Clinical trial NCT05668754: Placebo-Controlled, Double-Blind, Study to Determine the Safety and Efficacy of SDX in Patients With IH
Official title: A Phase 2, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study to Determine the Safety and Efficacy of Oral SDX in Patients With Idiopathic Hypersomnia (IH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Idiopathic Hypersomnia
Keywords: Disorders of Excessive Somnolence
Sleep Disorders
Intrinsic Dyssomnias
Sleep Wake Disorders
Nervous System Diseases
Mental Disorders
Lead sponsor: Zevra Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Rho, Inc.
First posted: 2022-12-30
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 2, placebo-controlled, double-blind, randomized withdrawal study to determine the safety and efficacy of oral SDX in patients with Idiopathic Hypersomnia (IH).
Primary purpose: TREATMENT

Brief summary: This is a study of the safety, efficacy and pharmacokinetics (PK) of Serdexmethylphenidate (SDX) compared to placebo in subjects with Idiopathic Hypersomnia (IH).

Detailed description: SDX is a prodrug of dexmethylphenidate (d-MPH). SDX behaves as a prototypical prodrug that is devoid of pharmacological effects until metabolized to active d-MPH. Central nervous system (CNS) stimulants, including d-MPH products, are being used off-label by patients with IH. The potential advantage of SDX-derived d-MPH is its unique PK profile with rising d-MPH plasma concentrations at approximately 3 hours postdose followed by a broad peak from approximately 8 to 12 hours postdose (without sharp exposure spikes), and a gradual decline after the peak.

The optimal dose of SDX will be determined for each participant by titration based on individual tolerability and response during the 5-week SDX-only Open-Label Titration period (OLTP), after which 2/3 of the participants will continue to receive SDX and 1/3 of the participants will receive placebo (withdrawal design) in the 2-week Double-Blind Withdrawal Period (DBWP).

The study will evaluate safety (primary endpoint), efficacy and PK in patients with IH after daily oral administration of SDX either once per day in the evening (qd pm) or twice per day (morning and evening: bid). The study is expected to inform about the optimal SDX dose range and the best dose regimen (nighttime dosing or twice-per-day) for further studies in patients with IH and narcolepsy. The evening dosing regimen (just before bedtime) is of interest since there is little or no exposure to d-MPH for the first several hours post-dose and the mean peak d-MPH concentration occurs at 10-12 hours post-dose (ie, in the morning after a nighttime dose).

Eligibility criteria: Inclusion Criteria:

1. At least 18 years of age at the time of consent
2. Body Mass Index (BMI) ≤35 kg/m2
3. Documented primary diagnosis of IH according to the International Classification of Sleep Disorders (ICSD-3) criteria
4. At the Screening Visit and Baseline Visit (start of OLTP), Epworth Sleepiness Scale (ESS) scores ≥11
5. Average nightly Total Sleep Time (TST) of ≥7 hours, per subject history and confirmed during screening.
6. Subject must be in general good health defined as the absence of any clinically relevant abnormalities as determined by the Investigator based on physical and neurological examinations, vital signs, ECGs, medical history, and clinical laboratory values (hematology, chemistry, and urinalysis) at Screening.
7. If currently treated with nicotine replacement therapy, must have been taking the same regimen and dose for at least 2 months prior to screening and must agree to take the same dose during the study.
8. Have used a medically acceptable method of contraception for at least 2 months prior to the first dose of study drug and consent to use a medically acceptable method of contraception from the first dose of study drug, throughout the entire study period, and for 90 days after the last dose of study drug.

Exclusion Criteria

1. Hypersomnia due to another medical, behavioral, or psychiatric disorder condition (eg, narcolepsy, depression disorders, multiple sclerosis, Parkinson's disease, stroke).
2. Clinically significant sleep-related breathing disorders, including sleep apnea, treatment with Continuous Positive Airway Pressure (CPAP) therapy, Obstructive Apnea Hypopnea Index (AHI) \>15 episodes per hour, or hypoventilation.
3. Clinically significant parasomnias (eg, sleep walking, rapid eye movement \[REM\] sleep behavior disorder, etc).
4. Periodic Limb Movement Disorder (PLMD) Arousal Index (PLMA-I) \>15 during Screening PSG, a historical diagnosis of PLMD (last 10 years), or a PLMD diagnosis older than 10 years with current (last 60 days) treatment or symptoms of rhythmic movements involving one or both legs during sleep.
5. Occupation requiring nighttime shift work or variable shift work with early work start times (before 6 AM), if this occurs more than once per week.
6. Planned travel during the study that includes more than 3 time zones, or planned travel that includes 3 time zones on more than 2 occasions during the study.
7. Going to sleep for the night later than 1 AM at a frequency of more than once per week.
8. Current or past (within 1 year) major depressive episode according to DSM-5 criteria.
9. Any history of attempted suicide (lifetime) or clinically significant suicidal ideation, in the opinion of the Investigator, based on the C-SSRS assessment at Screening.
10. Any clinically significant unstable medical abnormality, chronic disease (eg, asthma or diabetes), or a history of a clinically significant abnormality of the cardiovascular, central nervous system,
11. Any of the following out-of-range vital signs at Screening: systolic blood pressure outside 90-145 mmHg; diastolic blood pressure outside 50-90 mmHg; resting heart rate outside 40-100 beats per minute.
12. History or presence of abnormal ECGs, which in the Investigator's opinion is clinically significant, including the following:

    1. ECG findings of ischemia or infarct
    2. Complete bundle branch blocks
    3. Symptomatic arrhythmias as ventricular arrhythmias (non- sustained ventricular tachycardia (VT), multifocal or frequent premature ventricular contractions), bundle branch block, axis deviation, or abnormal or any predominantly non-sinus- conducted rhythm.
    4. QTcF \>450 msec for males or \>470 msec for females, on Screening ECG.
    5. PR interval outside the range of 120 to 220 msec on Screening ECG
13. Estimated glomerular filtration rate (GFR) at Screening \<60 mL/min/1.73 m2.
14. Malignant neoplastic disease requiring therapy within 2 years prior to Screening or during the study, or clinically relevant as judged by the Investigator.
15. Uncontrolled thyroid disorder as evidenced by thyroid stimulating hormone (TSH) ≤0.8 x the lower limit of normal (LLN) or ≥1.25 x the upper limit of normal (ULN) for the reference laboratory at Screening.
16. Laboratory value for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 x upper limits of normal (ULN).
17. Excessive caffeine use during the 10 days prior to first dose of study drug or anticipated excessive use defined as \>600 mg/day of caffeine during the treatment periods of the study.
18. Treatment or planned treatment with prohibited medications (including medications that may affect daytime sleepiness and nighttime sleep) or unwilling to refrain from any prohibited medications. Treatment must have been discontinued 14 days or 5 half-lives, whichever is longer, prior to the first dose of study medication (and at least 30 days for sedating antidepressants; at least 14 days for CNS stimulants).
19. Current or past (within 12 months prior to Screening) substance use disorder (including alcohol and psychoactive cannabinoids) according to DSM-5 criteria; current or past history of substance abuse treatment (including alcohol), or unwilling to refrain from substance use (including alcohol) during the study.
20. Nicotine dependence that has an effect on sleep (eg, a subject who routinely awakens at night to smoke).
21. Evidence of substance or alcohol use or has a positive urine or breath alcohol or positive urine drug screen at Screening.

Primary outcomes:
measure: Safety parameters - TEAEs
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
measure: Safety parameter - Heart Rate
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
measure: Safety parameter - Blood Pressure
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
measure: Safety parameter - Laboratory Tests
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
measure: Safety parameter - ECG
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
measure: Safety parameter - PSQI
timeFrame: Time Frame: Start of OLTP to end of DBWP (7 weeks)
Secondary outcomes:
measure: Change from baseline in Epworth Sleepiness Scale (ESS) score
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in Brain Fog score
timeFrame: Time Frame: Start to end of DBWP (2 weeks)
measure: Percentage of participants with increase (worsening) of 2 points or more from baseline in the Clinical Global Impression of Severity (CGI-S)
timeFrame: Start to end of DBWP (2 weeks)
measure: Percentage of participants with increase (worsening) of 2 points or more baseline in the Patient Global Impression of Severity (PGI-S).
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in Total Score of the Idiopathic Hypersomnia Severity Hypersomnia Scale (IHSS)
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in Modified Karolinska Sleepiness Scale in the morning and late afternoon.
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) total scores for depression, fatigue, and social functioning.
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in the Patient-Reported Wakefulness Questionnaire (ZOGIM-A) total scores.
timeFrame: Start to end of DBWP (2 weeks)
measure: Change from baseline in the Sleep Inertia Visual Analog Scale (SIVAS) score.
timeFrame: Start to end of DBWP (2 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Sleep Disorders Center Of Alabama
state: Alabama
city: Daphne
country: United States
facility: Amr Daphne
state: Alabama
city: Guntersville
country: United States
facility: Lakeview Clinical Research
state: Alabama
city: Huntington Beach
country: United States
facility: SOCAL Clinical Research
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: San Ramon
country: United States
facility: Sleep Medicine Specialists of California
state: California
city: Santa Ana
country: United States
facility: SDS Clinical Trials, Inc
state: California
city: Colorado Springs
country: United States
facility: Delta Waves, Inc.
state: Colorado
city: Clearwater
country: United States
facility: Saint Francis Sleep Allergy and Lung Institute LLC
state: Florida
city: Hialeah
country: United States
facility: New Generation of Medical Trials
state: Florida
city: Miami
country: United States
facility: Angels Clinical Research
state: Florida
city: Miami
country: United States
facility: Ivetmar Medical Group
state: Florida
city: Miami
country: United States
facility: Somnology Research Associates
state: Florida
city: Miami
country: United States
facility: Clinical Trial Services, Corp
state: Florida
city: Saint Petersburg
country: United States
facility: Pasadena Center for Medical Research
state: Florida
city: Winter Park
country: United States
facility: Clinical Site Partners, LLC - Winter Park
state: Florida
city: Atlanta
country: United States
facility: Global Research Associates
state: Georgia
city: Atlanta
country: United States
facility: Neurotrials Research, Inc
state: Georgia
city: Stockbridge
country: United States
facility: Clinical Research Institute - Stockbridge
state: Georgia
city: Kansas City
country: United States
facility: The University of Kansas Medical Center Research Institution Inc.
state: Kansas
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center - Bethesda
state: Maryland
city: Newton
country: United States
facility: Neurocare, Inc.
state: Massachusetts
city: Kalamazoo
country: United States
facility: Western Michigan University Homer Stryker Md School of Medicine
state: Michigan
city: Novi
country: United States
facility: Henry Ford Health - Columbus
state: Michigan
city: Sterling Heights
country: United States
facility: Clinical Neurophysiology Services PC
state: Michigan
city: Columbia
country: United States
facility: University of Missouri School Of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Clayton Sleep Institute, Llc
state: Missouri
city: La Vista
country: United States
facility: Barrett Clinic
state: Nebraska
city: Lawrence Township
country: United States
facility: Global Medical Institutes LLC- Princeton Medical Institute
state: New Jersey
city: Gastonia
country: United States
facility: Clinical Research of Gastonia (CRG)
state: North Carolina
city: Cincinnati
country: United States
facility: Intrepid Research
state: Ohio
city: Dublin
country: United States
facility: Ohio Sleep Medicine Institute
state: Ohio
city: Malvern
country: United States
facility: Brian Abaluck, LLC
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University Of South Carolina (MUSC) - Institute Of Psychiatry (IOP)
state: South Carolina
city: Columbia
country: United States
facility: Bogan Sleep Consultants
state: South Carolina
city: Austin
country: United States
facility: Futuresearch Trials Of Neurology
state: Texas
city: Fort Worth
country: United States
facility: Dfw Clinical Research Associates
state: Texas
city: Houston
country: United States
facility: Houston Clinical Research Associates
state: Texas
city: San Antonio
country: United States
facility: Sleep Therapy & Research Center
state: Texas
city: Williamsburg
country: United States
facility: TPMG Clinical Research - Williamsburg
state: Virginia
Study officials:
affiliation: Investigator
name: Christopher Drake, PhD
role: PRINCIPAL_INVESTIGATOR
References: