E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 | 10054380 |
E.1.2 | Term | Familial hypercholesterolemia |
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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 |
To evaluate the effect of APL180 on endothelial function in patients with familial hypercholesterolemia. |
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E.2.2 | Secondary objectives of the trial |
• To explore the relationship between APL180 exposure and pharmacodynamics. • To explore the effects of APL180 on biomarkers of oxidation. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients with familial hypercholesterolemia age 18 to 50 years of age included, and in generally good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening. Patients with familial hypercholesterolemia must have LDL levels ≥ 95th percentile and meet 1 of the following criteria: • DNA diagnosis for FH • Positive family history (1st degree relative) with either 1) LDL levels > 95th percentile as presented in Appendix 4 with premature CAD or 2) a DNA diagnosis for FH 2. At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes. Sitting vital signs should be within the following ranges: -oral body temperature between 35.0-37.5 °C -systolic blood pressure, 90-140 mm Hg -diastolic blood pressure, 50-90 mm Hg -pulse rate, 50 - 90 bpm If vital signs are out-of-range, the Investigator may obtain two additional readings, so that a total of up to three consecutive assessments are made, each after at least 30 minutes, and with the subject seated quietly during the five minutes preceding the assessment. At least the last reading must be within the ranges provided above in order for the subject to qualify. All blood pressure measurements at other time points should be assessed with the subject seated, unless stated otherwise in the protocol design, and utilizing the same arm for each determination. 3. Female patients must be of non-childbearing potential and thus meet one of the following criteria: • Postmenopausal females must have had no regular menstrual bleeding for at least one year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of >40 IU/L at screening. OR • Female patients who report surgical sterilization must have had the procedure at least six months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF. In addition, these female patients must have negative pregnancy test results at screening and baseline. 4. At Screening, subjects must weigh at least 50 kg to participate in the study, and must have a body mass index within the range of 18 to 30 kg/m2. 5. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria will be excluded from entry into or continuation in the study: 1. Patients who report smoking greater than an average of 10 cigarettes per day. Smoking should be stopped at least 24 hours prior to reporting to the center (Day 1, early morning) and urine cotinine tests must indicate adherence to this criteria. 2. Participation in any clinical investigation within four (4) weeks prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations. 3. History any acute cardiovascular events within 6 months of dosing 4. History or presence of diabetes mellitus, or HbA1c at Screening >7.0% 5. History or presence of any chronic inflammatory disease (e.g. rheumatoid arthritis, COPD, osteoarthritis, IBD, psoriasis) or a recent (within the last three [3] years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). 6. History or presence of any hepatic, renal or thyroid abnormalities (e.g. ESRD, CKD, dialysis, hyperthyroid, hypothyroid, Grave’s disease) or impaired renal function with eGFR < 60 according to the MDRD formula at screening. 7. Current/recent therapy with any of the following: anti-hypertensive drugs; anti-inflammatory drugs within 2 weeks of dosing; lipid modifying drugs, fibrates, niacin, and any other therapies that may affect study endpoints. Antioxidant vitamin use is acceptable with > 2 week washout prior to dosing. 8. 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. 9. Significant acute illness within two (2) weeks prior to initial dosing. 10. A past medical history of clinically significant ECG abnormalities. 11. Recent and/or recurrent history of autonomic dysfunction 12. History of multiple and recurring clinically significant allergies, allergy to the investigational compound being used in this study, or allergy to any peptide or protein therapy. 13. Any surgical or medical condition which might significantly alter the distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject’s medical history and/or clinical or laboratory evidence of any of the following: • Pancreatic injury or pancreatitis; • Liver disease or liver injury as indicated by abnormal liver function tests at Screening such as SGOT (AST), SGPT (ALT), γ-GGT, alkaline phosphatase, or serum bilirubin. The Investigator should be guided by the following criteria: • Any single parameter may not exceed 3 x upper limit of normal (ULN). A single parameter elevated up to and including 3 x ULN 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. • If the total bilirubin concentration is increased above 1.5 x ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum bilirubin should not exceed the value of 27 µmol/L (1.6 mg/dL). Re-check results must be returning to within normal limits in order for subject to qualify. • Evidence of urinary obstruction or difficulty in voiding at screening. 14. Total WBC count or platelets which fall outside the reference range for the analyzing lab at Screening. 15. Triglyceride levels at Screening > 2.26 mmol/L (~200 mg/dL). 16. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. 17. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening and at baseline. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary pharmacodynamic endpoint will be the percent change from the pre-acetylcholine or sodium nitroprusside forearm blood flow at each dose level for each drug infusion. |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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 | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
|
The last visit of the last subject undergoing the trial will be considered the end of 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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |