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

NCT ID: NCT07041814

Last Updated: 2025-07-04

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-15
• Study Completion Date: 2029-10-31

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 medicine 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 follow 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 18 months.

2. Tablet group: Swallow Progynova (estradiol valerate) tablets, starting twice a week, then daily with increasing doses over 18 months.

• Visit the clinic at 6, 12, and 18 months 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.

Detailed Description

Turner syndrome (TS) is a chromosomal condition in which 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 17 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 months 6, 12, and 18, 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 modeling-incorporating informative priors derived from matched historical TS cohorts-will yield posterior estimates of treatment effects and predictive checks, 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Oral Estradiol Valerate (Progynova)

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.

Group Type: ACTIVE_COMPARATOR

Oral estradiol valerate

Intervention Type: DRUG

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 estradiol (Oestrogel®)

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

Group Type: EXPERIMENTAL

Transdermal 17β estradiol

Intervention Type: DRUG

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.

Interventions

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, 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.

Intervention Type: DRUG

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 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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. 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

2. Confirmed estrogen deficiency with primary ovarian failure (high level of follicular stimulating hormone (FSH > 25 IU/L))

3. Patients who have not undergone pubertal development ( no breast development and underdeveloped uterus size).

4. Hormone Replacement Therapy (HRT)-naive TS patients

5. Breast Tanner Stage of 2 or less.

6. Patients on Growth Hormone (GH) will be allowed entry into the study.

7. 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

Exclusion Criteria

1. Patients with signs of spontaneous puberty

2. 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)

3. Previous history of exposure to estrogen treatment.

4. 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.

5. Acute or chronic hepatic disease

6. Patients with untreated hypothyroidism

7. Inflammatory bowel disease (Ulcerative Colitis, Crohn's disease) and coeliac disease

8. Cigarette smoking patients

9. Severely obese patients (BMI > 95th percentile)

10. Unknown abnormal genital bleeding

11. Porphyria

12. Recent involvement with clinical research studies (previous 6 months) investigating new HRT formulations

• Minimum Eligible Age: 11 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Universiti Kebangsaan Malaysia Medical Centre

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD

Role: STUDY_CHAIR

Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)

ANI AMELIA ZAINUDDIN, MBBS, PhD

Role: PRINCIPAL_INVESTIGATOR

FACULTY OF MEDICINE, UNIVERSITI KEBANGSAAN MALAYSIA

NUR AZURAH ABDUL GHANI, MBBS, MMed (Obs and Gynae)

Role: PRINCIPAL_INVESTIGATOR

National University of Malaysia

Locations

Hospital Canselor Tuanku Muhriz (HCTM)

Cheras, Kuala Lumpur, Malaysia

Countries

Malaysia

Central Contacts

ANI AMELIA ZAINUDDIN, MBBS, PhD

Role: CONTACT

aniamelia@ukm.edu.my

+60391455950 ext. +60193882078

MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD

Role: CONTACT

irfan.abduljalal@ukm.edu.my

+6039145 6321 ext. +60172107299

Facility Contacts

ANI AMELIA ZAINUDDIN, MBBS, PhD

Role: primary

aniamelia@ukm.edu.my

+60391455950 ext. +60193882078

MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD

Role: backup

irfan.abduljalal@ukm.edu.my

+60391456321 ext. +60172107299

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

NMRR ID-25-02169-7TA

Identifier Type: REGISTRY

Identifier Source: secondary_id

GUP-2024-011

Identifier Type: -

Identifier Source: org_study_id