Turner SyndromePhase 2TRIFECTA-DAREDNCT07041814
A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases
A Phase 2 study testing Oral estradiol valerate and Transdermal 17β estradiol in people with Turner Syndrome, run by Universiti Kebangsaan Malaysia Medical Centre at 1 site in Malaysia.
Trial 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… Read more about this study
- Who is it for?
- Ages 11 to 30 years, women only
- Conditions the study is for
- Turner Syndrome
- What is being tested?
- Oral estradiol valerate and Transdermal 17β estradiol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteMalaysia
- Study dates
- 15 Feb 2026to 31 Oct 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 11 to 30 years
- Women only
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD contact
Malaysia1 site
Hospital Canselor Tuanku Muhriz (HCTM)
Cheras, Kuala Lumpur, 56000
ANI AMELIA ZAINUDDIN, MBBS, PhD, +60391455950 ext. +60193882078, aniamelia@ukm.edu.my
MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD, +60391456321 ext. +60172107299, irfan.abduljalal@ukm.edu.my
About this study
Official title: Bayesian Pragmatic Trial for Pubertal Induction in Turner Syndrome: TRansformation Initiative For Efficient Clinical TriAl Design Advancement in RarE Diseases (TRIFECTA-DARED Framework)
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:
Read more
- Does taking an oral estrogen tablet (Progynova) or applying an estrogen gel (Oestrogel) lead to better breast development?
- Does one method lead to a larger uterine size as seen on ultrasound?
- Do participants start menstrual-like (withdrawal) bleeding, and does one method cause it sooner?
- 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):
- 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.
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.
Read the detailed description
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.
- Conditions
- Turner Syndrome
- Being tested
- Oral estradiol valerate, Transdermal 17β estradiol
- Keywords
- Turner Syndrome, Hormone Replacement Therapy, Progynova, Oestrogel, Transdermal 17β Estradiol, Estradiol Valerate, Pubertal Induction
- Medical subject headings
- Turner Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral estradiol valerateDrug
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.
Transdermal 17β estradiolDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Oral Estradiol Valerate (Progynova) | Active comparator | 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. 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. Receives: Drug: Oral estradiol valerate |
| Transdermal 17β estradiol (Oestrogel®) | Experimental | 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. 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 Receives: Drug: Transdermal 17β estradiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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
Self-reported by patients through documentation in a personal diary
Measured: From enrollment to 19 months after the commencement of intervention (end of follow-up)
Median time to withdrawal bleeding (in days)
The exact number of days of the time from the commencement of intervention until the occurrence of the first withdrawal bleeding. The occurrence of the first withdrawal bleeding is self-reported by patients through documentation in a personal diary. Withdrawal bleeding is defined as the occurrence of at least spotting (defined as bloody discharge that requires not more than a panty liner) based on Zhang and colleagues' criteria (reference 36)
Measured: From enrollment to 19 months after the commencement of intervention (end of follow up)
Serum Triglyceride levels (in mmol/L)
Serum triglyceride level of the participant as reported by the laboratory based on the blood samples taken during the follow-ups at the PAG unit of HCTM.
Measured: From enrollment to 19 months after the commencement of intervention (end of follow-up)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2025
- Study start15 Feb 2026 (estimated)
- Primary completion30 Apr 2029 (estimated)
- Study completion31 Oct 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Turner SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universiti Kebangsaan Malaysia Medical Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD, Study chair, Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)ANI AMELIA ZAINUDDIN, MBBS, PhD, Principal investigator, FACULTY OF MEDICINE, UNIVERSITI KEBANGSAAN MALAYSIANUR AZURAH ABDUL GHANI, MBBS, MMed (Obs and Gynae), Principal investigator, National University of Malaysia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07041814
- Sponsor's protocol ID
- GUP-2024-011
- Other IDs
- NMRR ID-25-02169-7TA
- Acronym
- TRIFECTA-DARED
- Status last verified
- Jan 2026
- First submitted
- 19 Jun 2025
- Last updated
- 2 Feb 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Bayesian Pragmatic Trial for Pubertal Induction in Turner Syndrome: TRansformation Initiative For Efficient Clinical TriAl Design Advancement in RarE Diseases (TRIFECTA-DARED Framework)
- ClinicalTrials.gov ID
- NCT07041814
- Acronym / sponsor ID
- TRIFECTA-DARED / GUP-2024-011
- Conditions
- Turner Syndrome
- Keywords
- Turner Syndrome, Hormone Replacement Therapy, Progynova, Oestrogel, Transdermal 17β Estradiol, Estradiol Valerate, Pubertal Induction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Universiti Kebangsaan Malaysia Medical CentreUniversity, hospital or other
- Study start
- 15 Feb 2026 (estimated)
- Primary completion
- 30 Apr 2029 (estimated)
- Study completion
- 31 Oct 2029 (estimated)
- First posted
- 27 Jun 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Does taking an oral estrogen tablet (Progynova) or applying an estrogen gel (Oestrogel) lead to better breast development?
- Does one method lead to a larger uterine size as seen on ultrasound?
- Do participants start menstrual-like (withdrawal) bleeding, and does one method cause it sooner?
- 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):
- 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.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Oral Estradiol Valerate (Progynova) | Active comparator | Drug: Oral estradiol valerateProgynova 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®) | Experimental | Drug: Transdermal 17β estradiolOestrogel® 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 |
Who may qualify
- Ages
- 11 to 30 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral estradiol valerateProgynova 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. | Drug | Oral Estradiol Valerate (Progynova) |
| Transdermal 17β estradiolOestrogel® 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. | Drug | Transdermal 17β estradiol (Oestrogel®) |
Primary outcome
Proportions of Turner Syndrome with Satisfactory Breast Development (defined as Turner Breast Stage 3 (B3) and above)
Time frame: From enrollment (baseline) to 19 months after the commencement of intervention (end of follow-up)
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)
Median time to achieving Tanner Breast Stage 4 (B4) and above (in days)
Time frame: From enrollment to 19 months after the commencement of interventions (end of follow-up)
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)
Uterine length (in cm)
Time frame: From enrollment to 19 months after the commencement of interventions (end of follow-up)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit performed by a trained PAG Specialist (trial outcome assessor)
Anteroposterior uterine fundal diameter (in cm)
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit, performed by a trained PAG Specialist (trial outcome assessor)
3 secondary outcomes
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
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
Median time to withdrawal bleeding (in days)
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow up)
Serum Triglyceride levels (in mmol/L)
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2026.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD contact
MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD study chair
Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)
ANI AMELIA ZAINUDDIN, MBBS, PhD principal investigator
FACULTY OF MEDICINE, UNIVERSITI KEBANGSAAN MALAYSIA
NUR AZURAH ABDUL GHANI, MBBS, MMed (Obs and Gynae) principal investigator
National University of Malaysia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Oral estradiol valerate and Transdermal 17β estradiol in people with Turner Syndrome, run by Universiti Kebangsaan Malaysia Medical Centre at 1 site in Malaysia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 2 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Malaysia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact ANI AMELIA ZAINUDDIN, MBBS, PhD (+60391455950 ext. +60193882078, aniamelia@ukm.edu.my), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportions of Turner Syndrome with Satisfactory Breast Development (defined as Turner Breast Stage 3 (B3) and above) (time frame: From enrollment (baseline) to 19 months after the commencement of intervention (end of follow-up)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2026.