A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases
TRIFECTA-DARED
Bayesian Pragmatic Trial for Pubertal Induction in Turner Syndrome: TRansformation Initiative For Efficient Clinical TriAl Design Advancement in RarE Diseases (TRIFECTA-DARED Framework)
2 other identifiers
interventional
24
1 country
1
Brief Summary
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:
- 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):
- Gel group: Apply Oestrogel (17β-estradiol) to the skin, starting twice a week, then daily with increasing doses over 19 months.
- 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:
- A physical exam (including breast staging).
- An ultrasound to measure uterine length and thickness.
- A blood test for safety checks (triglycerides and other markers).
- Keep a diary noting any spotting or bleeding (called withdrawal bleeding) and any side effects.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_2
Started Feb 2026
Typical duration for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 19, 2025
CompletedFirst Posted
Study publicly available on registry
June 27, 2025
CompletedStudy Start
First participant enrolled
February 15, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 30, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
October 31, 2029
February 2, 2026
January 1, 2026
3.2 years
June 19, 2025
January 28, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (4)
Proportions of Turner Syndrome with Satisfactory Breast Development (defined as Turner Breast Stage 3 (B3) and above)
Tanner Staging System for Breast Development as assessed by a trained pediatric and adolescent gynaecologist specialist at Hospital Canselor Tuanku Muhriz (HCTM)'s Pediatric and Adolescent Gynaecology (PAG) Unit. Tanner Staging System has a range between Tanner Breast Stage 1 (B1) (minimum value) and Tanner Breast Stage 5 (B5) (maximum value). Each stage is classified as follows: B1: Prepubertal - no glandular tissue. Only the nipple is raised. B2: Breast bud stage - small mound forms. Areola begins to enlarge. B3: Further enlargement of the breast and areola with no separation of their contours. B4: Areola and nipple form a secondary mound above the level of the breast. B5: Mature adult breast - breast contour is smooth. The areola recedes to the general contour of the breast (although in some women, the areola may remain raised). Higher Tanner breast stage means better breast development (i.e. better outcome)
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)
Tanner Staging System for the assessment of Breast Development as assessed by the paediatric and adolescent gynaecology specialist at Hospital Canselor Tuanku Muhriz (HCTM)'s Pediatric and Adolescent Gynaecologist. Tanner Staging System has a range between Tanner Breast Stage 1 (B1) (minimum value) and Tanner Breast Stage 5 (B5) (maximum value). Each stage is classified as follows: B1: Prepubertal - no glandular tissue. Only the nipple is raised. B2: Breast bud stage - small mound forms. Areola begins to enlarge. B3: Further enlargement of the breast and areola with no separation of their contours. B4: Areola and nipple form a secondary mound above the level of the breast. B5: Mature adult breast - breast contour is smooth. Areola recedes to the general contour of the breast (although in some women areola may remain raised). Higher Tanner breast stage means better breast development (i.e. better outcome)
From enrollment to 19 months after the commencement of interventions (end of follow-up)
Uterine length (in cm)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit performed by a trained PAG Specialist (trial outcome assessor)
From enrollment to 19 months after the commencement of interventions (end of follow-up)
Anteroposterior uterine fundal diameter (in cm)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit, performed by a trained PAG Specialist (trial outcome assessor)
From enrollment to 19 months after the commencement of intervention (end of follow-up)
Secondary Outcomes (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
From enrollment to 19 months after the commencement of intervention (end of follow-up)
Median time to withdrawal bleeding (in days)
From enrollment to 19 months after the commencement of intervention (end of follow up)
Serum Triglyceride levels (in mmol/L)
From enrollment to 19 months after the commencement of intervention (end of follow-up)
Study Arms (2)
Oral Estradiol Valerate (Progynova)
ACTIVE COMPARATORProgynova 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. Progynova tablets are supplied in blister packs of 28 tablets, with recommended storage at room temperature (15-30 °C), protected from moisture and direct sunlight. In this trial, Progynova will be administered starting at 1 mg twice weekly and titrated up to 4 mg daily over an 18-month period, in accordance with local clinical guidelines for pubertal induction in Turner Syndrome.
Transdermal 17β estradiol (Oestrogel®)
EXPERIMENTALOestrogel® 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. The gel is supplied in multi-dose pump bottles (150 g), each providing up to 120 actuations. In this trial, Oestrogel® will be administered starting at one pump actuation (0.75 mg) twice weekly, with dose escalation every 3 months according to predefined protocol milestones, up to a maximum of four actuations daily (3 mg estradiol) over an 18-month induction period. Participants will be instructed on correct application technique-applying gel to clean, dry skin and allowing at least 5 minutes for drying before dressing-to ensure optimal absorption and minimize residue transfer
Interventions
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, yielding a peak serum estradiol concentration within 4-8 hours of dosing and a biological half-life of approximately 20 hours. Progynova tablets are supplied in blister packs of 28 tablets, with recommended storage at room temperature (15-30 °C), protected from moisture and direct sunlight.
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 systemic absorption of estradiol, bypassing first-pass hepatic metabolism. Peak serum estradiol levels are generally reached within 6-12 hours post-application, with a half-life of approximately 10-20 hours, resulting in more physiological, steady- steady-state estradiol exposure compared to oral formulations. The gel is supplied in multi-dose pump bottles (150 g), each providing up to 120 actuations.
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Hospital Canselor Tuanku Muhriz (HCTM)
Cheras, Kuala Lumpur, 56000, Malaysia
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD
Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)
- PRINCIPAL INVESTIGATOR
ANI AMELIA ZAINUDDIN, MBBS, PhD
FACULTY OF MEDICINE, UNIVERSITI KEBANGSAAN MALAYSIA
- PRINCIPAL INVESTIGATOR
NUR AZURAH ABDUL GHANI, MBBS, MMed (Obs and Gynae)
National University of Malaysia
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 19, 2025
First Posted
June 27, 2025
Study Start
February 15, 2026
Primary Completion (Estimated)
April 30, 2029
Study Completion (Estimated)
October 31, 2029
Last Updated
February 2, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- 01/11/2029 until 31/10/2039 (10 years)
- Access Criteria
- The general public and all researchers will have access to the IPD. The supporting information (full trial protocol and statistical analysis plan, informed consent form and case report form (CRF; English version) is available for download as separate study documents uploaded on this website.
The final and cleaned-up version of the trial dataset containing individual clinical-trial participant data (IPD) for all study variables will be deposited in a public repository such as the Harvard Dataverse data repository (available from: https://dataverse.harvard.edu/) to ensure the transparency of trial reporting and compliance with the clinicaltrials.gov data sharing policies. The preliminary trial results will first be uploaded into the clinicaltrials.gov registry within 6 months after the completion of the last patient visit for early dissemination of trial results. The final trial findings (including trial objectives, the design of the trial (including revisions), the statistical analysis plan (including amendments) and the originally planned measurements of efficacy and safety parameters) will then be published as presentations at scientific conferences and in a complete published manuscript, even if the trial has to be prematurely halted.