| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| elevated lipoprotein (a) and high risk of atherosclerotic cardiovascular disease (ASCVD) events |
| lipoproteína (a) elevada y alto riesgo de episodios de enfermedad cardiovascular aterosclerótica (ECVA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| elevated lipoprotein (a) and high risk of atherosclerotic cardiovascular disease (ASCVD) events |
| lipoproteína (a) elevada y alto riesgo de episodios de enfermedad cardiovascular aterosclerótica (ECVA) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051615 |
| E.1.2 | Term | Atherosclerotic cardiovascular disease |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 | 10054009 |
| E.1.2 | Term | Lipoprotein (a) increased |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| 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 |
| The primary objective is to evaluate the effect of SLN360 on circulating levels of Lp(a) in participants with elevated Lp(a) at high risk of ASCVD events. |
| El objetivo principal es evaluar el efecto de SLN360 en los niveles circulantes de Lp(a) en participantes con Lp(a) elevada y alto riesgo de episodios de ECVA |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate safety and tolerability of SLN360 in participants with elevated Lp(a) at high risk of ASCVD events
- Evaluate the effects of SLN360 on LDL-C and apolipoprotein B (apoB) in this population |
-Evaluar la seguridad y la tolerabilidad de SLN360 en participantes con Lp(a) elevada y alto riesgo de episodios de ECVA.
-Evaluar los efectos de SLN360 sobre el C-LDL y la apolipoproteína B (apoB) en esta población. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female
2. Aged 18 to 80 years inclusive at screening
3. Lipoprotein(a) at screening equal to or greater than 125 nmol/L
4. At high risk of ASCVD, i.e., at least one of the following conditions:
a) Previous MI
b) Coronary angiographic diagnosis of CAD with or without previous MI
c) Computerised tomography/magnetic resonance imaging diagnosis of CAD with or without previous MI
d) Previous coronary revascularisation (percutaneous coronary intervention or coronary artery bypass graft)
e) Prior ischeamic stroke as previously confirmed by a documented brain imaging study (e.g. CT or MRI brain), and considered not to be caused by thromboembolic phenomena associated with atrial fibrillation, valvular heart disease, or mural thrombus
f) Peripheral arterial disease
g) Existing evidence of coronary artery calcium on computerised tomography (coronary artery calcium score ≥1 AU)
5. A body mass index at screening in the range 18.0 to 32.0 kg/m2, inclusive
6. Participants must be able to provide valid informed consent and to comply with all study requirements
7. Participants receiving lipid-modifying therapy (including statins, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, ezetimibe) must be on a stable, maximum tolerated regimen, according to the clinical judgement of the Investigator, at screening (i.e., receiving therapy for a minimum of 8 weeks) with no changes to existing regimens or introduction of new regimens made after screening. For monoclonal antibody PCSK9 inhibitors, a stable dose is defined as at least four doses at a consistent dose level |
1. Varón o mujer.
2. Edad de 18 a 80 años, ambos inclusive, en la selección.
3. Lipoproteína(a) en la selección igual o superior a 125 nmol/l.
4. Riesgo alto de ECVA, es decir, al menos una de las siguientes afecciones:
a. Infarto de miocardio (IM) previo.
b. Diagnóstico de enfermedad coronaria mediante angiografía coronaria, con o sin IM previo.
c. Diagnóstico de enfermedad coronaria mediante tomografía computarizada/resonancia magnética, con o sin IM previo.
d. Revascularización coronaria previa (intervención coronaria percutánea o injerto de derivación coronaria).
e. Ictus isquémico previo, confirmado previamente mediante un estudio de imagen cerebral documentado (p. ej., tomografía computarizada o resonancia magnética cerebral), que no se considere causado por fenómenos tromboembólicos asociados a fibrilación auricular, valvulopatía cardíaca o trombo mural.
f. Arteriopatía periférica.
g. Signos existentes de calcio en las arterias coronarias en la tomografía computarizada
h. (puntuación de calcio en las arterias coronarias ≥1 UA).
5. Índice de masa corporal en la selección en el intervalo de 18,0 a 32,0 kg/m2, ambos inclusive.
6. Los participantes deberán ser capaces de otorgar su consentimiento informado válido y cumplir todos los requisitos del estudio.
7. Los participantes que reciban tratamiento antidislipidémico (como estatinas, inhibidores de la proproteína convertasa subtilisina/kexina de tipo 9 [PCSK9] o ezetimiba) deberán estar recibiendo una pauta estable y en la dosis máxima tolerada, según el criterio clínico del investigador, en la selección (es decir, deberán haber recibido tratamiento durante un mínimo de 8 semanas) y no se podrá modificar las pautas existentes ni introducir nuevas pautas después de la selección. En el caso de los inhibidores del anticuerpo monoclonal PCSK9, una dosis estable se define como al menos cuatro dosis con un nivel de dosis constante. |
|
| E.4 | Principal exclusion criteria |
1. Cardiovascular disease-related:
a. Acute cardiovascular event within the 12 weeks before screening (including but not limited to acute MI, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, acute limb ischaemia, limb revascularisation)
b. Planned or expected cardiac surgery or coronary or other revascularisation within 12 weeks of screening or planned major non-cardiac surgery during the study period
2. Medical history:
a. Renal dysfunction with estimated glomerular filtration rate less than 30 mL/min/1.73 m2 at screening
b. Acute, chronic or historical liver disease, including viral hepatitis (hepatitis A, B or C virus) at screening. Participants with positive hepatitis B virus surface antibody titre reflecting hepatitis B virus immunisation are permitted to participate
c. Hepatic dysfunction based on liver function markers at screening: AST, ALT or total bilirubin >2 × ULN
d. Established diagnosis of Gilbert syndrome
e. Inherited or other bleeding disorders
f. Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, stage 1 prostate carcinoma, or benign tumours) within the 5 years before screening
g. Current or previous history of moderate to severe heart failure or last known left ventricular ejection fraction less than 30% at screening
h. Ventricular tachycardia, atrial fibrillation with rapid ventricular response or supraventricular tachycardia that are not controlled by medications in the 12 weeks before screening
i. Fasting triglycerides >400 mg/dL (4.5 mmol/L) at screening
j. Uncontrolled hypertension at screening
k. Type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus at screening
l. Known active infection or major haematological, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the Investigator at screening or Day 1
3. Concomitant medication:
a. Currently receiving or <12 weeks at Day 1 since receiving >200 mg/day niacin or niacin derivative drugs
b. Treatment with lipid/lipoprotein apheresis within the 12 weeks before screening
c. Treatment with a cholesteryl ester transfer protein inhibitor or lomitapide within the 52 weeks before screening
d. Treatment with aspirin, clopidogrel, ticagrelor or other antiplatelet agent unless prescribed at a low maintenance dose for the purpose of cardiovascular risk reduction
e. Participation in another clinical trial including an investigational medicinal product (IMP) within 12 weeks, or within five half-lives of that IMP, before screening
f. Any previous use of approved or experimental siRNA therapy NB: use of mRNA-based vaccines for infectious diseases is permitted
g. Use of approved or experimental antisense oligonucleotide therapy within the 24 weeks before screening. NB: use of mRNA-based vaccines for infectious diseases is permitted
h. Use of experimental Lp(a)-reducing therapy within the 52 weeks before screening
i. Use of herbal or complementary medicines, dietary supplements or vitamins known to substantially influence lipid metabolism or blood lipid or lipoprotein levels (e.g., fish oil, turmeric, red yeast rice) within the 4 weeks before Day 1
4. Alcohol and illegal drugs:
a. History or clinical evidence of alcohol misuse within the 26 weeks before screening
b. History or clinical evidence of recreational drug use within the 26 weeks before screening
5. Other exclusions:
a. Female participants of childbearing potential with a positive serum pregnancy test assessed at screening or positive urine pregnancy test on Day 1
b. Female participants of childbearing potential planning to become pregnant or breastfeed during treatment and for an additional 12 weeks after the last dose of study treatment
c. Female participants of childbearing potential unwilling to use a highly effective method of contraception during treatment and for an additional 12 weeks after the last dose of study treatment
d. Male participants must be surgically sterile or, if engaged in sexual relations with a female of childbearing potential, the participant must be using a highly effective contraception method from the time of signing the informed consent form (ICF) until at least 12 weeks after the last dose of study treatment
e. Known sensitivity to any of the products to be administered during dosing
f. Likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant and Investigator’s knowledge
g. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Sponsor, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion |
1.Relacionados con enfermdades cardiovasculares
a.Episodio cardiovascular agudo n ls 12smanas previas a l sel(pj, IM agudo, anginainestable, ICP, injerto d derivación d AC,ictus,isqmia aguda d una extremidad, revascularización d una extremidad)
b.Cirugía cardíacaprogramada o prevista o revascularizacióncoronaria o d otro tipo n ls 12semnas previasa l sel o cirugíamayor no cardíacaprogramada dte l período dl estudio
2.Antecdentes médicos a.Disfunción renalcon una FGE inferior a30ml/min/1,73m2(según l ecuación d l CKDE Collaboration) n l sel b.Hepatopatía aguda,crónica o prvia,incluida l HV (A,BoC) n l sel. Podrán participar pctes con títulos + d Ac contra l Ag d superficie dl VHB q reflejen l vacunación contra l VHB c.Disfunción hepática basada nmarcadores d l funciónhepática n l sel: AST, ALT o bilirrubin ttal >2veces l LSN. d.Dx establecido d síndrom d Gilbert e.Trastornos hemorrágicoshereditarios o d otrotipo f.Neoplasias malignas (excp cánceres d piel distintos dl melanoma,carcinoma in situ d cuellouterino, carcinomaductal dmama insitu,carcinoma d próstata n estadio1 o tumoresbenignos) n ls 5añosprvios a l sel g.Presencia oantecedntes d insuficiencia cardíaca moderada ograve (grado3o4 según l clasificaciónfuncional d l NYH Association n l sel) oúltima fracción deyección ventricularizquierda conocida inferior al30%en l sel h.Taquicardia ventricular, fibrilación auricular conrespuesta ventricularrápida o taquicardiasupraventricular q no esténcontroladas con mdc n ls 12smanas prvias a l sel i.Tgs n ayunas >400 mg/dl(4,5 mmol/l) n l sel j.HT no controlada n l sel, definida como una PAS n sedestación media>160mmHg o una pres PADmedia>110mmHg dspués d un mín d 3determinaciones k.DM d tipo1 o DM d tipo2 malcontrolada(HbA1c ≥10% o≥86 mmol/mol) n l sel.
l.Infección activaconocida o disfunciónhematológica,renal,metabólica,digestiva o endocrinaimportante acriterio dl inv. n l sel o l día1.
3.Mdc concomitante
a.Tx actual con>200 mg/día d niacina o fármacosderivados d l niacina (ej niceritrol, nicomol) o mnos d 12smanas entresu administración y l día1.
b.Tx con aféresis d lípids/lipproteínas n ls 12smanas previas a l sel
c.Tx con un inhibidor d l proteín d transferencia d ésteres dl colesterol (ej, anacetrapib,dalcetrapib,evacetrapib,obicetrapib) o lomitapida n ls 52smanas prvias a l sel
d.Tx con ácidoacetilsalicílico, clopidogrel, ticagrelor u otroantiagregante plaqtario, a mnos q s haya prescrito n una dosis d mantenimiento baja para reducir l riesgo cardiovascular (i.e, ácido acetilsalicílico hasta 325mg/día, clopidogrel 75mg/día, ticagrelor 180mgal/día)
e.Participaciónen otro ensayo clínico, incluido un producto n invest clínica, n ls 12smanaspreviasa l sel o n l períodoequivalente a 5semividas d dichoproducto n invest clínicaantes d l sel
f.Cquer uso prvio d terapia con ARNip aprobda o experimntal (ej, inclisirán)Nota: sepermite l uso d vacunas basadas n ARNm paraenfermdades infecciosas
g.Uso d una trapia conoligonucleótidos d antisentido aprobda o experimntal n ls 24smanas previasa l sel.Nota:se permite l uso d vacunas basadas n ARNm para nfermedades infecciosas
h.Uso d un tx reductor d l Lp(a) experimental n ls 52smanas prvias a l sel
i.Uso d productos d herbolario o mdc complementarios, suplementos dietéticos o vitaminas q se sabe q influyen sustancialmente n l metabolismo d ls lípidos o n ls [] sanguíneas d lípidos o lipproteíns (ej, aceite d pescado, cúrcuma, arroz d levadura roja) n ls 4smanas prvias l día1
4.Alchol y drogas ilegalesa.Antecedntes o signos clínicos d abuso dl alchol n ls 26smanas previasa l sel b.Antecedntes o signos clínicos d consumo d drogas n ls 26smanas prviasa l sel
5.Otras exclusiones
a.Mjers n edd fértilcon una prueba d embarazoen suero + n l sel o una prueba d embarazo n orina + l día1.
b.Mjers n edd fértil q tengan intención d qudarse embarazadas o dar l pecho dte l Tx y dte otras12smanas másdspués d l últimadosis dl Tx dl estudio
c.Mjers n edd fértil q noestén dispuestas autilizar un métodoanticonceptivo muy eficaz dte l Tx y dte otras 12smanas dspués d l última dosis dl Tx dlestudio
d.Ls varonesparticipantes deberánestar esterilizados quirúrgicamnte o, simantienen relaciones sexuales conuna mujer n edd fértil, deberánutilizar unmétodo anticoncptivo muy eficaz dsde l momnto d l firma dl documento d consentmto informado hsta almnos 12smanas dspués d l últimadosis dl Tx dl estudio
e.Sensibilidadconocida acquerra d ls productos q s vayan a administrar dte l Tx
f.Probablidd d q l pcte noesté dsponible paracompletar tods ls visitas o proc. dl estudioexigidos por l prtocolo o paracumplir tods ls proc. dl estudio obligatorios,según l saber yentender dl pcte y l inv
g.Antecedntes o indicios d cquer otro trastorno, proceso o enfrmdad d importanciaclínica(a excp d ls dscritos anteriormnte) q, n opinión dl inv. o dl prmotor, si se le consulta, suponga unriesgo pra l seguridad dl participante o puedainterferir n l evaluación, ls proc. o l realización dl estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the time-averaged change in Lp(a) from baseline to Week 36. |
| El criterio de valoración principal es la variación promediada en el tiempo de la Lp(a) entre el momento basal y la semana 36. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary safety endpoint is the safety and tolerability of SLN360, as assessed by:
- Adverse event reports
- Physical examination findings
- Twelve-lead electrocardiograms
- Vital signs
- Laboratory safety evaluations
The secondary pharmacodynamic and efficacy endpoints are:
- The change (time-averaged and by visit) in Lp(a) from the Day 1 pre dose assessment to Week 48
- The change (time-averaged and by visit) in Lp(a) from the Day 1 pre dose assessment to Week 60
- The change (time-averaged and by visit) in other lipids/lipoproteins, including LDL C and apoB, from the Day 1 pre dose assessment to Week 36
- The change (time-averaged and by visit) in other lipids/lipoproteins, including LDL C and apoB, from the Day 1 pre dose assessment to Week 48
- The change (time-averaged and by visit) in other lipids/lipoproteins, including LDL C and apoB, from the Day 1 pre dose assessment to Week 60
The exploratory endpoints are the pharmacogenetic effects of germline genetic variation on response to SLN360, measured by association analysis of genetic variants with markers of SLN360 efficacy, including change in Lp(a). |
El criterio de valoración secundario de la seguridad es la seguridad y la tolerabilidad de SLN360, evaluadas mediante:
• Notificación de acontecimientos adversos.
• Hallazgos de la exploración física.
• Electrocardiogramas de 12 derivaciones.
• Evaluaciones analíticas de la seguridad.
• Constantes vitales.
Los criterios de valoración secundarios farmacodinámicos y de la eficacia son:
• Variación (promediada en el tiempo y por visita) de la Lp(a) desde la evaluación del día 1 antes de la dosis hasta la semana 48.
• Variación (promediada en el tiempo y por visita) de la Lp(a) desde la evaluación del día 1 antes de la dosis hasta la semana 60.
• Variación (promediada en el tiempo y por visita) de otros lípidos/lipoproteínas, incluidos el C-LDL y la apoB, desde la evaluación del día 1 antes de la dosis hasta la semana 36.
• Variación (promediada en el tiempo y por visita) de otros lípidos/lipoproteínas, incluidos el C-LDL y la apoB, desde la evaluación del día 1 antes de la dosis hasta la semana 48.
• Variación (promediada en el tiempo y por visita) de otros lípidos/lipoproteínas, incluidos el C-LDL y la apoB, desde la evaluación del día 1 antes de la dosis hasta la semana 60.
Los criterios de valoración exploratorios son los efectos farmacogenéticos de la variación genética de la línea germinal en la respuesta a SLN360, determinados mediante un análisis de asociación entre variantes genéticas y marcadores de la eficacia de SLN360, incluida la variación de la Lp(a). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety secondary endpoints:
Throughout the study
PD and Efficacy Endpoints:
- change in Lp(a) from day 1 predose to week 48: day 1 predose and week 48
- change in Lp(a) from day 1 predose to week 60: day 1 predose and week 60
- change in other lipids from day 1 predose to week 36: day 1 predose and week 36
- change in other lipids from day 1 predose to week 48: day 1 predose and week 48
- change in other lipids from day 1 predose to week 60: day 1 predose and week 60
Exploratory endpoint: genotyping sample at day 1 |
Criterios de valoración secundarios de seguridad:
A lo largo del estudio
Criterios de valoración de farmacodinámica y eficacia:
- cambio en Lp(a) desde el día 1 predosis hasta la semana 48: día 1 predosis y semana 48
- cambio en Lp(a) desde el día 1 predosis hasta la semana 60: día 1 predosis y semana 60
- cambio en otros lípidos desde la predosis del día 1 hasta la semana 36: predosis del día 1 y semana 36
- cambio en otros lípidos desde la predosis del día 1 hasta la semana 48: predosis del día 1 y semana 48
- cambio en otros lípidos desde el día 1 predosis hasta la semana 60: día 1 predosis y semana 60
Criterio de valoración exploratorio: muestra de genotipado en el día 1 |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 5 |
| 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 | 25 |
| 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 |
| South Africa |
| United States |
| Netherlands |
| Spain |
| Czechia |
| Denmark |
| Slovakia |
| United Kingdom |
|
| 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
|
| Last patient last visit (LPLV) |
| Última visita al último paciente (UVUP) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
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