Evaluation of the Effectiveness of Hormonal Treatment in Adolescents Suffering From Gender Dysphoria (TRANSADO)

Gender dysphoria (GD) is a significant suffering lasting more than 6 months in a subject, regarding the gap felt between gender identity of someone and birth sex. From the start of puberty, most of these adolescents who identify as transgender will persist in this sense and will engage in hormonal-surgical reassignment at some stage. For these adolescents, International recommendations for good practice recommend early treatment at the beginning of pubertal development (Tanner 2) to block pubertal progression, with the possibility of hormonal transition by administration of sex hormones of the desired sex at the age of 16. However, in order to reduce the psychosocial consequences of GD, more and more reference teams are practicing this hormonal transition from the age of 14 without any randomized study showing its benefit compared to a transition at the age of 16 years old. Indeed, in the absence of treatment, comorbidities among adolescents suffering from gender dysphoria is very high, with anxiety and depression, suicidal risk and school dropout.

Our hypothesis is that when hormonal transition is started at an age closer to what physiological puberty would be, it will reduce comorbidities and improve quality of life of these adolescents. This is the first therapeutic randomized study in France on this transgender adolescent population, a field where international recommendations based on "Evidence Based Medicine" principles are scared. We hope that results of this study will guide transgender youth health care allowing them, if the study is positive, to access hormonal treatments earlier and improve their overall functioning, their anxious and depressive symptoms, their quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Cross Sex Hormonal Treatment in Adolescents With Gender Dysphoria
• Intervention / Treatment: Drug: hormonal treatment with cross sex hormones (testosterone or oestrogenes) started at 14 years old +/- 6 months; Drug: Cross sex hormones ( œstrogenes or testosterone) started at 16 years old +/- 6 months

Detailed Description

This study is a multicentered, controlled, randomized, open trial with blinded assessment of the primary outcome measure (Prospective Open Blinding Endpoint PROBE study). Randomization will be stratified by sex assigned at birth and the investigating center. The main analysis will be intention-to-treat and multiple imputation methods will be used to handle missing data. Once inclusion criteria are checked by the child psychiatrist (selection visit), and the pediatric endocrinologist (inclusion visit), the adolescent will be included in the study with an initial evaluation (T0) by a trained psychologist : primary measure (CGAS) and secondary psycho-affectif criteria. Then, the subject will randomized by the pediatric endocrinologist (via an IT platform) and, if included in the experimental arm will be given the cross sex hormonal treatment corresponding.Main objective: To evaluate, in adolescents with gender dysphoria (GD), having or not benefited from prior pubertal suppression, the effectiveness of cross sex hormonal treatment with estrogens or testosterone initiated at 14 years of age on the overall functioning of the teenager at 16 years old. Primary outcome measure: Children's Global Assessment Scale (CGAS) score at age 16. Secondary measures : Evaluate the effectiveness of cross sex hormonal treatment started at 14 years old vs. 16 years old on the overall functioning of the adolescent at 18 years old, - the safety (side effects) of hormonal treatment started at the age of 14, - and the relevance of hormonal treatment started at 14 years old on other measures assessed at 16 and 18 years old (gender identity, depression, anxiety, emotional, behavioral disorders and other comorbidities, objective and subjective quality of life, body image, height, waist/hip ratio, bone mineral density, BMI). Adolescents in both groups will be re-evaluated at 16 years +/- 6 months (T1). At the end of this evaluation, patients in the control group will begin their hormonal treatment. Adolescents will benefit from a final evaluation at 18 years +/- 6 months, (T2), the same criteria as at T0 and T1 will be collected.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Agnès CONDAT, MD,PhD; Phone Number: +33 1 42 16 23 32; Email: agnes.condat@aphp.fr
• Study Contact Backup: Name: Anne BISSERY; Phone Number: +33 (0)142162432; Email: anne.bissery@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adolescents aged 14 +/- 6 months,
• Having initiated puberty: Tanner score ≥2 for FtM; tanner score ≥2 and/or testosterone >0.3ng/mL for MtF
• presenting the criteria for gender dysphoria according to the DSM5 assessed by at least two child psychiatric interviews at least six months apart where the diagnosis of gender dysphoria was clinically established and that of associated autism spectrum disorder refuted and/or associated cognitive impairment, confirmed by specific scales (Gender Identity / Gender Dysphoria Questionnaire for Adults and Adolescents (GIDYQ-AA), and Recalled Childhood Gender Identity Scale),
• whose indication for hormonal transition has been validated in a multidisciplinary consultation meeting after at least one consultation with the pediatric endocrinologist with clinical examination, blood pressure measurement, and information on hormonal treatments in the context of gender dysphoria .

Exclusion Criteria:

• contraindication to experimental hormonal treatment (see paragraph 1.5)
• Need for adjustment of hormonal treatment (FtM patient treated with anticoagulants or with thrombophilia).
• Patient at risk of worsening of certain diseases under estrogen treatment (MtF patients with uncontrolled diabetes with an HBA1C > 8%, patients with cholelithiasis, cholelithiasis, systemic lupus erythematosus, severe asthma, severe arterial hypertension , severe migraines, otosclerosis, epilepsy not controlled by treatment.
• Patients with cancer with a risk of hypercalcemia (and associated hypercalciuria), linked to bone metastases.
• Severe cardiac, hepatic or renal failure or ischemic cardiac pathologies, due to the risk of severe complications characterized by edema, with or without congestive heart failure.
• Uncontrolled high blood pressure.
• Patients suffering from epilepsy and migraine.
• Patients with existence or history of thromboembolic accidents.
• Untreated severe chronic depression Ongoing treatment with anticoagulant
• Ongoing treatment with vitamin K antagonist
• autism spectrum disorders (clinical screening, confirmed in case of doubt by the Social Responsiveness Scale (SRS) > 65th percentile, carried out as part of usual care in the event of a clinical argument,
• Cognitive deficit (clinical screening, confirmed by an IQ < 80 on the Weschler scale (WISC IV), carried out as part of usual care in the event of a clinical argument.
• refusal to participate in the study on the part of the adolescent or one of the holders of parental authority (the two holders and the adolescent must sign written consent after having received appropriate information).
• absence of social security coverage with coverage under ALD 31
• Participation in another interventional research
• current pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: early hormonal treatment; early hormonal treatment with cross sex hormones at 14 years old +/- 6 months	Drug: hormonal treatment with cross sex hormones (testosterone or oestrogenes) started at 14 years old +/- 6 months; 4 years of follow up (FU) with evaluation at T0 (14 years old +/- 6 months), T1 (16 years old +/-6 months) and T2 (18 years old+/- 6 months) with eather ANDROGEL® 16.2 mg/g, gel (testostérone) or ESTREVA® 0.1 %, gel ou 1.3 PROVAMES® 1 mg, cp (oestrogenes)
Active Comparator: usual treatment; cross sex hormones as usual	Drug: Cross sex hormones ( œstrogenes or testosterone) started at 16 years old +/- 6 months; 2 years of hormonal treatment from 16 to 18 years old.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global functionning using the Children's Global Assessment Scale (CGAS)	The Children's Global Assessment Scale (CGAS), adapted from the Global Assessment Scale for adults, is a rating of general functioning for children and young people until 16 years old. The clinician assesses a range of aspects of psychological and social functioning and gives the child or young person a single score between 1 and 100, based on their lowest level of functioning. The score puts them in one of ten categories that range from "needs constant supervision" (1-10) to "superior functioning" (91-100). The measure can be used by clinicians as well as researchers to complement other scales measuring more specific symptoms.	16 years old +/- 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DEP-ADO	Dep-Ado is a 15 minutes questionnaire to evaluate alcohol and substance use adolescent population aged 12 to 17 years. No problem if total score <12; warning of >12 et <19; pathological use needing intervention if >20	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
WISC-V (weschler Test)	cognitive test with 4 subscales (verbal comprehension index, perceptual reasoning index, logical score, working memory index, processing speed index). IQ is calculated. If <80, it is an non inclusion criteria. Normal range between 80 and 120. when > 120 précocity	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
UGDS (Utrecht Gender Dysphoria Scale )	The Utrecht Gender Dysphoria Scale (UGDS) is a validated, 12-item screening measure for both adults and adolescents used extensively in gender clinics to assess gender dysphoria. Minimal score= 12; max=60. two versions (AFAB, AMAB)	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Beck Depression Inventory (BDI)	is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression.Min = 0 Max = 39 Between 0 and 3 = no Dépression	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Body Image Scale (BIS)	The 10-item BIS was developed to assess changes in body image assessed with a four-point scale from "not at all" to "very much." High scores indicate higher body image.(Min=30, Max=150 )	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
State and Anxiety Inventory for Children (STAI-C)	STAI-C includes 20-items that describe anxiety experiences a person might experience (e.g., item 6-"I worry too much"©). For each item, participants choose one of three options that indicate how often they experience the described situation - "hardly-ever", "sometimes" or "often"; these options are scored with 1, 2, and 3 points, respectively (total score range: 20-60). Higher scores indicate higher anxiety	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
CBCL (Youth Self Report YSR) Child Behaviour Chekcklist	The Youth Self-Report (YSR) is a widely used child-report measure that assesses problem behaviors along two "broadband scales": Internalizing and Externalizing. It also scores eight empirically based syndromes and DSM-oriented scales, and provides a summary of Total Problems. The measure assesses "Total Competency," which is a scale comprised of competency in activities, social functioning, and school performance. Clinical range of Total score >63	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
World Health Organization Quality Of Life (WHO QOL)	This 26-item instrument measures four fields, i.e. physical health, mental health, social relations and the environment. The analysis is based on the scores generated for each field (no overall score can be calculated). The user manual is comprehensive, which makes the instrument easy to use (WHO, 1996). While some studies call into question the construct validity (D'Abundo et al., 2011), the WHOQOL-BREF is generally recognized as a reliable, valid instrument to assess quality of life and is widely used in the literature for clinical and population-based surveys (Oliveira, Carvalho and Esteves, 2016; Skevington, Lotfy and O'Connell, 2004).	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Satisfaction With Life Scale (SWLS)	The SWLS is a short 5-item instrument designed to measure global cognitive judgments of satisfaction with one's life. The scale usually requires only about one minute of a respondent's time.Min=5, Max=35. The higher score means a greater satisfaction with life	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Adolescent Depression Rating Scale (ADRS)	It is a short 10-items instrument (10 minutes) to mesure the risk of depression in adolescents. The subject answers true or false to questions regarding depressive symptoms. Min=0, Max=10. A score> 4 means a risk of depression	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Mini International Neuropsychiatric Interview (MINI)	To assess the 17 most common psychiatric disorders and suicidality in DSM-III-R, DSM-IV and DSM-5 and ICD-10. The MINI was designed as a brief structured diagnostic interview to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings.	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)
Inventory of Parents and Peers Attachment (IPPA)	The Inventory of Parent and Peer Attachment (IPPA) is a self-report questionnaire that measures attachment styles in relation to parents and peers. It was developed by Patricia Crittenden in the 1980s. The IPPA consists of 25 items that are rated on a 5-point Likert scale. The items assess four attachment styles: secure, anxious-avoidant, anxious-resistant, and disorganized.The IPPA is a valuable tool for assessing attachment styles in both adults and children. It can be used to help clinicians diagnose attachment disorders and to develop treatment plans. It can also be used by researchers to study the effects of attachment styles on a variety of outcomes.	T0 (14 years old +/-6 mois); T1 (16 years old+/-6 monhs); T2 ( 18 years old +/-6 months)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Agnès CONDAT, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): June 6, 2024
• Primary Completion (Estimated): June 6, 2029
• Study Completion (Estimated): June 6, 2031

Study Registration Dates

• First Submitted: April 2, 2024
• First Submitted That Met QC Criteria: April 2, 2024
• First Posted (Actual): April 8, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: mental health; adolescents; hormonal treatment; Gender Dysphoria
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Sexual Dysfunctions, Psychological; Depressive Disorder; Gender Dysphoria; Depressive Disorder, Major; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Anabolic Agents; Hormones; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
• Other Study ID Numbers: P170923J; 2019-000300-16 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No