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

NCT ID: NCT01894958

Last Updated: 2018-02-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 72 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-31
• Study Completion Date: 2015-10-31

Brief Summary

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.

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.

Conditions

Fragile X Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

NNZ-2566

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

Group Type: EXPERIMENTAL

NNZ-2566

Intervention Type: DRUG

Glycyl-L-2-Methylpropyl-L-Glutamic Acid (NNZ-2566) supplied as a lyophilized powder (2g in 50mL vials or 3g in 30mL bottles) for reconstitution with strawberry flavored solution 0.5% v/v in Water for Injection.

Placebo (strawberry flavored solution)

Strawberry flavored solution and Water

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Strawberry flavored solution

Interventions

NNZ-2566

Glycyl-L-2-Methylpropyl-L-Glutamic Acid (NNZ-2566) supplied as a lyophilized powder (2g in 50mL vials or 3g in 30mL bottles) for reconstitution with strawberry flavored solution 0.5% v/v in Water for Injection.

Intervention Type: DRUG

Placebo

Strawberry flavored solution

Intervention Type: DRUG

Other Intervention Names

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

Eligibility Criteria

Inclusion Criteria

1. Fragile X Syndrome with a molecular genetic confirmation of the full FMR1 mutation.

• Results from previously completed testing are acceptable with written documentation of the genetic results.
• Results from PCR or Southern blot tests are acceptable
• Results from cytogenetic testing are not acceptable but subject may be eligible if molecular genetic testing is redone.
• A full mutation with mosaicism is allowed if:

• Subject manifests full phenotypic profile of Fragile X syndrome
• CGG Repeats >200 are detected
• Southern blot prevails over PCR, if Southern blot shows >200 repeats and PCR results show <200 repeats.
• The following results would not meet criteria:

• Deletions
• Point mutations
• Mosaicism without detection of >200 CGG repeats or absence of full phenotypic profile in an individual with mosaicism

2. Males, aged 12-45 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

Exclusion Criteria

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.

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 and bupropion.

2. 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.

3. 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.

4. History of, or current cerebrovascular disease or clinically significant brain trauma.

5. History of, or current clinically significant endocrine disorder, e.g. hypo or hyperthyroidism, or diabetes.

6. History of, or current malignancy.

7. Current major depressive disorder (patients have to be free of the most recent episode for 3 months prior to enrollment).

8. History of a DSM-5-defined substance use disorder in the 3 months prior to Screening.

9. Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as measured at Screening.

10. 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

11. Patients with significant hearing and/or visual impairments that may affect their ability to complete the test procedures.

12. Current treatment with insulin

13. Hgb A1C values outside of the normal reference range at Screening

14. Current or past treatment with insulin like growth factor IGF-1

15. Current or past treatment with growth hormone

16. Enrollment in another clinical trial within the 30 days preceding Screening

17. Previously randomized in this clinical trial

18. Allergy to strawberry

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Neuren Pharmaceuticals Limited

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elizabeth M Berry-Kravis, MD

Role: PRINCIPAL_INVESTIGATOR

Rush University Medical Center

Joseph Cubells, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Alexander Kolevzon, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Nicole Tartaglia, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Colorado

Jean Frazier, MD

Role: PRINCIPAL_INVESTIGATOR

University of Massachusetts, Worcester

Shivkumar Hatti, MD

Role: PRINCIPAL_INVESTIGATOR

Suburban Research Associates

Craig Erickson, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Thomas Challman, MD

Role: PRINCIPAL_INVESTIGATOR

Autism & Developmental Medicine Institute Geisinger Health System

Kevin Sanders, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Diane Treadwell-Deering, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Jeffrey Innis, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Howard Needleman, MD

Role: PRINCIPAL_INVESTIGATOR

University of Nebraska

Steve Skinner, MD

Role: PRINCIPAL_INVESTIGATOR

Greenwood Genetic Center

Bryan King, MD

Role: PRINCIPAL_INVESTIGATOR

Seattle Children's Hospital

Randi Hagerman, MD

Role: PRINCIPAL_INVESTIGATOR

UC Davis MIND Institute

Robert Findling, MD

Role: PRINCIPAL_INVESTIGATOR

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Locations

UC Davis MIND Institute

Sacramento, California, United States

Children's Hospital Colorado

Denver, Colorado, United States

Children's National Hospital

Washington D.C., District of Columbia, United States

Emory University

Atlanta, Georgia, United States

Rush University Medical Center

Chicago, Illinois, United States

Kennedy Krieger Institute

Baltimore, Maryland, United States

University of Massachusetts Medical School

Worcester, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

University of Nebraska

Omaha, Nebraska, United States

Mount Sinai School of Medicine

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Autism & Developmental Medicine Institute Geisinger Health System

Lewisburg, Pennsylvania, United States

Suburban Research Associates

Media, Pennsylvania, United States

Greenwood Genetic Center

Greenwood, South Carolina, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Texas Children's Hospital

Houston, Texas, United States

Seattle Children's Hospital

Seattle, Washington, United States

Countries

United States

References

Berry-Kravis E, Horrigan JP, Tartaglia N, Hagerman R, Kolevzon A, Erickson CA, Hatti S, Snape M, Yaroshinsky A, Stoms G; FXS-001 Investigators; Glass L, Jones NE. A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome. Pediatr Neurol. 2020 Sep;110:30-41. doi: 10.1016/j.pediatrneurol.2020.04.019. Epub 2020 May 23.

Reference Type: DERIVED

PMID: 32660869 (View on PubMed)

Related Links

http://ghr.nlm.nih.gov/

Genetics Home Reference

http://ghr.nlm.nih.gov/condition/fragile-x-syndrome

Fragile X Syndrome

http://ghr.nlm.nih.gov/condition/mecp2-duplication-syndrome

MECP2 duplication syndrome

http://ghr.nlm.nih.gov/condition/ppm-x-syndrome

PPM-X syndrome

http://ghr.nlm.nih.gov/condition/renpenning-syndrome

Renpenning syndrome

http://ghr.nlm.nih.gov/condition/tetrasomy-18p

tetrasomy 18p

http://www.nlm.nih.gov/medlineplus/

MedlinePlus

http://www.nlm.nih.gov/medlineplus/drinkingwater.html

Drinking Water

http://www.nlm.nih.gov/medlineplus/fragilexsyndrome.html

Fragile X Syndrome

http://www.clinicaltrials.gov/ct2/info/fdalinks

U.S. FDA Resources

Other Identifiers

Neu-2566-FXS-001

Identifier Type: -

Identifier Source: org_study_id