A Randomized, Placebo-Controlled Crossover Trial to Assess the Safety and Efficacy of NB-001 in Children and Adolescents With 22q11 Deletion Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 4
- 主要终点
- Safety and Tolerability of NB-001
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
NB-001 and matching placebo were supplied to the Investigator or designee in blinded plastic bottles, each containing 40 capsules. Additionally, subject and parent/guardian, the Investigator, clinical trial site personnel, home health nurses, centralized rater(s), and the Sponsor will be blinded to treatment sequence assignment.
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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
- •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
- •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.
排除标准
- •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
- •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-
- •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.
研究组 & 干预措施
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.
干预措施: NB-001 (Drug)
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.
干预措施: Placebo (Other)
结局指标
主要结局
Safety and Tolerability of NB-001
时间窗: 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.
次要结局
- Treatment Effect of NB-001 on the Social Responsiveness Scale, Second Edition (SRS-2)(6 weeks (Day 42/ET))
- Treatment Effect of NB-001 on the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5) - Inattention Score(6 weeks (Day 42/ET))
- Treatment Effect of NB-001 on the Clinical Global Impression Improvement (CGI-I) Scale(6 weeks (Day 42/ET))
- Treatment Effect of NB-001 on the Clinical Global Impression Severity (CGI-S) Scale(6 weeks (Day 42/ET))
- Treatment Effect of NB-001 on the Pediatric Anxiety Rating Scale (PARS)(6 weeks (Day 42/ET))
- Treatment Effect of NB-001 on the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5) - Hyperactivity Score(6 weeks (Day 42/ET))