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

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. This was a phase 2, multicente...

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Vydané v:	Neurology Ročník 92; číslo 16; s. e1912
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 16.04.2019
Predmet:	Adolescent Anti-Inflammatory Agents, Non-Steroidal - adverse effects Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Child Child, Preschool Double-Blind Method Female Glutamates - adverse effects Glutamates - pharmacokinetics Glutamates - therapeutic use Glutamic Acid - adverse effects Glutamic Acid - pharmacokinetics Glutamic Acid - therapeutic use Humans Rett Syndrome - drug therapy Treatment Outcome
ISSN:	1526-632X, 1526-632X
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Abstract	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. 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. 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. These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. 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.
AbstractList	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.OBJECTIVETo 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.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.METHODSThis 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.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.RESULTSAll 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.These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.CONCLUSIONThese results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.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.CLASSIFICATION OF EVIDENCEThis 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. 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. 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. 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. These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. 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.
Author	Jones, Nancy E Berry-Kravis, Elizabeth Condon, Sean Glass, Larry Oosterholt, Sean Stoms, George Glaze, Daniel G Della Pasqua, Oscar Percy, Alan K Neul, Jeffrey L Kaufmann, Walter E
Author_xml	– sequence: 1 givenname: Daniel G surname: Glaze fullname: Glaze, Daniel G organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 2 givenname: Jeffrey L surname: Neul fullname: Neul, Jeffrey L organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 3 givenname: Walter E surname: Kaufmann fullname: Kaufmann, Walter E organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 4 givenname: Elizabeth surname: Berry-Kravis fullname: Berry-Kravis, Elizabeth organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 5 givenname: Sean surname: Condon fullname: Condon, Sean organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 6 givenname: George surname: Stoms fullname: Stoms, George organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 7 givenname: Sean surname: Oosterholt fullname: Oosterholt, Sean organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 8 givenname: Oscar orcidid: 0000-0002-6211-1430 surname: Della Pasqua fullname: Della Pasqua, Oscar organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 9 givenname: Larry surname: Glass fullname: Glass, Larry organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN – sequence: 10 givenname: Nancy E surname: Jones fullname: Jones, Nancy E email: njones@neurenpharma.com organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN. njones@neurenpharma.com – sequence: 11 givenname: Alan K surname: Percy fullname: Percy, Alan K organization: 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 London, UK; Neuren Pharmaceuticals, Ltd. (L.G., N.E.J.), Camberwell, VIC, Australia; Department of Pediatrics (A.K.P.), Division of Neurology, University of Alabama at Birmingham. J.L.N. is currently affiliated with the Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN
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Contributor	Jones, Nancy E Berry-Kravis, Elizabeth Condon, Sean Glass, Larry Percy, Alan Oosterholt, Sean Stoms, George Glaze, Daniel G Pasqua, Oscar Della Neul, Jeffrey L Kaufmann, Walter E
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Copyright	Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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Snippet	To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a...
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SubjectTerms	Adolescent Anti-Inflammatory Agents, Non-Steroidal - adverse effects Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Child Child, Preschool Double-Blind Method Female Glutamates - adverse effects Glutamates - pharmacokinetics Glutamates - therapeutic use Glutamic Acid - adverse effects Glutamic Acid - pharmacokinetics Glutamic Acid - therapeutic use Humans Rett Syndrome - drug therapy Treatment Outcome
Title	Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome
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