<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01703533</url>
  </required_header>
  <id_info>
    <org_study_id>Neu-2566-RETT-001</org_study_id>
    <nct_id>NCT01703533</nct_id>
  </id_info>
  <brief_title>A Safety Study of NNZ-2566 in Patients With Rett Syndrome</brief_title>
  <official_title>A Phase II Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Escalation Study of NNZ-2566 in Rett Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Neuren Pharmaceuticals Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>International Rett Syndrome Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Neuren Pharmaceuticals Limited</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether NNZ-2566 is safe and well tolerated in the&#xD;
      treatment of Rett Syndrome in adolescent and adult females.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rett Syndrome is a developmental disorder primarily if not exclusively affecting females. The&#xD;
      disorder is characterized by apparent normal development in early infancy (6-18 months),&#xD;
      followed by a period of regression with onset of systemic and neurological signs. The CNS&#xD;
      symptoms of Rett Syndrome include learning disability, autism and epilepsy and these can be&#xD;
      severe and highly debilitating. Affected individuals also show signs of autonomic&#xD;
      dysfunction, reflected in cardiovascular and respiratory abnormalities. There is no currently&#xD;
      effective treatment for Rett Syndrome.&#xD;
&#xD;
      This study will investigate the safety and tolerability of treatment with oral administration&#xD;
      of NNZ-2566 at 35 mg/kg or 70 mg/kg BID in adolescent or adult females with Rett Syndrome.&#xD;
      The study also will also investigate measures of efficacy during treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2013</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Adverse events</measure>
    <time_frame>Through to Day 40</time_frame>
    <description>Incidence of adverse events (AE), including Serious adverse events (SAE), will be evaluated between the two NNZ-2566 doses and placebo. SAEs will be examined from randomization through to Day 40. AEs will be examined from dosing through to Day 40.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in EEG activity</measure>
    <time_frame>Baseline through to Day 40</time_frame>
    <description>Absolute change in the number of spikes in the EEG per hour during the awake state will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).&#xD;
Absolute change in the power of frequency bands in the EEG over an hour in the awake state as determined by the Fast Fourier method will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).&#xD;
Changes in the frequency of the characteristic repetitive stereotypic hand movements during wakefulness will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Behavior</measure>
    <time_frame>Baseline through to Day 40</time_frame>
    <description>The following measures will be assessed at baseline and Day 26 and the changes compared between active and placebo groups:&#xD;
Symptom severity according to the Rett Syndrome Natural History Motor Behavior Assessment (MBA), Clinical Severity Scale (CSS), Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Scale (VABS), and Clinical Global Impression of Severity (CGI-S).&#xD;
The following assessments will be undertaken at the additional time points specified: CGI-S (screening, baseline, Days 5, 14, 26, and 40), CGI-I (Days 5, 14, 26, and 40), MBA (Baseline, Days 26 and 40), CSS (screening, baseline, Days 26, and 40).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physiological changes</measure>
    <time_frame>Baseline through to Day 40</time_frame>
    <description>Changes in autonomic function, i.e. respiratory rhythm, hyperventilation, apneas, oxygen desaturation, and heart rate variation will be calculated between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Global and Functional outcome Measures</measure>
    <time_frame>Baseline through to Day 40</time_frame>
    <description>Global outcome as measured by the change in scores on the Rett Syndrome Clinical Severity Score (CSS), The Rett Syndrome Motor-Behavior Assessment Scale (MBA), and the Clinical Global Impression - Severity and Improvement scales (CGI-S and -I) from baseline, during treatment, and post treatment.&#xD;
Changes in caregiver assessment of the top three causes for concern as assessed via a Visual Analogue Scale (VAS) will be evaluated for each subject between baseline (pre-treatment), during treatment (Day 26) and after treatment (Day 40).&#xD;
Changes in the Aberrant Behavior Checklist (ABC) and Vineland Adaptive Behavior Scales (VABS) will be calculated for each subject between baseline (pre-treatment), and during treatment (Day 26).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Pharmacokinetics</measure>
    <time_frame>Baseline through to Day 40</time_frame>
    <description>The following pharmacokinetic measures will be calculated from NNZ-2566 concentrations in whole blood: Tmax, Cmax (peak), Cmin (trough), CAV at steady state, T1/2 and AUC.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">67</enrollment>
  <condition>Rett Syndrome</condition>
  <arm_group>
    <arm_group_label>NNZ-2566</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Glycyl-L-2-Methylpropyl-L-Glutamic Acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (strawberry flavored solution)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Strawberry flavored solution and Water for Injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NNZ-2566</intervention_name>
    <description>Glycyl-L-2-Methylpropyl-L-Glutamic Acid (NNZ-2566) supplied as a lyophilized powder (2g in 50mL vials) for reconstitution with strawberry flavored solution 0.5% v/v in Water for Injection.</description>
    <arm_group_label>NNZ-2566</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Strawberry flavored solution and Water for Injection</description>
    <arm_group_label>Placebo (strawberry flavored solution)</arm_group_label>
    <other_name>Strawberry flavored solution 0.5% v/v in Water for Injection</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of Rett Syndrome with proven mutation of the MeCP2 gene&#xD;
&#xD;
          -  Age 16 to 45 years&#xD;
&#xD;
          -  Severity rating of between 10 and 36 (Rett Syndrome Natural History/Clinical Severity&#xD;
             Scale)&#xD;
&#xD;
          -  Concomitant medications must be stable for &gt;4 weeks prior to enrollment. The following&#xD;
             concomitant medications are permitted: anticonvulsants which do not have liver&#xD;
             inducing effects; beta-blockers; medications for the treatment of gastroesophageal&#xD;
             reflux disease (GERD); medications for the treatment of chronic respiratory conditions&#xD;
             such as asthma; medications for the treatment of anxiety, of depression and of&#xD;
             psychosis, hormonal contraceptives. Melatonin for difficulties with sleep onset.&#xD;
&#xD;
          -  Ability to swallow study medication provided as a liquid solution, or via gastrostomy&#xD;
             tube&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No detectable abnormality of the EEG during screening period&#xD;
&#xD;
          -  Actively undergoing regression&#xD;
&#xD;
          -  QTcF exclusions (any of the following): baseline/screening QT/QTcF interval of 450&#xD;
             msec; history of risk factors for torsade de pointes (e.g. heart failure, hypokalemia&#xD;
             (serum potassium at screening &lt; 3.0 mmol/L) or family history of long QT syndrome;&#xD;
             QT/QTcF prolongation previously or currently controlled with medication&#xD;
&#xD;
          -  Current treatment with insulin&#xD;
&#xD;
          -  Hgb A1C values outside the normal reference range at screening&#xD;
&#xD;
          -  Current or past treatment with IGF-1&#xD;
&#xD;
          -  Current or past treatment with growth hormone&#xD;
&#xD;
          -  Current treatment with N-methyl-D-aspartate (NMDA) antagonists&#xD;
&#xD;
          -  Current or planned use of non-medication based interventional therapy during the&#xD;
             period of the study (defined as 4-6 week screening period followed by 4 week dosing&#xD;
             and 2 week follow-up period)&#xD;
&#xD;
          -  Current clinically significant cardiovascular, renal, hepatic or respiratory disease&#xD;
&#xD;
          -  Gastrointestinal disease which may interfere with the absorption, distribution,&#xD;
             metabolism or excretion of the the study medication&#xD;
&#xD;
          -  History of, or current cerebrovascular disease or brain trauma&#xD;
&#xD;
          -  History of, or current significant endocrine disorder e.g. hypo or hyperthyroidism or&#xD;
             diabetes mellitus&#xD;
&#xD;
          -  History of, or current malignancy&#xD;
&#xD;
          -  Clinically significant abnormalities in safety laboratory tests, vital signs or ECG,&#xD;
             as measured at screening or baseline&#xD;
&#xD;
          -  Confirmed pregnancy&#xD;
&#xD;
          -  Significant hearing and/or visual impairment that may affect ability to complete the&#xD;
             test procedures&#xD;
&#xD;
          -  Enrollment in another clinical trial within the previous 30 days&#xD;
&#xD;
          -  Previously randomized in this clinical trial&#xD;
&#xD;
          -  Allergy to strawberries&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daniel G Glaze, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeffrey L Neul, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alan Percy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alabama at Birmingham</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Timothy Feyma, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gillette Children's Specialty Healthcare</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Arthur Beisang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gillette Children's Specialty Healthcare</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294-0113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gillette Children's Specialty Healthcare</name>
      <address>
        <city>Saint Paul</city>
        <state>Minnesota</state>
        <zip>55101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor School of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <disposition_first_submitted>January 31, 2018</disposition_first_submitted>
  <disposition_first_submitted_qc>January 31, 2018</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 5, 2018</disposition_first_posted>
  <last_update_submitted>January 31, 2018</last_update_submitted>
  <last_update_submitted_qc>January 31, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Autism</keyword>
  <keyword>Rett's Syndrome</keyword>
  <keyword>Rett Disorder</keyword>
  <keyword>Rett's Disorder</keyword>
  <keyword>Ataxia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rett Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01703533
org study id: Neu-2566-RETT-001
nct id: NCT01703533
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine whether NNZ-2566 is safe and well tolerated in the
      treatment of Rett Syndrome in adolescent and adult females.
Rett Syndrome is a developmental disorder primarily if not exclusively affecting females. The
      disorder is characterized by apparent normal development in early infancy (6-18 months),
      followed by a period of regression with onset of systemic and neurological signs. The CNS
      symptoms of Rett Syndrome include learning disability, autism and epilepsy and these can be
      severe and highly debilitating. Affected individuals also show signs of autonomic
      dysfunction, reflected in cardiovascular and respiratory abnormalities. There is no currently
      effective treatment for Rett Syndrome.

      This study will investigate the safety and tolerability of treatment with oral administration
      of NNZ-2566 at 35 mg/kg or 70 mg/kg BID in adolescent or adult females with Rett Syndrome.
      The study also will also investigate measures of efficacy during treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Adverse events
time frame: Through to Day 40
description: Incidence of adverse events (AE), including Serious adverse events (SAE), will be evaluated between the two NNZ-2566 doses and placebo. SAEs will be examined from randomization through to Day 40. AEs will be examined from dosing through to Day 40.
measure: Change in EEG activity
time frame: Baseline through to Day 40
description: Absolute change in the number of spikes in the EEG per hour during the awake state will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).
Absolute change in the power of frequency bands in the EEG over an hour in the awake state as determined by the Fast Fourier method will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).
Changes in the frequency of the characteristic repetitive stereotypic hand movements during wakefulness will be calculated for each subject between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).
measure: Behavior
time frame: Baseline through to Day 40
description: The following measures will be assessed at baseline and Day 26 and the changes compared between active and placebo groups:
Symptom severity according to the Rett Syndrome Natural History Motor Behavior Assessment (MBA), Clinical Severity Scale (CSS), Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Scale (VABS), and Clinical Global Impression of Severity (CGI-S).
The following assessments will be undertaken at the additional time points specified: CGI-S (screening, baseline, Days 5, 14, 26, and 40), CGI-I (Days 5, 14, 26, and 40), MBA (Baseline, Days 26 and 40), CSS (screening, baseline, Days 26, and 40).
measure: Physiological changes
time frame: Baseline through to Day 40
description: Changes in autonomic function, i.e. respiratory rhythm, hyperventilation, apneas, oxygen desaturation, and heart rate variation will be calculated between baseline (pre-treatment), during treatment (Days 1 thru 4, 14 and 26) and after treatment (Day 40).
measure: Global and Functional outcome Measures
time frame: Baseline through to Day 40
description: Global outcome as measured by the change in scores on the Rett Syndrome Clinical Severity Score (CSS), The Rett Syndrome Motor-Behavior Assessment Scale (MBA), and the Clinical Global Impression - Severity and Improvement scales (CGI-S and -I) from baseline, during treatment, and post treatment.
Changes in caregiver assessment of the top three causes for concern as assessed via a Visual Analogue Scale (VAS) will be evaluated for each subject between baseline (pre-treatment), during treatment (Day 26) and after treatment (Day 40).
Changes in the Aberrant Behavior Checklist (ABC) and Vineland Adaptive Behavior Scales (VABS) will be calculated for each subject between baseline (pre-treatment), and during treatment (Day 26).
measure: Pharmacokinetics
time frame: Baseline through to Day 40
description: The following pharmacokinetic measures will be calculated from NNZ-2566 concentrations in whole blood: Tmax, Cmax (peak), Cmin (trough), CAV at steady state, T1/2 and AUC.
arm group label: NNZ-2566
arm group type: Experimental
description: Glycyl-L-2-Methylpropyl-L-Glutamic Acid
arm group label: Placebo (strawberry flavored solution)
arm group type: Placebo Comparator
description: Strawberry flavored solution and Water for Injection
intervention type: Drug
intervention name: NNZ-2566
description: Glycyl-L-2-Methylpropyl-L-Glutamic Acid (NNZ-2566) supplied as a lyophilized powder (2g in 50mL vials) for reconstitution with strawberry flavored solution 0.5% v/v in Water for Injection.
arm group label: NNZ-2566
intervention type: Drug
intervention name: Placebo
description: Strawberry flavored solution and Water for Injection
arm group label: Placebo (strawberry flavored solution)
other name: Strawberry flavored solution 0.5% v/v in Water for Injection
criteria: 
gender: Female
minimum age: 16 Years
maximum age: 45 Years
healthy volunteers: No
last name: Daniel G Glaze, M.D.
role: Principal Investigator
affiliation: Baylor College of Medicine
last name: Jeffrey L Neul, M.D., Ph.D.
role: Principal Investigator
affiliation: Baylor College of Medicine
last name: Alan Percy, MD
role: Principal Investigator
affiliation: University of Alabama at Birmingham
last name: Timothy Feyma, MD
role: Principal Investigator
affiliation: Gillette Children's Specialty Healthcare
last name: Arthur Beisang, MD
role: Principal Investigator
affiliation: Gillette Children's Specialty Healthcare
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Rett Syndrome
mesh term: Syndrome
sharing ipd: No