An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001)

Neuren Pharmaceuticals Limited28 enrolled

Overview

A study of the safety, tolerability and pharmacokinetics of NNZ-2591 and measures of efficacy in children and adolescents with Pitt Hopkins Syndrome.

The primary purpose of this study is to investigate the safety, tolerability and pharmacokinetics of treatment with NNZ-2591 oral solution in children and adolescents with Pitt Hopkins Syndrome. The secondary purpose is to investigate measures of efficacy. Subjects will receive treatment with NNZ-2591 oral solution (50 mg/mL) doses for a total of 13 weeks.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pitt Hopkins Syndrome

Interventions

NNZ-2591DRUG

NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose for 13 weeks.

Eligibility

Sex: ALLMin age: 3 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Clinical diagnosis of PTHS with a documented disease-causing genetic etiology for the disorder. 2. Males or females aged 3-17 years. 3. Body weight of 12kg or higher at screening 4. Subjects with a Clinical Global Impression- Severity (CGI-S) score of 4 or greater at the Screening visit. 5. Not actively undergoing regression or loss of skills, defined as no persistent loss of previously acquired developmental skills for a period within 3 months of the Screening visit 6. Each subject must be able to swallow the study medication provided as a liquid solution. 7. Caregiver(s) must have sufficient English language skills. Exclusion Criteria: 1. Body weight \<12kg at screening 2. Clinically significant abnormalities in safety laboratory tests and vital signs at Screening. 3. Abnormal QTcF interval or prolongation at Screening. 4. Any other clinically significant finding on ECG at the Screening visit. 5. Positive for severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) and previous COVID 19 infection with last 12 months that required hospitalization. 6. Unstable or changes Psychotropic treatment 2 weeks prior to screening 7. Excluded concomitant treatments. 8. Actively undergoing regression or loss of skills. 9. Unstable seizure profile. 10. Current clinically significant renal conditions and abnormalities 11. Current clinically significant cardiovascular, hepatic, gastrointestinal, respiratory, endocrine disease, or clinically significant organ impairment. 12. Current clinically significant hypo- or hyperthyroidism, Type 1 or Type 2 diabetes mellitus requiring insulin (whether well controlled or uncontrolled), or uncontrolled Type 1 or Type 2 diabetes. 13. Has planned surgery during the study. 14. History of, or current, cerebrovascular disease or brain trauma. 15. History of, or current catatonia or catatonia-like symptoms. 16. History of, or current, malignancy. 17. Current major or persistent depressive disorder (including bipolar depression). 18. Significant, uncorrected visual or uncorrected hearing impairment. 19. Allergy to strawberry. 20. Positive pregnancy test 21. Subject is judged by the Investigator or Medical Monitor to be inappropriate for the study

Locations (5)

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California at San Francisco

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Rush University Medical Center

Chicago, Illinois, United States

Outcomes

Primary Outcomes

Safety and Tolerability

To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591.

Time frame: 13 weeks

Pharmacokinetic - Mean AUC24

Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model.

Time frame: Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.

Pharmacokinetic - t1/2

Time frame: Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.

Secondary Outcomes

Pitt Hopkins Syndrome-specific Clinical Global Impression Scale (CGI-I) - Overall Improvement

Pitt Hopkins Syndrome-specific Clinical Global Impression Scale (CGI-I) - Overall Improvement. Score on a Likert scale (1-7) where lower scores are better.

Time frame: CGI-I was assessed at weeks 6, 13/EOT & 15. Overall improvement scores relate to week 13/EOT visit.

Caregiver Impression of Improvement: Overall Score

Caregiver Impression of Improvement: Overall Score. Measured on a 7 point Likert scale (1-7) where lower scores are better.

Data from ClinicalTrials.gov

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UT Southwestern

Dallas, Texas, United States

Time frame: CIC was assessed at Week13/EOT

Pitt Hopkins Syndrome-specific Clinical Global Impression Scale - Severity (CGI-S) - Overall Score

Pitt Hopkins syndrome-specific Clinical Global Impression Scale - Severity (CGI-S) - Change from baselines on overall Score based on a 7 point Likert scale (1-7) where lower scores are better.

Time frame: Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT).

Caregiver Top 3 Concerns

Caregiver Top 3 Concerns: Change from baseline in Average Concern Severity. The average concern severity defined as the average of the severity scores for the three concerns evaluated at a given visit, and was calculated as long as at least one concern was useable for analysis at the visit. Scores range from 0 - 10 with higher scores indicating greater concern severity. A negative change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in average concern severity.

MacArthur-Bates Communicative Development Inventory (MB-CDI)

MacArthur-Bates Communicative Development Inventory (MB-CDI): Words Understood Domain. Scores ranges from 0-396, with higher scores indicating greater language ability. A positive change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13).

Observer-Reported Communication Ability (ORCA)

Observer-Reported Communication Ability (ORCA): Change from baseline in Modified t-score. The ORCA measures an individual's communication abilities based on observations made by caregivers, parents, or other relevant observers, and is based on 4 domains: Expressive Communication, Receptive Communication, Social Communication, and Pragmatic Language Skills. Scores range from 25.8 - 83.8, with higher scores indicating greater communication ability. A positive change from baseline indicates improvement. A T-score standardizes the individual's performance relative to a normative sample. It typically has a mean of 50 and a standard deviation of 10. T score = 50 + 10 × (X-µ)/σ Where: X is the individual's raw score μ is the population mean σ is the standard deviation

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in Total Score.

Aberrant Behavior Checklist-2 (ABC-2)

Aberrant Behavior Checklist-2 (ABC-2): Change from baseline in Total Score. Range of scores is 0-174, with higher scores indicating more behavioral issues. A negative change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total score.

CSHQ

Child Sleep Habits Questionnaire (CSHQ). Total Score. Change from baseline. Range of scores was (33-99) with higher scores being worse.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total score.

GIHQ

Gastrointestinal Health Questionnaire (GIHQ). Change from baseline in total frequency score. Range of scores was (0-197) with higher scores being worse.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total frequency score.

Vineland Adaptive Behavior Scales-3, Interview Version

Vineland Adaptive Behavior Scales-3 (VABS-3), Interview version, Change from baseline in Adaptive Behavior Composite Standard Score. Scores range from 20 - 140 with higher scores indicating greater functional abilities. A positive change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in composite standard score.

Modified Two-minute Walk Test

Modified two-minute walk test. Change from baseline in distance travelled (m) on 2 minute walk test. The test was only administered for participants who were ambulatory and able to complete the assessment. A positive score on change from baseline indicates improvement in distance walked.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in distance travelled on two minute walk test.

QI-Disability

Quality of Life Inventory-Disability (QI-Disability). Overall Score change from baseline. Scores range from 0 - 100 with higher scores indicating better quality of life. A positive change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in overall score score.

ICND

Impact of Childhood Neurological Disability (ICND)-Overall quality of life rating, change from baseline. Score ranges from 1 - 6, with a higher score indicating better quality of life. A positive change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in overall quality of life rating score.

Behavior Problems Inventory - Short Form

Change from baseline in Behavior Problems Inventory - Short Form Total Frequency Score. Scores range from 0-120, with higher scores indicating greater frequency in behavior problems. A negative change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in Total Frequency score.

Bayley Scales of Infant Development (BSID-4): Non Verbal Development Quotient (NVDQ)

Change from baseline in Non Verbal Development Quotient (NVDQ). Scores range from 40 - 160, with higher scores indicating greater development. A positive change from baseline indicates improvement.

Time frame: Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in NVDQ score.