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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05290493
Recruitment Status : Recruiting
First Posted : March 22, 2022
Last Update Posted : November 21, 2022
Sponsor:
Information provided by (Responsible Party):
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 conditions.

Condition or disease Intervention/treatment Phase
22q11 Deletion Syndrome Drug: NB-001 Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Subjects will be 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). 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).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: NB-001 and matching placebo will be 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.
Primary Purpose: Treatment
Official Title: A Randomized, Placebo-Controlled Crossover Trial to Assess the Safety and Efficacy of NB-001 in Children and Adolescents With 22q11 Deletion Syndrome
Actual Study Start Date : February 10, 2022
Estimated Primary Completion Date : April 28, 2023
Estimated Study Completion Date : May 26, 2023


Arm Intervention/treatment
Active Comparator: NB-001
Active drug product, NB-001: Two (2) 100 mg capsules will be administered orally BID with liquids or, if the subject is unable to swallow a capsule whole, capsules may be opened, and the contents sprinkled on applesauce; total daily dose: 400 mg.
Drug: NB-001
NB-001 is a non-stimulant activator of multiple metabotropic glutamate receptors (mGluRs).
Other Names:
  • fasoracetam monohydrate
  • (5R)-5-(pyridine-1-carbonyl)pyrrolidin-2-one monohydrate

Placebo Comparator: Placebo
Placebo: Two (2) capsules (matching NB-001) will be administered orally BID with liquids or, if the subject is unable to swallow a capsule whole, capsules may be opened, and the contents sprinkled on applesauce.
Other: Placebo
Matching, inactive placebo




Primary Outcome Measures :
  1. Number of participants with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) Dictionary v.5.0 [ Time Frame: 6 weeks ]

    Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System Organ Class (SOC) and Preferred Term (PT) will be attached to the clinical database. AE severity will be graded using the CTCAE.

    Summaries (number and percentage of subjects) of TEAEs and TESAEs by SOC and PT will be provided by treatment group. TEAEs will also be summarized by relationship to study drugs and severity. In addition, TEAEs leading to premature discontinuation of study drugs and study, and SAEs leading to death will be summarized and listed.



Secondary Outcome Measures :
  1. Change from baseline in Clinical Global Impression Improvement (CGI-I) Scale [ Time Frame: 6 weeks ]
    Responder analyses will be performed for the CGI-I by classifying each subject as a responder or non-responder using an endpoint-specific threshold and computing the response rate in each treatment group. The CGI-S is a 7-point scale where 1=Very much improved and 7=Very much worse.

  2. Change from baseline in Clinical Global Impression Severity (CGI-S) Scale [ Time Frame: 6 weeks ]
    Responder analyses will be performed for the CGI-S by classifying each subject as a responder or non-responder using an endpoint-specific threshold and computing the response rate in each treatment group. The CGI-S is a 7-point scale where 1=Normal, Not at all impaired and 7=Among the most extremely impaired patients.

  3. Treatment effect of NB-001 on the Pediatric Anxiety Rating Scale (PARS) [ Time Frame: 6 weeks ]
    Treatment effect will be evaluated within the subset of subjects where the symptom of greatest impairment at baseline is anxiety as defined by the Pediatric Anxiety Rating Scale (PARS). 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.

  4. Treatment effect of NB-001 on the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5) [ Time Frame: 6 weeks ]
    Treatment effect will be evaluated within the subset of subjects where the symptom of greatest impairment at baseline is attention deficit as assessed by the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS-5). A score of >6 on the ADHD-RS-5 is indicative of psychiatric symptoms in the clinical range for attention deficit disorder, and a score of 4 or 5 is indicative of psychiatric symptoms in the subclinical range for attention deficit disorder.

  5. Treatment effect of NB-001 on the Social Responsiveness Scale, Second Edition (SRS-2) [ Time Frame: 6 weeks ]
    Treatment effect will be evaluated within the subset of subjects where the symptom of greatest impairment at baseline is one or more symptoms in autism spectrum disorder as assessed by the Social Responsiveness Scale, Second Edition (SRS-2). A score of >60 on the SRSTM-2 is indicative of psychiatric symptoms in the clinical range for autism spectrum disorder, and a score of 55-59 is indicative of psychiatric symptoms in the subclinical range for autism spectrum disorder.


Other Outcome Measures:
  1. Subject experience and meaningfulness of the change(s) while participating in NB-001-01 [ Time Frame: End of Treatment; approximately 13 weeks of trial participation ]
    Optional exit interviews will be conducted with clinicians and parent/guardian(s) of approximately 10 subjects who complete NB-001-01 per protocol



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. The subject is aged 6 to 17 years old, inclusive.
  3. 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
  4. 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
  5. 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.
  6. 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.
  7. 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:

  1. 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.
  2. The subject has a history of psychotic symptoms, current psychotic symptoms, or a diagnosis of a psychotic disorder based on clinical assessment.
  3. 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.
  4. 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.
  5. The subject has clinically significant unstable or uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases.
  6. The subject has uncontrolled, active seizure(s), within the 3 months prior to Screening.
  7. 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.
  8. The subject is pregnant or is a nursing mother.
  9. 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).
  10. 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.
  11. 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.
  12. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05290493


Contacts
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Contact: Cathi Sciacca (760) 271-5919 sciacca@nobiastx.com
Contact: Erin Castelloe, MD (858) 354-6441 castelloe@nobiastx.com

Locations
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United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Kiaira Coles    720-777-1497    Kiaira.Coles@childrenscolorado.org   
Principal Investigator: Naomi Meeks, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia (CHOP) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Panigrahi (Pree) Pratishtha    703-687-7772    panigrahip@chop.edu   
Principal Investigator: Sarah Hopkins, MD         
Sub-Investigator: Raquel Gur, MD, PhD         
Sub-Investigator: Madeline Chadehumbe, MD         
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98115
Contact: Maria Benitez-Cortez    206-987-6338    Maria.Benitez-Cortez@seattlechildrens.org   
Principal Investigator: Emily Gallagher, MD         
Canada, Ontario
The Hospital for Sick Children (SickKids) Recruiting
Toronto, Ontario, Canada, M5G1X8
Contact: Keshini Devakandan    (416) 813-7654    keshini.devakandan@sickkids.ca   
Principal Investigator: Jacob Vorstman, MD         
Sub-Investigator: Nancy Butcher, PhD         
Sponsors and Collaborators
Nobias Therapeutics, Inc.
Investigators
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Study Director: Neil Inala Nobias Therapeutics, Inc.
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Responsible Party: Nobias Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05290493    
Other Study ID Numbers: NB-001-01
First Posted: March 22, 2022    Key Record Dates
Last Update Posted: November 21, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nobias Therapeutics, Inc.:
22q11 Deletion Syndrome
22q11.2 Deletion Syndrome
22q11DS
Children and Adolescents
Additional relevant MeSH terms:
Layout table for MeSH terms
DiGeorge Syndrome
22q11 Deletion Syndrome
Syndrome
Disease
Pathologic Processes
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Lymphatic Abnormalities
Lymphatic Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Hypoparathyroidism
Parathyroid Diseases
Endocrine System Diseases
5-((2-(6-Amino-9H-purin-9-yl) ethyl) amino)-1-pentanol
Adenylyl Cyclase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action