A Safety Study of NNZ-2566 in Patients With Rett Syndrome

• ClinicalTrials.gov Identifier: NCT01703533
• Recruitment Status: Completed
• First Posted: October 10, 2012
• Last Update Posted: February 5, 2018
• Sponsor: Neuren Pharmaceuticals Limited
• Collaborators: Baylor College of Medicine; International Rett Syndrome Foundation
• Information provided by (Responsible Party): Neuren Pharmaceuticals Limited

Tracking Information

• First Submitted Date: October 4, 2012
• First Posted Date: October 10, 2012
• Last Update Posted Date: February 5, 2018
• Study Start Date: March 2013
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 16, 2013)

Adverse events [ Time Frame: Through to Day 40 ]

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.

Original Primary Outcome Measures (submitted: October 8, 2012)

• Adverse events [ Time Frame: Through to Day 33 ]
  Incidence of adverse events and serious adverse events
• Physiological changes [ Time Frame: Through to Day 33 ]
  Changes from baseline for selected serum chemistry parameters and changes in cardiac function as measured by electrocardiogram (ECG).

Current Secondary Outcome Measures (submitted: June 16, 2013)

• Change in EEG activity [ Time Frame: Baseline through to Day 40 ]
  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).
• Behavior [ Time Frame: Baseline through to Day 40 ]
  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).
• Physiological changes [ Time Frame: Baseline through to Day 40 ]
  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).
• Global and Functional outcome Measures [ Time Frame: Baseline through to Day 40 ]
  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).

Original Secondary Outcome Measures (submitted: October 8, 2012)

• EEG and video monitoring [ Time Frame: Baseline, daily during first five days of dosing, Days 11, 23 and 33 ]
  EEG monitoring for seizure activity
• Behavior [ Time Frame: Baseline and Day 23 ]
  Symptom severity according to various behavior and clinical severity assessment scales.
• Physiological changes [ Time Frame: Baseline and Days 2, 4, 11, 23 and 33. ]
  Blood gas levels (baseline, Days 23 and 33), fundoscopy and tonsil size.

Current Other Pre-specified Outcome Measures (submitted: June 16, 2013)

Pharmacokinetics [ Time Frame: Baseline through to Day 40 ]

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.

Original Other Pre-specified Outcome Measures (submitted: October 8, 2012)

Pharmacokinetics [ Time Frame: To be confirmed ]

Pharmacokinetic measures will be calculated from NNZ-2566 concentrations in whole blood.

Descriptive Information

• Brief Title: A Safety Study of NNZ-2566 in Patients With Rett Syndrome
• Official Title: A Phase II Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Escalation Study of NNZ-2566 in Rett Syndrome
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Rett Syndrome

Intervention

• Drug: NNZ-2566
  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.
• Drug: Placebo
  Strawberry flavored solution and Water for Injection
  Other Name: Strawberry flavored solution 0.5% v/v in Water for Injection

Study Arms

• Experimental: NNZ-2566
  Glycyl-L-2-Methylpropyl-L-Glutamic Acid
  Intervention: Drug: NNZ-2566
• Placebo Comparator: Placebo (strawberry flavored solution)
  Strawberry flavored solution and Water for Injection
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 13, 2014): 67
• Original Estimated Enrollment (submitted: October 8, 2012): 42
• Actual Study Completion Date: September 2014
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of Rett Syndrome with proven mutation of the MeCP2 gene
• Age 16 to 45 years
• Severity rating of between 10 and 36 (Rett Syndrome Natural History/Clinical Severity Scale)
• Concomitant medications must be stable for >4 weeks prior to enrollment. The following concomitant medications are permitted: anticonvulsants which do not have liver inducing effects; beta-blockers; medications for the treatment of gastroesophageal reflux disease (GERD); medications for the treatment of chronic respiratory conditions such as asthma; medications for the treatment of anxiety, of depression and of psychosis, hormonal contraceptives. Melatonin for difficulties with sleep onset.
• Ability to swallow study medication provided as a liquid solution, or via gastrostomy tube

Exclusion Criteria:

• No detectable abnormality of the EEG during screening period
• Actively undergoing regression
• QTcF exclusions (any of the following): baseline/screening QT/QTcF interval of 450 msec; history of risk factors for torsade de pointes (e.g. heart failure, hypokalemia (serum potassium at screening < 3.0 mmol/L) or family history of long QT syndrome; QT/QTcF prolongation previously or currently controlled with medication
• Current treatment with insulin
• Hgb A1C values outside the normal reference range at screening
• Current or past treatment with IGF-1
• Current or past treatment with growth hormone
• Current treatment with N-methyl-D-aspartate (NMDA) antagonists
• Current or planned use of non-medication based interventional therapy during the period of the study (defined as 4-6 week screening period followed by 4 week dosing and 2 week follow-up period)
• Current clinically significant cardiovascular, renal, hepatic or respiratory disease
• Gastrointestinal disease which may interfere with the absorption, distribution, metabolism or excretion of the the study medication
• History of, or current cerebrovascular disease or brain trauma
• History of, or current significant endocrine disorder e.g. hypo or hyperthyroidism or diabetes mellitus
• History of, or current malignancy
• Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as measured at screening or baseline
• Confirmed pregnancy
• Significant hearing and/or visual impairment that may affect ability to complete the test procedures
• Enrollment in another clinical trial within the previous 30 days
• Previously randomized in this clinical trial
• Allergy to strawberries

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 16 Years to 45 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01703533
• Other Study ID Numbers: Neu-2566-RETT-001
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Neuren Pharmaceuticals Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Neuren Pharmaceuticals Limited
• Original Study Sponsor: Same as current

Collaborators

• Baylor College of Medicine
• International Rett Syndrome Foundation

Investigators

• Principal Investigator: Daniel G Glaze, M.D.; Baylor College of Medicine
• Principal Investigator: Jeffrey L Neul, M.D., Ph.D.; Baylor College of Medicine
• Principal Investigator: Alan Percy, MD; University of Alabama at Birmingham
• Principal Investigator: Timothy Feyma, MD; Gillette Children's Specialty Healthcare
• Principal Investigator: Arthur Beisang, MD; Gillette Children's Specialty Healthcare

• PRS Account: Neuren Pharmaceuticals Limited
• Verification Date: January 2018