Clinical Trials Register

Summary
EudraCT Number:	2019-002622-79
Sponsor's Protocol Code Number:	IMIB-GU-2019-02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2019-002622-79

A.3

Full title of the trial

Gestational treatment with Ursodeoxycholic Acid compared to Placebo to Reduce Severity of Gestational Diabetes Mellitus diagnosed at 24-28 weeks’ gestation

Ácido ursodesoxicólico como tratamiento novel para la diabetes gestacional/tipo 2 diagnosticada a las 24-28 semanas de gestación

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Gestational treatment with Ursodeoxycholic Acid compared to Placebo to Reduce Severity of Gestational Diabetes Mellitus diagnosed at 24-28 weeks’ gestation

Ácido ursodesoxicólico como tratamiento novel para la diabetes gestacional/tipo 2 diagnosticada a las 24-28 semanas de gestación

A.3.2

Name or abbreviated title of the trial where available

GUARDS

A.4.1

Sponsor's protocol code number

IMIB-GU-2019-02

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fundación para la Formación e Investigación Sanitarias de la Región de Murcia
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación para la Formación e Investigación Sanitarias de la Región de Murcia
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación para la Formación e Investigación Sanitarias de la Región de Murcia
B.5.2	Functional name of contact point	Lola Serna Guirao
B.5.3	Address:
B.5.3.1	Street Address	C/ Luis Fontes Pagan, 9
B.5.3.2	Town/ city	Murcia
B.5.3.3	Post code	30003
B.5.3.4	Country	Spain
B.5.4	Telephone number	34968359763
B.5.5	Fax number	34968359777
B.5.6	E-mail	lola.serna@carm.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ursofalk
D.2.1.1.2	Name of the Marketing Authorisation holder	GUY'S AND ST THOMAS' NHS FOUNDATION TRUST
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ursodeoxycholic Acid
D.3.9.1	CAS number	128-13-2
D.3.9.2	Current sponsor code	Ursodeoxycholic Acid
D.3.9.3	Other descriptive name	URSODEOXYCHOLIC ACID
D.3.9.4	EV Substance Code	SUB11389MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Gestational Diabetes Mellitus

Diabetes Mellitus Gestacional

E.1.1.1

Medical condition in easily understood language

Gestational Diabetes Mellitus

Diabetes Mellitus Gestacional

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the clinical efficacy and acceptability of UDCA as a treatment to improve glycaemic control in women identified to be at high risk of GDM at 24-28 weeks’ gestation

Evaluar la eficacia clínica y la aceptabilidad de la UDCA como tratamiento para mejorar el control glucémico en mujeres identificadas con alto riesgo de DMG a las 24-28 semanas de gestación

E.2.2

Secondary objectives of the trial

• Proportion of women requiring insulin treatment (time until treatment and total dose of insulin required)
• Glucose metabolism
• Lipid metabolism
• Biochemical analysis of maternal blood for liver function tests
• Maternal gestational weight change
• Proportion of women willing to be randomised
• To evaluate UDCA safety during pregnancy
• Mode of delivery (rates of primary & repeat CS, elective & emergency LSCS)
• Gestational age at delivery, frequency of preterm delivery
• Cord blood C-peptide, triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations
• Infant birth weight
• Neonatal morbidity
• Neonatal intensive care unit admission
• Adverse events
• Feeding at hospital discharge

• Proporción de mujeres que requieren tratamiento con insulina
• Metabolismo de la glucosa
• Metabolismo de lípidos evaluado por concentraciones de triglicéridos en sangre, colesterol total, colesterol LDL, colesterol HDL y ácidos grasos libres.
• Análisis bioquímico de la sangre materna para pruebas de función hepática
• Cambio en el peso gestacional materno
• Proporción de mujeres dispuestas a ser randomizadas
• Evaluar la seguridad de UDCA durante el embarazo
• Modo de finalización de la gestación
• Edad gestacional al momento del parto, frecuencia del parto prematuro
• En sangre de cordón umbilical se evaluará: Péptido C, triglicéridos, colesterol total, colesterol LDL, colesterol HDL y concentraciones de ácidos grasos libres
• Peso fetal al nacer infantil
• Ingreso a la unidad de cuidados intensivos neonatales
• Eventos adversos
• Alimentación al alta hospitalaria

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Women with GDM diagnosed at 24-28 weeks’ gestation in accordance with Spanish guidelines in accordance with NDDG criteria, i.e. two or more glucose concentrations (fasting: ≥ 5.8 mmol/L (105 mg/dL), 1 h: ≥10.6 mmol/L, (190 mg/dL) 2 h: ≥9.2 mmol/L (165 mg/dL), 3 h: ≥ 8.1 mmol/L (145 mg/dL)) after a standard 100g OGTT.
• Planned antenatal care at the same centre (i.e. not planning to move before delivery).

• Mujeres con DMG diagnosticada a las 24-28 semanas de gestación según las guías actuales españolas según los criterios del NDDG, es decir, dos o más concentraciones de glucosa por encima del rango (en ayunas: ≥ 5,8 mmol/l (105 mg/dl), 1 h: ≥10.6 mmol/l, (190 mg/dl) 2 h: ≥9.2 mmol/l (165 mg/dl), 3 h: ≥ 8,1 mmol/l (145 mg/dl)) después de un test de SOG con 100grs.
• Atención prenatal planificada en el mismo centro (es decir, no planea mudarse antes del parto)

E.4

Principal exclusion criteria

• Multifetal pregnancies
• Severe congenital anomaly on ultrasound
• Previous diagnosis of diabetes outside of pregnancy
• Significant pre-pregnancy comorbidities that increase risk in pregnancy, for example renal failure, severe liver disease, transplantation, cardiac failure, psychiatric conditions requiring in-patient admission (<1 year)
• Significant co-morbidity in the current pregnancy, nephropathy (estimated GFR <60ml/min), other physical or psychological conditions likely to interfere with the conduct of the study and/or interpretation of the trial results
• Not fluent in local language and absence of interpreter
• Participating in another intervention study.

• Embarazos multiples (gemelos, trillizos, etc.)
• Anomalía congénita grave en la ecografía.
• Diagnóstico previo de diabetes fuera del embarazo o durante el primer trimestre del embarazo.
• Comorbilidades significativas antes del embarazo que aumentan el riesgo de complicaciones durante el embarazo, por ejemplo, insuficiencia renal, enfermedad hepática grave, trasplante, insuficiencia cardíaca, afecciones psiquiátricas que requieren ingreso hospitalario (<1 año)
• Co-morbilidad significativa en el embarazo actual, nefropatía (GFR estimada <60 ml / min), otras afecciones físicas o psicológicas que pueden interferir con la realización del estudio y / o la interpretación de los resultados del ensayo
• No domina el idioma local y no se disponga de intérprete
• Participar en otro estudio de intervención.

E.5 End points

E.5.1

Primary end point(s)

Maternal fasting glucose concentration

Concentración materna de glucosa en ayunas

E.5.1.1

Timepoint(s) of evaluation of this end point

at 35+0-37+4 weeks

a las 35+0- 37+4 semanas

E.5.2

Secondary end point(s)

Biomedical Maternal:
1. Proportion of women requiring insulin treatment (time until treatment and total dose of insulin required)
2. Glucose metabolism assessed by:
a) verified SMBG download (7-day mean capillary glucose, fasting glucose, 1-hr post meal glucose levels)
b) continuous glucose monitoring (CGM) to assess glycaemic control (measured at two time points: at approximately 30-32 weeks and at 35-37 weeks’ gestation). This will determine the percentage time spent within target (glucose levels 3.9-7.8mmol/L) (70 - 140 mg/dl), percentage time spent above target (>7.8mmol/l (140 mg/dl) and ≥6.7mmol/l (120 mg/dl), time spent below target (≤3.8 (70 mg/dl) and ≤2.8 mmol/l (50 mg/dl)), measures of glucose variability including glucose standard variation (SD), co-efficient of variation (CV), frequency and duration of glycaemic excursions measured by the area under the curve (AUC) for the pre-specified glucose thresholds.
c) Serum concentrations of 1,5-anhydroglucitol; a novel marker of short-term glycaemia 4,43
d) HbA1c concentration; a conventional marker of medium-term glycaemia
3. Lipid metabolism assessed by blood triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations
4. Biochemical analysis of maternal blood for liver function tests (24 and 36 week samples as taken in routine clinical care), bile acids, C-reactive protein (including highly sensitive analyses). Fasting and 1 hour post-prandial samples will be taken at 35-37+4 weeks for GLP-1, FGF19, C4, individual bile acids, insulin, C-peptide and incretins. Women will be given a voucher to buy a standardised breakfast with approximately 100g carbohydrate and 50g fat.
5. Maternal gestational weight change (from randomisation to 36 weeks)
6. Proportion of women willing to be randomised
Biomedical Neonatal:
1. Mode of delivery (rates of primary & repeat CS, elective & emergency LSCS)
2. Gestational age at delivery, frequency of preterm delivery
3. Cord blood C-peptide, triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations
4. Infant birth weight (SD scores and customised birth weight percentile, proportion of large for gestational age (LGA), proportion of small for gestational age (SGA)), neonatal anthropometry
5. Neonatal morbidity (treatment for neonatal hypoglycaemia, neonatal jaundice and respiratory distress)
6. Neonatal intensive care unit admission (duration of hospital stay, highest level care)
7. Adverse events (congenital malformation, stillbirth, neonatal death within 6 weeks’ of delivery)
8. Feeding at hospital discharge (breast, bottle, both)

Biomedical Maternal:
1. Proporción de mujeres que requieren tratamiento con insulina (tiempo hasta el tratamiento y dosis total de insulina requerida)
2. Metabolismo de la glucosa evaluado por:
a) descarga SMBG verificada (glucosa capilar media de 7 días, glucosa en ayunas, niveles de glucosa 1 hora después de la comida)
b) monitoreo continuo de glucosa (CGM) para evaluar el control glucémico (medido en dos puntos de tiempo: aproximadamente a las 30-32 semanas y a las 35-37 semanas de gestación). Esto determinará el porcentaje de tiempo pasado dentro del objetivo (niveles de glucosa 3.9-7.8mmol / L) (70-140 mg / dl), porcentaje de tiempo pasado por encima del objetivo (> 7.8mmol / l (140 mg / dl) y ≥6.7mmol / l (120 mg / dl), tiempo transcurrido por debajo del objetivo (≤3.8 (70 mg / dl) y ≤2.8 mmol / l (50 mg / dl)), medidas de variabilidad de glucosa, incluida la variación estándar de glucosa (DE), coeficiente de variación (CV), frecuencia y duración de las excursiones glucémicas medidas por el área bajo la curva (AUC) para los umbrales de glucosa previamente especificados.
c) concentraciones séricas de 1,5-anhidroglucitol; un nuevo marcador de glucemia a corto plazo 4,43
d) concentración de HbA1c; un marcador convencional de glucemia a medio plazo
3. Metabolismo lipídico evaluado por triglicéridos en sangre, colesterol total, colesterol LDL, colesterol HDL y concentraciones de ácidos grasos libres
4. Análisis bioquímico de sangre materna para pruebas de función hepática (muestras de 24 y 36 semanas tomadas en atención clínica de rutina), ácidos biliares, proteína C reactiva (incluidos análisis altamente sensibles). Se tomarán muestras en ayunas y 1 hora posprandiales a las 35-37 + 4 semanas para GLP-1, FGF19, C4, ácidos biliares individuales, insulina, péptido C e incretinas. Las mujeres recibirán un cupón para comprar un desayuno estandarizado con aproximadamente 100 g de carbohidratos y 50 g de grasa.
5. Cambio de peso gestacional materno (desde la asignación al azar a 36 semanas)
6. Proporción de mujeres dispuestas a ser aleatorizadas.
Neonatal biomédico:
1. Modo de entrega (tasas de CS primario y repetido, LSCS electivo y de emergencia)
2. Edad gestacional al momento del parto, frecuencia del parto prematuro
3. Péptido C de la sangre del cordón umbilical, triglicéridos, colesterol total, colesterol LDL, colesterol HDL y concentraciones de ácidos grasos libres
4. Peso al nacer del lactante (puntajes SD y percentil personalizado del peso al nacer, proporción de grande para la edad gestacional (LGA), proporción de pequeño para la edad gestacional (SGA)), antropometría neonatal
5. Morbilidad neonatal (tratamiento de hipoglucemia neonatal, ictericia neonatal y dificultad respiratoria)
6. Ingreso a la unidad de cuidados intensivos neonatales (duración de la estancia hospitalaria, atención de nivel más alto)
7. Eventos adversos (malformación congénita, muerte fetal, muerte neonatal dentro de las 6 semanas posteriores al parto)
8. Alimentación al alta hospitalaria (mama, biberón, ambos)

E.5.2.1

Timepoint(s) of evaluation of this end point

• Recording of adverse events/side effects
• IMP compliance
• Measurement of patient height and weight
• Routine fetal growth scan
• Measurement of mean arterial pressure
• Capillary glucose measurements
• Analysis Glucose & lipids metabolism
• Liver function, bile acids, 1,5 anhydroglucitol, HbA1c and research bloods for storage

• Registro de eventos adversos / efectos secundarios.
• Cumplimiento de IMP
• Medición de la altura y el peso del paciente.
• Exploración de crecimiento fetal de rutina.
• Medición de presión arterial
• Mediciones de glucosa capilar.
• Análisis del metabolismo de la glucosa y los lípidos.
• Función hepática, ácidos biliares, 1,5 anhidroglucitol, HbA1c

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

six weeks after the birth of the baby

seis semanas después del nacimiento

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

204

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

204

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Ninguno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-15

P. End of Trial
P.	End of Trial Status	Completed

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