A Safety Study of NNZ-2566 in Patients With Fragile X Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Neuren Pharmaceuticals Limited
Sponsor:
Information provided by (Responsible Party):
Neuren Pharmaceuticals Limited
ClinicalTrials.gov Identifier:
NCT01894958
First received: July 3, 2013
Last updated: July 27, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to determine whether NNZ-2566 is safe and well tolerated in the treatment of Fragile X Syndrome in adolescent and adult males.


Condition Intervention Phase
Fragile X Syndrome
Drug: NNZ-2566
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Fixed-Dose Study of NNZ-2566 in Fragile X Syndrome

Resource links provided by NLM:


Further study details as provided by Neuren Pharmaceuticals Limited:

Primary Outcome Measures:
  • Adverse events [ Time Frame: Through to Day 56 ] [ Designated as safety issue: Yes ]
    Incidence of adverse events (AE), including Serious adverse events (SAE), will be evaluated between the two NNZ-2566 doses and placebo. Incidence of AEs from randomized dosing through to Day 56 post randomization. Incidence of SAEs from randomization through to Day 56 post randomization.


Secondary Outcome Measures:
  • Physiological changes [ Time Frame: Baseline through to Day 56 ] [ Designated as safety issue: No ]
    Serum levels and changes of standard hematology, and chemistry parameters (including thyroid function) will be calculated from Baseline through to Day 56. Fundoscopy and tonsil size will be documented at Baseline, and Days 14, 28, 42 and 56. Flow cytometry will be used to assess the phosphorylation status of the enzymes Akt and extracellular signal-regulated kinase (ERK) in peripheral lymphocytes, on blood samples obtained on Days 14, 28, 42 and 56. Electrocardiogram (ECG) will be assessed at Screening, Days 14, 21, 28, 35, 42 and 56.

  • Behavior [ Time Frame: Baseline through to Day 56 ] [ Designated as safety issue: No ]
    Symptom severity according to the Fragile X Symptom Rating Scale, Clinician Domain Specific Top Three Concerns-VAS, Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Scale (VABS), Child and Adolescent Symptom Inventory-Anxiety Scale (CASI-16), Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS-PDD), Expressive Language Sampling and Clinical Global Impression of Severity (CGI-S).

  • Global and Functional outcome Measures [ Time Frame: Baseline through to Day 56 ] [ Designated as safety issue: No ]

    Global outcome as measured by the change in scores in the Clinical Global Impression - Severity and Improvement scales (CGI-S and -I) and the KiTap measure of cognition from baseline, during treatment, and post treatment.

    Global and Functional outcome as measured by changes in scores in the Fragile X Symptom Rating Scale, Clinician Domain Specific Top Three Concerns-VAS, Caregiver Top Three Concerns (related to the subject's Fragile X syndrome) as assessed via a Visual Analogue Scale (VAS), CASI-20, CYBOCS-PDD, Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Scales (VABS) and Expressive Language Sampling will be assessed during treatment.



Other Outcome Measures:
  • Pharmacokinetics [ Time Frame: During treatment ] [ Designated as safety issue: No ]
    The following pharmacokinetic measures will be calculated from NNZ-2566 concentrations in whole blood: Cmax (Peak), Cmin (trough), C0-6 at steady state, and area under the curve (AUC).

  • Computerized eye-tracking [ Time Frame: During treatment ] [ Designated as safety issue: No ]
    Computer-based eye tracking assessments will be done on Days 14, 28 and 42.


Estimated Enrollment: 60
Study Start Date: January 2014
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NNZ-2566
Glycyl-L-2-Methylpropyl-L-Glutamic Acid
Drug: NNZ-2566
Glycyl-L-2-Methylpropyl-L-Glutamic Acid (NNZ-2566) supplied as a lyophilized powder (2g in 50 milliliter vials) for reconstitution with strawberry flavored solution 0.5% v/v in Water for Injection.
Other Name: NNZ-2566
Placebo Comparator: Placebo (strawberry flavored solution)
Strawberry flavored solution and Water
Drug: Placebo
Strawberry flavored solution
Other Name: Strawberry flavored solution 0.5% v/v in Water for Injection

Detailed Description:

Fragile X Syndrome is a genetically determined neurological disorder in which affected individuals are intellectually handicapped to varying degrees and display a variety of associated psychiatric symptoms. Clinically, Fragile X Syndrome is characterized by intellectual handicap, hyperactivity and attentional problems, autism spectrum symptoms, emotional lability and epilepsy. The epilepsy seen in Fragile X Syndrome is most commonly present in childhood, but then gradually remits towards adulthood. Physical features such as prominent ears and jaw, and hyper-extensibility of joints are frequently present but are not diagnostic. Intellectual handicap is the most common feature defining the phenotype. Treatment for the disorder is symptomatic - focusing on the management of symptoms - and supportive, requiring a multidisciplinary approach.

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 males with Fragile X Syndrome. The study also will also investigate measures of efficacy during treatment.

  Eligibility

Ages Eligible for Study:   14 Years to 40 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Fragile X Syndrome with a molecular genetic confirmation of the full FMR1 mutation
  2. Males, aged 14-40 years
  3. Subjects with a Clinical Global Impression - Severity (CGI-S) score of 4 or greater at Screening
  4. Subjects with a total score of 30 or greater on the Aberrant Behavior Checklist (ABC) at Screening
  5. Current treatment with no more than 3 psychotropic medications. This includes medications used to treat problems with sleep onset and sleep continuity. Melatonin for difficulties with sleep onset is permissible and is excepted from the count of psychotropic medications. Similarly, anti-epileptic medications are permitted and are not denoted as "psychotropic medications" if they are used for treatment of seizures. Use of anti-epileptics for other indications such as the treatment of mood disorders counts towards the limit of permitted medications. Concurrent use of omega-3 fatty acids is also permissible and does not count towards the allowed number of concomitant psychotropic medications. A complete list of permitted concomitant psychotropic medications can be found in Appendix A.
  6. Concomitant medications for chronic medical conditions are permissible. Examples of chronic medical conditions include gastroesophageal reflux disease (GERD) and asthma. Every effort should be made to keep the doses and dosing regimens of these medications stable in the 4 weeks preceding Screening and during the period between Screening and the commencement of study medication.

    1. Permitted psychotropic concomitant medications (except for anti-epileptic medications-see below) must be stable, in terms of dose and dosing regimen, for at least 4 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication.
    2. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication
  7. Behavioral treatments excluding psychotherapy (see exclusion criteria) must be stable for 4 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication

    a. For each enrollee, every effort should be made to maintain stable regimens of allowed concomitant medications and allowed behavioral therapies from the time of commencement of single-blind study medication until the last study assessment.

  8. Sufficient expressive language capabilities to complete the Expressive Language Sampling Task.
  9. Individuals with a history of seizures should have a stable pattern of seizure activity in the 3 months preceding Screening.

Exclusion Criteria:

  1. Treatment within the two weeks prior to Screening with monoamine (MAO) inhibitors, lithium, minocycline, acamprosate, racemic baclofen, investigational metabotropic glutamate receptor subtype 5 (mGluR5) medications, d-cycloserine, oxytocin, carbetocin, tricyclic antidepressants, modafinil, armodafinil, benzodiazepines (unless used for seizure control), memantine, amantadine, and bupropion, lovastatin, and simvastatin.
  2. Current treatment with N-methyl-D-aspartate (NMDA) antagonists
  3. Patients planning to commence psychotherapy, including cognitive behavior therapy (CBT), during the period of the study or those who had begun psychotherapy, including CBT, within 6 weeks prior to Screening.
  4. History of, or current, cardiovascular, renal, hepatic, respiratory and/or gastrointestinal disease, which may interfere with the absorption, distribution, metabolism or excretion of the study medication, or which may interfere with the interpretation of the safety/tolerability or efficacy of the study medication.
  5. History of, or current cerebrovascular disease or clinically significant brain trauma.
  6. History of, or current clinically significant endocrine disorder, e.g. hypo or hyperthyroidism, or diabetes.
  7. History of, or current malignancy.
  8. Current major depressive disorder (patients have to be free of the most recent episode for 3 months prior to enrollment).
  9. History of a DSM-5-defined substance use disorder in the 3 months prior to Screening.
  10. Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as measured at Screening.
  11. QT/QTcF Exclusions (any of the following):

    • QTcF > 450 msec. Three ECGs should be obtained at the time of Screening, 5 minutes apart from each other, and the results should be averaged.
    • History of risk factors for torsade de pointes (e.g. heart failure, clinically significant hypokalemia or hypomagnesemia, or a family of long QT syndrome).
    • A serum potassium at screening <3.0 mmol/L.
    • QT/QTcF prolongation previously or currently controlled with medication, in which normal QT/QTcF intervals could or can only be achieved with medication
    • Current treatment with other medications that have demonstrated QT/QTc prolongation and have this risk described in the Warnings and Precautions section of their Prescribing Information
  12. Patients with significant hearing and/or visual impairments that may affect their ability to complete the test procedures.
  13. Current treatment with insulin
  14. Hgb A1C values outside of the normal reference range at Screening
  15. Current or past treatment with insulin like growth factor IGF-1
  16. Current or past treatment with growth hormone
  17. Enrollment in another clinical trial within the 30 days preceding Screening
  18. Previously randomized in this clinical trial
  19. Allergy to strawberry
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01894958

Contacts
Contact: Joseph Horrigan, MD jhorrigan@neurenpharma.com
Contact: Nancy Jones, PhD njones@neurenpharma.com

Locations
United States, Colorado
Children's Hospital Colorado Not yet recruiting
Denver, Colorado, United States, 80045
Contact: Nanastasia Welnick    720-777-8608    Nanastasia.Welnick@childrenscolorado.org   
Principal Investigator: Nicole Tartaglia, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30033
Contact: Krista Charen    404-778-8479    kharkre@emory.edu   
Principal Investigator: Jeannie Visootsak, MD         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Jamie A Chin    312-942-0025    Jamie_A_Chin@rush.edu   
Principal Investigator: Elizabeth M Berry-Kravis, MD         
United States, Massachusetts
University of Massachusetts Medical School Recruiting
Worcester, Massachusetts, United States, 01655
Contact: Kara Manchester    774-455-4115    kara.manchester@umassmed.edu   
Principal Investigator: Jean Frazier, MD         
United States, New York
Mount Sinai School of Medicine Recruiting
New York, New York, United States, 10029
Contact: Hillary Rieger    212-241-2826    hillary.rieger@mssm.edu   
Principal Investigator: Alexander Kolevzon, MD         
United States, Pennsylvania
Suburban Research Associates Recruiting
Media, Pennsylvania, United States, 19063
Contact: Nathan Blubaugh    610-891-9024 ext 103    nblubaugh@suburbanresearch.com   
Contact: Nikki Thomas    610-891-7200    Nthomas@suburbanresearch.com   
Principal Investigator: Shivkumar Hatti, MD         
Sponsors and Collaborators
Neuren Pharmaceuticals Limited
Investigators
Principal Investigator: Elizabeth M Berry-Kravis, MD Rush University Medical Center
Principal Investigator: Jeannie Visootsak, MD Emory University
Principal Investigator: Alexander Kolevzon, MD Mount Sinai School of Medicine
Principal Investigator: Nicole Tartaglia, MD Children's Hospital Colorado
Principal Investigator: Jean Frazier, MD University of Massachusetts, Worcester
Principal Investigator: Shivkumar Hatti, MD Suburban Research Associates
  More Information

Additional Information:
No publications provided

Responsible Party: Neuren Pharmaceuticals Limited
ClinicalTrials.gov Identifier: NCT01894958     History of Changes
Other Study ID Numbers: Neu-2566-FXS-001
Study First Received: July 3, 2013
Last Updated: July 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Neuren Pharmaceuticals Limited:
Fragile X disorder
Autism

Additional relevant MeSH terms:
Fragile X Syndrome
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Pharmaceutical Solutions
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 01, 2014