Clinical trial: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GRT9906 Prolonged Release Tablets After Dose Escalation in Healthy Subjects (NCT03776110)

Eligibility criteria:
Inclusion Criteria:

          -  Male or female Caucasian participants aged 45-70 years;

          -  Body Mass Index (BMI) between 18 and 30 kilograms per square meter (extremes
             included);

          -  Participants must be in good health as determined by medical history, physical
             examination, 12-lead electrocardiogram (ECG), electroencephalogram (EEG), vital signs
             and clinical laboratory parameters (haematology, sedimentation rate, clotting,
             clinical chemistry, urinalysis and virus serology). Minor deviations of laboratory
             values and ECG parameters from the normal range may be accepted, if judged by the
             investigator to have no clinical relevance and if not considered to interfere with the
             study objectives;

          -  Adequate contraception. For females of childbearing potential (i.e., all females
             except surgically sterilized or at least 2 years postmenopausal) this was defined as
             follows: any form of hormonal contraception or intra-uterine device had to be used, at
             least from 4 weeks prior to the first dosing up to 4 weeks after the last dosing and
             an additional barrier contraception (condom or diaphragm) had to be used from 2 weeks
             prior to the first dosing up to 4 weeks after the last dosing;

          -  Participants must give written informed consent to participate within this study;

          -  Negative human immunodeficiency virus-1/2-antibodies, surface antigen of the hepatitis
             B virus (HBs-antigen), hepatitis B core (HBc)-antibodies, hepatitis C virus
             (HCV)-antibodies determined at screening examination;

          -  Negative drug abuse screening test determined at screening examination and prior to
             first dose administration in each period (the test will include screening for
             amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids and opiates);

          -  Negative blood beta-human chorionic gonadotropin (beta-HCG) test for females of
             childbearing potential determined at screening examination and prior to first dose
             administration in each period (the test is not necessary in females who are in
             post-menopausal state for at least 2 years or in females with status after surgical
             sterilisation).

        Exclusion Criteria:

          -  Pulse rate below 50 or above 100 beats per minute. The measurement must be performed
             in supine position after a resting period of at least 5 minutes

          -  Systolic blood pressure below 100 or above 160 millimeters Mercury (mmHg), diastolic
             blood pressure below 50 or above 100 mmHg. The measurement must be performed in supine
             position after a resting period of at least 5 minutes;

          -  Participants with history or presence of diseases or functional disorders of the
             central nervous system, endocrinological system, gastrointestinal tract, connective
             tissue, hepatobiliary system, renal system, respiratory system or cardiovascular
             system or other conditions known to interfere with the absorption, distribution,
             metabolism or excretion of drugs;

          -  Marked repolarisation abnormality (e.g., suspicious or definite congenital long QT
             syndrome) or co-medication that is known to influence cardiac repolarisation
             substantially;

          -  History of seizures or at risk (i.e. head trauma, epilepsy in family anamnesis,
             unclear loss of consciousness); abnormal, clinically relevant EEG findings at
             screening;

          -  History of orthostatic hypotension;

          -  Bronchial asthma;

          -  Definite or suspected history of drug allergy or hypersensitivity;

          -  History of Raynaud´s disease or phenomenon;

          -  Malignancy;

          -  Participation in another clinical study within the last 3 month prior to the start of
             this study (exception: characterisation of metaboliser status);

          -  Blood donation (above 100 milliliters [mL]) or comparable blood losses within three
             month prior to the start of this study;

          -  Excessive consumption of food or beverages containing caffeine or other xanthines
             (more than 1000 mL coffee or equivalent per day) within 2 weeks before administration
             of the investigational products or during the study;

          -  Drinking of alcohol containing beverages within 48 hours before administration of the
             investigational products or during the study;

          -  Evidence of alcohol, medication or drug abuse;

          -  Smoking of more than 3 cigarettes per day. Smokers who are not able to abstain from
             smoking for 24 hours prior to the administration of any cold pressor test, and during
             the period of hospitalisation must be excluded;

          -  Intake of drugs that are substrates to cytochrome P2D6 (CYP2D6) isoenzyme within the
             last 4 weeks prior to the start of this study. Intake of more than 1000 mg paracetamol
             within 3 days prior to administration of the investigational products. Use of any
             other medication within 4 weeks prior to the start of the study (self-medication or
             prescription), if not on a stable basis;

          -  Neurotic personality, psychiatric illness or suicide risk;

          -  Known or suspected of not being able to comply with the study protocol or of not being
             able to communicate meaningfully with the investigator and staff;

          -  Participants who in the opinion of the investigator should not participate in the
             study;

          -  Not able to perform the Cold Pressor Test reproducibly, i.e., the difference in the
             area under the pain-time curves (AUC) is above 20 percent during the 2 tests performed
             to evaluate the reproducibility at screening;

          -  Not able to perform the Vienna Test System (Determination Test, Visual Pursuit Test,
             Tachistoscopic Traffic Test Mannheim for Screen or equivalent subtests);

          -  Pregnant or breastfeeding women.
No condition on gender to be admitted to the trial.
Accepts Healthy Volunteers
Subject must be at least 45 Years old.
Subject must be at most 70 Years

Patient description (medical language): A 43-year-old woman, gravida 3 para 3, comes to the clinic complaining of recently painful menstrual cycles.  The patient's last menstrual period was 2 weeks ago. Urine β-hCG is negative. Menarche was at age 12, and menstrual periods occur every 28 days and lasts for 5 days.  She is sexually active with her husband and does not have pain with intercourse. BMI is 23 kg/m2 and Vital signs are normal.  On physical examination, the uterus is uniformly enlarged and tender. She is candidate for hysterectomy with the diagnosis of adenomyosis.

Patient description (patient's own words): I'm 43, and I paid a visit to my doctor because my last few periods were insanely painful. My last periods were 2 weeks ago. I already had three pregnancies that gave me the three lovely children. I did a urine test to check for potential pregnancy, and it came back negative. I started to have my periods at the age of 12, and I have been pretty regular with periods every 28 days for 5 days. I'm sexually active with my husband and I do not have any pain when we have sex. My BMI is 23 and my vitals were normal. The doctor performed a physical exam and found that my uterus was tender and enlarged. She proposed me a hysterectomy and diagnosed me with adenomyosis.

Does the patient match the trial criteria? Contradiction