A Multiple Dose Study to Assess the Safety, Tolerability and PK of Risperidone Extended Release Capsules
Condition: Schizophrenia Schizoaffective
MeSH terms: Schizophrenia
Intervention: LYN-005
Intervention description: LYN-005 (14 or 28 mg weekly) plus IR risperidone matched placebo.
Intervention MeSH terms: Risperidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: LYN-005-C-004 was a blinded, multiple-dose, randomized, parallel group, safety, tolerability and PK study of LYN-005 in subjects with a primary diagnosis of schizophrenia or schizoaffective disorder in general good health. Eligible subjects were clinically stable and receiving a therapeutic dose of an approved oral antipsychotic drug for a minimum of 6 weeks at the time of Screening. Enrolled subjects were evaluated under steady-state conditions on commercially-available IR risperidone tablets and then assigned in blinded fashion either to LYN-005 weekly or continued encapsulated IR risperidone daily for 3 weeks to attain (or continue) steady-state exposure.
Masking: Double (Participant, Care Provider)
Masking description: Although treatment assignment was blinded; the dose level was not blinded. The dose of LYN-005 (14 or 28 mg)/IR risperidone (2 or 4 mg/day) administered was based on the subject's current antipsychotic medication dose. Randomization was stratified by risperidone dose (LYN-005 14 mg/IR risperidone 2 mg/day [low dose] and LYN-005 28 mg/IR risperidone 4 mg/day [high dose], with a maximum of 16 subjects enrolled in each stratum. Within each stratum, subjects were randomized on a 3:1 basis to either LYN-005 or risperidone, respectively.
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      Lyndra is developing an oral, extended release (ER) formulation of risperidone (LYN-005)
      presented in a capsule dosage form with the intent of reducing the frequency of dosing
      orally-administered medications to once weekly or less and thereby improving the management
      of schizophrenia.

      Study LYN-005-C-004 will evaluate the safety, tolerability, and pharmacokinetics (PK) of
      multiple dose administration of the ER formulation at two dose levels of LYN-005 relative to
      IR risperidone.
    

Eligibility criteria:

        Inclusion Criteria: Eligibility for this study was met if each one of the following
        inclusion criteria was satisfied at Screening (or at baseline when specified):

          1. Male or female aged ≥18 and ≤50 years.

          2. Current diagnosis of schizophrenia or schizoaffective disorder according to DSM-5
             criteria as confirmed by the MINI 7.0.2.

          3. The following psychiatric criteria were used to determine subject eligibility:

               1. Duration of diagnosis of schizophrenia or schizoaffective disorder of ≥2 years.

               2. Outpatient; not hospitalized for worsening of schizophrenia within the last 6
                  months (partial hospitalization for social management within this time period is
                  acceptable).

               3. Medically stable over the last month and psychiatrically stable without
                  significant symptom exacerbation over the last 3 months.

          4. Stabilized on an oral antipsychotic medication (single agent) for a minimum of 6 weeks
             at the time of Screening.

          5. On a stable dosage of all permitted non-antipsychotic medications (except for
             medication to be used on an as-needed basis) for at least 1 month prior to the
             Screening visit and for the duration of the study.

          6. CGI-S score of ≤4 (moderately ill).

          7. PANSS score of ≤80 points.

          8. Body mass index (BMI) of ≥18 kg/m2 and ≤35 kg/m2.

          9. Able to read and understand study procedures and provide written informed consent
             before the initiation of any protocol-specific procedures.

         10. Willing to comply with all protocol-specified procedures and availability for the
             duration of the study.

         11. Subject has identified a caregiver or personal contact with whom the subject
             communicates with at least once a week.

        Exclusion Criteria: Subject will not be considered eligible to participate in this study if
        any one of the following exclusion criteria is satisfied at Screening (or at baseline when
        specified):

          1. Subjects with known clinically significant esophageal or GI disease, including but not
             limited to:

               1. Known strictures such as esophageal web, pyloric stenosis, or small intestinal
                  stricture, or subjects with high risk of stricture, e.g., Crohn's disease.

               2. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria
                  or hypochlorhydria.

               3. Prior varices or small or large bowel obstructions.

               4. Prior abdominal or upper gastrointestinal surgery (prior uncomplicated
                  laparoscopic procedures including appendectomy or colectomy).

               5. History of dysphagia or aspiration in the last 5 years.

               6. History of an esophageal motility disorder or undergoing treatment for a gastric
                  motility disorder.

               7. Significant history of diarrhea or constipation within 3 months of Screening

               8. Multiple episodes of abdominal pain within 3 months of Screening.

               9. Subjects who experience moderate or severe dysmenorrhea or menorrhagia (with use
                  of pain medication) within 3 months of Screening.

              10. History of moderate to severe Acid Reflux Disease or a score of ≥2 on the Acid
                  Reflux Severity Scale (ARSS) [2], indicating moderate to severe symptoms. The
                  ARSS scale is as follows:

             None = 0 no symptoms Mild = 1 awareness of symptom, but easily tolerated Moderate = 2
             discomfort sufficient to cause interference with normal activities Severe = 3
             incapacitating, with inability to perform normal activities.

          2. Subjects with PILL-5 questionnaire score of 5 or greater.

          3. Medical history or current diagnoses indicating the presence of any of the below
             conditions:

               1. Presence of an uncontrolled, unstable, clinically significant medical condition
                  could that could put the subject at risk because of participation in the study,
                  interfere with the subject's ability to participate in the study or influence the
                  interpretation of safety or PK evaluations.

               2. History of a major cardiovascular event (myocardial infarction, cardiac surgery
                  or revascularization, unstable angina, stroke, or transient ischemic attack) or a
                  hospitalization for heart failure with 6 months of Screening.

               3. Any clinically significant illness, medical or surgical procedure or trauma
                  within 4 weeks of Screening.

               4. Known immunocompromised status, including individuals who have undergone organ
                  transplantation, on immunosuppression for an immunemediated disease, or are
                  positive for human immunodeficiency virus (HIV).

               5. Subjects with a positive test for active hepatitis B or C at Screening. Subjects
                  with successfully treated hepatitis B infection which has been resolved for
                  greater than 1 year or successfully treated hepatitis C infection will not be
                  excluded.

               6. Subjects who have donated more than 250 mL of blood within 30 days of Screening.

               7. Subjects who have difficulties with venipuncture/cannulation, including
                  difficulty accessing veins for blood sampling and/or history of coagulopathy or
                  endocarditis.

               8. Subjects with a current DSM-5 diagnosis of major depressive episode, panic
                  disorder, agoraphobia, social anxiety disorder, obsessive- compulsive disorder,
                  post-traumatic stress disorder, generalized anxiety disorder on the MINI 7.0.2 or
                  in the judgment of the Investigator. (Note that individuals with depression
                  secondary to schizoaffective disorder are eligible).

               9. Suicidal ideation associated with actual intent and a method or plan in the past
                  6 months, as measured by the C-SSRS (i.e., "Yes" answers on items 4 or 5) at
                  Screening or having made a suicide attempt within the last 2 years.

              10. Known or suspected (non-febrile) seizure disorder.

              11. History of neuroleptic malignant syndrome.

              12. Current or history of clinically significant tardive dyskinesia.

              13. Known or suspected diagnosis of intellectual disability or organic brain disorder
                  or other diagnosis that is primarily responsible for current symptoms and
                  functional impairment.

              14. Medically non-adherent in the management of their schizophrenia/schizoaffective
                  disorder.

          4. Use of the below medications/treatments in the 2 weeks before enrollment, including:

               1. Proton pump inhibitors or H2 blockers.

               2. Prokinetic agents.

               3. Medications that may interfere with the absorption, metabolism, or excretion of
                  risperidone, e.g.:

                  Drugs metabolized via CYP3A4 pathway, such as macrolide antibiotics and azole
                  antifungals). Moderate or strong CYP3A4 p-glycoprotein (P-gp) enzyme inducers and
                  inhibitors (carbamazepine, phenytoin, rifampicin, phenobarbital, itraconazole,
                  verapamil). Moderate or strong CYP2D6 inhibitors (e.g., fluoxetine, fluoxetine
                  combinations, paroxetine), or quinidine.

               4. Concomitant medications, natural remedies, supplements or vitamins which are
                  associated with changes to gastric motility or pH. Use of antacids is
                  permissible, except within 2 hours of dosing with LYN-005.

               5. Benzodiazepines; except lorazepam, diazepam and oxazepam, which are acceptable if
                  for the treatment of depression, anxiety or insomnia.

               6. Use of more than one antidepressant; or if on just one, a change in dose within 6
                  weeks of Screening.

               7. Depot antipsychotic use within 9 months of Screening.

               8. Electroconvulsive therapy within 3 months of Screening.

          5. Subjects with clinically significant abnormal safety (e.g. physical examination, vital
             sign) or safety laboratory assessments, specifically:

               1. Presence of a clinically significant abnormal laboratory result on blood or urine
                  safety tests at Screening.

               2. Anemia (hemoglobin below lower limit of normal reference range) at Screening.

               3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥3.0 × upper
                  limit of normal (ULN), or total bilirubin ≥1.5 × ULN.

               4. Moderate or severe renal insufficiency at Screening (glomerular filtration rate
                  <60 mL/min, as determined using the Cockcroft-Gault formula).

               5. Heart rate of <50 beats per minute (bpm) at Screening.

               6. Systolic blood pressure ≤100 or ≥150 and/or diastolic blood pressure ≤60 mmgHg or
                  ≥100 mmHg at Screening.

               7. HbA1c ≥6.5% at Screening.

               8. Positive fecal occult blood test at Screening

               9. Clinically significant prolactin elevation (≥200 ng/mL for females; ≥100 ng/mL
                  for males).

          6. Subjects with the below specified patterns of substance use at Screening:

               1. Fulfillment of the DSM-5 criteria for moderate or severe substance use disorder
                  (excluding nicotine and caffeine) within 6 months of Screening.

               2. History of alcohol consumption exceeding moderate use; in males exceeding 21
                  units per week and in females exceeding 14 units per week (1 unit = 360 ml beer,
                  25 mL of 40% spirit or a 125 mL glass of wine) over the past month. Subjects are
                  not permitted to consume alcohol during the inpatient stay nor 12 hours before
                  any clinic visit while outpatient.

               3. Positive ethanol breathalyzer.

               4. Positive urine drug screen for substances of abuse other than cannabis.

               5. Heavy nicotine use (consumption of >40 cigarettes or >36 mg of nicotine from
                  other sources [e.g., vaping products] daily) or daily use of smokeless tobacco.

          7. Subjects of reproductive potential who are (hetero) sexually active but unwilling to
             use acceptable means of contraception through the EOS. For clarity, subjects who are
             at least 1 year post-menopausal are not of reproductive potential. Acceptable means of
             contraception include:

               1. Subjects who have been surgically sterilized.

               2. Females of reproductive potential: diaphragm, injectable, oral/patch
                  contraceptives for a minimum of 6 weeks, contraceptive sponge, implant, or
                  intrauterine device in use prior to enrollment.

               3. Males: condom in combination with any of the above means of contraception.

               4. All subjects: abstinence may be an acceptable means of contraception as long as
                  the individual consents to initiate immediate use of double barrier protection
                  for the duration of the study should (hetero) sexual intercourse occur.

          8. Subjects who are nursing or who have positive or indeterminate pregnancy tests at
             either Screening (serum test) or enrollment (urine test).

          9. Use of any experimental agent within 1 month or 5 half-lives of Screening, whichever
             is longer.

         10. Subjects who are employees or immediate family members of employees of the site,
             Sponsor or study-related vendors.

         11. History of a serious allergic or hypersensitivity reaction to risperidone or LYN-005
             excipients (refer to Investigator's Brochure).

         12. Subjects with history of X-ray, computed tomography (CT) scan or angiogram of the
             abdomen within one year of Screening.

         13. Subjects with CYP2D6 poor or underdetermined metabolizer status based on genetic
             testing.