Clinical trial NCT05286762: Phase 3 Efficacy and Safety Fixed-Dose Study in Pediatrics (6-17) With ADHD Using CTx-1301
Official title: A Phase 3, Double-blind, Randomized, Placebo-controlled, Multi-center, Fixed-dose, Parallel Group Efficacy and Safety in Pediatrics (6-17) With Attention-Deficit/Hyperactivity Disorder (ADHD) Using CTx-1301 (Dexmethylphenidate)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: ADHD
Attention Deficit Hyperactivity Disorder
ADHD - Combined Type
Attention Deficit Hyperactivity Disorder Combined
Attention-deficit Hyperactivity
Attention Deficit Hyper Activity
Keywords: ADHD
Lead sponsor: Cingulate Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Premier Research Group plc
First posted: 2022-03-18
Enrollment: 103
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects are randomized in 1:1:1:1 order
Primary purpose: TREATMENT

Brief summary: A Phase 3, randomized, double-blind, placebo-controlled, multi-center, fixed-dose, parallel-group efficacy and safety study in a pediatric population (6-17) with Attention-Deficit/Hyperactivity Disorder (ADHD) using CTx-1301 (d-MPH). The study will be comprised of a screening period, a double-blind randomized phase, and a safety follow-up visit.

Detailed description: A Phase 3, double-blind, randomized, placebo-controlled, multi-center, fixed-dose, parallel group efficacy and safety study in pediatrics (6-17) with ADHD diagnosis confirmed by an ADHD-RS-5 score of at least 28 and CGI-S score of at least 4 (moderately ill) at screening. The study will be comprised of a screening period, a double-blind randomized phase, and a safety follow-up visit.

The Study will be comprised of 3 periods:

* Screening Period (Day -30 to Day -1): Subjects will undergo a Screening Visit (Visit 1) up to 30 days prior to entering the randomized treatment period. Only subjects that meet all inclusion and no exclusion criteria at screening may be considered for entry/randomization into the study. A reminder telephone call will be completed 5 days prior to Day 0 (Visit 2) to ensure washout of current prohibited medications, to confirm inclusion/exclusion criteria, and to confirm date of next visit.
* Randomized Treatment Period (Day 0 to Day 35 +/- 3 days): Subjects will be randomized on Day 0 to active or placebo (placebo, CTx-1301 18.75 mg, CTx-1301 25 mg, or CTx-1301 37.5 mg). Subjects randomized to the active dose will have a starting dose of 12.5 mg on Day 0. Each subject randomized to an active dose will be titrated (increased) weekly until they reach their assigned fixed dose; subjects must be on their assigned fixed dose a minimum of 2 sequential weeks prior to the primary efficacy assessment at Week 5/Visit 8. Subjects will be instructed to take their dose every morning at-home upon waking, no later than 8:00 am.
* Safety Follow-Up Visit (Day 42 +/- 5 days): Subjects will be evaluated for safety after washout of medication.

Subjects will participate in the study as outpatients for up to approximately 10 weeks (including screening); a 30-day screening period, a 5-week double-blind randomized period, and a 1-week follow-up safety visit.

Completion of the primary study is defined as LSLV at Visit 9.

Subjects will be randomized at baseline to CTx-1301 or placebo (CTx-1301 18.75 mg, CTx-1301 25 mg, CTx-1301 37.5 mg, or placebo). Starting dose for subjects randomized to active treatment is 12.5 mg. These subjects will then be titrated up to their assigned fixed dose (18.75, 25, or 37.5 mg) for the last two weeks of the study period. Subjects randomized to placebo will receive placebo treatment for the full 5 weeks of the study.

Sparse PK sampling will be conducted after a single dose and at steady state from the patient population with special attention given to the time the sample is obtained post-dose. These analyses will inform strategies that manage dosing and detail administration for a given subpopulation, planned subsequent studies, and support labeling.

Eligibility criteria: Inclusion Criteria:

1. Male or female subjects between 6 and 17 years of age (inclusive) at the time of Randomization (Visit 2). Subjects who are expected to turn 18 years of age during the trial will not be allowed.
2. Subject must have a body weight between the 5th and 95th percentile (≥5th percentile and ≤95th percentile) for their respective age and sex.
3. Subject is unsatisfied with his/her current pharmacological therapy for treatment of ADHD or not currently receiving pharmacological therapy for ADHD. Inclusion of subjects who are naïve to pharmacological therapy for ADHD is permitted.
4. Subjects of child-bearing potential at screening or that become of child-bearing potential during the study must agree to remain abstinent or agree to use a highly effective, medically acceptable form of birth control for the time of written assent and for at least 30 days after the last dose of study drug has been taken (females). Male subjects with female partners must agree at Screening to remain abstinent or agree to use an effective and medically acceptable form of birth control from Screening to 90 days after the last dose of study drug. Child-bearing potential is defined as any female who has had their first period or is 12 years or older (or will be 12 while in the study).
5. Subject must be in general good health defined as absence of any clinically relevant abnormalities as determined by the Investigator based on physical and neurological examinations, vital signs, ECGs (QTc less than or equal to 460 milliseconds), medical history, and laboratory values (hematology, chemistry, serology, TSH, or urinalysis) at Screening. If any of the exams or values are not within the laboratory reference range, the Investigator must review range and determine if clinically relevant. If clinically relevant, the subject is not eligible for the study.
6. Subject's intellectual function is at an age-appropriate level, as deemed by the Investigator.
7. Subject must meet Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria for the primary diagnosis of ADHD or any of the three presentations (combined, inattentive, or hyperactive/impulsive presentation) upon clinical evaluation and confirmed by the MINI International Neuropsychiatric Interview of Children and Adolescents (MINI-KID). The MINI should also be used to evaluate any other psychotic disorders.
8. Subject must score 28 or higher on the ADHD-RS-5 scale at the Baseline visit (Visit 2).
9. Subject must have a score of 4 (moderately ill) or higher on the clinician-administrated Clinical Global Impressions-Severity (CGI-S) scale at Baseline (Visit 2).
10. Subject must be able and willing to wash out of stimulant ADHD medications (except study drug as indicated per protocol), including herbal medication, from 5 days prior to the start of the randomized phase (Visit 2) and for the duration of the entire study, defined as completion of the safety follow-up visit (approximately 1.25 months, excluding screening). Additionally, subject must be able and willing to wash out from non-stimulant ADHD medications 21 days prior to the start of the randomized phase (Visit 2) and for the duration of the entire study (approximately 1.25 months, excluding screening), defined as completion of the safety follow-up visit.
11. Subject and parent/legal guardian, and/or caregiver (if applicable) must be able to read, write, speak, and understand English and be able to communicate with the Investigator and study coordinator in a satisfactory fashion and complete any study-related materials. Subject and parent/legal guardian, and/or caregiver (if applicable) must plan to be available for the entire duration of the study.
12. One or more of the parents/legal guardians/caregivers of the subject must voluntarily give written permission for him/her to participate in the study.
13. Subject must provide written assent prior to study participation.
14. Subject, subject's parent/legal guardian, and/or caregiver (if applicable) must understand and be willing and able to comply with study procedures as well as the visit schedule. If the subject is cared for by a caregiver for relevant portions of the day, the caregiver may be more suitable for certain assessments, and the caregiver will need to agree to the applicable procedures and visits.
15. Subject must be able to swallow the CTx-1301 tablet as evidenced by ability to swallow a similar size tablet (placebo) at screening.

Exclusion Criteria:

1. If female and of child-bearing potential, the subject must not be pregnant or breastfeeding at any time during the study or for 30 days following the completion of the study, defined as completion of safety visit at the end of study (Visit 9). If of child-bearing potential, urine hCG tests will be administered at protocol-specified time points. Any positive pregnancy test during the study will exclude them from further participation in the study.
2. Subject has any psychiatric diagnosis of bipolar I or II disorder, major depressive disorder, conduct disorder, disruptive mood dysregulation disorder (DMDD), intellectual disability, obsessive-compulsive disorder, eating disorder, anxiety disorder (including generalized anxiety disorder), any history of psychosis, autism spectrum disorder, a history of motor or vocal tics or Tourette's Syndrome, confirmed genetic disorder with cognitive and/or behavioral disturbances, or any other diagnosis/significant medical history that at the discretion of the Investigator excludes the subject from entry into the study.
3. Subject has evidence of any chronic disease of the central nervous system (CNS) such as tumors, inflammation, seizure disorder, vascular disorder, potential CNS-related disorders that might occur in childhood, or history of persistent neurological symptoms related to a serious head injury.
4. Subject has any clinically significant and/or unstable/uncontrolled medical abnormality or chronic medical condition, persistent neurological symptoms, history of cardiovascular abnormality, abnormalities of respiratory, hepatic, gastrointestinal, renal, or any disorder or history of a condition that would impact or interfere with drug absorption, distribution, metabolism, or excretion during the study or may interfere with the participants ability to participate in the study.
5. Subject has family history of early cardiovascular disease or sudden death.
6. Subject has any history of attempted suicide or clinically significant suicidal ideation based on the Columbia Suicide Severity Rating Scale (C-SSRS) assessment, or answers "yes" to "Suicidal Ideation" item 4 or 5 of any lifetime history on the C-SSRS Children's Lifetime/Recent assessment at screening.
7. Subject has history of seizures, excluding febrile seizures.
8. Subject has a known primary sleep disorder (e.g., sleep apnea, narcolepsy, etc.)
9. If the subject's blood pressure is \< 90th percentile for their age, sex, and height, the single read is sufficient. If the subject's blood pressure is ≥ 90th percentile, two additional reads will be taken, and the three reads will be averaged. If the average of the three readings is ≥ 95th percentile at screening they will be excluded.
10. Subject is considered treatment refractory by the Investigator or is intolerant to stimulant ADHD mediation.
11. Any use of anticonvulsants currently or within the past 2 years.
12. Uncontrolled thyroid disorder indicated by thyroid stimulating hormone (TSH) ≤0.8 x the lower limit of normal (LLN) or ≥ 1.25 x the upper limit of normal (ULN) from the reference laboratory.
13. Subject has first-degree relatives (biological parent or sibling) with a history of schizophrenia, schizoaffective disorder, bipolar I disorder, or bipolar II disorder.
14. Subject has history of substance abuse or shows evidence of substance use or has a positive urine drug screen at Screening or Baseline. Subjects with positive drug screens may be allowed to continue in the study if the result of the positive drug screen is from prescribed medications and the subject is willing to washout of the medication as required per protocol.
15. Previous treatment experience/exposure to CTx-1301.
16. Subject has a history of allergic reaction or sensitivity to methylphenidate, dexmethylphenidate, or any other substance contained in CTx-1301 or the placebo drug.
17. Subject has participated in any other clinical study with an investigational drug/product within 30 days prior to Screening or is currently participating in another clinical study.
18. Subject's family anticipates a move outside the geographic range of the investigative site during the duration of the study period or plans on travel that would not allow compliance to the protocol during the study period.
19. Subject is unsuitable in any other way, to participate in the study, as determined by the Investigator.
20. Subject is a family member of an employee at the study center, of the investigator, or those with direct involvement in the proposed study under the direction of that investigator or study center.

Primary outcomes:
measure: The primary efficacy analysis will analyze the mean change from Baseline (pre-dose) at Visit 2 of Attention Deficit Hyperactivity Disorder Rating Scale 5 (ADHD-RS-5) scores to ADHD-RS-5 at Visit 8.
timeFrame: Baseline (Day 0) to Week 5 (Visit 8)
Secondary outcomes:
measure: The primary efficacy analysis will analyze the mean change from Baseline (pre-dose) at Visit 2 of Clinical Global Impression - Severity (CGI-S) scores to CGI-S at Visit 8.
timeFrame: Baseline (Day 0) to Week 5 (Visit 8)
Other outcomes:
measure: Safety - incidence of TEAEs
timeFrame: Screening to Visit 9 (approximately 6-10 weeks, depending on screening window)
measure: Safety - incidence of changes in vital signs.
timeFrame: Baseline to Visit 8 (5 weeks)
measure: Safety - incidence of changes in blood labs
timeFrame: Screening to Visit 8 (approximately 5-9 weeks, depending on screening window)
measure: Safety - incidence of changes in physical exams
timeFrame: Baseline to Visit 8 (5 weeks)
measure: Safety - incidence of changes in BMI/weight
timeFrame: Baseline to Visit 8 (5 weeks)
measure: Safety - incidence of changes in C-SSRS
timeFrame: Baseline to Visit 8 (5 weeks)
measure: Safety - incidence of changes in ECGs
timeFrame: Screening to Visit 8 (approximately 5-9 weeks, depending on screening window)
measure: Population PK Analysis - AUC to Infinity
timeFrame: Day 1 (Visit 3) for single-dose pk and Week 5 (Visit 8) steady state.
measure: Population PK Analysis - Cmax
timeFrame: Day 1 (Visit 3) for single-dose pk and Week 5 (Visit 8) steady state.
measure: Population PK Analysis - Tmax
timeFrame: Day 1 (Visit 3) for single-dose pk and Week 5 (Visit 8) steady state.
Locations:
city: Jacksonville
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Maitland
country: United States
facility: Meridien Research
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Springfield
country: United States
facility: Sisu Bhr, Llc
state: Massachusetts
city: Bloomfield Hills
country: United States
facility: Neurobehavioral Medicine Group
state: Michigan
city: Saint Charles
country: United States
facility: St Charles Psychiatric Associates & Midwest Research Group
state: Missouri
city: Las Vegas
country: United States
facility: Center for Psychiatry and Behavioral Medicine. Inc.
state: Nevada
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Dayton
country: United States
facility: Dayton Clinical Research
state: Ohio
city: Oklahoma City
country: United States
facility: SP Research PLLC
state: Oklahoma
city: Portland
country: United States
facility: Summit Research Network, LLC
state: Oregon
city: Charleston
country: United States
facility: Coastal Pediatric Associates
state: South Carolina
city: North Charleston
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: Memphis
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Tennessee
city: Nashville
country: United States
facility: Access Clinical Trials Inc.
state: Tennessee
city: Austin
country: United States
facility: BioBehavioral Research of Austin
state: Texas
city: Beaumont
country: United States
facility: Gadolin Research
state: Texas
city: Bellaire
country: United States
facility: Houston Clinical Trials
state: Texas
city: Dallas
country: United States
facility: FutureSearch Trials
state: Texas
city: Houston
country: United States
facility: Red Oak Psychiatry Associates, PA
state: Texas
city: Woodland
country: United States
facility: Family Psychiatry of The Woodlands
state: Texas
city: Petersburg
country: United States
facility: Clinical Research Partners LLC
state: Virginia
Study officials:
affiliation: Cingulate
name: Matt Brams, MD
role: STUDY_DIRECTOR
affiliation: Center for Psychiatry And Behavioral Medicine Inc.
name: Ann Childress, MD
role: STUDY_CHAIR
References: