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

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

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

Open access
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
Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1212/wnl.0000000000007316

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Study design (A) and participant disposition (B) BID = twice daily dosing; ITT = intention to treat; mITT = modified intention to treat; PK = pharmacokinetic.
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.
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.
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.
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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 42 references

Cited by

Sorted by citations

Items 101–163 of 163

Related

See all

Metadata

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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review