A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases

Официальное название

Bayesian Pragmatic Trial for Pubertal Induction in Turner Syndrome: TRansformation Initiative For Efficient Clinical TriAl Design Advancement in RarE Diseases (TRIFECTA-DARED Framework)

Обзор

Turner syndrome is a condition in which a girl's body does not make enough estrogen on its own, so doctors give estrogen to help start breast and uterine (womb) development. Hence, the goal of this clinical trial is to learn whether two different ways of giving estrogen help girls and young women with Turner syndrome go through puberty normally, and to compare how well each method works and how safe they are. The main questions the trial aims to answer are: 1. Does taking an oral estrogen tablet (Progynova) or applying an estrogen gel (Oestrogel) lead to better breast development? 2. Does one method lead to a larger uterine size as seen on ultrasound? 3. Do participants start menstrual-like (withdrawal) bleeding, and does one method cause it sooner? 4. What side effects (for example, headaches, nausea, changes in blood tests) happen with each method? Who can take part? * Girls and young women aged 11-30 years with a confirmed diagnosis of Turner syndrome and no previous estrogen treatment. * They have not yet begun puberty (no breast growth, and a small uterus on ultrasound). * They agree to adhere to the study schedule and keep a diary of any bleeding or side effects What will happen to the participants during the clinical trial? * Get assigned at random to one of two groups (1:1 ratio): 1. Gel group: Apply Oestrogel (17β-estradiol) to the skin, starting twice a week, then daily with increasing doses over 19 months. 2. Tablet group: Swallow Progynova (estradiol valerate) tablets, starting twice a week, then daily with increasing doses over 19 months. * Visit the clinic at the start of study (baseline), month 1, 7, 13, and 19 for: 1. A physical exam (including breast staging). 2. An ultrasound to measure uterine length and thickness. 3. A blood test for safety checks (triglycerides and other markers). 4. Keep a diary noting any spotting or bleeding (called withdrawal bleeding) and any side effects. Why does this matter? Girls and young women with Turner syndrome often need estrogen to begin puberty safely. This trial will show which method-gel or tablets-best mimics natural puberty (breast and uterine growth), how quickly menstrual-like bleeding begins, and which has fewer unwanted effects. The findings will help doctors choose the most effective and safe treatment for people with Turner syndrome.

Подробное описание

Turner syndrome (TS) is a chromosomal condition in which the loss of one X chromosome leads to ovarian failure, absent or delayed natural puberty, reduced bone density, and elevated cardiovascular and metabolic risk. This interventional, Bayesian Phase II pragmatic trial is being undertaken within the TRIFECTA-DARED framework to address a critical gap in the management of pubertal induction for adolescent and young adult females with TS. While estrogen replacement therapies are standard, there remains uncertainty about which regimen best approximates natural pubertal development, optimizes uterine growth, and minimizes adverse metabolic or thromboembolic risks. Our trial arises from the need for robust, locally generated evidence in Malaysia to inform clinical practice in this rare-disease context.

This single-centre study, conducted at Hospital Canselor Tuanku Muhriz (HCTM) and Hospital Pakar Kanak-Kanak at the Cheras Campus of Universiti Kebangsaan Malaysia, received ethics approval from the Universiti Kebangsaan Malaysia Research Ethics Committee (UKMREC). The trial design uses an open-label, randomized,1:1 ratio design, augmented by matched historical control data. After providing informed consent, participants are allocated by a central, computer-generated sequence (stratified by age category and body mass index) to receive either oral estradiol valerate (Progynova) or transdermal 17β-estradiol gel (Oestrogel). Treating clinicians and participants remain unblinded, while the trial statistician is masked until the database lock.

Both regimens begin with twice-weekly dosing for the first four weeks, followed by once-daily administration for the remaining 18 months. Incremental dose doubling at month 7 and again at month 13 is designed to mimic the gradual rise in endogenous estradiol characteristic of normal puberty. Doses are dispensed and tracked through an electronic case report form (eCRF) with real-time logging of medication issuance and returns, and participants maintain a daily diary to record dosing adherence, any spotting or bleeding episodes, and all adverse experiences.

Scheduled study visits occur at baseline and at months 7, 13, and 19, with quarterly safety check-ins during the first year. At each visit, a pediatric or adolescent gynecologist performs a comprehensive physical examination-including growth measurements, vital signs, and breast development staging-and obtains a transabdominal ultrasound to document uterine dimensions. Blood samples are drawn for routine safety laboratories (liver function, lipid profile, complete blood count) and hormone assays.

Safety oversight is provided by an independent Data Monitoring Committee (DMC), which reviews periodic safety reports prepared by an external statistician. Adverse events are graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Any life-threatening or disabling event associated with the study drug triggers immediate notification to the ethics committee and regulatory authorities within 24 hours; other Grade 3 or higher events are reported within five business days. Prespecified halting criteria include unexplained severe laboratory abnormalities, life-threatening reactions deemed drug-related, or anaphylactic-type responses within 24 hours of dosing.

All data are captured in a secure REDCap eCRF with built-in validation and audit trails. Concomitant medications are coded using the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC ) classification system, and adverse events use MedDRA terminology. The database is backed up daily across multiple secure servers and locked after each monitoring visit. Quality assurance involves internal audits every six months by the sponsor, all in accordance with Good Clinical Practice (GCP) standards.

Data analysis follows an intention-to-treat framework with multiple imputation for missing values and sensitivity checks in a per-protocol subset. Although specific outcome measures are recorded elsewhere, continuous and categorical data will be analyzed using appropriate statistical models. In addition, Bayesian hierarchical modelling will be carried out to incorporate informative priors derived from matched historical TS cohorts, yielding posterior estimates of treatment effects and enabling predictive checks, thus providing robust inference despite the small sample inherent to this rare-disease study.

The trial is registered on ClinicalTrials.gov and the Malaysian National Medical Research Registry. Aggregate results will be posted within six months of study completion and disseminated through peer-reviewed publications and conference presentations following International Committee of Medical Journal Editors (ICMJE) authorship guidelines.

Вмешательства

• Препарат Oral estradiol valerate
  Progynova is an oral hormone replacement therapy containing the active ingredient estradiol valerate, a synthetic ester of 17β-estradiol that, upon ingestion, is rapidly converted to bioidentical estradiol. Each film-coated tablet delivers either 1 mg or 2 mg of estradiol valerate, with inactive excipients including lactose monohydrate, maize starch, povidone, magnesium stearate, and hypromellose. In terms of pharmacokinetics, oral estradiol valerate undergoes first-pass metabolism in the liver,
• Препарат Transdermal 17β estradiol
  Oestrogel® is a transdermal hormone replacement therapy containing 17β-estradiol in a hydroalcoholic gel formulation designed for topical application. Each pump actuation delivers 0.75 mg of estradiol in a 1.25 g dose of gel, which is formulated with excipients including ethanol, propylene glycol, carbomer, sodium hydroxide, and purified water to ensure consistent hormone release and skin penetration. Upon application to intact skin-typically the forearm or thigh-the gel allows for direct system

Первичные конечные точки

• Proportions of Turner Syndrome with Satisfactory Breast Development (defined as Turner Breast Stage 3 (B3) and above) [Срок оценки: From enrollment (baseline) to 19 months after the commencement of intervention (end of follow-up)]
• Median time to achieving Tanner Breast Stage 4 (B4) and above (in days) [Срок оценки: From enrollment to 19 months after the commencement of interventions (end of follow-up)]
• Uterine length (in cm) [Срок оценки: From enrollment to 19 months after the commencement of interventions (end of follow-up)]
• Anteroposterior uterine fundal diameter (in cm) [Срок оценки: From enrollment to 19 months after the commencement of intervention (end of follow-up)]

Вторичные конечные точки (3)

• Proportions of TS subjects achieving self-reported withdrawal bleeding (defined as spotting or bleeding episodes that occur at least for one day) during the treatment with Progynova or Oestrogel regimen [Срок оценки: From enrollment to 19 months after the commencement of intervention (end of follow-up)]
• Median time to withdrawal bleeding (in days) [Срок оценки: From enrollment to 19 months after the commencement of intervention (end of follow up)]
• Serum Triglyceride levels (in mmol/L) [Срок оценки: From enrollment to 19 months after the commencement of intervention (end of follow-up)]

Критерии участия

Критерии включения

• Females aged 11-30 years old with karyotype-verified (45, X or other similar karyotypes) and clinically confirmed Turner's syndrome prior at the time of pubertal induction
• Confirmed estrogen deficiency with primary ovarian failure (high level of follicular stimulating hormone (FSH > 25 IU/L))
• Patients who have not undergone pubertal development ( no breast development and underdeveloped uterus size).
• Hormone Replacement Therapy (HRT)-naive TS patients
• Breast Tanner Stage of 2 or less.
• Patients on Growth Hormone (GH) will be allowed entry into the study.
• Consented to trial participation (from individual TS patients (if aged 18 and above) or the parents or guardians (for under-18 TS patients) with individual's assent

Критерии исключения

• Patients with signs of spontaneous puberty
• Contraindications to trial products (e.g hypersensitivity to any components of the HRT) based on the most recent version of the British National Formulary (BNF 85)
• Previous history of exposure to estrogen treatment.
• Concomitant use of other drugs that affect the bone mineral density (BMD) of the participants (e.g. Bisphosphonates or prolonged use of systemic corticosteroids). Vitamin D supplementation and short corticosteroid usage are allowed.
• Acute or chronic hepatic disease
• Patients with untreated hypothyroidism
• Inflammatory bowel disease (Ulcerative Colitis, Crohn's disease) and coeliac disease
• Cigarette-smoking patients
• Severely obese patients based on the following criteria:

• For TS patients aged 11-17 years old: Based on the WHO chart with BMI > 95th percentile
• For TS patients aged 18 years until 30 years: BMI of 37.5 or above based on the Malaysian Clinical Practice Guideline for the Management of Obesity
• Unknown abnormal genital bleeding
• Porphyria
• Recent involvement with clinical research studies (previous 6 months) investigating new HRT formulations

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Малайзия · 1 центр

• Hospital Canselor Tuanku Muhriz (HCTM) — Cheras

Идентификаторы

NCT: NCT07041814 · GUP-2024-011 · NMRR ID-25-02169-7TA

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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