ABSTRACT
Objective
Trofinetide is the first approved treatment for Rett syndrome (RTT) in the United States and Canada. Trofinetide improved the core symptoms of RTT in clinical trials, and real‐world evidence supports the findings of clinical trials. As RTT experts in the United States have now gained nearly 3 years of real‐world experience with trofinetide, a modified Delphi process was conducted in the United States to establish consensus recommendations for the practical use of trofinetide in the treatment of RTT.
Methods
A multidisciplinary steering group of five trofinetide‐experienced RTT experts practicing at an International Rett Syndrome Foundation (IRSF)‐designated center of excellence convened and developed 72 consensus statements across six domains: first‐line use, pre‐treatment assessment, initiation, benefit evaluation, tolerability management, and discontinuation strategies. The statements were then assigned a 4‐point Likert scale for testing via email by the Delphi panel identified by the steering group. Consensus was reached for individual statements if they met the pre‐specified consensus threshold of ≥ 75% agreement.
Results
Two rounds of assessments were completed by 25 respondents in each round, resulting in agreement ≥ 75% being reached across the final statement set. The consensus supports trofinetide as the standard of care for eligible patients with early initiation and an individualized approach to titration to maximize efficacy and tolerability. The panel reflected the steering group's view that trofinetide is efficacious. While side effects can emerge with trofinetide, they are manageable in most cases.
Conclusions
Recommendations highlight a flexible, patient‐centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence.
Keywords: Delphi method, drug side effects, Rett syndrome, trofinetide
1. Introduction
Rett syndrome (RTT) is a severe, X‐linked neurodevelopmental disorder that predominantly affects females and is characterized by core symptoms of loss of purposeful hand skills, verbal communication, stereotypic hand movements, and gait abnormalities [1]. Moreover, patients may experience several multisystem comorbidities, including seizures, scoliosis, gastrointestinal (GI) conditions, breathing irregularities, and behavioral problems [2]. RTT is most commonly caused by de novo mutations in the MECP2 gene, which encodes the methyl‐CpG–binding protein 2, a critical regulator of gene expression and chromatin architecture in the central nervous system [3].
The clinical burden of RTT is profound and lifelong, with most affected individuals requiring round‐the‐clock care and support throughout their lives. Children with RTT typically lose the ability to walk, speak, or use their hands functionally, and many develop epilepsy, scoliosis, breathing irregularities, and GI dysfunction [1, 4, 5]. The impact of RTT, therefore, extends beyond the individual to families and caregivers. The often multisystemic complications of RTT result in significant caregiver burden, characterized by emotional distress, financial strain, and physical exhaustion [6, 7, 8]. The reported high levels of stress, anxiety, and depression among caregivers emphasize the need for comprehensive and sustained support systems.
Historically, the management of RTT has focused on improving comorbid conditions such as seizures, constipation, scoliosis, and gross motor control through interventions including pharmacological agents, physical and occupational therapy, nutritional support, surgical intervention, and assistive technologies [9, 10]. While these approaches aim to improve comorbidities, analysis of Rett Syndrome Behaviour Questionnaire (RSBQ) scores from the Australian RTT Natural History Study in 298 individuals showed a negligible decrease over time in RTT symptoms, highlighting the limitations of this approach, which lacks RTT‐specific treatment [11].
A significant advancement in RTT therapeutics has emerged with the development of trofinetide, a synthetic analog of glycine‐proline‐glutamate (GPE), a naturally occurring neurotrophic tripeptide derived from insulin‐like growth factor‐1 (IGF‐1) [10, 12]. Trofinetide is believed to exert neuroprotective and anti‐inflammatory effects by modulating synaptic function, reducing neuroinflammation, and enhancing neuronal and glial cell health [13]. In clinical trials, trofinetide demonstrated statistically significant improvements in core symptoms of RTT as measured by validated outcome scales such as the RSBQ and the Clinical Global Impression–Improvement (CGI‐I) scale [12, 14, 15, 16]. The phase 3, 12‐week LAVENDER trial showed statistically significant improvements in both caregiver‐ and clinician‐reported outcomes, as measured using the RSBQ and the CGI‐I scale [12]. Results from open‐label extension studies (LILAC and LILAC‐2) demonstrated that improvements in RSBQ and CGI‐I scores were maintained long‐term [15, 16]. These improvements had an impact beyond the individual, with more than half of the caregivers reporting that their daily lives were improved as a result of these treatment‐related improvements [17]. These findings led to the US Food and Drug Administration (FDA) approval of trofinetide in March 2023, marking the first disease‐specific treatment for RTT and a critical milestone in the management of this disorder [18]. The results of the real‐world LOTUS study confirmed and expanded the findings of the trofinetide clinical trial program, with caregivers reporting behavioral improvements including nonverbal communication, alertness, and social interaction/connectedness [19]. Case studies also suggest that trofinetide treatment may improve aspects of RTT outside of those measured by the RSBQ and CGI‐I scores in clinical studies, although this is anecdotal [20].
Clinical experience with trofinetide is growing, and the cumulative experience established over the past 3 years since FDA approval, from both International Rett Syndrome Foundation (IRSF)‐designated centers of excellence (COEs) [21, 22] and non‐COE providers, is critical to establishing consensus recommendations. This consensus will support more streamlined and consistent use of trofinetide across all sites and providers.
Here, we present the results of a modified Delphi methodology approach, with practical recommendations on trofinetide use in RTT related to initiation, evaluation of treatment benefit, and management of tolerability.
2. Methods
The process followed a modified Delphi methodology (Supporting Information S1: Figure 1) guided by the ACcurate COnsensus Reporting Document (ACCORD) checklist 2024.
In December 2024, a brief review of literature on the topic of RTT and trofinetide was conducted using PubMed and Google Scholar. Search terms included, but were not limited to, RTT, treatment, trofinetide, assessment, outcomes, and efficacy. A general web search using free‐text terms was also conducted to locate any additional publications relevant to this topic. The findings were used to inform the agenda and stimulus for a steering group meeting.
Guided by an independent facilitator (Triducive Partners Limited), a steering group of RTT experts practicing at IRSF‐designated COEs (one complex care pediatrician, three pediatric neurologists, and one pediatric neurology nurse practitioner) was convened in January 2025. During the meeting, the steering group agreed to focus on six broad domains to develop consensus statements around trofinetide as a first‐line treatment for RTT, pre‐trofinetide assessments and counseling, trofinetide initiation, assessment of trofinetide benefits, assessment and management of trofinetide tolerability, and trofinetide discontinuation or pausing. Each domain was discussed, and 72 statements were developed by the steering group working collaboratively. The statements were then collated, and the steering group independently reviewed the statements as either “accept,” “remove,” or “reword,” or suggested additional statements. Each statement was designed to stand alone, with no dependencies on other statements in the set to allow for individual evaluation of each statement. The statements were then assigned a 4‐point Likert scale (“strongly agree,” “tend to agree,” “tend to disagree,” “strongly disagree”), which was distributed using a convenience sampling approach by the steering group members in March 2025. An electronic invitation to assess consensus statements was sent to all trofinetide‐experienced RTT experts who also practiced at a US RTT COE. Respondents consented to participate and did not receive compensation for participation. The respondents' current COE and time in the RTT expert role were also captured. All responses were anonymized before being shared with the steering group.
Each round of statement assessment was open for 4 weeks or until 22 responses were received, whichever was longer, representing a 51% response rate of the 43 invited panel members. The number of responses required reflects the relatively low number of trofinetide‐experienced RTT experts. The threshold for consensus for each statement was set a priori at 75% agreement [23].
Responses were analyzed to produce an arithmetic agreement score for each statement using Microsoft Excel software. The responses were aggregated to provide an overall agreement level (i.e., the number of respondents expressing agreement as a percentage of the overall number of responses for each statement). This information was then reviewed by the steering group to review any changes to the statements ahead of round 2. Analysis of round 1 was carried out in April 2024, and the second steering group meeting was held 2 weeks later for analysis and discussion of results. The steering group agreed to amend six statements that failed to achieve consensus in round 1 and reissue these to the wider panel for testing in round 2. Round 2 statements were distributed to the panel in May 2025. The steering group reconvened in June 2025 to analyze the final results and develop appropriate commentary for discussion.
Ethical approval for this consensus project was not needed as it only collected the anonymous opinions of healthcare professionals, and no patient‐specific data were captured.
3. Results
In both rounds, a total of 25 responses were received. Respondents had been in their RTT‐specific practice from < 5 years to ≥ 20 years, with the majority of respondents having ≥ 10 years' experience in the treatment of RTT (Supporting Information S1: Table 1). All consensus statements (Table 1) reached ≥ 75% consensus after round 2 (Supporting Information S1: Figure 2). Some statements were reworded or removed after round 1 (Supporting Information S1: Table 2).
Table 1.
Final consensus statement set and corresponding levels of agreement at the end of round 2.
| No. | Statement | Strongly agree | Tend to agree | Tend to disagree | Strongly disagree | Overall agreement |
|---|---|---|---|---|---|---|
| Topic A. Trofinetide as a first‐line treatment for Rett syndrome (RTT) | ||||||
| 1 | Trofinetide is the first FDA‐approved treatment to demonstrate improvement in several core symptoms of RTT, in contrast to other therapies, which primarily target one symptom of RTT | 64% | 24% | 12% | 0% | 88% |
| 2 | Trofinetide should be part of the standard of care for RTT individuals at least 2 years of age, as indicated | 56% | 32% | 12% | 0% | 88% |
| 3 | Trofinetide is generally well‐tolerated | 20% | 56% | 24% | 0% | 76% |
| 4 | The side effects of trofinetide can be successfully managed in most cases | 36% | 60% | 4% | 0% | 96% |
| 5 | Trofinetide can be prescribed by any eligible member of the patient's healthcare team who is involved in the management of RTT | 56% | 44% | 0% | 0% | 100% |
| 6 | Trofinetide may be used as chronic therapy | 60% | 36% | 4% | 0% | 96% |
| 7 | Trofinetide can be given at any time throughout the patient's lifetime as indicated | 68% | 32% | 0% | 0% | 100% |
| 8 | Trofinetide may improve patients' attention and (nonverbal and verbal) communication within a month of initiation | 44% | 48% | 8% | 0% | 92% |
| 9 | Trofinetide may improve patients' (fine and gross) motor skills, hand use, hyperventilation, altered breathing patterns, bruxism, sleep patterns, anxiety, and irritability, as early as 3 months after initiation | 32% | 52% | 12% | 4% | 84% |
| 10 | Chronic use of trofinetide that results in improved (nonverbal and verbal) communication may help patients better express their needs | 40% | 48% | 12% | 0% | 88% |
| 11 | Chronic use of trofinetide may improve the quality of life of both the caregiver and the patient | 32% | 56% | 12% | 0% | 88% |
| Topic B. Pre‐trofinetide assessments and counseling | ||||||
| 12 | Clinical function and RTT severity should be documented prior to initiating trofinetide, if possible | 64% | 24% | 8% | 4% | 88% |
| 13 | All core symptoms of RTT (communication, motor function, altered breathing patterns, bruxism, and repetitive hand movements/stereotypes) should ideally be fully documented prior to initiating trofinetide, to help assess any improvements while on trofinetide | 80% | 12% | 8% | 0% | 92% |
| 14 | Functional status (daily living activities, communication, and motor function) should ideally be documented prior to initiating trofinetide, to help assess any improvements while on trofinetide | 80% | 12% | 8% | 0% | 92% |
| 15 | Patient history of seizures should be taken prior to initiating trofinetide, if possible | 76% | 16% | 8% | 0% | 92% |
| 16 | Caregivers should be encouraged to keep a detailed diary of a patient's symptoms prior to and in the months after initiating trofinetide | 56% | 32% | 12% | 0% | 88% |
| 17 | Patient history of bowel activity, vomiting, and nutritional status should be obtained prior to initiating trofinetide, to help individualize bowel management | 80% | 20% | 0% | 0% | 100% |
| 18 | Consider discontinuing all constipation medications prior to initiating trofinetide | 48% | 36% | 16% | 0% | 84% |
| 19 | Consider decreasing the dose of all constipation medications prior to initiating trofinetide, as deemed appropriate based on the individual patient | 48% | 44% | 8% | 0% | 92% |
| 20 | Consulting with specialists should be considered before offering trofinetide to a patient who is severely underweight or malnourished, or has significant GI comorbidities or renal disease | 72% | 20% | 4% | 4% | 92% |
| 21 | Counsel patients and/or caregivers that they may not experience immediate benefits | 88% | 8% | 4% | 0% | 96% |
| 22 | Counsel patients and/or caregivers that improvements may be subtle, incremental, and variable depending on the patient | 92% | 8% | 0% | 0% | 100% |
| 23 | Counsel patients and/or caregivers that the results of treatment may appear in different symptom domains based on the individual patient | 88% | 12% | 0% | 0% | 100% |
| 24 | Counsel patients and/or caregivers that potential side effects may occur (diarrhea and vomiting), and guidance for managing them | 96% | 4% | 0% | 0% | 100% |
| 25 | Counsel patients and/or caregivers that if a patient experiences vomiting, they should contact their healthcare provider, particularly for patients at risk of aspiration | 88% | 12% | 0% | 0% | 100% |
| 26 | Plan to remain in close communication with the patient and/or caregiver for the first 3 months to evaluate dose, improvements, and side effects until either a stable or target dose is reached | 88% | 8% | 0% | 4% | 96% |
| 27 | Encourage patients to start or restart supportive therapies (e.g., physical therapy, occupational therapy, speech therapy) to maximize the benefits of trofinetide after initiation | 88% | 12% | 0% | 0% | 100% |
| 28 | Trofinetide is not typically initiated at the full weight‐banded dose | 80% | 16% | 4% | 0% | 96% |
| 29 | A dose titration schedule should be created prior to initiation, with flexibility to adapt as needed based on tolerability | 84% | 16% | 0% | 0% | 100% |
| 30 | Titration should be adapted based on the patient's individual tolerance of the dose | 92% | 8% | 0% | 0% | 100% |
| 31a | Particularly if there are tolerability concerns (e.g., GI comorbidities), most physicians initiate trofinetide at either 5 mL (1000 mg) BID or 25% of the recommended weight‐banded dose BID and titrate thereafter; however, the starting dose should be individualized, taking into account factors such as the ability to consume liquids | 48% | 36% | 16% | 0% | 84% |
| 32a | Particularly if there are tolerability concerns (e.g., GI comorbidities), most physicians initiate trofinetide at either 5–10 mL (1000–2000 mg) BID or 25%–50% of the recommended weight‐banded dose BID and titrate thereafter; however, the starting dose should be individualized, taking into account factors such as the ability to consume liquids | 56% | 28% | 16% | 0% | 84% |
| 33a | Flexibility in management approaches is essential to accommodate individual patient history, tolerability, and clinical needs when initiating and titrating trofinetide | 80% | 20% | 0% | 0% | 100% |
| 34 | Patients should be titrated at a rate of 5 mL (1000 mg) per dose every 1–2 weeks, if they are tolerating trofinetide well | 32% | 44% | 20% | 4% | 76% |
| 35 | For patients unable to tolerate titration of 5–10 mL (1000–2000 mg) per dose every 1–2 weeks, slower titrations should be considered | 60% | 32% | 4% | 4% | 92% |
| 36 | Most patients achieve their full recommended weight‐banded dose, but those who do not may still achieve significant benefits from trofinetide treatment on a lower dose | 44% | 44% | 8% | 4% | 88% |
| 37 | Dosage should be reassessed at every visit and ideally every 6 months until reaching the target dose | 68% | 28% | 0% | 4% | 96% |
| 38 | Dosage should be reassessed once the patient progresses to the next weight band | 72% | 24% | 4% | 0% | 96% |
| 39 | Periodic dose rechallenges to achieve the recommended weight‐banded dose are encouraged, particularly if patients have been tolerating their current dose | 52% | 40% | 8% | 0% | 92% |
| Topic C. Assessing trofinetide benefits | ||||||
| 40 | While there may be evidence of improvement during acute periods of intolerability, proper assessment of improvement should take place after tolerability has been properly managed | 48% | 44% | 8% | 0% | 92% |
| 41 | Patients should receive trofinetide for 6 months after titrating to their weight‐banded, or highest tolerable, dose to properly assess the efficacy of the treatment | 56% | 40% | 4% | 0% | 96% |
| 42 | The decision to continue a patient on trofinetide should be guided by improvements in the patient's function and/or quality of life | 88% | 12% | 0% | 0% | 100% |
| 43 | Documentation of improvements on trofinetide should be mainly based on caregiver and/or clinician observations, rather than the exclusive use of CGI‐I or RSBQ assessments, as not all improvements can be captured by these assessments | 80% | 16% | 4% | 0% | 96% |
| 44a | CGI‐I and RSBQ assessments are primarily used as research instruments and are not routinely used in clinical practice | 72% | 20% | 8% | 0% | 92% |
| 45a | Improvements that may be meaningful to patients and caregivers are not always captured by CGI‐I or RSBQ | 64% | 28% | 8% | 0% | 92% |
| Topic D. Assessing and managing trofinetide tolerability | ||||||
| 46 | Reducing a patient's trofinetide dose to a level at which side effects can be managed, or pausing and restarting on a lower dose with the intention to increase as tolerated, is preferable to stopping the dose entirely | 72% | 28% | 0% | 0% | 100% |
| 47 | For patients experiencing severe side effects, their dosage should be reduced to a level at which they no longer experience side effects | 88% | 12% | 0% | 0% | 100% |
| 48 | Should any side effect require dose reduction, the side effect should be carefully managed until it is safe to increase the dose again | 80% | 20% | 0% | 0% | 100% |
| 49 | For patients experiencing severe and/or persistent side effects, healthcare providers should consider alternative underlying causes not related to trofinetide (e.g., diet, other medications) | 36% | 60% | 0% | 4% | 96% |
| 50 | The healthcare provider should adapt the titration schedule first before introducing additional medications, such as loperamide, to manage diarrhea | 52% | 28% | 20% | 0% | 80% |
| 51 | Fibrous foods such as bananas, peanut butter, avocado, or fiber bars may be used to manage diarrhea | 60% | 36% | 4% | 0% | 96% |
| 52 | For those receiving nutrition through gastrostomy, consider switching to an alternative brand of formula or a blenderized diet to improve digestive tolerance and manage diarrhea | 32% | 44% | 20% | 4% | 76% |
| 53 | If a patient's stool becomes “peanut butter consistency,” they should be encouraged to increase their fiber intake | 32% | 44% | 24% | 0% | 76% |
| 54a | Imodium may be considered short‐term (i.e., a few days) to manage severe diarrhea, but only if other options are unsuitable or ineffective, and should be discontinued as soon as clinically appropriate | 48% | 32% | 12% | 8% | 80% |
| 55a | Ongoing monitoring and management of bowel activity is important, as patients may develop or redevelop constipation after their body adjusts to prolonged use of trofinetide | 64% | 36% | 0% | 0% | 100% |
| 56a | Despite trofinetide's risk of diarrhea, maintaining adequate hydration and routinely monitoring bowel activity are important to prevent or minimize the development or redevelopment of constipation as the body adjusts to trofinetide | 80% | 20% | 0% | 0% | 100% |
| 57a | For patients experiencing severe side effects (i.e., incapacitating and/or preventing normal everyday activities), their dosage should be reduced to a level at which they no longer experience severe side effects | 84% | 12% | 4% | 0% | 96% |
| 58 | Positioning the patient upright during trofinetide administration may be used to manage vomiting | 28% | 52% | 16% | 4% | 80% |
| 59 | Smaller feeds, or slower rates of feed, may be used to manage vomiting | 52% | 44% | 0% | 4% | 96% |
| 60 | A patient's trofinetide dose may be further divided into more doses (i.e., smaller volume) as needed to manage vomiting | 40% | 56% | 0% | 4% | 96% |
| 61 | Proton pump inhibitors or H2 receptor antagonists may be used to suppress acid in an effort to reduce discomfort, the amount regurgitated, or feeding intolerance | 56% | 40% | 4% | 0% | 96% |
| 62 | Prokinetic agents may be used in cases where impaired motility is suspected | 40% | 60% | 0% | 0% | 100% |
| 63a | In the unlikely event that a patient experiences severe vomiting (i.e., incapacitating and/or preventing normal everyday activities) as a result of taking trofinetide, they should be referred to a GI specialist for further evaluation | 40% | 36% | 12% | 12% | 76% |
| 64 | For patients with a history of medication refusal or administration difficulty, caregivers should avoid mixing trofinetide with the patient's main nutritional source to reduce the risk of weight loss | 48% | 40% | 8% | 4% | 88% |
| 65 | Based on limited data, trofinetide is generally accepted as “seizure neutral” (i.e., the majority will not experience changes in seizures, while the minority may experience improvement or worsening during treatment, depending on the individual patient) | 64% | 36% | 0% | 0% | 100% |
| 66 | For patients experiencing administration difficulty, foods or liquids can be added to enhance taste | 68% | 28% | 4% | 0% | 96% |
| 67 | For patients who have previously responded well to rewards or incentives, they can be used to facilitate medication adherence | 56% | 40% | 4% | 0% | 96% |
| Topic E. Discontinuing or pausing trofinetide | ||||||
| 68 | In general, trofinetide can be safely paused and restarted | 84% | 12% | 4% | 0% | 96% |
| 69 | Pausing the dose is an option if a patient is traveling, hospitalized, or experiencing acute, severe side effects | 76% | 24% | 0% | 0% | 100% |
| 70 | Discontinuing trofinetide should be a shared decision with the patient and/or caregiver(s) | 84% | 16% | 0% | 0% | 100% |
| 71 | Trofinetide can be safely discontinued without tapering | 60% | 36% | 4% | 0% | 96% |
| 72 | Stopping trofinetide may lead to the loss of improvements acquired during treatment, although further observation and research are required | 44% | 44% | 8% | 4% | 88% |
Abbreviations: BID, twice a day; CGI‐I, Clinical Global Impression–Improvement; FDA, US Food and Drug Administration; GI, gastrointestinal; RSBQ, Rett Syndrome Behaviour Questionnaire; RTT, Rett syndrome.
Statement added/updated for round 2.
The final response rate for both rounds was 58%. While all statements achieved consensus according to the methodology, some statements achieved a greater proportion of “tend to agree” responses than “strongly agree,” suggesting that the strength of agreement varies between statements (Table 1; Supporting Information S2: Figure 2). Based on the final consensus, the authors proposed summative recommendations for trofinetide use (Figure 1).
Figure 1.
Summative recommendations for trofinetide use for Rett syndrome (RTT).
Agreement (88%–100%) across statements 1–2 and 5–7 supports trofinetide as first‐line therapy in the standard of care for eligible patients with RTT aged ≥ 2 years (Figure 2). Early initiation of trofinetide in the disease course is supported by respondents (statements 6–11; 84%–100%). Generally, respondents agree that some improvements may become apparent within 1 month for some individuals, particularly in attention and communication (statement 8; 92%), and that broader improvements in motor function, hyperventilation, bruxism, and sleep emerge by 3 months (statement 9) (Figure 2). Furthermore, consistent use over time will maintain these early gains and support improved communication and enhanced quality of life for both patients and caregivers (statements 10–11; both 88%).
Figure 2.
Decision support tool for trofinetide implementation and side effect management in Rett syndrome (RTT). BID, twice a day; GI, gastrointestinal; PPI, proton‐pump inhibitor; QID, four times a day; TID, three times a day.
In order to provide a comprehensive understanding of symptom severity and function prior to treatment, a thorough baseline assessment of clinical severity, functional status, seizure history, bowel function, and nutritional status is needed (Figure 2). This baseline can then be used to both inform the approach to dosing and titration and assess subsequent therapeutic response (statements 12–17; 84%–100%).
Importantly, the panel agreed that a general approach of initiating trofinetide at a low dose (either 5–10 mL twice a day [BID; 1000–2000 mg] or 25%–50% of the recommended weight‐banded dose BID) and then titrating in 5 mL (1000 mg) increments every 1 or 2 weeks is recommended to reduce the risk of significant side effects (Figure 2). Above all, flexibility in approach is key and particularly important in those individuals with tolerability concerns (statements 32, 33, 35; 84%–100%).
The consensus supported the use of caregiver‐reported diaries (statement 16; 88%), which can offer valuable insights into the individual's symptom profile and treatment efficacy not currently captured through standardized instruments like the RSBQ or the CGI‐I scale (statements 43–45). In the face of tolerability concerns with trofinetide, respondents unanimously favored the approach of dose reduction or temporary pausing, followed by restarting at a lower dose, rather than permanent discontinuation (statements 46–48; all 100%) (Figure 2).
The panel agreed on the need for a flexible approach to managing side effects, particularly diarrhea, which can often be addressed through dietary adjustments (e.g., food‐ and supplement‐based fiber, slower feeding) or short‐term loperamide use (statements 50–54; 76%–96%) (Figure 2). Adherence may also be improved through the use of flavoring or reward systems (statements 66–67; both 96%) (Figure 2). To support continued treatment, ongoing monitoring is essential due to risks of subsequent constipation during long‐term treatment (statements 55–56; both 100%) (Figure 2).
4. Discussion
The objective of this consensus program was to create recommendations for clinicians on how to initiate trofinetide, how to evaluate the impact of trofinetide on RTT symptoms, and how to manage side effects with trofinetide. Over two rounds, consensus was achieved for all statements. The members of the steering group and panel were all based at IRSF‐designated COEs and had experience in using trofinetide in the treatment of RTT. While the final results indicate agreement for all statements, there was a lack of consensus for 10 of the statements at the end of round 1, suggesting that the panel reviewed each statement with rigor to ensure that the final statement set was both appropriate and agreeable.
4.1. Enlist Trofinetide as Part of the Standard of Care for Eligible Patients With RTT
Trofinetide is approved for the treatment of RTT in the United States and Canada [18, 24] and has demonstrated efficacy in the largest and longest‐running clinical trial program in RTT syndrome to date [12, 15, 16]. It is the first disease‐specific treatment for RTT and the first to demonstrate the ability to improve the core symptoms of RTT, marking a critical milestone in the management of this disorder. Altogether, these findings advocate for the integration of trofinetide as the standard of care and as the foundation of comprehensive RTT management.
4.2. Conduct Baseline Functional Assessments and Provide Education on Potential Improvements and Side Effects
In order to provide a comprehensive understanding of symptom severity prior to treatment, baseline assessment of RTT clinical severity and patient functional status, seizure history, bowel function, and nutritional status should be carried out. This is essential to both accurately assess any therapeutic response to treatment and characterize any comorbidities [25]. Given the heterogeneity of RTT presentation, initial improvements with trofinetide may be subtle and easily overlooked without a clear reference point. Therefore, thorough pretreatment evaluation is essential to capture meaningful clinical change. To support clinician assessment, caregivers should be encouraged to keep a symptom diary to help track nuanced shifts in daily function and behavior.
4.3. Initiate Trofinetide Early, Monitor Broadly for Improvements, and Personalize Care
Early initiation of trofinetide is supported by both clinical trial data and the results reported here. Improvements have been observed within 1 month for some individuals, particularly in attention and communication, with broader effects (improvements in motor function, hyperventilation, bruxism, and sleep) emerging by 3 months [12, 19]. These findings reflect data from the RTT Natural History Study, which showed that RTT symptoms evolve dynamically after a period of apparently normal development; therefore, earlier intervention has the potential to arrest this process and help mitigate progression [26]. Early improvements in communication can lead to a greater understanding of symptomology and support treatment decisions. In addition, caregivers reported changes in their own daily lives as a result of improvements from treatment with trofinetide, including the family being happier, greater ability to attend family and social gatherings as a family, and improved interactions with their child [17, 27], supporting the early and sustained use of trofinetide.
The panel agrees that the RSBQ and CGI‐I scales do not adequately capture the true extent of improvements seen in clinical practice as a result of trofinetide treatment. Small symptomatic improvements (e.g., in communication or sleep) can result in meaningful improvements in both patient and caregiver quality of life. While the RSBQ is a validated assessment tool that has been accepted by the FDA as a primary outcome measure for clinical studies in RTT [2], its utility in practice has been questioned due to its subjectivity and reliance on on‐the‐day assessment. In addition, its use of a 3‐point scale does not capture incremental improvements in presentation and is subject to floor and ceiling effects due to the limited range between the absence and presence of a characteristic [2]. Hence, although the RSBQ remains valuable for research purposes, clinical practice should be guided by caregiver reports and clinician observations to reflect real‐world functioning and change over time. Where practical, the RSBQ can be augmented with objective measures (e.g., use of wearable devices to capture movement, sleep, etc.) and caregiver diaries to assess symptoms over time. In addition, when the RSBQ is used, clinicians and caregivers should consider behaviors over the prior 2 weeks in their assessment to reduce the impact of daily variation.
4.4. Start Trofinetide at a Low Dose, Titrate Slowly, and Tailor the Dose to Patient Needs
GI side effects such as diarrhea and vomiting remain the most common barriers to adherence with trofinetide. To minimize the impact of side effects, this consensus supports initiation at 5–10 mL (1000–2000 mg) BID or 25%–50% of the recommended weight‐banded dose BID and then titrate carefully at 5 mL (1000 mg) increase every 1–2 weeks based on tolerance. Real‐world data show the dose‐response relationship between trofinetide and side‐effect severity, where individuals receiving < 75% of the target as a first recorded dose experienced less severe diarrhea (as determined by stool type and frequency of clothing changes) and lower incidence of vomiting in the early weeks of treatment [27]. If tolerability remains a concern, the committee suggested considering further dividing doses and administering more frequently as three or four times daily (to achieve the same intended daily dose) [28], and slowing down food intake to reduce the occurrence of gastroesophageal reflux and emesis. If after this process the patient remains stable on a dose below the recommended weight‐banded dose, clinicians should consider periodic dose rechallenges to achieve the recommended weight‐banded dose, although meaningful clinical improvements have been achieved at doses below the target.
4.5. Customize Administration Strategies to Fit Each Patient's Unique Needs
Both the results of this consensus and prior recommendations support the personalization of administration strategies to minimize tolerability or adherence concerns. Trofinetide can be administered via oral syringes or through gastrostomy tubes using the G‐port [18]. For those taking trofinetide orally, dividing the trofinetide dose into three or four times daily may aid in reducing volume per dose for those with feeding difficulties [29]. Additionally, flavor enhancement or implementation of behavioral incentives for individuals who have previously responded well to incentives might support administration. However, trofinetide should not be mixed with the primary nutrition source of a patient with RTT so as not to encourage food aversion. This is particularly important in this population, who tend to be underweight and for whom feeding and nutrition are problematic. These techniques are consistent with strategies used in pediatric populations to overcome challenges related to medication aversion or administration difficulty [30].
4.6. Allow Adequate Time, at Least 6 Months, to Fully Assess Trofinetide Benefits
Patients and caregivers should understand that the therapeutic benefits of trofinetide may be delayed and incremental, particularly amid dose titration. Full therapeutic effects often emerge only after reaching a stable dose and allowing sufficient time for clinical improvements to manifest. Respondents supported maintaining treatment with trofinetide for at least 6 months post titration to determine efficacy, which is consistent with observations from extension trials and real‐world use [15, 16, 19, 21, 22, 31]. This extended observation period reflects the gradual nature of improvements and the estimated onset of trofinetide response [32].
4.7. Manage Side Effects With Dose Adjustments, Pauses, and Other Interventions Prior to Discontinuation
Recommendations for the management of trofinetide‐associated diarrhea were published in 2023 [33], but with an additional 3 years' clinical experience, there is an opportunity for further refinement. Although the use of loperamide was recommended to manage diarrhea, the authors advise caution in practice. For short‐term use (up to 3 days), loperamide remains an option to gain initial control of significant diarrhea, but in the longer term, fiber and dose adjustments should be employed. If diarrhea emerges, caregivers should consider increasing soluble fiber through the use of supplements such as psyllium, supported by dietary modifications as appropriate to normalize stool formation, combined with cessation of any constipation medications. Fiber supplementation can be maintained once diarrhea recedes but should be stopped if constipation emerges. If available, consultation with a gastroenterologist is recommended to support these interventions.
If necessary, the safety profile of trofinetide supports cessation without the need for dose reductions, so if GI side effects are severe, temporary cessation of trofinetide followed by reinitiation at a reduced dose with slowed dose titration is recommended above discontinuation. Importantly, our results show firm agreement among experienced clinicians that trofinetide is considered “seizure neutral,” reflecting the findings of a meta‐analysis of three randomized controlled trials [34] and making it suitable for a broad spectrum of RTT patients, including those with epilepsy. However, reports of trofinetide in the real world suggest that trofinetide may improve seizures in some cases, although this is an evolving area of research [20, 31, 35]. Ultimately, if an increase in seizures is observed on initiation of trofinetide, a neurology consultation is recommended.
5. Limitations
This consensus study has several limitations. Consensus was achieved for all statements over two rounds using a panel of practitioners selected for their experience with trofinetide. For this purpose, the use of a small, targeted panel is appropriate. However, the panel was recruited solely from the IRSF‐designated RTT COEs; as such, bias toward practice in these centers will exist. However, as the steering group and Delphi panel represent a significant proportion of the current clinical experience concerning trofinetide, for the purposes of providing insights into best practice, this was considered appropriate. It is not known why specific statements failed to achieve consensus in round 1; an improvement to the method would have been to capture free‐text feedback from the panel to provide some insights regarding consensus. Without such information, the steering group was only able to infer the reasons based on their own understanding. Finally, as trofinetide experience grows outside of specialist centers, this process should be repeated with a larger and more diverse panel to further redefine best practice.
6. Conclusion
The findings of this modified Delphi consensus support the integration of trofinetide as a foundational component of the standard of care for RTT, supported by therapies such as occupational, speech, and physical therapies, as well as nutritional support, use of assistive technologies, and treatment of RTT‐related comorbidities. Agreement was achieved across statements regarding early initiation, sustained use, and flexible dosing strategies. Clinicians and caregivers should be aware of the timescales required before symptom improvements become evident, and that permanent cessation of trofinetide may lead to loss of therapeutic gains. The panel advocated for managing side effects such as diarrhea with temporary dose adjustments, dietary strategies, and short‐term interventions rather than discontinuation. A flexible, patient‐centered approach is needed to maximize the benefits of trofinetide, which can realize quality‐of‐life improvements beyond the individual to family and caregivers.
Author Contributions
Erin O'Connor Prange: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation, supervision, resources. Arthur Beisang: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation, supervision, resources. Davut Pehlivan: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation, supervision, resources. Bernhard Suter: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation, supervision, resources. Paula Schleifer: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation, supervision, resources.
Conflicts of Interest
E.O. Prange has received consulting fees from Acadia Pharmaceuticals Inc. A. Beisang is a consultant for Acadia Pharmaceuticals Inc. D. Pehlivan is supported by the Doris Duke Charitable Foundation (#2023‐0235) and NINDS 1K23 NS125126‐01A1 and is a consultant to Ionis Pharmaceuticals and M2DS Therapeutics. B. Suter has received funding for clinical trials with Acadia Pharmaceuticals Inc., Grace Science Foundation, Ionis Pharmaceuticals, Marinus Pharmaceuticals, Neuren, Neurogene, and Rett Syndrome Research Trust, as well as funding for consultancy from Neurogene and Taysha Gene Therapies. P. Schleifer has received consulting fees from Acadia Pharmaceuticals Inc and Taysha Gene Therapies. All steering group members received honoraria from Acadia while undertaking this study.
Supporting information
Delphi_Supporting_Information_FINAL.
Acknowledgments
The authors thank Dr. Nupur Garg of the International Rett Syndrome Foundation for their support and collaboration.
The authors thank the following for their willingness to act as Delphi panel members:
Payal Kenia Gu, MD, Clinical Assistant Professor of Pediatrics and Neurology (Clinician Educator), Keck School of Medicine of USC.
Emily C. de los Reyes, MD, Clinical Professor of Pediatrics and Neurology at The Ohio State University College of Medicine.
Eric D. Marsh. MD, PhD, Professor of Neurology and Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania.
Judith Leona Zwiebel Weisenberg, MD, Associate Professor of Neurology in the Division of Pediatric Neurology at Washington University.
Christopher W. Beatty, MD, Assistant Professor of Neurology at Nationwide Children's Hospital, Ohio.
Grace Correa, MSN, RN, CPNP, Pediatric Nurse Practitioner, Neurogenetics Program, Boston Children's Hospital.
Alan K. Percy, Professor Emeritus, Department of Pediatrics (Neurology), University of Alabama at Birmingham.
Constance Smith‐Hicks, MD, PhD, Associate Professor, Department of Neurology, Johns Hopkins University School of Medicine.
Rochelle M. Witt, MD, PhD, Assistant Professor Divisions of Child Neurology, Pulmonary Medicine, and The Sleep Center, Cincinnati Children's Hospital Medical Center.
Richard H. Haas, MB, BChir, MRCP, Department of Neurosciences, University of California San Diego.
Sailaja Golla, MD, Pediatric Neurodevelopmental Neurologist, Children's Hospital of Orange County.
Amitha L. Ananth, Department of Pediatrics (Neurology), Heersink School of Medicine, University of Alabama at Birmingham.
David N. Lieberman, MD, PhD, Department of Neurology, Boston Children's Hospital.
Maria del Pilar Gennaro, ARNP, Pediatric Nurse Practitioner, Nicklaus Children's Hospital, Miami, Florida.
Elizabeth Berry‐Kravis, MD, PhD, Professor of Pediatrics and Neurological Sciences, Rush University Medical Center, Chicago.
Steven A. Skinner, MD, Senior Clinical Geneticist, Greenwood Genetic Center.
Natalie Guido‐Estrada, MD, Pediatric Neurology Rady Children's Health, Associate Clinical Professor UCSD Department of Neurosciences.
Peter Heydemann, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center.
Aleksandra Jacobs, MD, PhD, Director, Rett Syndrome Center at the Children's Hospital at Montefiore, New York.
Colleen Buhrfiend, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center.
Remaining participants who wished to remain anonymous.
The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). Editing support was provided by Evidence Scientific Solutions, Inc., and funded by Acadia Pharmaceuticals Inc. The authors wish to thank Emily Lassman and Ian Walker from Triducive Partners Limited (St Albans, Herts, UK) for their support in collating the data, analyzing the results, and supporting the Delphi methodology.
Data Availability Statement
Acadia Pharmaceuticals Inc. supports data sharing consistent with the Principles for Responsible Clinical Trial Data Sharing and International Committee of Medical Journal Editors' (ICMJE) Recommendations. Acadia Pharmaceuticals Inc. shares data from completed clinical trials through public registries (ClinicalTrials.gov), presentations at scientific congresses, and open access articles in peer‐reviewed journals. The authors will provide access to individual de‐identified participant‐level data that underlie the data presented in this paper to any researcher who provides a methodologically sound proposal for academic purposes to interpret, verify, and extend research in the article, beginning 6 months and ending 5 years after article publication. Requests for the “minimum dataset” should go through Acadia Pharmaceuticals Inc. Medical Information and will be reviewed by the sponsor (Acadia Pharmaceuticals Inc.) to verify whether the request is subject to any intellectual property or confidentiality obligations. For additional information, please contact Acadia Pharmaceuticals Inc. Medical Information at medicalinformation@acadia-pharm.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Delphi_Supporting_Information_FINAL.
Data Availability Statement
Acadia Pharmaceuticals Inc. supports data sharing consistent with the Principles for Responsible Clinical Trial Data Sharing and International Committee of Medical Journal Editors' (ICMJE) Recommendations. Acadia Pharmaceuticals Inc. shares data from completed clinical trials through public registries (ClinicalTrials.gov), presentations at scientific congresses, and open access articles in peer‐reviewed journals. The authors will provide access to individual de‐identified participant‐level data that underlie the data presented in this paper to any researcher who provides a methodologically sound proposal for academic purposes to interpret, verify, and extend research in the article, beginning 6 months and ending 5 years after article publication. Requests for the “minimum dataset” should go through Acadia Pharmaceuticals Inc. Medical Information and will be reviewed by the sponsor (Acadia Pharmaceuticals Inc.) to verify whether the request is subject to any intellectual property or confidentiality obligations. For additional information, please contact Acadia Pharmaceuticals Inc. Medical Information at medicalinformation@acadia-pharm.com.