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

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

NNZ-2566

Placebo

About this trial

This is an interventional treatment trial for Rett Syndrome focused on measuring Autism, Rett's Syndrome, Rett Disorder, Rett's Disorder, Ataxia

Eligibility Criteria

16 Years - 45 Years (Child, Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

University of Alabama
Gillette Children's Specialty Healthcare
Baylor School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

NNZ-2566

Placebo (strawberry flavored solution)

Arm Description

Glycyl-L-2-Methylpropyl-L-Glutamic Acid

Strawberry flavored solution and Water for Injection

Outcomes

Primary Outcome Measures

Adverse events

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.

Secondary Outcome Measures

Change in EEG activity

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

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

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

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).

Full Information

NCT ID

NCT01703533

First Posted

October 4, 2012

Last Updated

January 31, 2018

Sponsor

Neuren Pharmaceuticals Limited

Collaborators

Baylor College of Medicine, International Rett Syndrome Foundation

1. Study Identification

Unique Protocol Identification Number

NCT01703533

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Completed

Study Start Date

March 2013 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Neuren Pharmaceuticals Limited

Collaborators

Baylor College of Medicine, International Rett Syndrome Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rett Syndrome

Keywords

Autism, Rett's Syndrome, Rett Disorder, Rett's Disorder, Ataxia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

67 (Actual)

8. Arms, Groups, and Interventions

Arm Title

NNZ-2566

Arm Type

Experimental

Arm Description

Glycyl-L-2-Methylpropyl-L-Glutamic Acid

Arm Title

Placebo (strawberry flavored solution)

Arm Type

Placebo Comparator

Arm Description

Strawberry flavored solution and Water for Injection

Intervention Type

Drug

Intervention Name(s)

NNZ-2566

Intervention 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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Strawberry flavored solution 0.5% v/v in Water for Injection

Intervention Description

Strawberry flavored solution and Water for Injection

Primary Outcome Measure Information:

Title

Adverse events

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.

Time Frame

Through to Day 40

Secondary Outcome Measure Information:

Title

Change in EEG activity

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).

Time Frame

Baseline through to Day 40

Title

Behavior

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).

Time Frame

Baseline through to Day 40

Title

Physiological changes

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).

Time Frame

Baseline through to Day 40

Title

Global and Functional outcome Measures

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).

Time Frame

Baseline through to Day 40

Other Pre-specified Outcome Measures:

Title

Pharmacokinetics

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.

Time Frame

Baseline through to Day 40

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

No

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

Overall Study Officials: