Gender incongruence Other
Conditions
Interventions
The PATHWAYS TRIAL is designed as a Randomised Controlled Trial (RCT) comparing immediate vs. delayed start (at 1 year post-randomisation) of GnRHa amongst 226 CYP with primary endpoint at 2 years pos
Sponsors
King's College London
South London and Maudsley NHS Foundation Trust
Eligibility
Sex/Gender
All
Age
11 Years to 16 Years
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 17/07/2026: TRIAL Clinical Inclusion Criteria: 1. The child or young person meets diagnostic criteria for gender incongruence according to ICD-11. This diagnosis should be made or confirmed within the CYPGS. Specifically: 1.1. The CYP has a strong desire to be a different gender than the birth-registered sex 1.2. The CYP has a strong dislike of sexual anatomy or anticipated secondary sex characteristics 1.3. The incongruence must have persisted for a minimum of 2 years 1.4. The CYP has a strong desire to ‘transition’, to live and be accepted as a person of the experienced gender 2. The CYP wants puberty suppression for their gender incongruence and this care preference persists after receiving other care deemed appropriate from the CYPGS and other sources prior to the initiation of GnRHa 3. The CYP is confirmed by the CYPGS to be in Tanner stage 2-5 4. Age: At the time of randomisation, for birth-registered females, the CYP is between 11 years and up to the 16th birthday; For birth-registered males, the CYP is between 12 years and up to the 16th birthday 5. The clinician in the CYPGS leading on care for that CYP considers that GnRHa for puberty suppression offers a reasonable prospect of benefit. This benefit might be achieved in relation to quality-of-life parameters (e.g., confidence in peer and family relations, participation in school and/or leisure activities, improved sense of well-being), mental or physical health. 6. The clinician in the CYPGS leading on care for an individual patient considers they have participated sufficiently for their holistic health and well-being in other forms of care for puberty suppression to be considered, in line with NMDT recommendations and this participation is reviewed by the NMDT. 7. The CYP has demonstrated sufficient understanding of the possible advantages and disadvantages of the proposed treatment including immediate psychological and physical impacts and also long-term implications, benefits and harms in the context of their personal situation and needs. Having considered this information, the child or young person has indicated that they wish to proceed with the treatment (assented). 7.1. To achieve this, this will involve serial discussions with clinicians, including those with specialist knowledge of endocrine interventions (e.g., paediatric endocrinologist, clinical nurse specialist, paediatrician with specialistic knowledge) 7.1.1. There will be written information provided and recording of how the child or young person flexibly demonstrates an understanding of possible risks and benefits 7.1.2. Information may also be provided in other, additional formats that are bespoke for the individual child or young person’s cognitive and learning style. For example, this may include visual supports and audio recordings 7.1.3. The child or young person will be asked to explain their understanding of treatment with GnRHa in their own words 7.1.4. A checklist will be used by the clinical services to ensure all key points have been covered and understood 7.2. Fertility preservation will have been discussed with each CYP, with developmentally appropriate and/or adapted language/ other forms of communication (as described above) descriptions of what would be involved, how it can be accessed, and the potential long-term implications if fertility preservation is not accessed. CYP will not be referred to the Trial until the NMDT is satisfied this has been adequately con
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 17/07/2026: TRIAL Clinical Exclusion Criteria: 1. Physical conditions where puberty will not commence or advance in a patient. This may include gonadal failure (e.g. due to genetic disorders such as Turner syndrome) or central hypogonadotropic hypogonadism. 2. Unstable physical health. The purpose of this criterion is to ensure that that the CYP is not undergoing concurrent high-intensity physical interventions which might affect their response to GnRHa or their ability to adhere to the trial protocol. These include but are not limited to: 2.1. Very low or very high BMI (or rapid changes in BMI), particularly if there is a concerning trajectory or associated nutritional or metabolic concerns. This could include eating disorders or body dysmorphic disorder. 2.2. Any poorly controlled medical disorder, such as uncontrolled epilepsy, inflammatory bowel disease, cystic fibrosis. This includes any other condition where participation may pose a risk to the individual’s health or compromise study integrity. 2.3. Concerns about bone health or significant risk of fractures (this may also include a low baseline bone density). 2.4. QTc interval above 470 milliseconds at screening, or concomitant high-risk QT-prolonging drugs that cannot be ceased 3. Hypersensitivity to gonadotropin releasing hormone (GnRH), its analogues, or to any of its excipients 4. Known congenital long QT syndrome 5. Unstable mental health that may impair ability to provide informed assent/consent or lead to risk of serious harm to self or others. Many CYP with gender incongruence experience anxiety and/or depression which they relate to gender dysphoria or distress. It is not the intention to exclude those with mild to moderate levels of mental health symptoms. However, severe or unstable symptoms may affect the ability to engage in all aspects of the clinical protocol. Examples would include (but are not limited to): 5.1. Severe or profound depression with significant effects on the ability to accurately evaluate choices and future outcomes; 5.2. Severe body dysmorphic disorder that is confounded with secondary sexual characteristics or physique not conforming to the desired gender; 5.3. Active psychotic symptoms; 5.4. Significant risk of harm to self or others as exemplified by consistent suicidal thoughts, repeated and ongoing acts of self-harm and/or the need for emergency plans with the child or young person and family; 6. Aspects of family/home situation that makes it likely the CYP will not be able to adhere to aspects of the protocol such as attending regular follow-up appointments. This last requirement will have been assessed in relation to the CYP’s ability to find ways of attending appointments in the CYPGS. 7. Clinical concerns about the young person’s capacity to consent. 8. Insufficient understanding of PATHWAYS TRIAL. 9. New or ongoing safeguarding concerns. 10. Birth-registered females with undiagnosed vaginal bleeding. 11. Birth-registered females who are pregnant or lactating. 12. People of child-bearing potential (i.e. sexually active birth-registered female not using effective contraception as compatible with GnRHa**) who are at risk of pregnancy during the trial. TRIAL Research Exclusion Criteria: 1. The CYP has previously taken or is currently using GnRHa for this indication. This will be identified by (i) asking CYP and their parents/legal guardians about off-label use and (ii) through hormone blood tests at baseline
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Quality of life measured using KIDSCREEN-10 Electronic Participant Reported Outcome (ePRO) at Baseline, month 6, month 12, month 18, month 24, and annually during follow up period (months 36 and 48) for TRIAL participants; For HORIZON INTENSIVE participants: Baseline, month 12, month 24, annually during follow up period (months 36 and 48) | — |
Secondary
| Measure | Time frame |
|---|---|
| Quality of life measured using KIDSCREEN-52 ePRO at Baseline, month 6, month 12, month 18, month 24, and annually during follow up period (months 36 and 48) for TRIAL participants; For HORIZON INTENSIVE participants: Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender-related distress measured using Utrecht Gender Dysphoria Scale – Gender Spectrum (UGDS-GS) ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Mental health symptoms measured using Revised Children’s Anxiety and Depression Scale (RCADS) ePRO at Baseline, month 3, month 6, month 12, month 15, month 18, month 24, and annually during follow up period (months 36 and 48) for TRIAL participants. For HORIZON INTENSIVE participants: Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender-related distress measured using Body Image Scale – Gender Spectrum (BIS-GS) ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender-related distress measured using Parental Attitudes of Gender Expansiveness Scale for Youth (PAGES-Y) ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Mental health symptoms measured using SCOFF questionnaire ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender identity measured using Sexual attraction questionnaire (participants 12+) ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender identity measured using ALSPAC Romantic Relations measure (participants 12+) ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Gender identity measured using Gender Identity Question ePRO at Baseline, month 12, month 24, annually during follow up period (months 36 and 48);Mental health symptoms measured using Adolescent Primary Care Traumatic Stress Screen (APCTSS) ePRO at Baseline, month 12, month 24, | — |
Countries
England, United Kingdom
Contacts
Public ContactEmily Simonoff
Outcome results
None listed