Effects of Vortioxetine (Lu AA21004) on the Concentrations of Selected Neurotransmitters in Healthy Male Adults

A Phase 1, Single-Center, Randomized, Single-Blind, Placebo-Controlled, Multiple-Dose Study to Assess the Effects of Oral Administration of Lu AA21004 20 mg on the Concentrations of Selected Neurotransmitters in Healthy Male Subjects

The purpose of this study is to evaluate the pharmacodynamics (the drug's effect on the body), the pharmacokinetics (the body's handling of the drug), and the safety and tolerability of vortioxetine, once daily (QD) in healthy men.

This study will look at an investigational medicine called vortioxetine to see how the drug affects the body and how the body handles the drug.

The study enrolled 17 patients. Participants were randomly assigned at a 2:1 ratio to one of the following two treatment groups-which remained undisclosed to both the participant and study doctor during the study (unless there was an urgent medical need):

• Vortioxetine 20 mg
• Placebo (dummy inactive pill) - this was a capsule that looked like the study drug but had no active ingredient.

All participants were asked to take one capsule at the same time each day throughout the study.

This single-center trial was conducted in the United States. The overall time to participate in this study was approximately 7 weeks. Participants made 2 visits to the clinic, including 18 days confinement to the clinic, and were contacted by telephone 1 day and 27 days after leaving confinement for a follow-up assessment.

Inclusion Criteria:

• Weighs at least 50 kg and has a body mass index between 19.0 and 32.0 kg/m^2, inclusive at Screening.
• Males who are nonsterilized and sexually active with a female partner of childbearing potential must agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 6 weeks after last dose of study medication. The acceptable method of contraception is defined as one that has no higher than a 1% failure rate.

Exclusion Criteria:

• Received any investigational compound within 45 days prior to Check-in (Day -2).

• Received Lu AA21004 in previous clinical study or as therapeutic agent.

• History of or uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, central nervous system, hepatic hematopoietic disease, renal metabolic, gastrointestinal, or endocrine disease, serious allergy, asthma, hypoxemia, hypertension, seizures, allergic skin rash or other abnormality, which may impact the ability of the participant to participate or potentially confound study results.

• Participant has 1 or more of the following:

  • Any current psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).
  • Current or history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
  • Presence or history of a clinically significant neurological disorder (including epilepsy).
  • Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).
  • Any Axis II disorder.

• Has a known hypersensitivity to any component of the formulation of Lu AA21004.

• Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -2).

• Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular consumption of 4 or more units per day) within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.

• The participant intends to impregnate or donate sperm during the course of this study or for 6 weeks after last dose.

• Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (e.g., a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis; frequent (more than once per week) occurrence of heartburn, or any intra-abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy).

• Has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to Day 1.

• Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody at Screening or a known history of human immunodeficiency virus infection.

• Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in (Day -2) or is unwilling to abstain from these products for the duration of the study.

• Cotinine test is positive at Screening or Check-in (Day 2).

• Has poor peripheral venous access.

• Has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1.

• Has a Screening or Check-in (Day -2) abnormal (clinically significant) electrocardiogram (ECG). Entry of any patient with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator.

• Has abnormal Screening or Day -2 laboratory values that suggest a clinically significant underlying disease or with the following lab abnormalities: alanine aminotransferase and/or aspartate aminotransferase >1.5 times the upper limit of normal.

• Has had cerebrospinal fluid (CSF) collection performed within 30 days prior to Check-in (Day -2).

• Has taken any selective serotonin reuptake inhibitor (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors, antipsychotics, tricyclic antidepressants, or mood stabilizers within the last year prior to Screening.

• Has a known hypersensitivity to the anesthetic or its derivatives used during CSF collection, or any medication used to prepare the area of lumbar puncture.

• Has significant vertebral deformities (scoliosis or kyphosis) which, in the opinion of the investigator, may interfere with lumbar puncture procedure.

• Has a history of clinically significant back pain and/or injury.

• Has local infection at the puncture site.

• Has a history of significant bleeding or coagulation disorder and/or low platelet levels (<130x10^9/L) or increased international normalized ratio (INR) (>1.3) at Screening.

• Answers positive to any suicidal ideation and/or suicidal behavior questions during administration of the Columbia-Suicide Severity Rating Scale.

• Has an orthostatic blood pressure drop of ≥20 mm Hg (based on the drop between supine and standing [3 minutes] systolic blood pressure) at Screening or Check-in (Day -2).

• Has abnormal Screening or Day -2 vital signs: resting systolic blood pressure ≤90 or ≥140 mm Hg or a resting diastolic blood pressure ≤50 or ≥90 mm Hg in supine position; resting pulse or heart rate (as read on ECG) <45 bpm or >100 bpm. No more than 2 repeat measurements.

• Exercises extensively in his normal life (e.g., marathon running, triathlon, physical sports at a contest level etc).