E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Homozygous Familial Hypercholesterolemia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048373 |
E.1.2 | Term | Hypercholesterolaemia aggravated |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the efficacy of AEGR-733 as defined by percent change in LDL-C at the maximum tolerated dose compared to baseline after 26 weeks of treatment in combination with other lipid lowering therapy in patients with homozygous familial hypercholesterolemia (FH). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate other lipid parameters, long-term safety, percent change in hepatic fat and pharmacokinetics of AEGR-733 in combination with other lipid lowering agents in patients with homozygous FH during the full length of the clinical study. In particular we will assess: a. Percent change in TC, non-HDL-C, HDL-C, TG, VLDL, Lp(a), as well as apolipoproteins B and AI. b. Long term safety of AEGR-733 in patients with homozygous FH as assessed by changes in laboratory parameters, the number of subjects developing biopsy-proven evidence of steatohepatitis, reported adverse events, changes noted on the electrocardiogram, pulmonary function tests, physical examinations, and weight. c. Percent change in hepatic fat as measured by MRI/NMRS. d. Pharmacokinetics of AEGR-733 using a population PK and sparse sampling approach |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females &#8805; 18 years of age 2. Diagnosis of functional homozygous FH by at least one of the following clinical criteria: a. documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality OR b. skin fibroblast LDL receptor activity < 20% normal OR c. untreated TC > 500 mg/dL and TG < 300 mg/dL AND both parents with documented untreated TC > 250 mg/dL 3. Subject understands and agrees that concurrent lipid lowering medication must be stable for &#8805; 6 weeks before the baseline visit and must remain stable through week 26. These include but are not limited to: statins, ezetimibe, nicotinic acid, bile acid sequestrants, fibrates and LDL apheresis. 4. Body weight &#8805; 40 kg and < 136 kg (due to MRI weight limit) 5. Negative screening pregnancy test if female of child-bearing potential (females of childbearing potential and all males must be following a medically accepted form of contraception) 6. Subjects must be willing to comply with all study-related procedures. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria: 1. Uncontrolled hypertension defined as: systolic blood pressure >180 mmHg, diastolic blood pressure > 95 mmHg on medication 2. History of chronic renal insufficiency (serum creatinine >2.5 mg/dL) 3. History of biopsy proven cirrhosis or abnormal LFTs at screening (AST or ALT >2x upper limit of normal and/or Total Bilirubin of > 1.5 mg/dl unless patient has unconjugated hyperbilirubinemia due to Gilberts syndrome) 4. Chronic hepatitis B as defined by positive for HBs Ag 5. Chronic hepatitis C as defined by positive for HepC Ab 6. Any major surgical procedure occurring less than 3 months prior to the screening visit 7. Cardiac insufficiency defined by the NYHA classification as functional Class III or Class IV 8. Previous organ transplantation 9. History of a non-skin malignancy within the previous 3 years 10. Male subjects reporting more than 2 drinks per day or females reporting more than 1 drink per day (1 drink= 12 oz beer, 1 oz hard liquor, 5 oz wine). 11. Participation in an investigational drug study within 6 weeks prior to the screening visit 12. Known significant gastrointestinal bowel disease or malabsorption such as inflammatory bowel disease or chronic pancreatitis requiring use of daily pancreatic enzymes. 13. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subjects safety or successful participation in the study. 14. Certain prohibited medications known to be potentially hepatotoxic, especially those that can induce microvesicular or macrovesicular steatosis. These include but are not limited to: acutane, amiodarone, heavy acetaminophen use (4g/day > 3 x q week), methotrexate, tetracyclines, and tamoxiphen 15. Documented diagnosis of any of the following pulmonary conditions: a. Asthma b. Chronic Obstructive Pulmonary Disease (COPD) c. Idiopathic pulmonary fibrosis 16. Documented diagnosis of any of the following liver diseases: a. Nonalcoholic Steatohepatitis b. Alcoholic liver disease c. Autoimmune hepatitis d. primary biliary cirrhosis e. primary sclerosing cholangitis f. Wilsons disease g. hemochromatosis h. &#945;1 anti-trypsin deficiency 17. Current use of corticosteroids or betaine |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy will be assessed through the following lipid and lipoprotein parameters: LDL-C, non-HDL, TC, VLDL, HDL,apolipoproteins B and AI and Lp(a). Safety will be assessed through findings noted on the physical exam and ECG, changes in laboratory parameters and weight, reported adverse events, & number of patients developing biopsy-proven evidence of steatohepatitis. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | No |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |