| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus |
| Diabetes Mellitus de tipo 2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes Mellitus |
| Diabetes Mellitus de tipo 2 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 |
(1) After 24 weeks, to assess the effect of treatment with MK-3102 compared with placebo on A1C.
(2) To assess the safety and tolerability of MK-3102. |
(1) Al cabo de 24 semanas, evaluar el efecto del tratamiento con MK-3102, en comparación con placebo, sobre la A1C.
(2) Evaluar la seguridad y la tolerabilidad del MK-3102. |
|
| E.2.2 | Secondary objectives of the trial |
1) After 24 weeks, to assess the effect of MK-3102 compared with placebo on fasting plasma glucose (FPG).
(2) After 24 and 54 weeks, to assess the effect (change from baseline) of MK-3102 on eGFR.
(3) After 54 weeks, to assess the effect (change from baseline) of MK-3102 on a) A1C; and b) FPG. |
(1)Al cabo de 24 semanas, evaluar el efecto del tratamiento con MK-3102, en comparación con placebo, sobre la glucosa plasmática en ayunas (GPA).
(2) Al cabo de 24 y 54 semanas, evaluar el efecto (cambio respecto al valor basal) del MK-3102 sobre la TFGe.
(3) Al cabo de 54 semanas, evaluar el efecto (cambio respecto al valor basal) del MK-3102 sobre a) la A1C; y b) la GPA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At Visit 1
- Have T2DM and be >/=30 years of age on day of signing informed consent. Note: For India only: Subject has T2DM and is >/=30 and </=65 years of age on day of signing informed consent.
- Have moderate or severe chronic renal insufficiency as indicated by an eGFR <60 mL/min/1.73 m2. Note: Glomerular filtration rate is estimated using the Modification of Diet in Renal Disease (MDRD) formula (see Section 12.5); OR, Subject is on dialysis (hemodialysis or peritoneal dialysis) for at least 6 months on the day of signing informed consent.
- Meet one of the following criteria as indicated by a yes answer: a) Subject is currently not on an AHA (off therapy for >/=12 weeks) and has a Visit 1 A1C >/=7.0% (53 mmol/mol) and </=10.0% (86 mmol/mol); OR b) Subject is currently on a single oral AHA or low-dose dual oral combination AHA (i.e., at </=50% of maximum labeled dose of each agent) and has a Visit 1 A1C of >/=6.5% (48 mmol/mol) and</=9.0% (75 mmol/mol); OR c) Subject is currently on a stable insulin regimen, at a dose of at least 15 U/day, for >/=10 weeks, with no oral AHA, and has a Visit 1 A1C >/=7.5% (58 mmol/mol) and </=10.0% (86 mmol/mol) and FPG >130 mg/dL (7.22 mmol/L). Subjects may be receiving pre-mixed (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30®), intermediate-acting (e.g., NPH), or long-acting (e.g., glargine, detemir, degludec) insulin therapy. Pre-meal short-acting (e.g., regular insulin) or rapid- acting (e.g., lispro aspart, glulisine) insulins are not allowed. Note: a stable insulin regimen is defined as all daily doses within 10% of a usual administered daily dose (i.e., if usual daily dose is 50 U/day, doses 45-55 U/day would be considered as stable).
- Meets one of the following criteria:
a. Subject is a male;
b. Subject is a female not of reproductive potential defined as one who has either:
(1) reached natural menopause (defined as >/=12 months of spontaneous amenorrhea in women >45 years of age, or >/=6 months of spontaneous amenorrhea with serum follicular stimulating hormone [FSH] levels in the postmenopausal range as determined by the laboratory), or
(2) had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to screening.
c. Subject is a female of reproductive potential and:
(1) agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control), or
(2) agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 28 days after the last dose of blinded study medication. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
- Use of one of the following double-barrier methods: diaphragm with spermicide and a condom; cervical cap and a condom; or contraceptive sponge and a condom.
- Use of hormonal contraception (any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intrauterine device (IUD).
- Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge; vasectomy; or hormonal contraception.
- Vasectomy with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception - Understand the trial procedures, alternative treatments available, and risks involved with the trial and voluntarily agrees to participate by giving written informed consent. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
At Visit 3/Week -2
- Have an eGFR(using MDRD formula)<60 mL/min/1.73 m2.
- Meet one of the following criteria measured at or within 2 weeks prior to Visit 3/Week -2 as indicated by a yes answer:
a) Subject not on an AHA or washed-off from AHA therapy has A1C >/=7.0% (53 mmol/mol) and </=10.0% (86 mmol/mol).
b) Subject on insulin monotherapy at screening has A1C >/=7.5% (58 mmol/mol) and </=10.0% (86 mmol/mol) and FPG >130 mg/dL (7.22 mmol/L).
Note: Once a subject has initiated placebo run-in at Visit 3/Week -2, if the Visit 3 A1C is not within the Visit 3 A1C inclusion criterion, a single repeat measurement may be performed at the discretion of the investigator. If the repeat value meets Visit 3 A1C inclusion criterion, the subject may continue in the trial.
At Visit 4/Day 1 Randomization
- Must be 100% compliant with MK-3102 matching placebo study medication during the single-blind placebo run-in(as determined by site-performed capsule count). |
En la visita 1:
-Tener DMT2 y >/=30 años de edad el día de la firma del consentimiento informado. Nota: En la India solamente: El sujeto tiene DMT2 y >/=30 pero </=65 años de edad el día de la firma del consentimiento informado.
-Tener insuficiencia renal crónica moderada o severa a juzgar por una TFGe <60 mL/min/1.73 m2. Nota: La tasa de filtración glomerular se calcula con la fórmula del estudio MDRD (Modification of Diet in Renal Disease; véase la sección 12.5); O BIEN, estar en diálisis (hemodiálisis o diálisis peritoneal) desde como mínimo 6 meses antes del día de la firma
del consentimiento informado.
-Cumplir por lo menos uno de los siguientes criterios (respuesta afirmativa):
a)El sujeto no está actualmente en tratamiento con un AHG (desde >/=12 semanas antes) y presenta en la visita 1 una A1C >/=7.0 % (53mmol/mol) y </=10.0 % (86 mmol/mol); O BIEN
b)El sujeto está actualmente en tratamiento con un AHG oral único o con dos AHG orales en dosis bajas (es decir, con </=50 % de la dosis máxima recogida en la ficha técnica de cada fármaco) y presenta en la visita 1 una A1C >/=6.5 % (48 mmol/mol) y </=9.0 % (75 mmol/mol); O BIEN
c)El sujeto está actualmente en tratamiento insulínico estable, con una dosis de al menos 15 U/día, desde hace >/=10 semanas, sin AHG orales, y presenta en la visita 1 una A1C >/=7.5 % (58 mmol/mol) y </=10.0 % (86 mmol/mol) y una GPA >130 mg/dL (7.22 mmol/L). El sujeto podría estar recibiendo tratamiento con premezcla insulínica (por ejemplo, Novolog 70/30®, Novolin 70/30®, Humalog 75/25® o Humulin 70/30®), insulina de acción intermedia (por ejemplo, NPH) o insulina de acción prolongada (por ejemplo, glargina, detemir, degludec). No se permite el uso de insulinas preprandiales de acción corta (por ejemplo, insulina regular) o de acción rápida (por ejemplo, lispro aspart, glulisina). Nota: se define como tratamiento insulínico estable aquel en que todas las dosis diarias administradas difieren en menos del 10 % de
la dosis diaria administrada habitualmente (por ejemplo, si la dosis diaria habitual es de 50 U/día, unas dosis de 45 55 U/día se considerarían estables).
-Cumplir uno de los siguientes criterios:
-El sujeto es un varón;
-El sujeto es una mujer que no es potencialmente fértil, definida como aquella que:
(1)ha alcanzado la menopausia natural (definida como >/=12 meses de amenorrea espontánea en las mujeres >45 años de edad, o >/=6 meses de amenorrea espontánea con concentraciones séricas de hormona foliculoestimulante [FSH] en el intervalo posmenopáusico según el laboratorio), o
(2)ha sido sometida a histerectomía y/u ovariectomía bilateral, o ligadura u oclusión bilateral de trompas como mínimo 6 semanas antes de la selección.
c. El sujeto es una mujer potencialmente fértil y:
(1)se compromete a abstenerse de actividad heterosexual (si las autoridades sanitarias y los comités éticos locales aceptan esta forma de control anticonceptivo como único método anticonceptivo), o
(2)se compromete a utilizar (o hacer que su pareja utilice) métodos anticonceptivos aceptables para prevenir el embarazo a lo largo de la duración prevista del ensayo y los 28 días siguientes a la última dosis de la medicación enmascarada del estudio. Se usarán dos métodos anticonceptivos para evitar el embarazo. Las combinaciones de métodos aceptables son:
Uso de uno de los siguientes métodos de doble barrera: diafragma con espermicida y preservativo; capuchón cervical y preservativo; o esponja anticonceptiva y preservativo.
Uso de anticoncepción hormonal (cualquier anticonceptivo registrado y comercializado que contenga un estrógeno y/o un gestágeno [incluidos productos orales, subcutáneos, intrauterinos e intramusculares y en parches cutáneos]) con uno de los siguientes: diafragma con espermicida; capuchón cervical; esponja anticonceptiva; preservativo; vasectomía; o dispositivo intrauterino (DIU). Uso de un DIU con uno de los siguientes: preservativo; diafragma con espermicida; esponja anticonceptiva; vasectomía; o anticoncepción hormonal (véase anteriormente).
Vasectomía con uno de los siguientes: diafragma con espermicida; capuchón cervical; esponja anticonceptiva; preservativo; DIU; o anticoncepción hormonal (véase anteriormente).
-Comprender los procedimientos del ensayo, los tratamientos alternativos disponibles y los riesgos que puede suponer el ensayo, y aceptar voluntariamente participar otorgando su consentimiento informado por escrito. El sujeto también puede otorgar su consentimiento para la futura investigación biomédica. No obstante, un sujeto podrá participar en el ensayo principal sin participar en la futura investigación biomédica.
En la visita 3/semana -2
-Presentar una TFGe (con la fórmula del estudio MDRD) <60mL/min/1.73 m2.
Por favor, vean el resto en el protocolo sección 5.1.3 |
|
| E.4 | Principal exclusion criteria |
- Has a history of T1DM or a history of ketoacidosis, OR is assessed as possibly having T1DM confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L).
- Has been treated with any incretin mimetic or TZD within the prior 12 weeks of Visit 1/screeningor with MK-3102 at any time prior to signing informed consent.
- Has a history of hypersensitivity to a DPP-4 inhibitor.
- Is currently participating, or has participated, in a trial in which the subject received an investigational compound or used an investigational device within the prior 12 weeks of signing ICF
- Has a history of intolerance or hypersensitivity or other contraindication to glipizide (ONLY for subjects who are not on background therapy with insulin). Note: Subjects with severe chronic renal insufficiency or ESRD are allowed to take glipizide in this trial, except if prohibited by the local regulatory authority or ethics committee overseeing the investigational site. OR Has a history of intolerance or hypersensitivity to insulin glargine or any contraindication to insulin glargine based upon the label in the country of the investigational site.
- Is on a weight loss program and is not in the maintenance phase, or has been on a weight loss medication in the past 6 months or has undergone bariatric surgery within 12months prior to signing the ICF.
- Has undergone a surgical procedure within 4weeks prior to signing ICF or has planned major surgery during the trial.
- Is on or likely to require treatment for >/=14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
- Is currently being treated for hyperthyroidism or is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks.
- Is currently on or likely to require treatment with a prohibited medication
- If subject is on dialysis and does not regularly adhere to dialysis schedule.
- Has a diagnosis of CHF with NYHA Class IV
- Has a medical history of active liver disease or symptomatic gallbladder disease.
- Has HIV as assessed by medical history.
- Has had new or worsening signs or symptoms of CHD or CHF within the past 3 months
- Has poorly controlled hypertension.
- Has severe active peripheral vascular disease
- Has a history of malignancy </=5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
- Has a clinically significant hematological disorder
- Has exclusionary laboratory values as listed in the protocol
- Has a positive pregnancy test.
- Is pregnant or breast-feeding, or is expecting to conceive during the trial, including 28 days following the last dose of blinded study medication, OR Is expecting to undergo hormonal therapy in preparation to donate eggs during the period of the trial, including 28 days following the last dose of blinded study medication.
- Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history of drug abuse OR subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking.
- Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that makes participation not in the subject´s best interest, might interfere with the subject´s participation for the full duration of the trial, or might confound the results of the trial.
- Is unlikely to adhere to the trial procedures, keep appointments, or is planning to relocate during the trial.
- Has a FPG consistently >260 mg/dL (14.43 mmol/L) and is not considered likely to improve glycemic control with diet and exercise counseling.
- Has a clinically significant ECG abnormality
- Has a FPG consistently >260 mg/dL (14.43 mmol/L).
- Has symptomatic hyperglycemia that, in the investigator´s opinion, requires immediate initiation, adjustment, or addition of antihyperglycemic therapy.
- Has poorly controlled hypertension defined as a systolic blood pressure of >/=160 mmHg or diastolic blood pressure of >/=90 mmHg.
- Is on lipid-lowering medication or thyroid replacement therapy, and has not been on a stable regimen for the 4 weeks (lipid-lowering medication) or 6 weeks (thyroid replacement therapy) prior to Visit 4/Day 1. - Has a site FFSG of <130 mg/dL (7.22 mmol/L) or >260 mg/dL (14.43
mmol/L).
- Has symptomatic hyperglycemia that, in the investigator's opinion,requires immediate initiation, adjustment, or addition of antihyperglycemic therapy.
- Has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory abnormality or ECG abnormality, or required a new treatment or medication during the pre-randomization period which meets any previously described trial exclusion criteria or which, in the opinion of the investigator, exposes
the subject to risk by enrolling in the trial. |
-Antecedentes de diabetes mellitus de tipo 1 o antecedentes de cetoacidosis.O El investigador considera que el sujeto tiene
posiblemente una diabetes de tipo 1, confirmada por un péptido C <0.7 ng/mL (0.23 nmol/L).
-Ha sido tratado con algún incretinomimético o TZD en las 12 semanas previas a la V 1/selección, o con MK-3102 en cualquier momento antes de la firma del consentimiento informado.
-Antecedentes de hipersensibilidad a un inhibidor de la DPP-4.
-Está participando actualmente o ha participado en otro ensayo en el que ha recibido un fármaco en investigación o ha utilizado un producto sanitario en investigación en el plazo de las 12 semanas previas a la firma del consentimiento informado
-Antecedentes de intolerancia, hipersensibilidad o cualquier otra contraindicación a la glipizida (SOLO en el caso de los sujetos que no reciban tratamiento de fondo con insulina). Nota: En este ensayo, se permite tomar glipizida a los sujetos con insuficiencia renal crónica severa o nefropatía terminal, excepto si lo prohíben las autoridades sanitarias locales o el comité ético a cargo de la supervisión del centro de investigación O Antecedentes de intolerancia o hipersensibilidad a la
insulina glargina o cualquier contraindicación a la insulina glargina según la ficha técnica del país en el que se encuentra el centro de investigación.
-Está participando en un programa de adelgazamiento y no se encuentra en fase de mantenimiento; o ha estado recibiendo medicación para adelgazar en los últimos 6 meses; o se ha sometido a cirugía bariátrica en los 12 meses previos a la firma del consentimiento informado.
-Se ha sometido a un procedimiento quirúrgico en las 4 semanas previas a la firma del consentimiento informado o tiene programada una intervención quirúrgica mayor durante el ensayo.
-Está recibiendo o es probable que precise tratamiento durante >/=14 días consecutivos o ciclos repetidos de corticosteroides en dosis farmacológicas.
-Actualmente en tratamiento por hipertiroidismo o está en tratamiento tiroideo sustitutivo y no ha logrado mantenerse con una dosis estable durante como mínimo 6 semanas.
-Recibe actualmente o es probable que precise tratamiento con un medicamento prohibido.
-se encuentra en diálisis, no cumple con regularidad el calendario de diálisis.
-Diagnóstico de insuficiencia cardiaca congestiva de clase IV
-Antecedentes de enfermedad hepática activa, incluidas las hepatitis B o C crónicas activas (según su historia clínica), cirrosis biliar primaria o colecistopatía sintomática.
-Portador del VIH, según su historia clínica.
-Signos o síntomas nuevos o en deterioro de cardiopatía coronaria o de insuficiencia cardiaca congestiva en los 3 últimos meses
-Hipertensión mal controlada
-Vasculopatía periférica activa severa.
-Antecedentes de neoplasia maligna </=5 años antes de la firma del consentimiento informado, con excepción del carcinoma cutáneo basocelular o espinocelular o el cáncer de cuello uterino in situ adecuadamente tratados.
-Trastorno hematológico clínicamente importante.
-Valores de los parámetros analíticos enumerados en el protocolo, que no permiten su participación en el estudio.
-Prueba de embarazo positiva.
-La sujeto está embarazada o en periodo de lactancia materna o tiene intención de concebir durante el ensayo, incluidos los 28 días siguientes a la última dosis de la medicación enmascarada del estudio.O Tiene previsto iniciar un tratamiento hormonal como preparación para la donación de óvulos durante el periodo del ensayo, incluidos los 28 días siguientes a la última dosis de la medicación enmascarada del estudio
-Consume drogas o las utiliza con fines recreativos en el momento de la firma del consentimiento informado, o tiene antecedentes recientes de drogadicción, O el sujeto consume habitualmente >2 bebidas alcohólicas al día o >14 bebidas alcohólicas a la semana, o presenta intoxicaciones etílicas agudas.
-Antecedentes o indicios de cualquier proceso, tratamiento, anomalías analíticas u otra circunstancia que hace que su participación no sea lo mejor para el sujeto, pueda interferir en la participación del sujeto a lo largo de todo el ensayo, pueda confundir los resultados del ensayo.
-No es probable que cumpla los procedimientos del ensayo o que acuda a las citas, o tiene previsto cambiar de domicilio durante el ensayo.
-GPA uniformemente >260 mg/dL (14.43 mmol/L) y no se considera probable que vaya a mejorar el control glucémico con las recomendaciones sobre dieta y ejercicio.
-Anomalía ECG clínicamente importante
-Hiperglucemia sintomática que, en opinión del investigador, precisa de inmediato el inicio, el ajuste o la adición de tratamiento antihiperglucemiante.
-Hipertensión mal controlada, lo que se define por una presión arterial sistólica >/=160 mm Hg o una diastólica >/=90 mm Hg.
Por favor, vean el resto en el protocolo sección 5.1.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Change from baseline in A1C at Week 24 |
| -Cambio de la A1C en la semana 24 con respecto al valor basal |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in A1C at Week 54
- Change from baseline in FPG at Week 24/Week 54 |
- Cambio de la A1C en la semana 54 con respecto al valor basal
- Cambio de la GPA en la semana 24/semana 54 con respecto al valor basal |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 24 and 54 |
| Semanas 24 y 54 |
|
| 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 | No |
| 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) | 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 | 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) | Yes |
| 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
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Canada |
| Croatia |
| European Union |
| Hong Kong |
| Israel |
| Malaysia |
| Mexico |
| Philippines |
| Russian Federation |
| Serbia |
| South Africa |
| Turkey |
| 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
|
| LVLS |
| Última Visita Último Paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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