| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Homozygous Familial Hypercholesterolemia |
| Ipercolesterolemia familiare omozigote |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypercholesterolemia (high cholesterol), familial |
| Ipercolesterolemia (elevato livello di colesterolo) familiare |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| 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 | 10057100 |
| E.1.2 | Term | Homozygous familial hypercholesterolaemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 |
| To characterize the safety and tolerability of long-term administration of AMG 145 among patients with severe familial hypercholesterolemia |
| Definire la sicurezza e la tollerabilità della somministrazione a lungo termine di AMG 145 nei soggetti con ipercolesterolemia familiare severa |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the durable efficacy of long-term administration of AMG 145 as assessed by low density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and
ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with severe familial hypercholesterolemia |
| Definire l'efficacia della somministrazione a lungo termine di AMG 145 in termini di valori di colesterolo LDL (lipoproteina a bassa densità) e non colesterolo HDL (lipoproteina non ad alta densità), apolipoproteina B (ApoB), rapporto colesterolo totale/HDL-C, rapporto ApoB/Apolipoproteina A-1 (ApoA1), e risposta in termini di riduzione dei livelli di LDL-C (pari o superiore al 15%) in soggetti con ipercolesterolemia familiare severa |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Subjects participating in the apheresis substudy will complete a separate informed consent. The apheresis substudy will provide additional information for treatment with AMG 145 in this grevious patient population. Approximately 10 subjects will participate in the substudy. Subjects in the substudy will be required to visit the study site for additional blood draws and assessments. Fasting lipids, PCSK9, PK, vital signs, concomitant medication changes, and adverse events will be evaluated and will include a total of 17 additional visits during the study. Apheresis subjects must have their apheresis schedule aligned with the Q2W dosing of AMG 145. |
I soggetti che accetteranno di partecipare al sottostudio di aferesi forniranno un consenso informato separato. Il sottostudio di aferesi fornirà ulteriori informazioni sul trattamento con AMG 145 in questa popolazione di pazienti affetti da malattia grave. Si prevede che circa 10 soggetti parteciperanno al sottostudio. Ai soggetti che parteciperanno al sottostudio sarà chiesto di recarsi presso il centro di sperimentazione per prelievi del sangue ed accertamenti aggiuntivi.
Nello specifico: test lipidico a digiuno, PCSK9, PK, segni vitali, cambiamenti nei farmaci concomitanti, e valutazione degli eventi avversi, per un totale di 17 visite addizionali nel corso dello studio. I soggetti con aferesi dovranno avere un programma di aferesi allineato con il dosaggio Q2W di AMG 145.
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|
| E.3 | Principal inclusion criteria |
Subjects will be eligible for the study if they:
- Completed study 20110233 or another qualifying Amgen parent protocol, did not experience a treatment related serious adverse event that led to IP discontinuation, and are still taking investigational product at the end of the study, or
- Have severe familial hypercholesterolemia due to genetic causes (beyond LDL receptor mutations), such as PCSK9 gain of function mutations, as evidenced by genetic or functional evidence and have not participated in a parent protocol. Eligibility must be approved by Amgen’s medical monitor, or
- Have a diagnosis of homozygous familial hypercholesterolemia and are ineligible to meet inclusion criteria for another AMG 145 protocol (for example, patients actively receiving apheresis). Eligibility must be approved by Amgen’s medical monitor, or
- Have a diagnosis of homozygous familial hypercholesterolemiaand are eligible to participate in study 20110233 but study 20110233 has closed. As stated in protocol 20110233, the diagnosis of homozygous familial hypercholesterolemia will be based on genetic confirmation or a clinical diagnosis based on a history of an untreated LDL cholesterol concentration greater than 500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
Non-parent study subjects that meet inclusion criteria 4.1.2, 4.1.3, or 4.1.4 must also meet all of the following inclusion criteria:
- Are male or female ≥ 12 to ≤ 80 years of age
- Are on a stable low-fat diet and taking pre-existing lipid-lowering therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants or nicotinic acid, or combinations thereof) for at least 4 weeks, with fasting central lab LDL cholesterol concentration and meet the following LDL-C values based on risk factor status (NCEP ATPIII risk categories Grundy et al, 2004):
- > 100 mg/dL (2.6 mmol/L) for subjects with diagnosed CHD or CHD risk equivalent (includes clinical manifestations of noncoronary forms of atherosclerotic disease [peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease], diabetes, and 2+ risk factors with 10-year risk for hard CHD >20%). Risk factors include cigarette smoking, hypertension (BP ≥ 140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years of age; CHD in female first-degree relative < 65 years of age), and age (men ≥ 45 years; women ≥ 55 years) or
- > 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or CHD risk equivalent or
- There is No LDL-C entry requirement for apheresis patients - because their LDL-C values fluctuate and may not be representative of their overall LDL-C burden.
- Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening
- Bodyweight of 40 kg or greater at screening
|
Soggetti di sesso maschile e femminile, di età compresa tra ≥ 12 e ≤ 80 anni con diagnosi di ipercolesterolemia familiare severa che per poter partecipare allo studio devono soddisfare i seguenti criteri: 1. Aver completato lo studio 20110233 o un protocollo di studio originario qualificante su AMG 145, non aver riportato eventi avversi seri correlati al trattamento che abbiano portato alla sospensione del prodotto sperimentale (PS) e siano ancora in trattamento con il prodotto sperimentale alla fine di quello studio. Tutti gli altri soggetti: 2. Possono essere arruolati altri soggetti con ipercolesterolemia familiare omozigote che soddisfino i criteri di inclusione ed esclusione dello studio 20110233 dopo la chiusura dello stesso.
3. I soggetti con ipercolesterolemia familiare omozigote non eleggibili per un altro studio AMG 145 (per esempio soggetti in aferesi) possono essere eleggibili alla partecipazione previa approvazione del Medical Monitor Amgen.
4. I soggetti con ipercolesterolemia familiare severa con cause genetiche diverse dalle mutazioni del recettore delle LDL (per esempio mutazioni di PCSK9 con guadagno di funzione) che non hanno partecipato a uno studio originario su AMG 145 possono essere eleggibili previa approvazione del Medical Monitor di Amgen.
Per l'arruolamento i soggetti devono avere una dieta stabile ipolipidica e una terapia preesistente ipolipemizzante (ad esempio con statine, inibitori dell'assorbimento di colesterolo, sequestranti degli acidi biliari, acido nicotinico o una combinazione dei suddetti) da almeno 4 settimane, con una concentrazione di colesterolo LDL a digiuno misurata da un laboratorio centrale ≥ 100 mg/dL (2,6 mmol/L) per soggetti con diagnosi di coronariopatia (CHD) o con equivalente di rischio CHD (definito dalle linee guida NCEP ATP III) o ≥ 130 mg/dL (3,4 mmol/L) per soggetti senza diagnosi di coronariopatia (CHD) o equivalente di rischio CHD (definito dalle linee guida NCEP ATP III), concentrazione di trigliceridi accertata da laboratorio centrale ≤ 400 mg/dL (4,5 mmol/L), e peso corporeo pari o superiore ai 40 kg al momento dello screening.
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| E.4 | Principal exclusion criteria |
All subjects will be ineligible for the study if they fulfill any of the following criteria:
- Female subject is not willing to use at least one highly effective method of birth control during treatment and for an additional 15 weeks after the end of treatment unless subject is sterilized or postmenopausal;
- Menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral oophorectomy”
-Highly effective methods of birth control include abstinence, birth control pills, shots, implants, or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
- Subject is pregnant or breast feeding, or might become pregnant during treatment and/or within 15 weeks after the end of treatment
- Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the subject (eg, inability or unwillingness to adhere to the protocol)
- Experienced a treatment related serious adverse event that led to IP discontinuation in the AMG 145 parent protocol
- Disorder that would interfere with understanding and giving informed consent or compliance with protocol requirements
- Have an unstable medical condition, in the judgment of the investigator.
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s).
In addition, all subjects that undergo screening procedures will be ineligible for the study if they fulfill any of the following criteria:
- Use of Mipomersen within 5 months of screening
- NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%
- Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 3 months prior to screening
- Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to screening
- Planned cardiac surgery or revascularization within 20 weeks of screening
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg, confirmed with repeat measurement
- Subject requires uptitration of their current statin dose within 4 weeks of screening (these subjects can be uptitrated and rescreened one month later)
- Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
- Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at screening
- Unexplained CK > 5 times the ULN at screening, confirmed by a repeat measurement at least 1 week apart
- Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
- Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to screening
- History of malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma)
- Subject has previously received a non-AMG 145 investigational therapy to inhibit PCSK9
- Currently enrolled in a non-AMG 145 investigational device or drug study, or less than 30 days since ending a non-AMG 145 investigational device or drug study(s), or receiving other investigational agent(s)
|
| I principali criteri di esclusione sono: utilizzo di Mipomersen nei 5 mesi precedenti lo screening; frazione di eiezione ventricolare sinistra della classe III o IV della New York Heart Failure Association (NYHA) o ultimo valore noto < 30%; aritmia cardiaca negli ultimi 3 mesi non controllata da farmaci; infarto del miocardio, angina instabile, intervento percutaneo coronarico (PCI), innesto di bypass coronarico (CABG) o ictus nei 3mesi precedenti l'arruolamento; intervento programmato di cardiochirurgia o rivascolarizzazione; pressione arteriosa sistolica (SBP) > 180 mmHg o diastolica (DBP) > 110 mmHg; pazienti che richiedono una titolazione incrementale della dose di statine nelle 4 settimane precedenti lo screening; tasso di filtrazione glomerulare stimato (eGFR) < 30 ml/min/1,73m2; aumento persistente di aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) > 3x ULN, di creatin kinasi (CK) > 5x ULN in assenza di una causa nota; infezione maggiore attiva conosciuta, o disfunzione ematologica, renale, metabolica, gastrointestinale o endocrina maggiore; trombosi venosa profonda o embolia polmonare nei 3 mesi precedenti l'arruolamento; anamnesi di neoplasia; soggetto precedentemente sottoposto a terapia sperimentale con un inibitore della PCSK9 diverso da AMG 145; soggetto attualmente arruolato in uno studio su un farmaco o un dispositivo diverso da AMG 145 oppure che abbia terminato da meno di 30 giorni la sua partecipazione a studi su un farmaco o un dispositivo diverso da AMG 145 o in terapia con altri farmaci sperimentali. Le donne non devono essere in gravidanza né in allattamento. Le donne in premenopausa devono essere disposte ad adottare almeno un metodo contraccettivo di elevata efficacia durante il trattamento e per altre 15 settimane dopo la fine del trattamento. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Subject incidence of treatment emergent adverse events. |
| Incidenza nei soggetti degli eventi avversi emersi durante il trattamento |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to week 24 Q4W, at interval visits (week 16 and 20) and quaterly after week 24 until EoS |
Dal basale alla settimana 24 Q4W, a visite alternate (settimana 16 e 20) e
trimestrale dopo la settimana 24 fino EoS
|
|
| E.5.2 | Secondary end point(s) |
• Percent change in LDL-C from baseline at each scheduled visit
• Percent change in non-HDL-C from baseline at each scheduled visit
• Percent change in ApoB from baseline at each scheduled visit
• Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
• Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
• Response of LDL-C reduction of 15% or greater from baseline at each scheduled visit
|
| - Variazione percentuale di LDL-C rispetto al basale ad ogni visita programmata - Variazione percentuale di non HDL-C rispetto al basale ad ogni visita programmata - Variazione percentuale di ApoB rispetto al basale ad ogni visita programmata - Variazione percentuale del rapporto colesterolo totale/HDL-C rispetto al basale ad ogni visita programmata - Variazione percentuale del rapporto ApoB/ApoA1 rispetto al basale ad ogni visita programmata - Tasso di risposta per ogni visita programmata dei soggetti che presentano una riduzione pari o superiore al 15% dei valori di LDL-C. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Percent change in LDL-C from baseline at each scheduled visit
• Percent change in non-HDL-C from baseline at each scheduled visit
• Percent change in ApoB from baseline at each scheduled visit
• Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
• Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
|
- Variazione percentuale del colesterolo LDL dal basale ad ogni visita programmata
- Variazione percentuale di non-HDL-C rispetto al basale ad ogni visita programmata
- Variazione percentuale rispetto al basale ApoB ad ogni visita programmata
- Variazione percentuale del colesterolo totale / HDL-C rapporto rispetto al basale in ogni visita programmata
- Variazione percentuale rispetto al basale ApoB/ApoA1 rapporto ad ogni visita programmata
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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 | 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 | 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Altra frequenza di somministrazione |
| Other schedule of administration |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Greece |
| Hong Kong |
| Israel |
| Italy |
| Japan |
| Malaysia |
| New Zealand |
| Norway |
| Poland |
| South Africa |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The study will continue for 5 years or until AMG 145 becomes commercially available, whichever is earlier. |
| lo Studio avrà una durata di 5 anni o continuerà fino all’entrata in commercio di AMG 145, che potrebbe avvenire anche prima dei 5 anni |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
| 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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