Cited by 163Genetics and Neurodevelopmental DisordersPharmacological Effects and Toxicity StudiesAlzheimer's disease research and treatments

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Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome

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Glaze, Daniel G., Neul, Jeffrey L., Kaufmann, Walter E., Berry-Kravis, Elizabeth, Condon, Sean, Stoms, George, Oosterholt, Sean, Della Pasqua, Oscar, Glass, Larry, Jones, Nancy E., Percy, Alan K., Rett 002 Study Group, Glaze, Daniel G., Neul, Jeffrey L., Kaufmann, Walter E., Berry-Kravis, Elizabeth, Condon, Sean, Stoms, George, Oosterholt, Sean, Pasqua, Oscar Della, Glass, Larry, Jones, Nancy E., Percy, Alan·2019·Neurology

DOI 10.1212/wnl.0000000000007316PMC PMC6550498

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Abstract

OBJECTIVE: To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. METHODS: This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. RESULTS: All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. CONCLUSION: These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

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Figure 1 Study design (A) and participant disposition (B) BID = twice daily dosing; ITT = intention to treat; mITT = modified intention to treat; PK = pharmacokinetic.CC BY-NC-ND · PubMed Central

Figure 2 Core efficacy measures demonstrating improvement in the 200 mg/kg group compared to placebo (A) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RSBQ total score. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. LSmeans: placebo response included as covariate in the model. (B) Absolute values of the 200 mg/kg group compared to placebo in the mITT population for the CGI-I. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is lower score. LSmeans. (C) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RTT-DSC. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. Exact median test. Treatment baseline = day 14. CGI-I = Clinical Global Impression Scale–Improvement; EOT = end of treatment; LSmean = least-squares mean; mITT = modified intention to treat; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.CC BY-NC-ND · PubMed Central

Figure 3 Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and trofinetide exposure Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and AUC0–12 at different visits and over the active treatment period. (A) Relationship between percentage change from treatment baseline in RSBQ-total score and AUC0–12 at day 28. (B) Relationship between percentage change from treatment baseline in RSBQ-total score and cumulative AUC during the active dosing period. (C) Relationship between CGI-I scores and AUC0–12 at day 28. (D) Relationship between CGI-I score and cumulative AUC during the active dosing period. (E) Relationship between percentage change from treatment baseline in RTT-DSC score and AUC0–12 at day 28. (F) Relationship between percentage change from treatment baseline in RTT-DSC score and cumulative AUC during the active dosing period. Visit 3 (day 14, end of placebo run-in), visit 4 (day 21), visit 5 (day 28), visit 6 (day 42), visit 7 (day 54, end of treatment), visit 8 (day 66, posttreatment). Solid lines are obtained by linear regression. Where applicable, placebo data (AUC = 0) from different visits are pooled together. AUC = area under the concentration vs time curve; CGI-I = Clinical Global Impression Scale–Improvement; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns.CC BY-NC-ND · PubMed Central

Figure 4 Cohen d effect sizes for the RSBQ and RTT-DSC-VAS (200 mg/kg vs placebo at day 54) Cohen d effect sizes for the RSBQ (A) and RTT-DSC-VAS (B). Cohen d values are unadjusted, that is, do not incorporate covariate information from treatment baseline or placebo response. bid = twice a day; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.CC BY-NC-ND · PubMed Central

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“…slices Low frequency stimulation ↑ LTD Koekkoek et al., 2005 Fmr1−/Y Hippocampal slices High frequency stimulation No difference in LTP Godfraind et al., 1996 Fmr1−/Y Hippocampal slices (P35–P56) Paired-pulse facilitation, theta-burst stimulation No difference in LTP Paradee et…”
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Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome
Leonard, H., Gold, W. A., Samaco, R. C., Şahin, M., Benke, T. A., & Downs, J. A. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02240-w · Cited by 21
“Scores for the fear and anxiety subscales slightly worsened in the rhIGF-1 trial (NCT01777542) [60], while improvement in the total RSBQ was found in the paediatric trofinetide trial (NCT02715115) [62].”
BackgroundMethodInfluential
Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges
Guerreiro, S. R., & Maciel, P. (2023) · Cells · doi:10.3390/cells12040538 · Cited by 20
“Of note, a new and more powerful analog of IGF1 was developed and revealed safety, tolerability and efficacy in RTT females in a phase II clinical trial (NCT02715115), ameliorating the breathing problems, the motor dysfunction, the mood abnormalities and disruptive behavior as well as the frequency of seizures [435].”
Background
The Rare Diseases Clinical Research Network: a model for clinical trial readiness
Lumsden, J. M., & Urv, T. K. (2023) · Therapeutic Advances in Rare Disease · doi:10.1177/26330040231219272 · Cited by 22
Development of trofinetide for the treatment of Rett syndrome: from bench to bedside
Kennedy, M., Glass, L., Glaze, D. G., Kaminsky, S., Percy, A. K., Neul, J. L., Jones, N. E., Tropea, D., Horrigan, J. P., Nues, P., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1341746 · Cited by 20
Rett Syndrome and the Role of MECP2: Signaling to Clinical Trials
Lopes, A. M. A. D. P., Loganathan, S. K., & Caliaperumal, J. (2024) · Brain Sciences · doi:10.3390/brainsci14020120 · Cited by 19
“In a double-blind, randomized, placebo-controlled clinical trial named LAVENDER, a phase 3 study of trofinetide [21] evaluated 187 females with RTT and showed improvements for patients treated with 50, 100 or 200 mg/kg received twice a day [113,114].”
Method
A Comprehensive Review on Plant-Based Medications and Chemical Approaches for Autism Spectrum Disorders (ASDs) Psychopharmacotherapy
Ashwlayan, V. D., Ratnesh, R. K., Sharma, D., Sharma, A. K., Sangal, A., Saifi, A., & Singh, J. (2024) · Indian Journal of Microbiology · doi:10.1007/s12088-024-01265-y · Cited by 19
“Sulforaphane has been studied in animal models & people with neurological & neurodevelopmental disorder as an anti-oxidant, anti-inflammatory, and mitochondrial protective compound [98].”
Recommendations for the management of diarrhea with trofinetide use in Rett syndrome
Marsh, E. D., Beisang, A., Buie, T. M., Benke, T. A., Gaucher, B., & Motil, K. J. (2023) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2023.2217328 · Cited by 18
“…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].”
Background
Insulin‐Like Growth Factor and Insulin‐Like Growth Factor Receptor Expression in Human Idiopathic Autism Fusiform Gyrus Tissue
Cioana, M., Michalski, B., & Fahnestock, M. L. (2020) · Autism Research · doi:10.1002/aur.2291 · Cited by 16
“…showed significant and clinically relevant improvements relative to placebo, which correlated with trofinetide exposure, across a range of symptoms including repetitive behaviors, breathing problems, mood abnormalities/disruptive behavior, ambulation impairment, and seizures [Glaze et al., 2019].”
Background
Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2–4 years with Rett syndrome
Percy, A. K., Ryther, R. C. C., Marsh, E. D., Neul, J. L., Benke, T. A., Berry‐Kravis, E., Feyma, T. J., Lieberman, D. N., Ananth, A., Fu, C., et al. (2025) · Med · doi:10.1016/j.medj.2025.100608 · Cited by 16
Gastrointestinal Health Questionnaire for Rett Syndrome
Motil, K. J., Khan, N., Coon, J. L., Barrish, J. O., Suter, B., Pehlivan, D., Schultz, R., & Glaze, D. G. (2020) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000002951 · Cited by 17
“We recently completed the Phase I/II trial of Trofinetide, an insulin-like growth factor 1 neuropeptide analogue that has favorable outcomes in RTT (7,8).”
Method
A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations
Hardan, A. Y., Jo, B., Frazier, T. W., Klaas, P., Busch, R. M., Dies, K. A., Filip‐Dhima, R., Snow, A. V., Eng, C., Hanna, R., et al. (2021) · Contemporary Clinical Trials Communications · doi:10.1016/j.conctc.2021.100733 · Cited by 16
Rett Syndrome: A Timely Review From Recognition to Current Clinical Approaches and Clinical Study Updates
Ivy, A. S., & Standridge, S. (2021) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2021.100881 · Cited by 16
Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions
Guan, J., Li, F., Kang, D., Anderson, T., Pitcher, T. L., Dalrymple‐Alford, J. C., Shorten, P. R., & Singh‐Mallah, G. (2023) · Molecules · doi:10.3390/molecules28031021 · Cited by 16
“Several clinical trials that have evaluated the efficacy of cGP-related compounds also report the benefits in mood [49,54].”
Background
Rett Syndrome Behaviour Questionnaire in Children and Adults With Rett Syndrome: Psychometric Characterization and Revised Factor Structure
Oberman, L. M., Leonard, H., Downs, J. A., Cianfaglione, R., Stahlhut, M., Larsen, J. L., Madden, K. V., & Kaufmann, W. E. (2023) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-128.3.237 · Cited by 16
“However, use of the RSBQ has been expanded far beyond its initial purpose to include observational studies in adults with RTT and assessment of efficacy in FDA-regulated clinical trials (Glaze et al., 2019; Khwaja et al., 2014; O’Leary et al., 2018).”
Method
Hypermetabolism on Pediatric PET Scans of Brain Glucose Metabolism: What Does It Signify?
Chugani, H. T. (2021) · Journal of Nuclear Medicine · doi:10.2967/jnumed.120.256081 · Cited by 16
Modeling Rett Syndrome with Human Pluripotent Stem Cells: Mechanistic Outcomes and Future Clinical Perspectives
Gomes, A. R., Fernandes, T. G., Cabral, J. M. S., & Diogo, M. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073751 · Cited by 15
“A phase 2 clinical trial for trofinetide (NCT02715115) in RTT females revealed safety, tolerability and promoted significant improvements in several symptoms, like breathing problems, mood abnormalities/disruptive behavior, neuromotor impairment, and frequency of seizures [102].”
Background
Network-Medicine-Guided Drug Repurposing for Alzheimer’s Disease: A Multi-Dimensional Systems Pharmacology Approach
Akgüller, Ö., Balcı, M. A., & Cioca, G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010003 · Cited by 13
Psychometric perspectives on developmental outcome and endpoint selection in treatment trials for genetic conditions associated with neurodevelopmental disorder
Farmer, C., Kaat, A. J., Berry‐Kravis, E., & Thurm, A. E. (2022) · International review of research in developmental disabilities · doi:10.1016/bs.irrdd.2022.05.001 · Cited by 12
Validating the Communication and Symbolic Behavior Scales–Developmental Profile Infant–Toddler Checklist (CSBS–DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder
Saldaris, J. M., Leonard, H., Wong, K., Jacoby, P. A., Spence, M., Marsh, E. D., Benke, T. A., Demarest, S., & Downs, J. A. (2023) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-023-06002-w · Cited by 13
Trofinetide in Rett syndrome: A brief review of safety and efficacy
Singh, A., Balasundaram, M. K., & Gupta, D. (2023) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2023.01060 · Cited by 13
Effect of non‐invasive brain stimulation on behavior and serum brain‐derived neurotrophic factor and insulin‐like growth factor‐1 levels in autistic patients
Robinson‐Agramonte, M. D. L. Á., Michalski, B., Fernández, L. G., Vidal-Martínez, B., Cuesta, H. V., Rizo, C. M., & Fahnestock, M. L. (2021) · Drug Development Research · doi:10.1002/ddr.21808 · Cited by 16
“Trofinetide, an analog of the amino-terminal tripeptide of IGF-1, has also shown clinically relevant improvements in RTT (Glaze et al., 2019).”
Background
Trofinetide receives FDA approval as first drug for Rett syndrome
Mughal, Z. U. N., Ahmed, B., Rangwala, B. S., Rangwala, H. S., Fatima, H., Ali, M., & Farah, A. A. (2024) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000001896 · Cited by 13
“The 200 mg/kg dose signi ﬁ cantly improved ef ﬁ cacy measures as determined by care takers and medical professionals [20] .”
Background
Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS)
Raspa, M., Gwaltney, A. Y., Bann, C., von Hehn, J., Benke, T. A., Marsh, E. D., Peters, S. U., Ananth, A., Percy, A. K., & Neul, J. L. (2024) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-024-06238-0 · Cited by 12
“Subsequently. several Phase 1, 2, and 3 clinical trials have been initiated (Glaze et al., 2017, 2019; Hurley et al., 2022; National Library of Medicine, 2023a, 2023b; Neul et al., 2022; Neul et al., 2023a).”
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R. J., & Restrepo, B. (2024) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.24022006 · Cited by 16
Biochemical and molecular determinants of the subclinical inflammatory mechanisms in Rett syndrome
Cordone, V. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.110046 · Cited by 12
Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy
Camillo, L., Pozzi, M., Bernardo, P., Pisano, S., & Nobile, M. (2024) · Drug Design Development and Therapy · doi:10.2147/dddt.s383133 · Cited by 12
Organic features of autonomic dysregulation in paediatric brain injury – Clinical and research implications for the management of patients with Rett syndrome
Singh, J., Lanzarini, E., & Santosh, P. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.08.012 · Cited by 12
“In addition, trofinetide, an insulin like growth factor analogue is being evaluated in Rett patients (Glaze et al., 2019, 2017) and in those with traumatic brain injury (https://clinicaltrials.gov/ct2/ show/NCT00805818).”
Background
Electrophysiological Biomarkers in Genetic Epilepsies
Armstrong, C., & Marsh, E. D. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01132-4 · Cited by 12
Fragile X Syndrome: Lessons Learned and What New Treatment Avenues Are on the Horizon
Hagerman, R. J., & Hagerman, P. J. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052120-090147 · Cited by 12
Meaningful Improvements in Rett Syndrome: A Qualitative Study of Caregivers
McGraw, S. A., Smith‐Hicks, C. L., Nutter, J., Henne, J. C., & Abler, V. (2023) · Journal of Child Neurology · doi:10.1177/08830738231172066 · Cited by 12
Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations
Lebeda, D., Fierenz, A., Werfel, L., Rosin‐Arbesfeld, R., Hofhuis, J., & Thoms, S. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-024-02436-6 · Cited by 10
Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline
Hu, L., Lin, J., Qin, F., Xu, L., & Luo, L. (2024) · Marine Drugs · doi:10.3390/md22060271 · Cited by 10
“Additionally, a phase II study targeting Prader–Willi syndrome received FDA accelerated approval in 2023 [104].”
Background
Insulin-Like Growth Factor 1 Has the Potential to Be Used as a Diagnostic Tool and Treatment Target for Autism Spectrum Disorders
Shen, J., Liu, L., Yang, Y., Zhou, M., Xu, S., Zhang, W., & Zhang, C. (2024) · Cureus · doi:10.7759/cureus.65393 · Cited by 13
“Trofinetide therapy resulted in clinically relevant improvements in a phase 2 randomized investigation of 82 patients with RTT aged 5 to 15 [114].”
Background
Fragile X Syndrome and Targeted Treatments
Tassanakijpanich, N., Cabal-Herrera, A. M., Salcedo‐Arellano, M. J., & Hagerman, R. J. (2020) · Journal of Biomedicine and Translational Research · doi:10.14710/jbtr.v6i1.7321 · Cited by 10
“been proven to have potential for treating core symptoms in patients with Rett syndrome, such as anxiety-like behaviors, disruptive behavior and mood dysregulation.(88) Deacon et al.”
Background
Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome
Keogh, C., Pini, G., Gemo, I., Kaufmann, W. E., & Tropea, D. (2020) · Brain Sciences · doi:10.3390/brainsci10080515 · Cited by 9
“These results have led to multiple clinical trials involving IGF1 and analogues, such as trofinetide [36] and recombinant IGF1.”
Background
Characterization of the Pharmacokinetics and Mass Balance of a Single Oral Dose of Trofinetide in Healthy Male Subjects
Darwish, M., Núñez, R., Youakim, J. M., & Robertson, P. (2023) · Clinical Drug Investigation · doi:10.1007/s40261-023-01322-2 · Cited by 9
“Two Phase 2 studies have demonstrated a clinical benefit with trofinetide (70 and 200 mg/kg twice daily) in pediatric, adolescent, and adult females with RTT [7, 8].”
BackgroundMethod
Inhibitory Synaptic Influences on Developmental Motor Disorders
Fogarty, M. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24086962 · Cited by 9
Safety and efficacy of trofinetide in Rett syndrome: a systematic review and meta-analysis of randomized controlled trials
Abbas, A., Fayoud, A. M., Moawad, M. H. E. D., Hamad, A. A., Hamouda, H., & Fouad, E. A. (2024) · BMC Pediatrics · doi:10.1186/s12887-024-04526-3 · Cited by 10
“At the 50 mg dosage, one study assessed CGI-I scores [13].”
BackgroundMethodInfluential
Recommendations for the management of gastrointestinal comorbidities with or without trofinetide use in Rett syndrome
Motil, K. J., Beisang, A., Smith‐Hicks, C. L., Lembo, A. J., Standridge, S. M., & Liu, E. (2024) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2024.2368014 · Cited by 9
“Diarrhea was less common in the phase 2 trials of trofinetide for RTT (11–56%), but lower doses of trofinetide were used [42,43].”
Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis
Kaufmann, W. E., Luu, S., & Budimirovic, D. B. (2024) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-024-01394-3 · Cited by 8
“…by preclinical (i.e., mouse models) studies demonstrating efficacy of the drug or related compounds on FXS-or RTT-relevant phenotypes [104–109] and, in the case of the phase 3 trials, by early phase open label [110] or randomized controlled trials of the drug or related compounds [111–114].”
Exposure–Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome
Darwish, M., Passarell, J. A., Youakim, J. M., Bradley, H., & Bishop, K. M. (2024) · Advances in Therapy · doi:10.1007/s12325-024-02796-y · Cited by 8
“…participants (including a food effect study [15] and mass balance study [16]), two phase 2 studies in participants with RTT (Neu-2566-Rett-001 [4] and Rett-002 [5]), one phase 2 study in fragile X syndrome [17], one phase 2 study in traumatic brain injury, and the phase 3 LAVENDER study [7].”
Influential
Optimized Administration of the M 4 PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mecp2 +/ – Mice
Cikowski, J., Holt, C., Arthur, B., Smith, M., Gonzalez, S., Lindsley, C. W., Niswender, C. M., & Gogliotti, R. G. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00113 · Cited by 7
“6,7 Historically, therapeutic development for RTT has followed the same path as other neurodevelopmental disorders, where targets are identi ﬁ ed and optimized in mouse models.”
Rett Syndrome: A Tale of Altered Genetics, Synaptic Plasticity, and Neurodevelopmental Dynamics
Oluigbo, D. (2023) · Cureus · doi:10.7759/cureus.41555 · Cited by 8
“The highest trofinetide dosage administered (200 mg/kg twice daily) corresponded to statistically significant improvements in efficacy compared to a placebo and core RTT symptoms as measured by the Rett Syndrome Behavior Questionnaire (RSBQ), RTT-Clinician Domain Specific Concerns-Visual analog Scale (RTT-DSCVAS), and…”
Influential
Cryptic Host Defense Peptides: Multifaceted Activity and Prospects for Medicinal Chemistry
Costa, B. O., & Franco, O. L. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200325112425 · Cited by 7
Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives
Moore, R., Poulsen, J., Reardon, L., Samples-Morris, C., Simmons, H., Ramsey, K. M., Whatley, M. L., & Lane, J. B. (2024) · Advances in Therapy · doi:10.1007/s12325-024-02782-4 · Cited by 6
“…troﬁnetide for RTT than in LAVENDER, with rates of 0%, 11%, and 0% with twice-daily troﬁnetide 35 mg/kg, troﬁnetide 70 mg/kg, and placebo, respectively [12] and 7%, 13%, 22%, and 13% with twice-daily troﬁnetide 50 mg/kg, troﬁnetide 100 mg/ kg, troﬁnetide 200 mg/kg, and placebo, respectively [13].”
Background
Neurology’s vital role in preventing unnecessary and potentially harmful pediatric studies
Rose, K., Ettienne, E. B., Grant-Kels, J. M., Striano, P., Neubauer, D., & Tanjinatus, O. (2022) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2022.2045953 · Cited by 5
“children and adolescents with Rett syndrome was reported [18].”
Background
Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome
Shovlin, S., Delepine, C., Swanson, L. C., Bach, S., Şahin, M., Sur, M., Kaufmann, W. E., & Tropea, D. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.868008 · Cited by 6
Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation
Darwish, M., Marbury, T. C., Núñez, R., Youakim, J. M., An, D., Darling, I. M., Lukáčová, V., & Bishop, K. M. (2024) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-024-00924-1 · Cited by 5
A Blueprint for Translational Precision Medicine in Autism Spectrum Disorder and Related Neurogenetic Syndromes
Thom, R. P., Warren, T. L., Khan, S., Muhle, R., Wang, P. P., Brennand, K., Zürcher, N. R., Veenstra-VanderWeele, J. M., & Hoffman, E. J. (2025) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2025.0023 · Cited by 5
A meta-analysis of the efficacy and safety of trofinetide in patients with rett syndrome
Zeid, M. A., Elrosasy, A., Mohamed, R. G., Ghazou, A., Goufa, E., Hassan, N., & Abuzaid, Y. (2024) · Neurological Sciences · doi:10.1007/s10072-024-07584-8 · Cited by 5
“One study [18] showed a high risk of bias mainly in the randomization process and the missing outcome data domains, another one [19] showed a low risk of bias, while the third one [20] showed some concerns mainly in the fifth domain (Selection of the reported result) (Fig.”
Background
Post-marketing safety concerns with trofinetide: a disproportionality analysis of the first therapeutic agent for Rett syndrome based on the FDA adverse event reporting system (FAERS)
Yu, X., Zhong, J., Lin, Z., Fu, H., & Zhang, Y. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1643906 · Cited by 4
The Ketogenic Diet: An Underrecognized Therapy for Rett Syndrome
Haridas, B., Bessone, S. K., Turner, Z., & Kossoff, E. H. (2025) · Journal of Child Neurology · doi:10.1177/08830738251329139 · Cited by 4
Rett Syndrome: Thinking Beyond Brain Borders
Liu, Y., Guo, R., & Jaenisch, R. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-89525-8_9 · Cited by 5
Gastrointestinal manifestations of Rett syndrome: An updated analysis using the Gastrointestinal Health Questionnaire
Ihekweazu, F. D., & Motil, K. J. (2024) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1002/jpn3.12394 · Cited by 6
A Physiologically Based Pharmacokinetic Modeling Approach to Assess the Potential for Drug Interactions Between Trofinetide and CYP3A4-Metabolized Drugs
Darwish, M., Youakim, J. M., Darling, I. M., Lukáčová, V., Owen, J. S., & Bradley, H. (2024) · Clinical Therapeutics · doi:10.1016/j.clinthera.2023.12.007 · Cited by 4
Pharmacological Treatments for Fragile X Syndrome Based on Synaptic Dysfunction
Telias, M. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666191102165206 · Cited by 4

Authors: Glaze, D. G., Neul, J. L., Kaufmann, W. E., Berry-Kravis, E., Condon, S., Stoms, G., Oosterholt, S., Della Pasqua, O., Glass, L., Jones, N. E., Percy, A. K., Rett 002 Study Group, Glaze, D. G., Neul, J. L., Kaufmann, W. E., Berry-Kravis, E., Condon, S., Stoms, G., Oosterholt, S., Pasqua, O. D., Glass, L., Jones, N. E., & Percy, A.
Affiliations: From the Department of Pediatrics and Neurology (D.G.G.), Baylor College of Medicine, Houston, TX; Department of Neurosciences (J.L.N.), University of California, San Diego; Greenwood Genetic Center (W.E.K.), Center for Translational Research, Greenwood, SC; Pediatrics, Neurological Sciences, and Biochemistry (E.B.K.), Rush University Medical Center, Chicago, IL;Vital Systems, Inc. (S.C., G.S.), Rolling Meadows, IL; Clinical Pharmacology & Therapeutics Group (S.O., O.D.P.), University College...
Rush University Medical Center (US)
ORCID: Della Pasqua, Oscar
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2019-04-16
Volume: 92
Issue: 16
Pages: e1912-e1925
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/wnl.0000000000007316
PMC: PMC6550498
OpenAlex: W2922881551
Cited by: 160
References: 42
Citations by year: 2026: 8 · 2025: 14 · 2024: 46 · 2023: 33 · 2022: 14 · 2021: 15 · 2020: 22 · 2019: 6
FWCI: 8.59
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
Locations: Neurology (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: trofinetide, Rett syndrome, pediatric patients, safety and tolerability, pharmacokinetics, neurodevelopmental disorders, symptom improvement, Clinical Global Impression Scale, dose-response relationship
MeSH terms: Adolescent, Anti-Inflammatory Agents, Non-Steroidal, Child, Child, Preschool, Double-Blind Method, Female, Glutamates, Humans, Rett Syndrome, Treatment Outcome, Glutamic Acid

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Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome

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