Towards a treatment for accelerated maturation in girls testing spiomet.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospital Universitari De Girona Doctor Josep Trueta

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Female

Therapeutic area

Phenomena and Processes [G] - Physiological processes [G07]

Trial duration

2 Dec 2022 → ongoing

Decision date (initial)

2024-10-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Instituto de Salud Carlos III

External identifiers

EU CT number

2024-518675-55-00

EudraCT number

2021-006766-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Efficacy

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).

Secondary objectives 4

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)

Conditions and MedDRA coding

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

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age at baseline: 8,0 ≤ age ≤ 9,5 years
2. Birth weight for gestational age (BW-GA) in lower tertile: -2,5 ≤ PN-EG Z-score ≤ 0
3. Body mass index for chronological age at 1st visit in upper tercile: +0 ≤ BMI Z-score ≤ +2,5
4. Progressive advanced puberty [bilateral breast development (Tanner stage 2)] of onset between 7,7 and 9,3 years, with a minimum of 2 months progression
5. White ethnicity
6. Term or late preterm pregnancy: 34 ≤ gestational age < 42 weeks
7. Height at 1st visit: 3rd percentile ≤ height ≤ 97th percentile (adjusted for pubertal stage)
8. Written informed consent of parents or legal guardian.

Exclusion criteria 10

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 +2,5 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, antiandrogens, 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.
9. Previous history of hypersensitivity to any of the medicinal products used in the clinical trial, or to their excipients.
10. Any disease which, in the opinion of the investigator, compromises the inclusion of the subject in the clinical trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 5

1. 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.
2. 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, HMWadiponectin, CXCL14].
3. 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.
4. Abdominal fat distribution (subcutaneous and visceral area) and liver fat: distribution of abdominal fat and intrahepatic fat shall be analysed by MRI.
5. Additional secondary outcomes: 1) Dietary habits; 2) Tablet acceptability; 3) Adherence study; 4) Adverse events report.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospital Universitari De Girona Doctor Josep Trueta

Sponsor organisation

Hospital Universitari De Girona Doctor Josep Trueta

Address

Avinguda De Franca S/n

City

Girona

Postcode

17007

Country

Spain

Scientific contact point

Organisation

Hospital Universitari De Girona Doctor Josep Trueta

Contact name

Abel López Bermejo

Public contact point

Organisation

Hospital Universitari De Girona Doctor Josep Trueta

Contact name

Abel López Bermejo

Third parties 4

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications