Thorough QT Study of Intravenous Amisulpride
Condition: Healthy
Intervention: APD421 5 mg; APD421 40 mg; Moxifloxacin; Placebo
Intervention description: Therapeutic dose of amisulpride; Supra-therapeutic dose of amisulpride; Positive control for assay sensitivity; Placebo comparator to establish baseline for calculating change in QTcF
Intervention MeSH terms: Moxifloxacin; Amisulpride
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 40.0
Sex: All
Minimum age: 20 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: TQT; amisulpride; volunteer; ECG

Summary:

      Randomised, single-dose, crossover, placebo-controlled study to see if intravenous
      amisulpride has any effect on the heart rhythm, in particular the QT interval, in healthy
      adult volunteers.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male or female subjects aged between 20 and 45 years (inclusive) at screening.

          2. Signed informed consent in the local language prior to any study-mandated procedure.

          3. Japanese subjects defined as a person carrying a Japanese passport, who is a
             descendant of four Japanese grandparents and has not been outside Japan for more than
             five years prior to screening.

          4. The Caucasian subjects should be distinguished especially by very light to brown skin
             pigmentation and straight to wavy or curly hair, and should be indigenous to Europe,
             northern Africa, western Asia, and India. Therefore, the study may as well include
             Caucasian subjects from North America, Australia and South Africa

          5. No clinically significant findings on the physical examination at screening and at
             admission on Day -2.

          6. Body mass index (BMI) between 18 and 25 kg/m2 (inclusive) at screening and at
             admission on Day -2, body weight at least 48 kg.

          7. Systolic blood pressure (SBP) 90-145 mmHg, diastolic blood pressure (DBP) 40-90 mmHg,
             and heart rate (HR) 40-90 bpm (all inclusive), measured on the left arm, after 10
             minutes in the supine position at screening and at admission on Day -2.

          8. Triplicate 12-lead ECG without clinically relevant abnormalities measured after ten
             minutes in the supine position at screening and on admission on Day -2.

          9. 24-hour 12-lead Holter ECG or an equivalent assessment and/or submaximal exercise test
             without clinically relevant abnormalities measured at screening.

         10. Haematology, biochemistry and urinalysis test results not deviating from the normal
             range to a clinically relevant extent at screening and at admission.

         11. Subjects must agree to use acceptable methods of contraception:

             Male subjects

             Male subjects must use medically acceptable methods of contraception if their female
             partner(s) is (are) pregnant or lactating from the time of the first administration of
             treatment or study medication until three months following administration of the last
             treatment or dose of study medication. Acceptable methods include:

               -  Condom used with spermicidal foam/gel/film/cream/suppository

               -  If the subject has undergone surgical sterilisation (vasectomy with documentation
                  of azoospermia) a condom with spermicidal foam/gel/film/cream/suppository must be
                  used.

             Use acceptable methods of contraception if the male subject's partner could become
             pregnant from the time of the first administration of treatment or study medication
             until three months following administration of the last treatment or dose of study
             medication. The acceptable methods of contraception are as follows:

               -  Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal
                  foam/gel/film/cream/suppository.

               -  Surgical sterilisation (vasectomy with documentation of azoospermia) and a
                  barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used
                  with spermicidal foam/gel/film/cream/suppository).

               -  The female partner uses oral contraceptives (combination oestrogen/progesterone
                  pills), injectable progesterone or subdermal implants and a barrier method
                  (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal
                  foam/gel/film/cream/suppository).

               -  The female partner uses medically prescribed topically-applied transdermal
                  contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or
                  cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository).

               -  The female partner has undergone documented tubal ligation (female
                  sterilisation). In addition, a barrier method (condom or occlusive cap [diaphragm
                  or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
                  must be used.

               -  The female partner has undergone documented placement of an intrauterine device
                  (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or
                  occlusive cap [diaphragm or cervical/vault caps] used with spermicidal
                  foam/gel/film/cream/suppository).

               -  True abstinence: When this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

             Female subjects

             Female subjects of childbearing potential must use medically acceptable methods of
             contraception from the time of the first administration of treatment or study
             medication until three months following administration of the last treatment or dose
             of study medication. Acceptable methods include:

               -  A documented placement of an IUD or IUS and the use of a barrier method (condom
                  or occlusive cap [diaphragm or cervical/vault caps) used with spermicidal
                  foam/gel/film/cream/suppository]).

               -  Documented tubal ligation (female sterilisation). In addition, a barrier method
                  (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal
                  foam/gel/film/cream/suppository) should also be used.

               -  Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault
                  caps) with spermicidal foam/gel/film/cream/suppository.

               -  True abstinence: When this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) are not acceptable methods of contraception.

         12. Ability to communicate well with the Investigator in the local language, and to
             understand and comply with the requirements of the study.

        Exclusion Criteria:

          1. Women who are pregnant and/or breastfeeding.

          2. Received amisulpride for any indication within the last 2 weeks.

          3. Allergy to amisulpride or any of the excipients of APD421.

          4. History of vestibular disorder or history of dizziness.

          5. Received anti-emetic therapy including corticosteroids within the last 2 weeks.

          6. History or clinical evidence of any disease and/or existence of any surgical or
             medical condition which might interfere with the absorption, distribution, metabolism
             or excretion of the study drug (appendectomy and herniotomy allowed, cholecystectomy
             not allowed).

          7. History of epilepsy.

          8. History of clinically significant syncope.

          9. Family history of sudden death.

         10. Family history of premature cardiovascular death.

         11. Clinically significant history or family history of congenital long QT syndrome (e.g.
             Romano-Ward syndrome, Jervell and Lange-Nielson syndrome) or Brugada's syndrome.

         12. History of clinically significant arrhythmias and ischemic heart disease (especially
             ventricular arrhythmias, atrial fibrillation (AF), recent conversion from AF or
             coronary spasm).

         13. Conditions predisposing the volunteer to electrolyte imbalances (e.g. altered
             nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa).

         14. ECG abnormalities in the standard 12-lead ECG (at screening and Day -2) and 24-hour
             12-lead Holter ECG or an equivalent assessment and/or submaximal exercise test (at
             screening) which in the opinion of the Investigator will interfere with the ECG
             analysis.

         15. Any clinically important abnormalities in rhythm, conduction or morphology of resting
             ECG that may interfere with the interpretation of QTc interval changes. This includes
             subjects with any of the following (at screening and Day -2 of Period 1):

               -  Sinus node dysfunction.

               -  Clinically significant PR (PQ) interval prolongation.

               -  Intermittent second or third degree atrioventricular (AV) block.

               -  Incomplete or complete bundle branch block.

               -  Abnormal T-wave morphology.

               -  Prolonged QT interval corrected with Bazett's formula (QTcB) >450 ms or shortened
                  QTcB < 350 ms or family history of long QT syndrome.

             Subject with borderline deviations from these criteria may be included if the
             deviations do not pose a safety risk, and if agreed between the appointed Cardiologist
             and the PI.

         16. Signs and/or symptoms of a clinically relevant acute illness in the four-week period
             prior to screening.

         17. Veins unsuitable for intravenous puncture or cannulation on either arm (e.g. veins
             that are difficult to locate, access or puncture, veins with a tendency to rupture
             during or after puncture).

         18. Known hypersensitivity to any medicines administered in the trial.

         19. Treatment with any prescribed medication during the two weeks prior to first baseline
             day.

         20. Treatment with any over-the-counter (OTC) medications during the two weeks prior to
             first baseline day.

         21. Treatment with vitamins and/or minerals within 48 hours prior to the first baseline
             day.

         22. Treatment with another investigational drug within four weeks prior to dosing or
             having participated in more than three investigational drug studies within one year
             prior to dosing.

         23. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
             cocaine, cannabinoids, opiates, barbiturates and methadone) or from the alcohol breath
             test at screening and on Day -2.

         24. History or clinical evidence of alcoholism or drug abuse. Alcohol abuse is defined as
             regular weekly intake of more than 14 units (Using alcohol tracker
             http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx); drug abuse is defined as
             compulsive, repetitive and/or chronic use of drugs or other substances with or without
             problems related to their use and/or where stopping or a reduction in dose will lead
             to withdrawal symptoms.

         25. Excessive caffeine consumption, defined as ≥800 mg per day at screening (800 mg = 7
             cups of coffee or 16 cups of tea).

         26. Smoking within three months prior to screening or during the screening period.

         27. Loss of 250 mL or more blood within three months prior to screening.

         28. Positive results from the hepatitis serology, except for vaccinated subjects, at
             screening.

         29. Positive results from the HIV serology at screening.

         30. Any circumstances or conditions, which, in the opinion of the Investigator, may affect
             full participation in the study or compliance with the protocol.

         31. Legal incapacity or limited legal capacity at screening.