E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
lipodystrophy patients, patients after liver transplantation and healthy controls |
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E.1.1.1 | Medical condition in easily understood language |
patients suffering from partial or total disease of fat storage in adipose tissue patients with liver transplant healthy controls |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 |
Define the role of leptin action in regulating hepatic VLDL secretion, lipid content and energy metabolism in healthy human subjects |
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E.2.2 | Secondary objectives of the trial |
Assess leptin action in denervated livers. Assess the effects of leptin in patients with lipodystrophy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
+ Age between 18 – 70 years + Plasma trigylcerides ≤ 700 mg/dl (aim 2 and 3 – lipodystrophic/LTX cohort; Healthy human subject cohort: < 150 mg/dl + male sex (healthy human subject cohort); female patients are eligible in LTX/lipodystrophic cohort + patients with generalized or partial lipodystrophy (based on clinical/genetic diagnosis): drug-naive patients will be preferentially recruited in case an N of 4-5 cannot be met, patients off-treatment are also recruited; no metreleptin treatment 2-3 weeks prior to the study (note that metreleptin treatment will be tapered before discontinuation to avoid triglyceride rebound in case patients are on metreleptin + LTX cohort: no major change (i.e. drug-class switch; dose adjustments are allowed) in immunosuppressive therapy regime in the last 4 weeks; > 6 months after LTX |
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E.4 | Principal exclusion criteria |
+ overt diabetes mellitus (HbA1c ≥ 6.5%); except for lipodystrophy patients (aim 3) + history of recent acute pancreatitis (< 6 months) + serum TGs > 700mg/dl + severe liver disease (LFTs 3x ULN) + pregnancy + T-Cell Lymphoma + Autoimmune disease + consummation of alcoholic beverages during the last 48 hours + history of polyneuropathy or gastropareses (including regular use of gabapentin and/or metoclopramide or other common drugs to treat gastropareses or neuropathy) + body-Mass-Index > 35 kg/m² + tendency towards claustrophobia + simultaneous participation in another active clinical study + allergies against soy products, eggs, peanuts (in case intralipid is infused) + glomerular filtration rate < 65 mL/min/1.73 m2 (calculated with the MDRD formula) + healthy subjects with a hepatic lipid content ≥ 10 % water signal are excluded + metal devices or other magnetic material in or on the subjects body which will be hazardous for NMR investigation [heart pacemaker, coronary stents and heart valves (in case these devices are not compatible with a 7T MT), brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt-spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips), embolization coil, or any metal fragments or shrapnel in the body. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Leptin induced changes in VLDL secretion • Impact of vagal stimulation on VLDL secretion
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at baseline and 180 minutes after s.c. injection of metreleptin or placebo |
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E.5.2 | Secondary end point(s) |
• Changes in hepatic lipid content • Changes in metabolism of energy rich phosphates (ATP turnover) • Impact of hepatic denervation on VLDL secretion
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at baseline and 180 minutes after s.c. injection of metreleptin or placebo |
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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 | No |
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 | 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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |