| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Hypercholesterolemia & Mixed Dyslipdemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Abnormal blood cholesterol levels |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. Evaluate the LDL-C-lowering effects of ERN/LRPT/SIM 2 g/40 mg compared to
ERN/LRPT 2 g coadministered with simvastatin 40 mg.
Hypothesis: ERN/LRPT/SIM 2 g/40 mg is equivalent to ERN/LRPT 2 g
coadministered with simvastatin 40 mg in reducing LDL-C. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate the HDL-C-raising effects of ERN/LRPT/SIM 2 g/40 mg compared to
ERN/LRPT 2 g coadministered with simvastatin 40 mg.
Hypothesis: ERN/LRPT/SIM 2 g/40 mg is equivalent to ERN/LRPT 2 g
coadministered with simvastatin 40 mg in raising HDL-C.
Note: For HDL-C secondary hypothesis, the criterion for bioequivalence is that the
95% confidence interval (CI) of the difference in percent change from baseline
between the two treatments falls within ±4% .
2. Estimate the differences in percent change in LDL-C from baseline between
ERN/LRPT/SIM 1 g/40 mg and ERN/LRPT 1 g coadministered with 40 mg of
simvastatin, respectively, for 4 weeks.
3. Estimate the differences in percent change in HDL-C from baseline between
ERN/LRPT/SIM 1 g/40 mg and ERN/LRPT 1 g coadministered with 40 mg of
simvastatin, respectively, for 4 weeks.
4. Evaluate the tolerability of ERN/LRPT/SIM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female ≥18 and ≤85 years of age on day of signing informed
consent.
2. Patient understands the study’s procedures; alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written
informed consent.
3. A female patient must meet ONE of the following:
a. Of reproductive potential and agrees to remain abstinent or use (or have their
partner use) 2 acceptable methods of birth control for the study duration. An
acceptable method of birth control is defined as intrauterine device (IUD)
diaphragm with spermicide condom vasectomy
contraceptive sponge (with spermicide) is acceptable as a single method of
birth control but requires one of the following as a second method:
intrauterine device (IUD), diaphragm, condom or vasectomy.
Vasectomy: A successful vasectomy is defined as: (1) microscopic documentation
of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant
pregnancy despite sexual activity without birth control postvasectomy.
b. Not of reproductive potential is eligible without requiring the use of
contraception.
Definition of "not of reproductive potential": one who has either of the
following:
-Reached natural menopause, defined as: 6 months of spontaneous
amenorrhea with serum FSH levels (at Visit 1) in the postmenopausal
range (per central lab) or 12 months of spontaneous amenorrhea.
Spontaneous amenorrhea does not include cases for which there is an
underlying disease that causes amenorrhea (e.g., anorexia nervosa).
-6 weeks post surgical hysterectomy, or bilateral oophorectomy with or
without hysterectomy.
- Bilateral tubal ligation without subsequent restorative procedure.
Protocol-Specific Inclusion Criteria
4. Patient has a history of primary hypercholesterolemia or mixed dyslipidemia.
Note: Determined by medical history, historical and/or current lab values, and
Investigator’s judgment.
5. Patient meets one of the following criteria at Visit 2:
Patient is high risk (CHD or CHD risk equivalent based on NCEP ATP III
guidelines) AND has LDL-C ≤ 200 mg/dL (≤ 5.17 mmol/L).
Patient is NOT high risk (based on NCEP ATP III guidelines) AND has LDL-C
≤ 250 mg/dL (≤ 6.47 mmol/L).
6. Patient meets one of the following triglyceride (TG) criteria at Visit 2:
a. Patient on niacin, statin, or fibrate must have TG <500 mg/dL (5.65 mmol/L).
b. Patient not on an LMT or on LMT other than niacin, statin, or fibrate must have
TG <600 mg/dL (6.77 mmol/L).
Please refer to protocol for full list of principal inclusion criteria |
|
| E.4 | Principal exclusion criteria |
1. Patient is pregnant or breast-feeding, or expecting to conceive during the study
including the 14-day post study follow-up.
2. Patient has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
3. Female patient is expecting to donate eggs during the study, including the 14-day
follow-up or a male patient is expecting to donate sperm during the study, including
the 14-day follow-up.
4. Patient is unlikely to adhere to the study procedures, keep appointments, or is
planning to relocate during the study, and has a history or current evidence of any
condition, therapy, or lab abnormality that might confound the results of the study,
interfere with the patient’s participation for the full duration of the study, or is not in
the best interest of the patient to participate.
5. Patient consumes more than 3 alcoholic drinks on any given day or more than 14
drinks per week. Please see Section 3.2.3 for definition of alcoholic drinks.
6. Patient is currently participating in or has participated in a study with:
an investigational compound (other than lipid-modifying) within 30 days after the
post-study follow-up period, prior to randomization.
a lipid-modifying compound (investigational or marketed), other than fibrate
within 6 weeks after the post-study follow-up period, prior to randomization.
a fibrate (investigational or marketed) within 8 weeks after the post-study followup
period, prior to randomization.
a CETPi (cholesteryl ester transfer protein inhibitors) within 12 weeks after the
post-study follow-up period, prior to randomization.
7. Patient has donated and/or received blood as follows:
donated blood products or has had phlebotomy of >300 mL within 8 weeks prior
to signing informed consent.
intends to give or receive blood products during the study.
intends to donate more than 250 mL of blood products within 8 weeks following
the last study visit.
8. Patient has the following exclusionary central laboratory values. (Table 3-1 provides
retest guidelines).
Creatinine clearance (eGFR) < 30 mL/min (0.50 mL/s) (using the Modification of
Diet in Renal Disease [MDRD] formula – Appendix 6.4)
ALT (SGPT) >1.5 x upper limit of normal (ULN)
AST (SGOT) >1.5 x ULN
CK >2 x ULN
9. Patient has used recreational or illicit drugs within 1 year of signing informed
consent.
Protocol Specific Exclusion Criteria
10. Patient is high risk (CHD or CHD risk equivalent based on NCEP ATP III) AND is
on a statin at Visit 1(Appendix 6.1 and 6.2).
Note: High risk patients not currently being treated with a statin at Visit 1 are
eligible.
11. Patient is on simvastatin 80 mg, or another LMT dose of equivalent or greater LDLC-lowering efficacy than that of simvastatin 80 mg
12. Patient with Type 1 or Type 2 diabetes mellitus and:
is on statin therapy.
is poorly controlled (HbA1C >8%)
is newly diagnosed (within 3 months of Visit 1)
has recently experienced repeated hypoglycemia or unstable glycemic control.
is taking new or recently adjusted anti-diabetic pharmacotherapy (with the
exception of ≤ ± 10 units of insulin) within 3 months of Visit 1.
13. Patient currently engages in, or during the study plans to engage, in vigorous exercise or an aggressive diet regimen. (See Section 3.2.3 for definition of vigorous exercise, and Appendix 6.3 for diet recommendations.)
14. Patient was <80% compliant with dosing during the Placebo Run-in period AND, in the opinion of the investigator, is believed to be unable to maintain at least an 80% compliance with dosing during the active study dosing period.
Please refer to protocol for full list of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint – percent change from baseline to the end of the 8-week treatment
period in LDL-C. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
percent change from baseline at the end of the 8-week treatment period in HDL-C.
percent change from baseline at the end of the 4-week treatment period
(Period I) in LDL-C and HDL-C |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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