| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Familial Chylomicronemia Syndrome |
| Sindrome Chilomicronemica Familiare |
|
| E.1.1.1 | Medical condition in easily understood language |
| Familial hypercholesterolemia is a rare inherited disease that causes high levels of cholesterol in the blood and serious cardiovascular consequences. |
| L'ipercolesterolemia familiare è una rara malattia ereditaria che causa elevati livelli di colesterolo nel sangue e gravi conseguenze cardiovascolari. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058108 |
| E.1.2 | Term | Dyslipidaemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 Lomitapide in combination with other lipid lowering therapy in patients with Familial Chylomicronemia Syndrome (FCS). |
| L'obiettivo primario dello studio è valutare l'efficacia di Lomitapide in combinazione con altre terapie ipolipemizzanti in pazienti affetti da Sindrome Chilomicronemica Familiare (SCF). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate:
1. other lipid parameters
2. long-term safety of Lomitapide
3. hepatic fat and liver stiffness and Chylomicron kinetics in combination with other lipid lowering agents in patients with FCS during the full length of the clinical study. |
Gli obiettivi secondari dello studio sono di valutare:
1. altri parametri lipidici
2. sicurezza a lungo termine di Lomitapide
3. grasso epatico e rigidità epatica e cinetica dei chilomicroni in combinazione con altri agenti ipolipemizzanti in pazienti con FCS durante l'intera durata dello studio clinico. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent
2. Age = 18 years at time of informed consent
3. History of chylomicronemia as evidenced by documentation of lactescent serum or documentation of fasting TG measurement = 885 mg/dl (10 mmol/L)
4. A diagnosis of Familial Chylomicronemia Syndrome by documentation of at least one of the following: confirmed homozygote, compound heterozygote or double heterozygote for known loss-of-function mutations in genes causing FCS
5. Fasting TG = 750 mg/dl (8.4 mmol/L) at screening
6. History of pancreatitis
7. Willing to follow a diet comprising = 20 g fat per day during the study con quanto riportato a pag. 21 “Screening procedures include also dietary counseling with regard to low-fat diet (=20% energy from fat) and to avoid alcohol completely while receiving Lomitapide
8. Satisfy one of the following:
• Females: non-pregnant and non-lactating; surgically sterile, post-menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, patient is using an acceptable contraceptive method
• Males: Surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, patient is utilizing an acceptable contraceptive method |
1. Consenso informato scritto
2. Età = 18 anni al momento del consenso informato
3. Storia di chilomicronemia documentata dall’evidenza di siero lattescente o TG a digiuno = 885 mg/dl (10 mmol/L)
4. Diagnosi di Sindrome Chilomicronemica Familiare documentata con le seguenti modalità: pazienti omozigoti, eterozigoti composti o doppi eterozigoti per mutazioni con perdita di funzione nei geni candidati noti responsabili di FCS
5. TG a digiuno = 750 mg/dl (8.4 mmol/L) al momento dello screening
6. Storia di pancreatiti
7. Disponibili a seguire una dieta con contenuto giornaliero di energia da grassi = 20% durante lo studio
8. Soddisfare uno dei seguenti requisiti:
• Donne: non in stato di gravidanza o allattamento; chirurgicamente sterile, post-menopausa, in età fertile utilizzare una forma accettabile di contraccezione
• Uomini: chirurgicamente sterili, utilizzare una forma accettabile di contraccezione |
|
| E.4 | Principal exclusion criteria |
1. Diabetes mellitus with any of the following: newly diagnosed within 12 weeks of screening; HbA1c = 9.0% at screening; recent change in anti-diabetic pharmacotherapy; anticipated need to change dose or type of medication during the treatment period of the study; current use of GLP-1 agonists.
2. Severe hypertriglyceridemia other than due to FCS.
3. Active pancreatitis within 4 weeks prior to screening.
4. History within 6 months of screening of acute or unstable cardiac ischemia, stroke, transient ischemic attack or unstable congestive cardiac failure requiring a change in medication or major surgery within 3 months of screening.
5. Any of the following laboratory values at screening: total bilirubin > upper limit of normal (ULN); AST > 2.0 x ULN; ALT > 2.0 x ULN; persistently positive for protein on urine dipstick; persistently positive for blood or urine dipstick; estimated creatinine clearance calculated according to the formula of Cockcroft and Gault < 50 mL/min.
6. Uncontrolled hypertension (BP > 160/100 mmHg).
7. History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at screening.
8. History of heart failure with NYHA greater than Class II.
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to begin treatment with Lomitapide (Baseline Visit).
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B.
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
12. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer.
13. Unwilling to comply with lifestyle requirements.
14. Known lactose intolerance.
15. Use of the following:
• Statins, omega-3 fatty acids or fibrates unless on a stable dose for at least 3 months prior to screening and dose and regimen expected to remain constant during the treatment period. Patients taking omega-3 fatty acids should make every effort to remain on the same brand throughout the study
• Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening
• Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless approved by the Investigator
• Atypical antipsychotic medications unless on a stable dose for at least 4 weeks prior to screening and dose and regimen expected to remain constant during the treatment period
• Glybera gene therapy within 2 years prior to screening
• Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on a stable dose for at least 4 weeks prior to screening and regular clinical monitoring is performed
• Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to screening and dose and regimen expected to remain constant during the treatment period
• Plasma apheresis within 4 weeks prior to screening or planned during the study
• Any of the medication unless stable at least 4 weeks prior to screening
16. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of screening
17. Have any other conditions, which, in the opinion of the Investigators or the Sponsor would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study |
1. Diabete mellito se: recentemente diagnosticato (entro 12 settimane dalla visita di screening), HbA1c = 9,0% (alla visita di screening); variazioni recenti della terapia ipoglicemizzante; previsione di variazione della dose o tipo di farmaco durante il periodo di trattamento ; trattamento con agonisti del GLP-1.
2. Ipertrigliceridemia severa diversa da FCS.
3. Episodio di pancreatite acuta nelle 4 settimane che precedono la visita di screening.
4. Nei 6 mesi che precedono lo screening: ischemia cardiaca acuta o instabile (infarto miocardico, sindrome coronarica acuta, angina di nuova insorgenza), ictus, attacco ischemico transitorio o insufficienza cardiaca congestizia instabile che richiede un cambiamento nel trattamento farmacologico o chirurgia maggiore entro 3 mesi dallo screening.
5. Riscontro di uno dei seguenti valori di laboratorio durante lo screening
• Fegato: bilirubina totale > limite superiore della norma (ULN), a meno di una diagnosi e/o documentazione precedente di sindrome di Gilbert; AST> 2,0 x ULN; ALT> 2,0 x ULN;
• Renale: proteinuria persistente positiva al dipstick; ematuria persistente positiva al dipstick positiva; determinazione della clearance della creatinina calcolata secondo la formula di Cockcroft e Gault <50 ml/min.
6. Ipertensione non controllata (BP> 160/100 mmHg)
7. Storia di diatesi emorragica o coagulopatia o anomalie clinicamente significative nei parametri della coagulazione allo screening.
8. Storia di scompenso cardiaco con NYHA superiore alla Classe II.
9. Infezione attiva che richiede una terapia antivirale o antimicrobica sistemica che non sarà completata prima dell’inizio del trattamento con lomitapide (Baseline Visit).
10. Anti-HCV e HBsAg positività, infezione da HIV
11. Neoplasie diagnosticate nei 5 anni che precedono la vista di screening, ad eccezione del carcinoma basocellulare o squamoso della pelle o del carcinoma in situ della cervice trattato con successo.
12. Trattamento con un altro farmaco sperimentale, agente biologico o dispositivo entro un mese dallo screening o 5 emivite dell'agente utilizzato per la sperimentazione.
13. Riluttante per soddisfare i requisiti di stile di vita.
14. Intolleranza nota al lattosio.
15. Una delle seguenti condizioni:
• Statine, acidi grassi omega-3 o fibrati a meno che non a dose stabile da almeno 3 mesi prima dello screening e si prevede rimangano costanti durante il periodo di trattamento.
• Per i pazienti in trattamento con acidi grassi omega-3 è consigliabile l’utilizzo dello stesso marchio o formulazione durante lo studio
• Acido nicotinico o derivati dell'acido nicotinico entro 4 settimane prima dello screening
• Corticosteroidi sistemici o steroidi anabolizzanti entro 6 settimane prima dello screening, a meno che non siano approvati dallo sperimentatore
• Farmaci antipsicotici atipici a meno che non a dose stabile per almeno 4 settimane prima dello screening e che si prevede rimangano costanti durante il periodo di trattamento
• Terapia genica con Glybera nei 2 anni che precedono la visita di screening
• Anticoagulanti orali (ad es. Warfarin, dabigatran, rivaroxaban e apixaban) a meno che non siano somministrati a dose stabile da almeno 4 settimane prima dello screening e venga eseguito un monitoraggio clinico regolare
• Tamoxifene, estrogeni o progestinici a meno che non assumano una dose stabile da almeno 4 mesi prima dello screening e si prevede che rimangano costanti durante il periodo di trattamento
• Plasmaferesi o plasma exchange entro 4 settimane prima dello screening o programmata durante lo studio
• Qualsiasi farmaco a meno che non sia a dose stabile da almeno 4 settimane prima dello screening
16. Donazione di sangue di 50-499 mL entro 30 giorni dallo screening o > 499 mL entro 60 giorni dallo screening
17. Qualsiasi altra condizione che, secondo il parere degli Investigatori, renderebbero il paziente inadatto all'inclusione o potrebbero interferire con la partecipazione o completamento dello studio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in tryglicerides (TG) at the maximum tolerated dose compared to baseline after 26 weeks of treatment in combination with other lipid lowering therapy in patients with Familial Chylomicronemia Syndrome (FCS). |
| Variazione percentuale dei trigliceridi tra il valore al basale e dopo 26 settimane di trattamento in combinazione con altre terapie ipolipemizzanti in pazienti affetti da Sindrome Chilomicronemica Familiare (SCF). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Other lipid parameters, hepatic fat and liver stiffness and Chylomicron kinetics of Lomitapide in combination with other lipid lowering agents in term of changes at 26 weeks from baseline.
In particular we will assess:
a) Percent change in TC, non-HDL-C, LDL-C, VLDL, Lp(a), as well as apolipoproteins B and A1.
b) Safety of Lomitapide in patients with FCS assessed by changes in laboratory parameters, electrocardiogram, physical examinations and weight.
c) Record of episodes of pancreatitis
d) Change in hepatic fat liver stiffness measured by MRI and/or Transient Elastography (Fibroscan).
e) Chylomicron kinetics. |
Altri parametri lipidici, rigidità del fegato dovuta alla componente grassa e la cinetica dei Chilomicroni di Lomitapide in combinazione con altri agenti ipolipemizzanti in termini di cambiamenti a 26 settimane dal basale.
In particolare sarà valutato:
a) Variazione percentuale di colesterolo totale, non-HDL, LDL, VLDL, Lp(a), apolipoproteine B e A1
b) Sicurezza di Lomitapide in pazienti affetti da SCF determinata in base alle modifiche dei parametri di laboratorio, ECG, esame obiettivo e peso
c) Registrazione degli episodi di pancreatite
d) Variazione della rigidità del fegato dovuta alla componente grassa, valutata mediante risonanza magnetica (RMI) e/o elastografia epatica (Fibroscan)
e) Cinetica dei Chilomicroni |
|
| 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 | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Studio in aperto |
| Open Label |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Information not present in EudraCT |
| 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
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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