Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GRT9906 Prolonged Release Tablets After Dose Escalation in Healthy Subjects

NCT03776110 | Completed Phase 1

• 1 other identifier: HP9906-07
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

The safety and tolerability of multiple oral administrations of GRT9906 at different doses was investigated in this clinical study. The prolonged-release tablets slowly release the active compound in the intestine. In addition, absorption into the body, distribution, metabolization and excretion of GRT9906 was characterized. Pharmacological effects of GRT9906 in healthy participants was assessed using pupillometry (diameter and reactions of the pupil) and a Cold Pressor Test where pain is measured while hands are placed in icy water for two minutes.

Conditions

Pharmacokinetics

Keywords

Dose escalation

Outcome Measures

Primary Outcomes (1)

• Number of participants with treatment emergent adverse events

  Treatment emergent adverse events were collected from first dose of investigational medicinal product (IMP) throughout each treatment period up to and including the 48-hour assessment at the second follow-up day (F2) which was performed after 5.6 days (first dose group) or 6.6 days (second and subsequent dose groups).

  From Day M1/T (first dose) to Day F2 (5.6 or 6.6 days after first dose)

Secondary Outcomes (17)

• Area under the plasma concentration time curve (AUC0-inf) of GRT9906 after first dose

  On Day M1/T (pre-dose and from 0.5 to 12 hours post-dose [11 timepoints in total])

• Maximum plasma concentration (Cmax) of GRT9906 after first dose

  On Day M1/T (pre-dose and from 0.5 to 12 hours post-dose [11 timepoints in total])

• Terminal half life (t half) of GRT9906 after first dose

  On Day M1/T (pre-dose and from 0.5 to 12 hours post-dose [11 timepoints in total])

• Time to maximum serum concentration (tmax) of GRT9906 after first dose

  On Day M1/T (pre-dose and from 0.5 to 12 hours post-dose [11 timepoints in total])

• Apparent volume of distribution during the terminal phase (Vz/f) of GRT9906 after first dose

  On Day M1/T (pre-dose and from 0.5 to 12 hours post-dose [11 timepoints in total])

Study Arms (4)

GRT9906 80-mg dose group

EXPERIMENTAL

In one period, 80 mg GRT9906 (2 GRT9906 PR tablets) were administered twice daily at 12 hours apart with non-carbonated water. A total of 7 doses were administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4. In the second period, a total of 7 doses of placebo (2 tablets per dose) was administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4.

Drug: GRT9906 PR tablet; Drug: Placebo

GRT9906 120-mg dose group

EXPERIMENTAL

In one period, 120 mg GRT9906 (3 GRT9906 PR tablets) were administered twice daily at 12 hours apart with non-carbonated water. A total of 7 doses were administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4. A 'titration dose' of 80 mg was administered on the day before Day T. The dose administration on Day T was also performed twice daily with 12 hours apart and with non-carbonated water. In the other period, a total of 7 doses of placebo (3 tablets per dose) was administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4.

Drug: GRT9906 PR tablet; Drug: Placebo

GRT9906 160-mg dose group

EXPERIMENTAL

In one period, 160 mg GRT9906 (4 GRT9906 PR tablets) were administered twice daily at 12 hours apart with non-carbonated water. A total of 7 doses were administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4. A 'titration dose' of 80 mg was administered on Day T. The dose administration on Day T was also performed twice daily with 12 hours apart and with non-carbonated water. In the other period, a total of 7 doses of placebo (4 tablets per dose) was administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4.

Drug: GRT9906 PR tablet; Drug: Placebo

GRT9906 200-mg dose group

EXPERIMENTAL

In one period, 200 mg GRT9906 (5 GRT9906 PR tablets) were administered twice daily at 12 hours apart with non-carbonated water. A total of 7 doses were administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4. A 'titration dose' of 120 mg was administered on Day T. The dose administration on Day T was performed twice daily with 12 hours apart and with non-carbonated water. In the other period, a total of 7 doses of placebo (5 tablets per dose) was administered with the first administration in the morning of Day M1 and the last administration in the morning of Day M4.

Drug: GRT9906 PR tablet; Drug: Placebo

Interventions

GRT9906 PR tablet DRUG

40 mg GRT9906 PR tablet oral (minimal release of 80 percent after 480 minutes)

GRT9906 120-mg dose group; GRT9906 160-mg dose group; GRT9906 200-mg dose group; GRT9906 80-mg dose group

Placebo DRUG

Placebo tablet matching 40 mg GRT9906 PR tablet

GRT9906 120-mg dose group; GRT9906 160-mg dose group; GRT9906 200-mg dose group; GRT9906 80-mg dose group

Eligibility Criteria

• Age: 45 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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;

Sponsors & Collaborators

• Grünenthal GmbH: lead

Study Sites (1)

FOCUS Clinical Drug Development GmbH

Neuss, 41460, Germany

Location

Study Officials

• Grünenthal Study Director

  Grünenthal GmbH

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single center, multiple dose, dose escalation (within dose-group randomized, double-blind, placebo-controlled, 2-way cross-over)

Study Record Dates

• First Submitted: December 11, 2018
• First Posted: December 14, 2018
• Study Start: September 15, 2004
• Primary Completion: March 23, 2005
• Study Completion: March 23, 2005
• Last Updated: December 14, 2018

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)