Clinical Trials Register

Summary
EudraCT Number:	2021-006766-21
Sponsor's Protocol Code Number:	MINI-SPIOMET
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-30
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

2021-006766-21

A.3

Full title of the trial

Towards a treatment for accelerated maturation in girls testing spiomet in a randomised placebo controlled, multicentre study.

Efectos del tratamiento con spiomet a mitad de dosis en niñas con pubertad adelantada y aceleración de la maduración ósea: estudio multicéntrico, aleatorizado y controlado con placebo.

A.3.1

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

Towards a treatment for accelerated maturation in girls testing spiomet.

Efectos del tratamiento con spiomet a mitad de dosis en niñas con pubertad adelantada y aceleración de la maduración ósea.

A.3.2

Name or abbreviated title of the trial where available

MINI-SPIOMET

A.4.1

Sponsor's protocol code number

MINI-SPIOMET

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Hospital de Girona Dr. Josep Trueta
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	Instituto de Salud Carlos III
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	Hospital de Girona Dr. Josep Trueta
B.5.2	Functional name of contact point	Dr. Abel López Bermejo
B.5.3	Address:
B.5.3.1	Street Address	Av. Francia s/n
B.5.3.2	Town/ city	Girona
B.5.3.3	Post code	17007
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34972940200

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	No
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.3.1	Product name	SPIOMET
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Yes
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	Spironolactone
D.3.9.3	Other descriptive name	Spironolactone
D.3.9.4	EV Substance Code	SUB10631MIG
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	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pioglitazone
D.3.9.1	CAS number	111025-46-8
D.3.9.4	EV Substance Code	SUB09857MIG
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	3.75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Metformin
D.3.9.1	CAS number	657-24-9
D.3.9.4	EV Substance Code	SUB08831MIG
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	425
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	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

Girls with advanced puberty and accelerated bone maturation.
Polycystic Ovary Syndrome (PCOS)

Niñas con pubertad adelantada y aceleración de la maduración ósea.
Síndrome de Ovario Poliquístico (SOPQ)

E.1.1.1

Medical condition in easily understood language

Girls with advanced puberty and accelerated bone maturation.
Polycystic Ovary Syndrome (PCOS)

Niñas con pubertad adelantada y aceleración de la maduración ósea.
Síndrome de Ovario Poliquístico (SOPQ)

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

MedDRA Classification

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	10014054
E.1.2	Term	Early puberty
E.1.2	System Organ Class	100000004860

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 determine whether a low-dose combination of generics that collectively reduce ectopic adiposity through different pathways can slow accelerated maturation in early pubertal girls with a history of low prenatal weight (resulting in reduced subcutaneous adipogenesis and reduced capacity for safe lipid storage) and high postnatal weight (resulting in more lipogenesis and more need for lipid storage).

Determinar si una combinación a dosis bajas de genéricos que reducen colectivamente la adiposidad ectópica a través de diferentes vías puede ralentizar la maduración acelerada en niñas con pubertad temprana y con antecedentes de bajo peso prenatal (lo que resulta en una adipogénesis subcutánea reducida y una capacidad reducida para el almacenamiento seguro de lípidos) y elevado peso posnatal (lo que resulta en más lipogénesis y más necesidad de almacenamiento de lípidos).

E.2.2

Secondary objectives of the trial

1) To determine whether pharmacological intervention with a low-dose combination of spironolactone, pioglitazone and metformin in a single tablet (MD-spiomet) for 1 year in girls with early puberty reduces liver and visceral fat significantly more than placebo.
2) To determine whether in girls treated with MD-spiomet, the reduction in hepatic and visceral fat is associated with 1) a greater slowing of bone maturation; 2) slower pubertal tempo (as judged by Tanner stage progression of breast development); 3) more normal levels of insulin, IGF-I, inflammatory markers, sex steroids, HMW-adiponectin, CXCL14 and GDF15; compared to girls receiving placebo.
3) To assess whether the benefits of MD-spiomet on hepato-visceral fat and endocrine-metabolic markers during treatment are still detectable one year after treatment discontinuation.
4) To assess the tolerability and safety of MD-spiomet over 1 year, as well as the acceptability of the tablet (through a specific visual questionnaire)

1) Determinar si la intervención farmacológica con una combinación a dosis bajas de espironolactona, pioglitazona y metformina en un solo comprimido (MD-spiomet) durante 1 año en niñas con pubertad temprana, reduce la grasa hepática y visceral más que el placebo, según lo evaluado por resonancia magnética.
2) Determinar si en las niñas tratadas con MD-spiomet, la reducción de la grasa hepática y visceral se asocia a 1) una mayor desaceleración de la maduración ósea; 2) un tempo puberal más lento; 3) niveles más normales de insulina, IGF-I, marcadores de inflamación, esteroides sexuales, HMW-adiponectina, CXCL14 y GDF15; en comparación con las niñas que recibieron placebo.
3) Evaluar si los beneficios de MD-spiomet sobre la grasa hepato-visceral y los marcadores endocrino-metabólicos durante el tratamiento son aún detectables un año después de la interrupción del tratamiento.
4) Evaluar la tolerancia y seguridad de MD-spiomet durante 1 año, así como la aceptación del comprimido.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age at start of study: 8.0 ≤ age ≤ 9.3 years
2.Birth weight for gestational age (BW-GA) in lower tertile: -1.96 (3rd percentile) ≤ PN-EG Z-score ≤ -0.44 (33rd percentile)
3.Body mass index for chronological age at 1st visit in upper tercile: +0,44 (66th percentile) ≤ BMI Z-score ≤ +1,96 (97th percentile) (1)
4.Progressive advanced puberty [bilateral breast development (Tanner stage 2)] onset between 7.7 and 9.0 years, with a minimum of 4 months progression
5.White ethnicity
6.Pregnancy at term: 37 ≤ gestational age < 42 weeks
7.Height at 1st visit: 3rd percentile ≤ height ≤ 97th percentile
8.Written informed consent of parents or legal guardian.

1.Edad al inicio del estudio: 8,0 ≤ edad ≤ 9,3 años
2.Peso al nacer para la edad gestacional (PN-EG) en tercil inferior: −1,96 (percentil 3) ≤ PN-EG Z-score ≤ −0,44 (percentil 33)
3.Índice de masa corporal para la edad cronológica en la 1ª visita en tercil superior: +0,44 (percentil 66) ≤ IMC Z-score ≤ +1,96 (percentil 97) (1)
4.Pubertad adelantada progresiva [desarrollo mamario bilateral (estadio 2 de Tanner)] de inicio entre los 7,7 y los 9,0 años, con un mínimo de 4 meses de progresión
5.Etnia blanca
6.Embarazo a término: 37 ≤ edad gestacional < 42 semanas
7.Talla en la 1ª visita: percentil 3 ≤ altura ≤ percentil 97
8.Consentimiento informado por escrito de progenitores o representante legal.

E.4

Principal exclusion criteria

1) Excessive delay or advancement of bone age (more than 2 years for chronological age).
A bone age radiograph taken within the previous 3 months is acceptable for screening purposes. In this case, a new bone age radiograph should be taken within one week before or after the start of treatment.
2) Tanner's stage of breast development greater than 2
3) Twin pregnancy
4) Obesity at the 1st visit (BMI Z-score above +1.96 for chronological age)
5) Evidence of a pathological cause of rapid maturation (including but not limited to: congenital adrenal hyperplasia due to 21-hydroxylase deficiency)
6) Known genetic abnormality or chronic conditions, including cardiovascular, neurological, immunological, metabolic, renal, endocrine, digestive, respiratory, or oncological diseases
7) Chronic use of medications, including but not limited to: anticoagulants, anti-inflammatory drugs, oral hypoglycaemics, anti-androgens, oestrogens, progestogens, glucocorticoids, digoxin. Only the use of paracetamol before or during the course of the study will be accepted.
8) Acute infections or intake of antibiotics or anti-inflammatory drugs within the last 14 days.
This criterion applies only to blood collections. Blood draws should be postponed for 14 days after the patient no longer has symptoms and stops taking any of these medications.

1)Retraso o adelanto excesivo de la edad ósea (más de 2 años para la edad cronológica)
De cara al cribado, se aceptará una radiografía de edad ósea realizada dentro de los 3 meses anteriores. En este caso, se deberá realizar una nueva radiografía de edad ósea dentro de la semana anterior o siguiente al inicio del tratamiento
2)Estadio de Tanner de desarrollo mamario superior a 2
3)Embarazo gemelar
4)Obesidad en la 1ª visita (Z-score del IMC por encima de +1,96 para la edad cronológica)
5)Evidencia de una causa patológica de maduración rápida (entre otros: hiperplasia suprarrenal congénita debido a deficiencia de 21-hidroxilasa)
6)Anomalía genética conocida o condiciones crónicas, incluidas enfermedades cardiovasculares, neurológicas, inmunológicas, metabólicas, renales, endocrinas, digestivas, respiratorias u oncológicas
7)Uso crónico de medicamentos, entre otros: anticoagulantes, antiinflamatorios, hipoglucemiantes orales, antiandrógenos, estrógenos, progestágenos, glucocorticoides, digoxina. Solo se aceptará el uso de paracetamol antes o durante el curso del estudio
8)Infecciones agudas o ingesta de antibióticos o antiinflamatorios en los últimos 14 días.
Este criterio se aplica únicamente a las extracciones de sangre. Las extracciones de sangre deben aplazarse 14 días después de que el paciente deje de tener síntomas y deje de tomar alguno de estos medicamentos.

E.5 End points

E.5.1

Primary end point(s)

Bone age advancement 0-1 year (X-ray of hand and wrist of the left hand) using an automated method, BoneXpert (Visiana, Denmark).

Avance de la edad osea 0-1 año (radiografía de mano y muñeca de la mano izquierda) mediante un método automatizado, BoneXpert (Visiana, Dinamarca)

E.5.1.1

Timepoint(s) of evaluation of this end point

The duration of the patient inclusion period will be 12 months. The treatment period will be 12 months with a post-treatment observation period of 18 months.

La duración del periodo de inclusión de pacientes será de 12 meses. El tiempo de tratamiento será de 12 meses siendo el periodo de observación post-tratamiento de 18 meses.

E.5.2

Secondary end point(s)

- Clinical variables: weight, height, BMI, waist and hip circumference and their ratio (incide CC), systolic arterial pressure (SAD), diastolic arterial pressure (DBP) and Tanner stage (3).
- Endocrine-metabolic variables: 1) insulinaemia [fasting glucose, insulin, HOMA-IR (5)]; 2) IGF-I; 3) gonadotropins (LH, FSH); 4) sex steroids [circulating androgens (total testosterone, androstenedione, SHBG, FAI) and oestradiol]; 5) lipids [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides]; 6) markers of inflammation, insulin sensitivity and brown adipose tissue activity [ultrasensitive C-reactive protein (usCRP), GDF-15, HMW-adiponectin, CXCL14].
- Safety markers: blood count, circulating levels of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), thyroid stimulating hormone (TSH), urea, creatinine, electrolyte panel, vitamin B12, folic acid.
- Abdominal fat distribution (subcutaneous and visceral area) and liver fat: distribution of abdominal fat and intrahepatic fat shall be analysed by MRI.
- Additional secondary outcomes: 1) Dietary habits; 2) Tablet acceptability; 3) Adherence study; 4) Adverse events report.

- Variables clínicas: peso, talla, IMC, circunferencia de cintura y cadera y su relación (íncide CC), tesión arterial sistólica (TAS), tesión arterial diastólica (TAD) y estadio de Tanner (3).
- Variables endocrino-metabólicas: 1) insulinemia [glucosa en ayunas, insulina, HOMA-IR (5)]; 2) IGF-I; 3) gonadotropinas (LH, FSH); 4) esteroides sexuales [andrógenos circulantes (testosterona total, androstenediona, SHBG, FAI) y estradiol]; 5) lípidos [colesterol total, lipoproteína de baja densidad (LDL), lipoproteína de alta densidad (HDL), triglicéridos]; 6) marcadores de inflamación, sensibilidad a la insulina y actividad del tejido adiposo pardo [proteína C reactiva ultrasensible (usCRP), GDF-15, HMW-adiponectina, CXCL14].
- Marcadores de seguridad: hemograma, niveles circulantes de alanina transaminasa (ALT), aspartato transaminasa (AST), gammaglutamiltransferasa (GGT), hormona estimulante del tiroides (TSH), urea, creatinina, panel de electrolitos, vitamina B12, ácido fólico.
- Distribución de la grasa abdominal (zona subcutánea y visceral) y grasa hepática: la distribución de la grasa abdominal y la grasa intrahepática se analizará mediante resonancia magnética.
- Resultados secundarios adicionales: 1) Hábitos dietéticos; 2) Aceptabilidad del comprimido; 3) Estudio de la adherencia; 4) Informe de eventos adversos

E.5.2.1

Timepoint(s) of evaluation of this end point

The duration of the patient inclusion period will be 12 months. The treatment period will be 12 months with a post-treatment observation period of 18 months.

La duración del periodo de inclusión de pacientes será de 12 meses. El tiempo de tratamiento será de 12 meses siendo el periodo de observación post-tratamiento de 18 meses.

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

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

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

LPLV

Última visita del último paciente

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

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

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

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

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

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

2022-09-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-20

P. End of Trial
P.	End of Trial Status	Ongoing

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