deacetyl norgestimate, levonorgestrel, gestodene,
norethindrone are allowed to be administered. Use of oral, injected or
implanted hormonal contraceptive agents that are CYP2C9 or 2B6 substrate
are not allowed.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
10. Sexually active males must use a condom during intercourse while taking the drug and for
14 days after stopping treatment and should not father a child in this period. A condom is
required to be used also by vasectomized men in order to prevent delivery of the study
drug via seminal fluid.
11. Heavy smokers (smoke more than 10 cigarettes a day routinely and who cannot refrain
from smoking during the study).
12. Use of lipid modifying agents (e.g. fenofibrate, niacin, omega-3 fatty acids, etc) other than
statins, herbal supplements, within four (4) weeks or at least a time period equivalent to
five half-lives prior to initial dosing, and/or over-the-counter (OTC) medication other than
aspirin, dietary supplements (vitamins included) within two (2) weeks or at least a time
period equivalent to five half-lives prior to initial dosing. If needed, (i.e. an incidental and
limited need) acetaminophen is acceptable, but must be documented in the concomitant
medications/ significant non-drug therapies page of the eCRF. A patient can continue to
take current medications if he/ or she has been taking at a stable dose for at least 3 months.
13. Donation or loss of 400 ml or more of blood within eight (8) weeks prior to initial dosing,
or longer if required by local regulation.
14. Significant illness within two (2) weeks prior to initial dosing.
15. Recent (within the last three [3] years) and/or recurrent history of autonomic dysfunction
(e.g., recurrent episodes of fainting, palpitations, etc).
16. Any surgical or medical condition which may jeopardize the patient in case of
participation in the study. The Investigator should make this determination in
consideration of the patient’s medical history and/or clinical or laboratory evidence of any
of the following:
• Inflammatory bowel disease;
• Active ulcers, gastrointestinal or rectal bleeding;
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel
resection;
• Pancreatic injury or pancreatitis;
• Liver disease or liver injury as indicated by abnormal liver function tests such as AST,
ALT, GGT, alkaline phosphatase, or serum bilirubin. The Investigator should be
guided by the following criteria:
• Any single parameter may not exceed 2x upper limit of normal (ULN) for
subjects to be enrolled. A single parameter elevated up to and including that level
should be re-checked once more as soon as possible, and in all cases, at least
prior to enrollment/randomization, to rule out lab error.
17. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result.
18. Total WBC count which falls more than 25% outside normal range would exclude patients
to be enrolled, or number of platelets more than 15% lower than the lower limit of normal
at screening.
19. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
20. Active drug or alcohol abuse or evidence of such abuse as indicated by the laboratory
assays conducted during screening and/or baseline.
No additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.