Pharmacokinetics and Safety Study of Diazepam Buccal Film (DBF) in Pediatric Subjects With Epilepsy
Condition: Epilepsy
MeSH terms: Epilepsy
Intervention: Diazepam Buccal Film
Intervention description: Subjects received a single DBF dose determined by age and body weight during the interictal state and during the ictal/peri-ictal period with at least 14 days washout between doses.
Intervention MeSH terms: Diazepam
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: This was a multicenter study comprised of 2 treatment periods with a minimum 14 days between the 2 treatment periods.
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 2 Years
Maximum age: 16 Years
Healthy volunteers: No
Keywords: interictal state; ictal/peri-ictal state

Summary:

      Open-label study to assess the pharmacokinetics of a single diazepam buccal film (DBF) dose
      in 3 age cohorts of pediatric patients with epilepsy (age 2-5 years, age 6-11 years, and age
      12-16 years). Subjects in the 6-11 years and 12-16 years age cohorts received a single DBF
      dose during the interictal period (Period A) and ictal/peri-ictal period (Period B) with at
      least 14 days washout between doses. Subjects in the age 2-5 years age cohort received a
      single DBF dose only during the ictal/peri-ictal period (Period B).
    

Eligibility criteria:

        Inclusion Criteria:

        Potential subjects meeting all of the following criteria may be included in the study:

          1. Subjects have a clinical diagnosis of epilepsy (GTC seizures or focal seizures with
             impaired awareness) and were scheduled for admission to an Epilepsy Monitoring Unit
             (EMU), General Clinical Research Center (GCRC), or similar facility for evaluation.

          2. Male and female subjects between 2 and 16 years of age, inclusive.

          3. Subjects had a body weight of at least 6 kg and less than or equal to 111 kg.

          4. Subjects had an average frequency of at least 1 clinically apparent seizure every 3
             days or ≥10 clinically apparent seizures per month, with alteration of consciousness
             as documented by reliable subject report, personal seizure diary records, and/or by
             seizure diaries dispensed at screening and verified prior to study entry.

          5. Female subjects of childbearing potential (i.e., were having periods, were not
             surgically sterile) must have had a negative serum pregnancy test (using Beta-hCG) at
             Screening and a negative urine pregnancy test on Study Day I prior to drug dosing.
             Female subjects of childbearing potential must have agreed to abstinence, have had a
             partner who was sterile, or have been practicing double barrier contraception or have
             been using an FDA-approved contraceptive (e.g., licensed hormonal or barrier methods)
             for greater than 2 months prior to screening visit, and must have committed to an
             acceptable form of birth control for the duration of the study and for 30 days after
             participation in the study.

          6. Male subjects with a female sexual partner of childbearing potential must have agreed
             to abstinence or to practice adequate birth control during the study, including at
             least 1 barrier method such a condom, diaphragm, or spermicide for more than 2 months
             prior to the screening visit, and must have committed to an acceptable form of birth
             control for the duration of the study and for 30 days after participation in the
             study. Also, male subjects must have agreed not to donate sperm during the study and
             for 90 days after the follow-up visit.

          7. Subjects were currently receiving at least one antiepileptic medication.

          8. Subject's parent or legally authorized representative must have been willing and able
             to complete informed consent and HIPAA authorization. Subjects must have been willing
             to give assent as required by the Institutional Review Board (IRB).

          9. Subject must have agreed to be available or subject's parent(s) or legally authorized
             representative(s) must have agreed to have the subject be available for both Treatment
             Periods and the Follow-up Visit, and must have been willing to comply with all
             required study procedures and adhere to all protocol requirements.

         10. Subject or subject's parent(s) or legally authorized representative(s) must have been
             able to comprehend and be informed of the nature of the study, as assessed by the
             Investigator.

        Exclusion Criteria:

        Potential subjects meeting any of the following criteria were excluded from participating
        in the study:

          1. Subjects with a progressive neurological disorder such as a brain tumor, demyelinating
             disease, or degenerative central nervous system (CNS) disease that was likely to
             progress in the 12 months after screening.

          2. Subjects with respiratory failure (or is at risk for respiratory failure) or other
             severe cardiorespiratory disease with New York Heart Association Class Ill or IV
             functional status, or who required supplemental oxygen.

          3. Female subjects who were lactating, had a positive serum pregnancy test (β-hCG) at
             screening, or had a positive urine pregnancy test at Check-in for treatment periods.

          4. Subjects with psychiatric disease that in the Investigator's judgment would prevent
             the subject's successful completion of the study.

          5. Subjects with recent history of suicide attempt (defined as an active, interrupted, or
             aborted attempt within the previous 5 years) or reported suicidal ideation in the
             previous 6 months as indicated by a positive response ("Yes") to either Question 4 or
             Question 5 of the Columbia-Suicide Severity Rating Scale performed at the screening
             visit.

          6. Subjects with known history or presence of any clinically significant hepatic (e.g.,
             hepatic impairment), renal/genitourinary (renal impairment, kidney stones),
             psychiatric, dermatological, or hematological disease or condition, unless determined
             as not clinically significant by the Investigator or designee and confirmed by Sponsor
             via written communication prior to subject enrollment. Abnormal laboratory results
             considered clinically significant by the Investigator or designee were to be evaluated
             by the Investigator in consultation with the Medical Monitor.

          7. Subjects with any clinically significant illness other than epilepsy within 30 days
             prior to study drug administration, as determined by the Investigator.

          8. Subjects with any significant physical or organ abnormality or other condition that
             would interfere with study participation or constitute a safety risk in the judgment
             of the Investigator.

          9. Subjects with any significant lesion of the oral cavity or having oral prophylactic or
             dental procedures within 30 days prior to study drug administration.

         10. Subjects with a QT interval corrected by Fridericia's formula (QTcF) >450 ms for males
             or QTcF >470 ms for females on screening ECG unless determined as not clinically
             significant by the Investigator.

         11. Subjects with a positive test result for any of the following drugs of abuse:

             amphetamines, cocaine, opiates, phencyclidine, or a positive breath alcohol test.
             Subjects who tested positive for tetrahydrocannabinol (THC) at screening were excluded
             unless the Investigator was able to affirm in writing that the use of a medical
             marijuana product was part of the subject's treatment plan as recommended by a
             physician for treatment of a medical condition. In such case, the subject was to be
             allowed to continue with screening, and the medical marijuana product was to be
             recorded as a concomitant medication.

         12. Subjects with a known history or presence of any of the following:

               1. Substance abuse or dependence (including alcohol) within 1 year prior to first
                  study drug administration

               2. Hypersensitivity or idiosyncratic reaction to diazepam, its excipients, sodium
                  phosphates, and/or related substances, e.g., benzodiazepines

               3. Glaucoma (open or acute narrow angle)

               4. Severe allergic reactions (e.g., anaphylactic reactions, angioedema) to
                  investigational product and excipients

         13. Subjects who had participated in another clinical trial or who had received an
             investigational drug within 30 days prior to study drug administration or 5 half-lives
             of the investigational drug-whichever was the longer period.

         14. Subjects with presence of mouth jewelry, dentures, oral implants, braces, or piercings
             in the mouth or tongue that, in the opinion of the Investigator, would have been
             likely to interfere with successful completion of the dosing procedure.

         15. Subjects with a blood or plasma donation within 30 days prior to screening.

         16. Subjects not willing or unable to tolerate blood draws.

         17. Consumption of alcohol within 48 hours before dosing; or food or beverages containing
             grapefruit, star fruit, Seville oranges, and/or pomelo, or their derived products
             (e.g., fruit juice) within 10 days prior to study drug administration.

         18. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome (CYP) 450
             enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin,
             fluconazole, ketoconazole, diltiazem, or HIV antivirals) and strong inducers of CYP
             enzymes (e.g., glucocorticoids, St. John's Wort, or rifampicin), in the previous 30
             days prior to study drug administration. (Barbiturates, carbamazepine, phenytoin, and
             other enzyme-modifying antiepileptic drugs (AEDs) that were medically needed were
             permitted.)

         19. Use of any monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine ),
             and/or phenothiazines (chlorpromazine) within 30 days prior to first study drug
             administration.

         20. Employee or immediate relative of an employee of Aquestive Therapeutics, any of its
             affiliates or partners, or Syneos Health.