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.
