E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypoglycemia associated with congenital hyperinsulinism |
Hipoglucemia asociada a hiperinsulinismo congénito |
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E.1.1.1 | Medical condition in easily understood language |
Low blood glucose levels associated with abnormally high level of insulin due to a specific birth defect |
Bajos niveles de glucosa debido a niveles altos de insulina causados por un defecto de nacimiento. |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077227 |
E.1.2 | Term | Hyperinsulinemic hypoglycemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020644 |
E.1.2 | Term | Hyperinsulinism NOS |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 | 10061211 |
E.1.2 | Term | Hyperinsulinism |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022484 |
E.1.2 | Term | Insulin hypoglycaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and glycemic efficacy of multiple ascending doses of RZ358 administered for 8 weeks in patients with hyperinsulinemic hypoglycemia due to congenital hyperinsulinism (CHI). |
Los objetivos de este estudio son evaluar la seguridad, tolerabilidad, farmacocinética (FC), farmacodinámica (FD) y eficacia glucémica de dosis múltiples ascendentes de RZ358 administradas durante 8 semanas en pacientes con hipoglucemia hiperinsulínica debido al hiperinsulinismo congénito (HIC). |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provide written informed consent and, as applicable, assent, before any study specific procedures are performed 2. At Screening, aged ≥ 2 years and ≤ 45 years 3. An established clinical diagnosis, with or without a genetic diagnosis, of congenital hyperinsulinism 4. Patient is currently receiving SOC medications (i.e corticosteroids, diazoxide, lanreotide, sirolimus, and octreotide) and/or nutritional supplementation for CHI, with at least 2 months of stable treatment; OR is not on treatment, at the time of Screening. 5. Glucose values <70 mg/dL (3.9 mmol/L) for ≥ 8% of the overall monitored time and for ≥ 60 min per day on at least 5 of the 10 days of a 10-day Screening CGM evaluation 6. Hepatic ultrasound at Screening without clinically significant findings, gallstones or evidence of peliosis hepatitis 7. For female patients of childbearing potential, a negative serum or urine pregnancy test within 7 days before dosing Females of childbearing potential are defined as fertile following menarche and until becoming postmenopausal or permanently sterile. Note: Postmenopausal is defined as absence of vaginal bleeding or spotting for at least 1 year. Permanently sterile is defined as having had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 8. For female patients of childbearing potential, a willingness to use highly effective* contraceptive measures adequate to prevent a new pregnancy for the duration of the study, including for at least 105 days after receiving the last dose of study drug. For women with reproductive potential who use a hormonal method of contraception, concurrent use of a second (barrier) method is recommended. (*Highly effective methods of birth control are defined as those that result in a low failure rate [ie, less than 1% per year] when used consistently and correctly [eg, implants, injectables, oral contraceptives, some intrauterine devices, bilateral tubal occlusion, true sexual abstinence in line with the preferred and usual lifestyle of the patient, or vasectomized partner.]) 9. For sexually active males, a willingness to use highly effective* contraceptive measures, e.g. a condom, for the duration of the study, including for at least 105 days after receiving the last dose of study drug. In addition, males must agree not to donate sperm over the same study period. |
1. Proporcionar el consentimiento informado por escrito y, según corresponda, el asentimiento, antes de realizar cualquier procedimiento específico del estudio. 2. En la selección, tener ≥ 2 años y ≤ 45 años. 3. Un diagnóstico clínico establecido, con o sin diagnóstico genético, de hiperinsulinismo congénito. 4. El paciente está recibiendo actualmente medicamentos de la SOC (p. ej., diazóxido, lanreótida, sirolimus, pasireotida u octreótida) y/o suplementos nutricionales para HIC, con al menos 2 meses de tratamiento estable; O no está en tratamiento, en el momento de la selección. 5. Valores de glucosa < 70 mg/dl (3,9 mmol/l) durante ≥ 8 % del tiempo total monitorizado y durante ≥ 60 min al día durante al menos 5 de los 10 días de una evaluación de la MCG para la selección. 6. Ecografía hepática en la selección sin hallazgos clínicamente significativos, cálculos biliares o evidencia de peliosis o hepatitis. 7. Para las pacientes en edad fértil, una prueba de embarazo en suero u orina negativa en los 7 días anteriores a la dosis: Las mujeres en edad fértil se definen como fértiles después de la menarquia y hasta que se vuelvan posmenopáusicas o estériles permanentemente. (La posmenopausia se define como ausencia de hemorragia vaginal o manchas durante al menos 1 año. La esterilidad permanente se define como haber tenido una histerectomía, salpingectomía bilateral u ovariectomía bilateral). 8. En el caso de las pacientes en edad fértil, la voluntad de utilizar medidas anticonceptivas altamente eficaces* adecuadas para evitar un nuevo embarazo durante el estudio, incluidos al menos 105 días después de recibir la última dosis del fármaco del estudio. Para las mujeres con potencial reproductivo que utilizan un método anticonceptivo hormonal, se recomienda el uso simultáneo de un segundo método (de barrera). 9. Para hombres sexualmente activos, la voluntad de utilizar medidas anticonceptivas altamente eficaces*, por ejemplo, preservativo, durante el estudio, incluidos al menos 105 días después de recibir la última dosis del fármaco del estudio. Además, los hombres deben aceptar no donar esperma durante el mismo periodo del estudio. *Los métodos anticonceptivos altamente eficaces se definen como aquellos que tienen una tasa baja de fracaso (es decir, menos del 1 % al año) cuando se utilizan de forma uniforme y correcta (p. ej., implantes, inyectables, anticonceptivos orales, algunos dispositivos intrauterinos, oclusión tubárica bilateral, abstinencia sexual real en consonancia con el estilo de vida preferido y habitual del paciente o pareja vasectomizada). |
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E.4 | Principal exclusion criteria |
1. Any out-of-range laboratory value at Screening that has not been reviewed, approved, and documented as not clinically significant by the Investigator, with the exception of liver function tests for total bilirubin, ALT, AST, and ALP, which must be within 1.5X the upper limit of normal (ULN) for the reference range 2. Body mass index ≥ 35 kg/m2 for patients aged 18 years and above and, for patients aged less than 18 years, BMI ≥ 95% percentile for age 3. History of malignancy within 3 years before Screening other than carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell carcinoma of the skin 4. History of seropositivity for HIV antibody, hepatitis B, or hepatitis C antibody 5. Major general surgery within 3 months before Screening or anticipated during the study period 6. Use of systemic corticosteroids within 30 days before Screening 7. Known allergy or sensitivity to RZ358 or any component of the study drug 8. Treatment with an investigational drug or device within 30 days or 5 half-lives of the investigational drug before Day 1 of Week 1, whichever is longer. Participation in registries and purely diagnostic studies is allowed. 9. Female patients who are pregnant, planning to become pregnant during the course of the study, have recently delivered (within 3 months before Screening), or are breastfeeding 10. Male patients who are planning a pregnancy with a female partner during the course of the study or within 105 days after administration of study drug 11. Any organ condition, concomitant disease (eg, psychiatric illness, severe alcoholism, or drug abuse, cardiac, hepatic, or kidney disease), or other abnormality that itself, or the treatment of which, could interfere with the conduct of the study (eg, may affect absorption, distribution, metabolism, or elimination of the study drug) or that, in the opinion of the Investigator and/or Sponsor´s medical monitor, would pose an unacceptable risk to the patient in the study. |
1. Cualquier valor analítico fuera de intervalo en la selección que no haya sido revisado, aprobado y documentado como no clínicamente significativo por el investigador, con la excepción de las pruebas de función hepática para la bilirrubina total, alanina transaminasa (ALT), aspartato transaminasa (AST) y fosfatasa alcalina (ALP), que debe estar dentro de 1,5 veces el límite superior de la normalidad (LSN) para el intervalo de referencia. 2. Índice de masa corporal (IMC) ≥ 35 kg/m2 para pacientes de 18 años o mayores y para pacientes de menos de 18 años, IMC ≥ 95 % percentil para la edad. 3. Antecedentes de neoplasia maligna en los 3 años anteriores a la selección, excepto carcinoma in situ del cuello uterino o carcinoma de células basales no metastásico o carcinoma basocelular de la piel tratados adecuadamente. 4. Antecedentes de seropositividad para anticuerpos contra el VIH, el virus de la hepatitis B o de la hepatitis C. 5. Cirugía general importante en los 3 meses anteriores a la selección o prevista durante el periodo del estudio. 6. Uso de corticoesteroides sistémicos en los 30 días anteriores a la selección. 7. Alergia o sensibilidad conocidas a RZ358 o a cualquier componente del fármaco. 8. Tratamiento con un fármaco o dispositivo en investigación en un plazo de 30 días o 5 semividas del fármaco en investigación antes del día 1 de la semana 1, lo que sea más largo. Se permite participar en registros y estudios puramente diagnósticos. 9. Las pacientes que estén embarazadas, que planeen quedarse embarazadas durante el transcurso del estudio, hayan dado a luz recientemente (en los 3 meses anteriores a la selección) o estén en periodo de lactancia. 10. Pacientes varones que estén planeando un embarazo con una pareja femenina durante el transcurso del estudio o en los 105 días posteriores a la administración del fármaco del estudio. 11. Cualquier afección orgánica, enfermedad concomitante (p. ej., enfermedad psiquiátrica, alcoholismo grave o abuso de drogas, enfermedad cardíaca, hepática o renal) u otra anomalía que pueda interferir en la realización del estudio (p. ej., puede afectar a la absorción, distribución, metabolismo o eliminación del fármaco del estudio) o que, en opinión del investigador y/o del supervisor médico del promotor, supondría un riesgo inaceptable para el paciente en el estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Glycemic efficacy of RZ358 as evaluated by the average daily percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by continuous glucose monitoring (CGM); • Repeat-dose safety and tolerability of RZ358 administered for a total of 8 weeks; • Repeat-dose pharmacokinetics of RZ358. |
• Eficacia glucémica de RZ358 evaluada por el porcentaje medio diario de tiempo dentro de un intervalo objetivo de glucosa de 70-180 mg/dl (3,9-10 mmol/l) mediante monitorización continua de la glucosa (MCG); • Seguridad y tolerabilidad de dosis repetidas de RZ358 administradas durante un total de 8 semanas; • Farmacocinética de dosis repetidas de RZ358. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measured at various timepoints (see schedule of events) |
Medidos en distintos momentos (ver el esquema de visitas y procedimientos) |
|
E.5.2 | Secondary end point(s) |
• Average daily duration and percent time with hypoglycemia at thresholds of: < 70 mg/dL (3.9 mmol/L) < 60 mg/dL (3.3 mmol/L) < 50 mg/dL (2.8 mmol/L) by CGM
• Average daily hypoglycemia incidence (event rate) at each of the specified glucose thresholds by CGM; • Average 8h overnight percent time in glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by CGM; • Occurrence of hypoglycemia during a 12h overnight fasting challenge |
• Duración media diaria (min) y porcentaje de tiempo con hipoglucemia a umbrales de < 70, < 60 y < 50 mg/dl (3,9, 3,3 y 2,8 mmol/l, respectivamente) según MCG; • incidencia media diaria de hipoglucemia (tasa de acontecimientos) en cada uno de los umbrales de glucosa especificados por MCG; • media de porcentaje de tiempo de 8 horas de la noche en el intervalo objetivo de glucosa de 70-180 mg/dl (3,9-10 mmol/l) según MCG; • aparición de hipoglucemia durante un estímulo nocturno de ayuno de 12 horas. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measured at various timepoints (see schedule of events) |
Medidos en distintos momentos (ver el esquema de visitas y procedimientos) |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
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 | No |
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 | No |
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 | 12 |
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 |
Bulgaria |
Croatia |
Denmark |
France |
Germany |
Israel |
Netherlands |
Serbia |
Spain |
Turkey |
United Kingdom |
United States |
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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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LVLS |
Ultima visita del ultimo paciente |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |