Recommendations for the management of diarrhea with trofinetide use in Rett syndrome

ABSTRACT

Background

Trofinetide is a recently approved treatment for Rett syndrome (RTT), a rare neurodevelopmental disorder with no previously approved therapy. The phase 3 LAVENDER trial showed improvements in efficacy measures compared with placebo, but diarrhea rates were high in trofinetide-treated participants. To manage possible diarrhea, recommendations that can be used by health care providers are needed.

Research design and methods

Additional analyses were conducted on LAVENDER data to elucidate predictors of trofinetide-associated diarrhea. A panel of advisors was convened to refine a set of practical recommendations for the prevention and management of diarrhea in individuals with RTT treated with trofinetide.

Results

No examined demographic or treatment factors appeared to influence trofinetide-associated diarrhea. Advisors recommend establishing baseline bowel activity and providing caregivers with diarrhea management information. On initiation of trofinetide, constipation medications should be stopped or reduced, concomitant liquid medications with sugar alcohols should be substituted if possible, and fiber should be initiated. Bowel movements should be tracked and loperamide started following the onset of diarrhea. Dietary and hydration measures are also recommended.

Conclusions

Trofinetide treatment confers improvements in RTT-related symptoms. With these recommendations, diarrhea associated with trofinetide use can be managed, enhancing the lives of individuals with RTT and caregivers.

KEYWORDS:

• gastrointestinal
• neurodevelopmental disorder
• recommendations
• stool patterns
• Rett syndrome
• trofinetide

This article is related to:

Recommendations for Managing Diarrhea from Trofinetide use in Individuals with Rett Syndrome: A Plain Language Summary

1. Introduction

Rett syndrome (RTT) is a rare, X- linked neurodevelopmental disorder that is usually caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) [1]. Individuals with RTT appear to undergo normal development until about 6 months of age, when RTT progressively impairs the central nervous system, leading to losses in communication skills and fine and gross motor skills, as well as the development of hand stereotypies, respiratory dysfunction, and seizures [2–4]. RTT may lead to a variety of symptoms, including gastrointestinal complications, cardiac conduction abnormalities, neuroendocrine problems, and skeletal abnormalities [2,4,5]. Gastrointestinal problems, which confer an adverse effect on quality of life [6], are reported by 92% of caregivers of individuals with RTT, with 80% reporting constipation; 69%, straining with bowel movements; and 61%, passage of hard stools [7]. Constipation is usually managed with additional fluid intake, encouragement of regular toileting and physical activity, and the use of laxatives [8].

Trofinetide (glycyl-L- 2- methylprolyl-L- glutamic acid) is a synthetic analog of glycine-proline-glutamate (GPE), a naturally occurring tripeptide enzymatically cleaved from insulin-like growth factor-1 [9]. Both trofinetide and GPE show neuroprotective effects, but trofinetide has a longer half-life and better oral bioavailability than GPE [10,11].

The randomized, placebo-controlled, phase 3 LAVENDER trial (ClinicalTrials.gov NCT04181723) evaluated weight-based dosing of trofinetide in females 5–20 years of age with classic/typical RTT and a documented disease-causing MECP2 gene mutation over a 12-week, double-blind treatment period [12]. Trofinetide and matching placebo were supplied as a strawberry-flavored solution to be administered orally or via gastrostomy tube. The group that was administered trofinetide demonstrated significant and clinically relevant improvements over placebo at week 12 in physician- and caregiver-reported outcome measures of RTT symptoms, including the coprimary outcome measures (Rett Syndrome Behaviour Questionnaire and Clinical Global Impression-Improvement) and the key secondary endpoint (Communication and Symbolic Behavior Scales Developmental Profile™ Infant Toddler Checklist Social Composite) [13].

During the trial, although data were blinded, it was noticed that a significant portion of participants were reporting diarrhea. To manage the diarrhea associated with trofinetide, a management plan was developed at the Children’s Hospital of Philadelphia and was provided to the clinical trial sites while the phase 3 study was ongoing. This diarrhea management plan involved discontinuation or adjustment of bowel medications for constipation as well as administration of psyllium fiber and loperamide, with adjustments based on the individual’s bowel movement frequency and consistency. These recommendations were not protocolized or required. Dose reductions up to 50% were permitted.

In order to more thoroughly provide management recommendations for diarrhea associated with trofinetide, additional analyses were conducted on the phase 3 data regarding diarrhea in order to determine whether there were predictors of the diarrhea associated with trofinetide. In addition, a panel of advisors and experts in gastroenterology and RTT was convened in order to refine a set of practical recommendations for a wide range of health care providers and RTT caregivers for the prevention and management of diarrhea in individuals with RTT using trofinetide.

2. Patients and methods

In order to examine and potentially explain the diarrhea associated with trofinetide use, analysis of data from the LAVENDER trial was conducted upon its completion, including participant age, weight at baseline, preexisting bowel issues, gastrostomy tube status, and dose/volume of trofinetide. The study protocol was approved by local institutional review boards (IRB) and ethics committees (central IRB was WCG IRB), and written informed consent was obtained [12]. Descriptive statistics (mean, median, standard deviation) are presented, but statistical testing was not performed because these data were not powered for statistical analysis, many sample sizes were small, and the analysis was post hoc in nature.

Diarrhea management recommendations were based on the plan developed at the Children’s Hospital of Philadelphia. These recommendations were refined based on a literature search performed by Interactive Forums, Inc. (Conshohocken, PA). The draft recommendation statements underwent a second round of edits, and authors attended an online panel meeting to further discuss and refine the statements. All authors gave additional input during manuscript development.

3. Results

3.1. Prevalence of diarrhea treatment- emergent adverse events in the LAVENDER trial

Although trofinetide is generally well tolerated, diarrhea was the most commonly reported treatment-emergent adverse event (TEAE) in the LAVENDER trial, with rates of 80.6% in the trofinetide group and 19.1% in the placebo group [13]. Of the diarrhea TEAEs, 97.3% were of mild to moderate severity (mild: easily tolerated, caused minimal discomfort, did not interfere with normal everyday activities; moderate: sufficiently discomforting to interfere with normal everyday activities; severe: incapacitating and/or prevented normal everyday activities) [13]. Diarrhea TEAEs started about 1 week (range 1–49 days) after starting trofinetide (data on file). The duration of diarrhea varied but resolved within a median of 3 days after stopping trofinetide (data on file). Of those in the trofinetide group with diarrhea, 40.0% had a dose reduction, and 10.7% resumed their original dose. Twelve (12.9%) participants who received trofinetide withdrew from the study due to a TEAE of diarrhea [13]. None of the diarrhea TEAEs were serious [13] or associated with hospitalization; 1 occurred with a TEAE of dehydration (data on file). Loperamide was used in 50.5% of participants on trofinetide and 3.2% on placebo [13].

3.2. Potential contributors to diarrhea TEAEs in the LAVENDER trial

On further examination of diarrhea TEAEs from the LAVENDER trial, no demographic, disease, or other characteristics were found to influence diarrhea TEAEs. For example, the incidence of diarrhea TEAEs and severity did not differ by age (Table 1). The time to onset and duration of diarrhea TEAEs were also similar across age groups (Table 1). Diarrhea TEAE rates did not differ in those with (80.0%) or without (82.6%) a history of constipation. The route of administration of trofinetide did not appear to confer a large difference in diarrhea TEAE rates, with reports of diarrhea in 89.5% (34/38) with gastrostomy tube administration and 74.5% (41/55) with oral administration. The frequency of diarrhea TEAEs was not notably greater with a higher initial dose of trofinetide, with rates of 69.2%, 88.0%, 83.3%, and 83.3% in those receiving initial doses of 150–<250, 250–<300, 300–<350, and 350–<500 mg/kg twice daily, respectively. Fewer trofinetide-treated participants with diarrhea TEAEs experienced weight loss of ≥7% from baseline (10.7%) compared with those without diarrhea (16.7%). Overall, 9.7% (9/93) of participants in the trofinetide group took probiotics at any time during the study. Of those who received probiotics, 88.9% (8/9) reported diarrhea, a similar rate to the 80.6% in the entire trofinetide group.

Table 1. Incidence, severity, time to onset, and duration of diarrhea TEAEs by age group at baseline in the phase 3 LAVENDER trial (safety analysis set).

				Maximum severity
Treatment and age group, y	N	Participants with diarrhea, n (%)	Diarrhea events, n	Mild, n (%)	Moderate, n (%)	Severe, n (%)	Mean time to onset, days (min, max)	Mean event duration, days (min, max)
Placebo
5–10	52	10 (19.2)	11	9 (17.3)	1 (1.9)	0	11.8 (2, 33)	13.8 (1, 78)
11–15	24	4 (16.7)	4	3 (12.5)	1 (4.2)	0	23.0 (1, 78)	5.8 (2, 12)
16–20	18	4 (22.2)	5	3 (16.7)	1 (5.6)	0	19.0 (8, 36)	33.5 (3, 77)
Trofinetide
5–10	49	39 (79.6)	48	26 (53.1)	13 (26.5)	0	6.6 (1, 38)	52.2 (1, 92)
11–15	25	22 (88.0)	28	9 (36.0)	12 (48.0)	1 (4.0)	8.4 (1, 49)	50.6 (4, 89)
16–20	19	14 (73.7)	27	4 (21.1)	9 (47.4)	1 (5.3)	3.4 (1, 8)	50.6 (8, 84)

Note: TEAE: treatment-emergent adverse event.

3.3. Diarrhea management recommendations

Based on the diarrhea management plan initiated during the LAVENDER trial, a set of recommendations is proposed (Table 2) and described below. For the purpose of these recommendations, diarrhea is defined as any softening of stool or increased frequency of bowel movements, corresponding to types 6 or 7 on the Bristol stool scale [14].

Table 2. Recommendations for diarrhea management for individuals being treated with trofinetide.

Prior to initiating trofinetide
1	Obtain a 7- day baseline of bowel activity (stool frequency and consistency, presence of blood) and provide caregiver education on diarrhea management
Upon initiation of trofinetide
2	Upon the start of trofinetide, stop or reduce all constipation medications
3	At initiation of trofinetide, examine any concomitant medications and switch as many liquid medications that contain sugar alcohols as possible to pill form
4	Start fiber (e. g. psyllium, wheat dextrin, flaxseed) as a stool normalizer when starting trofinetide according to the following dosing instructions: Children: 0.5–1 tsp 1–3 times daily in 4 oz water Adolescents/adults: 1–2 tsp 1–4 times daily in 8 oz water Continue fiber to promote bowel health, even in the absence of diarrhea or if diarrhea resolves
Upon occurrence of diarrhea
5	At the onset of diarrhea, start oral loperamide according to the following dosing instructions: Children 2–<12 years of age : ○ 2–5 years of age and/or weighing 13–<21 kg: initially 1 mg with first loose stool, followed by 1 mg/dose every 8 hours; maximum: 3 mg/day ○ 6–8 years of age and/or weighing 21–27 kg: initially 2 mg with first loose stool, followed by 1 mg/dose every 8 hours; maximum: 4 mg/day ○ 9–11 years of age and/or weighing 27.1–43 kg: initially 2 mg with first loose stool, followed by 1–2 mg/dose every 8 hours; maximum: 6 mg/day Children ≥12 years of age and adolescents weighing >43 kg: ○ Initially 4 mg with first loose stool, followed by 2 mg/dose every 8 hours; maximum: 8 mg/day Adults: ○ Initially 4 mg with first loose stool, followed by 4 mg/dose every 6 hours; maximum: 16 mg/day Use the lowest effective dose of loperamide that maintains symptomatic control If no bowel movement occurs for 24 hours, withhold loperamide until a bowel movement occurs If bloody diarrhea occurs, loperamide is contraindicated and should not be used Other antidiarrheal medications to consider include bismuth subsalicylate and cholestyramine; anticholinergic medication may be considered for severe cramping. Consult with the individual’s gastroenterologist
6	If diarrhea occurs, ask the caregiver to contact the prescriber and to begin tracking the consistency and frequency of bowel movements or the occurrence of new fecal incontinence. If diarrhea persists despite the discontinuation of constipation medications and the initiation of fiber supplements, a 50% dose reduction of trofinetide may be considered. Following resolution of the diarrhea, trofinetide may be titrated back up to the full dose
Other
7	Initiate the following dietary and hydration measures: Diet ○ For a child who is not dehydrated, continue a regular diet ○ Regular milk, yogurt, complex carbohydrates (e. g. bread, potatoes, rice, wheat), fruits, vegetables, and lean meats are recommended ○ High-fat foods should be avoided ○ Food should be provided in smaller and more frequent volumes ○ Fruit juice should be given at half-strength (i. e. mixed with an equal amount of water) Hydration ○ Review daily fluid requirements and intake in light of potential increased fluid output due to diarrhea ○ Monitor for dehydration Signs of mild dehydration include increased thirst, a slightly dry mouth, and slightly decreased urination Signs of moderate or severe dehydration include dry mouth, significantly decreased urination, lack of tears, and sunken eyes Administer an oral rehydration solution (e. g. Pedialyte® or generic) for mild dehydration 5 tsp/lb should be given over 4 hours Small volumes of the dose can be given as frequently as every few minutes or as tolerated Contact the prescriber in the event of moderate or severe dehydration
8	If the individual has stopped constipation medications and does not have diarrhea or a bowel movement for 24 hours, regular constipation medications may be resumed as needed

3.3.1. Prior to initiating trofinetide

3.3.1.1. Recommendation 1

Obtain a 7- day baseline of bowel activity (stool frequency and consistency, presence of blood) and provide caregiver education on diarrhea management before initiation of trofinetide. A 7- day daily bowel record should be sufficient to document a typical elimination pattern. Stool consistency may be subject to the interpretation of the caregiver or family. While the Bristol stool scale [14] is appropriate for research and possibly caregivers, practical comparisons may be helpful for describing stool texture. For example, it may help to ask caregivers whether the stool is shaped like a ball or pebble, stringy, or formed like a log. Blood in stool should be evaluated to rule out a side infection or fissures from constipation and should prompt a general pediatric or gastroenterology consultation.

3.3.2. Upon initiation of trofinetide

3.3.2.1. Recommendation 2

Upon the start of trofinetide, stop or reduce all constipation medications. This recommendation allows flexibility for stopping or reducing constipation medications to avoid a lapse into a diarrhea routine in susceptible individuals. When there is a history of severe constipation, a gastroenterology consultation may be warranted. Caregiver input should be considered as to whether constipation or diarrhea is more problematic. Some clinicians may also prefer adjusting the approach to constipation management during an up-titration of trofinetide. Strategies may include suppositories or enemas, as needed, in place of daily medications.

3.3.2.2. Recommendation 3

At initiation of trofinetide, examine any concomitant medications and switch as many liquid medications that contain sugar alcohols as possible to pill form. Many sugar alcohols have a laxative effect [15], and the altered gut microbiome in individuals with RTT may influence their susceptibility to diarrhea [16–18], so it is helpful to eliminate any other potential causes of diarrhea during trofinetide treatment.

3.3.2.3. Recommendation 4

Start fiber (e. g. psyllium, wheat dextrin, flaxseed) as a stool normalizer when starting trofinetide. Recommended dosing for children is 0.5–1 tsp 1–3 times daily in 4 oz water; for adolescents/adults, 1–2 tsp 1–4 times daily in 8 oz water. Continue fiber to promote bowel health, even in the absence of diarrhea or diarrhea resolution. A proactive approach to diarrhea prevention is advised, considering the rates of diarrhea TEAEs in trials. In the authors’ experience, prophylactic fiber appears to be more acceptable to families compared with prophylactic loperamide. Initial gas and bloating may be experienced with fiber, which is often temporary [19], so practitioners may adjust fiber as needed. Fiber is often used to improve stool consistency in the setting of either diarrhea or constipation [20], so taking fiber with trofinetide may help in this regard. For this reason, fiber should be continued, assuming it is well tolerated, regardless of diarrhea status.

3.3.3. Upon occurrence of diarrhea

3.3.3.1. Recommendation 5

At the onset of diarrhea, start oral loperamide according to the dosing instructions by age and weight in Table 2, using the lowest effective dose of loperamide that maintains symptomatic control. For example, one might start with a dose every 8 hours but, through trial and error, find that once- or twice-daily dosing suffices. Even a single daily dose may be effective for diarrhea management.

If no bowel movement occurs for 24 hours, withhold loperamide until a bowel movement occurs. If bloody diarrhea occurs, loperamide is contraindicated and should not be used. Prophylactic use of loperamide upon initiation of trofinetide is not recommended due to concerns over unnecessarily inducing impaction. Although loperamide is not recommended when the cause of diarrhea is unknown, it is helpful in the management of trofinetide-induced diarrhea. (There is resistance to the use of loperamide for diarrhea of unknown causes because it may cause accumulation of the infectious agent if gastroenteritis is the cause of diarrhea.)

Other antidiarrheal medications to consider include bismuth [21] and cholestyramine. Families may prefer milder forms of antidiarrheal treatment such as bismuth subsalicylate for short-term use. Like other medications containing salicylate, it must be avoided in those with chicken pox exposure or illness [22]. Anticholinergic medication may be considered for severe cramping. Caregivers should consult with the individual’s gastroenterologist to address the use of other antidiarrheal medications and cramping. For unresolved diarrhea, the duration of antidiarrheal treatment and other management approaches may be determined through close collaboration with the individual’s gastroenterologist.

3.3.3.2. Recommendation 6

If diarrhea occurs, ask the caregiver to contact the prescriber and to begin tracking the consistency and frequency of bowel movements or occurrence of new fecal incontinence. Frequency and consistency of stool are key characteristics to capture in the diarrhea event diary. ‘New fecal incontinence’ is included in consideration of those who may lose bowel control with trofinetide treatment. In the authors’ experience, most individuals with RTT are not fully continent at baseline, although they may be ‘time-trained.’ For individuals who are trained, development of fecal incontinence may be a deterrent to continued treatment.

Hydration status should be monitored by the caregiver as well as the clinician, but it is not necessary to track with diarrhea events. Caregivers should track hydration status by monitoring fluid intake, moisture of mucus membranes, presence of tears (if crying), voiding frequency during the daytime, and any deviance from the normal voiding routine. Consistency and frequency of stool should provide information for assessing hydration.

The presence of visible blood is not anticipated for trofinetide-induced diarrhea. As noted above, visible blood in the stool should prompt a general pediatric or gastroenterology visit.

If diarrhea persists despite discontinuation of constipation medications and initiation of fiber, a 50% dose reduction of trofinetide may be considered. Following diarrhea resolution, trofinetide may be titrated back to the full dose.

3.3.4. Other

3.3.4.1. Recommendation 7

If hydration status is normal, the individual with RTT should continue a regular diet: regular milk, yogurt, complex carbohydrates (e. g. bread, potatoes, rice, wheat), fruits, vegetables, and lean meats are recommended [23]. High-fat foods should be avoided, and a low-fat diet, rather than a bananas, rice, applesauce, and toast (BRAT) diet, is preferred, since BRAT is considered to be unsuitable for diarrhea management [23,24]. Food should be provided in smaller and more frequent volumes. Fruit juice should be given at half-strength (i. e. mixed with an equal amount of water).

To ensure adequate hydration, review daily fluid requirements and intake in light of potential increased fluid output due to diarrhea. Total daily fluid requirements are calculated on an individual basis with the recommendation that caregivers meet at least 80% of their child’s total daily fluid needs. Hypernatremia can occur due to diarrhea, which may be avoided by calculating and providing adequate fluid to counter the fluid output with diarrhea.

Caregivers should also monitor for dehydration. Signs of mild dehydration include increased thirst, a slightly dry mouth, and slightly decreased urination [23]. Moderate or severe dehydration signs include dry mouth, significantly decreased urination, lack of tears, and sunken eyes [23]. Because urinary retention may occur in individuals with RTT [25], a duration for decreased urine output is not specified.

For mild dehydration, administer an oral rehydration solution (e. g. Pedialyte® or generic) at 5 tsp/lb, given over 4 hours. Small volumes of the dose can be given as frequently as every few minutes or as tolerated. The prescriber should be contacted in the event of moderate or severe dehydration.

3.3.4.2. Recommendation 8

If the individual has stopped constipation medications and does not have diarrhea or a bowel movement for 24 hours, regular constipation medications may be resumed as needed, similar to the recommended timeframe for withholding loperamide.

4. Discussion

The use of a diarrhea management plan in the phase 3 LAVENDER trial led to refined recommendations on the management of diarrhea in individuals with RTT treated with trofinetide. The recommendations here are in line with those on management of diarrhea occurring during treatment with other therapies, including maintenance of hydration, electrolyte replacement, discontinuation of laxatives, initiation of loperamide, consumption of a low-fat diet, dose reduction or temporary interruption of medication, and use of fiber [26–31]. Several clinical trials have shown that addition of dietary fiber led to improvements in diarrhea or loose stools [32,33], including in tube-fed participants [34–36].

A therapeutic approach to diarrhea control is imperative in order to sustain treatment with trofinetide for maintenance of improvements in RTT symptoms. Addressing the diarrhea immediately and aggressively as outlined here was considered the best remediation strategy.

Managing possible diarrhea with the use of trofinetide occurs in the background of existing disease-associated gastrointestinal comorbidities, such as constipation. Here, it is noted that regular constipation medications may be resumed if there has been no bowel movement for 24 hours. Ultimately, the postmarketing experience with trofinetide may guide the recommendation to continue or withdraw constipation medications with trofinetide use.

In the phase 3 LAVENDER trial, a TEAE of diarrhea was reported by 80.6% of those in the trofinetide group, and 97.3% of these diarrhea TEAEs were of mild/moderate severity [13]. No demographic, disease, or other characteristics, including age, history of constipation, route of administration, and initial dose, were identified as associated with diarrhea TEAEs. Generally, probiotic use reduces the duration of diarrhea [37], but it is not known whether they are useful for trofinetide-associated diarrhea. Fewer than 10% of participants in the trofinetide group used probiotics during the study, and their incidence of diarrhea was similar to that of the entire trofinetide group.

Excipients in both the trofinetide and placebo formulations used in the LAVENDER trial were water, maltitol, strawberry flavor, sucralose, methylparaben sodium, propylparaben sodium, and FD&C Red #40. While sugar alcohols such as maltitol (and sorbitol, a metabolite of maltitol) are known to have a laxative effect [15], identical amounts of maltitol were used in the preparations of trofinetide and placebo in the LAVENDER trial. The composition of the gut microbiome influences the ability to metabolize sugar alcohols [17], and the gut microbiome may be altered in individuals with RTT relative to healthy controls [16,18], so the gut microbiome may play a role in the susceptibility to developing diarrhea with the use of trofinetide. Further, the use of certain classes of antibiotics, such as aminopenicillins and aminoglycosides, was shown to shift the composition of the gut microbiome and increase sugar alcohol–induced diarrhea in mice [17], so the benefit of the use of these medications should be assessed in individuals with RTT who will be treated with trofinetide. In addition, macrolide antibiotics such as erythromycin are often used to increase gastric motility in individuals with RTT, but these may also cause antibiotic-associated diarrhea [38].

Individuals with RTT may be more susceptible than others to trofinetide-induced diarrhea. A phase 1 study in which 41 healthy adult individuals received 12 g trofinetide (corresponding to about 160 mg/kg once daily) reported no diarrhea TEAEs [39]. Trofinetide has also been tested in 72 adolescent and adult males with fragile X syndrome, and diarrhea rates of 8% and 9% were reported in the trofinetide 35 and 70 mg/kg twice daily groups, respectively [40]. Dosing could also play a role, as participants in the LAVENDER trial received trofinetide at a range equivalent to 200–500 mg/kg twice daily, though diarrhea rates in the phase 2 RTT studies were still higher than those in the fragile X syndrome trial, with rates of 39% and 11% in those who respectively received trofinetide 35 or 70 mg/kg twice daily [41] and 27% and 13% in those who received trofinetide 50 or 100 mg/kg twice daily [42].

The analyses of diarrhea in the LAVENDER trial are limited by no direct measurement of stool volume. In addition, there was no laboratory assessment of potential causes of diarrhea with trofinetide (e. g. secretory, osmotic, malabsorptive, inflammatory diarrhea). Further, the effect of the clinical severity of RTT on diarrhea TEAEs is not known, as the trial participants’ mutations in the MECP2 gene were not examined in relation to the occurrence of diarrhea. Dietary fiber consumption prior to the trial may have affected diarrhea rates, but these data were not collected. Furthermore, since the trial was ongoing during the nationwide formula shortage, some participants switched formulas due to lack of supply. These formula changes may have resulted in different levels of fiber intake, may not have been optimal for each trial participant, and could have affected rates of diarrhea. Finally, as mentioned in the introduction, the plan to manage diarrhea in the LAVENDER trial was not prospectively designed into the protocol, so a future consideration is to study the effectiveness of this plan in a prospective manner.

Whether the administration of trofinetide with other medications or with food affects the occurrence of diarrhea is unknown. LAVENDER study investigators were instructed to administer trofinetide in a consistent manner, but whether it should be in the absence of food or other medications was not specified. Notably, a negligible effect of food on trofinetide pharmacokinetic parameters was found in the phase 1 study of healthy individuals [39]. In addition, trofinetide does not appear to affect the function of CYP3A4, the enzyme involved in the metabolism of antimotility drugs like loperamide, in the liver [43].

5. Conclusions

Despite the observed incidence of diarrhea in the clinical trials, treatment of individuals with RTT with trofinetide led to improvements in RTT-related symptoms [13]. Of note, not all individuals with RTT who are treated with trofinetide develop diarrhea: nearly 20% of those in the trofinetide group in the LAVENDER trial reported no diarrhea TEAEs. Because there is no currently approved treatment for RTT, the authors note that participants in the trials were often willing to tolerate diarrhea in order to experience the potential effect of trofinetide, and this attitude may persist in clinical practice. The diarrhea management recommendations proposed here will hopefully mitigate this adverse effect of trofinetide treatment, improve the lives of individuals with RTT, and reduce caregiver burden.

Abbreviations

BRAT bananas, rice, applesauce, and toast

GPE glycine-proline-glutamate

RTT Rett syndrome

TEAE treatment-emergent adverse event

Declaration of interest

ED Marsh has received funding from the International Rett Syndrome Foundation, Rett Syndrome Research Trust, Curaleaf, and the National Institutes of Health; funding for clinical trials from Acadia Pharmaceuticals Inc., Stoke Therapeutics, Takeda Pharmaceuticals, GW Pharmaceuticals, Marinus Pharmaceuticals, and Zogenix Pharmaceuticals; and consultancy fees from Stoke Therapeutics and Acadia Pharmaceuticals Inc. A Beisang is a consultant to Acadia Pharmaceuticals Inc. T Buie served as a consultant for Acadia Pharmaceuticals Inc. TA Benke has received funding for consulting from Acadia Pharmaceuticals Inc., Alcyone Therapeutics, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neuren Pharmaceuticals, Neurogene, Ovid Therapeutics, Takeda Pharmaceutical Company Limited, Ultragenyx, and Zogenix; and funding for clinical trials from Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust; all remuneration has been made to his department. B Gaucher has no disclosures to report. KJ Motil has received funding for clinical research studies from the International Rett Syndrome Foundation and funding for consulting from Acadia Pharmaceuticals Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium for their review work. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Author contributions

ED Marsh developed the initial diarrhea management recommendations used in the LAVENDER trial and revised them for this manuscript. A Beisang, T Buie, TA Benke, and KJ Motil revised the diarrhea management recommendations. B Gaucher developed the initial diarrhea management recommendations used in the LAVENDER trial. All authors have reviewed and approved the final version of the manuscript.

Acknowledgments

Jennifer L. Giel, PhD, on behalf of Evidence Scientific Solutions, Philadelphia, PA, provided medical writing and editing services in the development of this manuscript. The authors acknowledge Dr. Anthony Lembo for reviewing the draft recommendations.

The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04181723).

Data availability statement

The data that support the findings of this study are available from the corresponding author KJM upon reasonable request.

Additional information

Funding

Acadia Pharmaceutics Inc. provided funding for the development of this manuscript and received courtesy reviews for medical accuracy but did not direct the content.