NB-001 in Children and Adolescents With 22q11 Deletion Syndrome

Phase 2

Completed

Conditions: 22q11 Deletion Syndrome

Interventions: Drug: NB-001
Other: Placebo

Registration Number: NCT05290493

Lead Sponsor: Nobias Therapeutics, Inc.

Brief Summary: This is a Phase 2, randomized, placebo-controlled crossover trial to assess the safety and efficacy of NB-001 in children and adolescents with 22q11DS that manifest commonly associated neuropsychiatric symptoms.

Detailed Description: The trial is designed to allow all visits to be conducted via telephone and/or video (i.e., telemedicine) or by home health nurse. An in-person visit is required at Screening unless site or government mandates restrict this due to coronavirus disease-2019 (COVID-19). Other in-person visit(s) may occur, if indicated, based on the Investigator's clinical judgement. Subjects will be screened to confirm eligibility and then randomized in a 1:1 ratio to one of two treatment sequences: NB-001 (active drug product) followed by placebo (treatment sequence A/P) or placebo followed by NB-001 (treatment sequence P/A). During the Double-Blind Treatment Phase of the trial, the subject and/or parent/legal guardian (henceforth, 'parent/guardian') will be contacted at Day 0 to complete baseline symptom scales and will begin dosing with the investigational product (IP; NB-001 or placebo) on the morning of Day 1. Subjects or their parent/guardian will administer the IP twice daily (BID) and will be contacted at Days 0, 1, 14, 28, 42, 49, 50, 63, 77 and 91 to evaluate measures of safety and efficacy, including the completion of symptom scales. In addition, the subject and/or parent/guardian will be contacted at Days 7, 21, 35, 56, 70 and 84 to assess subject safety. Blood samples for pharmacokinetic analysis, 4β-hydroxycholesterol and plasma proline will be collected at multiple timepoints. During the Double-Blind Treatment Phase, subjects will receive IP corresponding with their first treatment assignment for 6 weeks (Treatment Period 1), followed by an intervening wash-out period of 1 week, and then will receive their second treatment assignment for the subsequent 6-week period (Treatment Period 2). All symptom scales will be centrally and/or locally administered. Approximately 10 parents/guardians and paired clinical trial site clinicians for subjects who complete the trial per protocol through Visit Day 91 will be invited to participate in an optional, one-hour (approximately), exit interview to discuss the observations of the subject's experience(s) and functioning while participating in the treatment periods of the trial. The subject and/or parent/guardian will be contacted for an End of Trial Visit to occur 4 weeks following the last dose of IP to assess safety.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

Inclusion Criteria

The subject has a genotype with a pathologic deletion in the 22q11 region confirmed by documentation (e.g., genetic test results) available at the clinical trial site.
The subject is aged 6 to 17 years old, inclusive.
The subject has a CGI-S scale score of ≥4 (i.e., moderately, markedly, severely, or among the most extremely ill patients) at Screening. Note that the Severity score of 4 could be from a composite of 2 or more sub-threshold scores.

And either:
1. Psychiatric symptoms in the clinical range for at least 1 of 3 disorders, anxiety disorder, ADHD, or ASD, respectively, as demonstrated by score(s) at or above the following numbers on at least 1 of 3 scales:
  - PARS 5-Item Severity Score ≥12 (i.e., sum of items 2+3+5+6+7 ≥12)
  - ADHD-RS-5 Scores of 2 or 3 (i.e., "Often" or "Very Often") on at least 6 questions, with the majority of symptoms related to inattention (common in 22q11DS) rather than hyperactivity (less common in 22q11DS)
  - SRS-2 >60
  OR:
2. Psychiatric symptoms in the subclinical range for at least 2 of 3 disorders, anxiety disorder, ADHD, and/or ASD, respectively, as demonstrated by scores at or above the following numbers on at least 2 of 3 scales:
  - PARS 5-Item Severity Score of 10 or 11 (i.e., sum of items 2+3+5+6+7=10 or 11)
  - ADHD-RS-5 Scores of 2 or 3 (i.e., "Often" or "Very Often") on 4 or 5 questions, with the majority of symptoms related to inattention (common in 22q11DS) rather than hyperactivity (less common in 22q11DS)
  - SRS-2 of 55-59
The subject has adequate renal and hepatic function indicated by:
- Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (per the revised Schwartz equation; Fadrowski and Furth 2011, Staples et al. 2010)
- Serum bilirubin ≤2.5 × upper limit of normal (ULN; unless documented Gilbert's Disease); aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN
If the subject is female and of reproductive potential, she has a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 0.
If the subject is of reproductive potential, s/he agrees to abstain from reproductive cell donation, per below, and, if ever heterosexually active, to use dual effective/highly effective contraception (including at least one effective and at least one highly effective contraceptive method; Section 9.2.1) from Screening through the End of Trial Visit.
- If the subject is female and of reproductive potential, she agrees to abstain from oocyte donation from Screening through the End of Trial Visit.
- If the subject is male and of reproductive potential, he agrees to abstain from sperm donation from Screening through the End of Trial Visit.
The subject's parent/guardian understands the trial procedures and agrees to the subject's participation in the trial, as well as to the parent/guardian trial involvement, as indicated by parent/guardian signature on the informed consent form and, if applicable, subject signature on the subject assent form.

Exclusion Criteria

The subject or parent/guardian is, in the opinion of the Investigator, mentally or legally incapacitated, or has significant emotional problems at the time of Screening or expected emotional problems during the conduct of the trial which would interfere with the conduct of the trial evaluations.
The subject has a history of psychotic symptoms, current psychotic symptoms, or a diagnosis of a psychotic disorder based on clinical assessment.
The subject has an intelligence quotient (IQ) score of <65 based on the WASI-II assessment. NOTE: A maximum of 3 (i.e., 10% of the total N) nonverbal subjects will be allowed in the trial on a first-come-first-served basis.
The subject has a history of any illness that, in the opinion of the Investigator, might confound the results of the trial or pose an additional risk to the subject by participation in the trial.
The subject has clinically significant unstable or uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases.
The subject has uncontrolled, active seizure(s), within the 3 months prior to Screening.
The subject has known human immunodeficiency virus (HIV), a detectable viral load for hepatitis C, or hepatitis B surface antigen indicative of chronic active infection.
The subject is pregnant or is a nursing mother.
The subject has suicidal ideation and behavior, based on Investigator assessment of the completed Columbia-Suicide Severity Rating Scale at Screening, or when repeated on Day 0 (if more than 21 days elapse between Screening and Day 1).
The subject is currently taking neuropsychiatric medication(s) at a dose that has not been stable for ≥3 months prior to Day 1 or psychotherapy that has not been stable for ≥3 months prior to Day 1. If the subject is taking medication(s) or receiving psychotherapy, the subject and parent/guardian must agree to continue the intervention(s) at the same dose and frequency through the End of Trial Visit.
The subject has received any investigational therapy (i.e., used for a non-approved indication and in the context of a research investigation) <14 days prior to the first dose of NB-001 (i.e., Day 1) or within 5 drug half-lives prior to the first dose of NB-001.
The subject uses illicit drugs (e.g., marijuana, amphetamines or cocaine), or has known alcohol or drug abuse or dependence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association 2013). Medically approved marijuana use, where usage is legal, is allowed; however, the dose and frequency of use should remain stable during trial participation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
NB-001	NB-001	Two (2) 100 mg capsules administered orally BID (400 mg total daily dose) with liquids or, if the subject is unable to swallow a capsule whole, capsules were opened, and the contents sprinkled on applesauce.
Placebo	Placebo	Two (2) capsules (matching, inactive) administered orally BID with liquids or, if the subject is unable to swallow a capsule whole, capsules were opened, and the contents sprinkled on applesauce.

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability of NB-001	6 weeks (Day 42/ET)	Type, frequency, severity, and causality of treatment-emergent adverse events (TEAEs),treatment-emergent serious adverse events (TESAEs), clinically significant changes from baseline in laboratory tests, electrocardiograms (ECGs), vital signs, and physical examination findings during treatment with NB-001.

Secondary Outcome Measures

Name	Time	Method
Treatment Effect of NB-001 on the Social Responsiveness Scale, Second Edition (SRS-2)	6 weeks (Day 42/ET)	The SRS-2 identifies the presence and severity of social impairment within the autism spectrum. It is a 65-item, parent-completed questionnaire which incorporates 5 content areas of social deficits. The sum of all items is calculated to provide a maximum total score of 195. However, a total derived T-score is calculated centrally and reported for this trial. A higher T-score indicates more severe impairment. The population mean T-score is 50, with a standard deviation of 10. Thus, a T-score considered within the normal range is 59 or below (i.e., minimum T-score value), and a T-score indicating a severe range is 76 or above (i.e., maximum T-score value). Scores between 60-75 fall into the mild to moderate range.
Treatment Effect of NB-001 on the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5) - Inattention Score	6 weeks (Day 42/ET)	The ADHD-RS-5 is a parent/guardian reported scale to measure behaviors of children and adolescents with ADHD. It consists of 18 items grouped into two subscales: inattention (items 1-9) and hyperactivity (items 10-18). Each item is scored on a scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms). The total inattention score (reported here) can range from a minimum value of 0 to a maximum value of 27. Higher total inattention scores reflect more severe symptoms.
Treatment Effect of NB-001 on the Clinical Global Impression Improvement (CGI-I) Scale	6 weeks (Day 42/ET)	The CGI-I scale is a 7-point scale that measures how much a patient's condition has improved or worsened over time. The CGI-I is scored on a scale of 1-7, with a score of 1 indicating "Very much improved" and 7 indicating "Very much worse". The least squares mean of the score on the CGI-I scale at the end of the 6-week treatment period is reported here.
Treatment Effect of NB-001 on the Clinical Global Impression Severity (CGI-S) Scale	6 weeks (Day 42/ET)	CGI-S: 7-point scale that measures a participant's overall disease severity. A 1-point improvement in the CGI-S scale is an appropriate meaningful change threshold. Possible scores are: 1 = Normal, not at all impaired; 2 = Borderline impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most extremely impaired patients.
Treatment Effect of NB-001 on the Pediatric Anxiety Rating Scale (PARS)	6 weeks (Day 42/ET)	The PARS is a clinician-rated instrument for assessing severity of anxiety symptoms associated with common anxiety disorders. The first section is a 50-item symptom checklist and the second section is comprised of 7 severity/impairment items reflecting the severity/impairment of all symptoms noted in the first section. The PARS total severity score is calculated as the sum of items 2, 3, 5, 6, and 7 from the second section of the instrument. Each item is rated on a 6-point Likert scale from 0-5 with the higher scores indicating more severe anxiety. The total severity score can range from a minimum value of 0 to a maximum value of 25. Higher scores indicate more severe anxiety. Additionally, per protocol, at baseline, a score of \>12 on the PARS 5-item total severity score (items 2+3+5+6+7) is indicative of psychiatric symptoms in the clinical range for anxiety disorder, and a score of 10 or 11 is indicative of psychiatric symptoms in the subclinical range for anxiety disorder.
Treatment Effect of NB-001 on the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5) - Hyperactivity Score	6 weeks (Day 42/ET)	The ADHD-RS-5 is a parent/guardian reported scale to measure behaviors of children and adolescents with ADHD. It consists of 18 items grouped into two subscales: inattention (items 1-9) and hyperactivity (items 10-18). Each item is scored on a scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms). The total hyperactivity score (reported here) can range from a minimum value of 0 to a maximum value of 27. Higher total hyperactivity scores reflect more severe symptoms.

Trial Locations

Locations (4): The Hospital for Sick Children (SickKids)
🇨🇦
Toronto, Ontario, Canada
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Children's Hospital of Philadelphia (CHOP)
🇺🇸
Philadelphia, Pennsylvania, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States