Fragile X Syndrome
Conditions
Keywords
Fragile X disorder, Autism
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.
Interventions
DRUGNNZ-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.
DRUGPlacebo
Strawberry flavored solution
Sponsors
Neuren Pharmaceuticals Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
12 Years to 45 Years
Healthy volunteers
No
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Through to Day 56 | 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
| Measure | Time frame | Description |
|---|---|---|
| Physiological changes | Baseline through to Day 56 | 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 | Baseline through to Day 56 | 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 | Baseline through to Day 56 | 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
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics | During treatment | 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 | Baseline through to Day 56 | Computer-based eye tracking assessments will be done on Days 14, 28 and 42. |
Countries
United States
Outcome results
None listed