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

Abbreviations

BRAT bananas, rice, applesauce, and toast

GPE glycine-proline-glutamate

RTT Rett syndrome

TEAE treatment-emergent adverse event

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).

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.

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.