Clinical trial NCT04107805: A Study in Healthy Men and Women to Test How Well Different Doses of BI 1323495 Are Tolerated
Official title: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Rising Oral Doses of BI 1323495 Versus Placebo in Healthy Subjects, Including an Investigation of Drug-drug Interaction With Microdose Midazolam (Double-blind, Randomised, Placebo-controlled [Within Dose Groups] Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2019-09-27
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in healthy subjects following bid oral administration of multiple rising doses, each over an 11 day treatment period.

Secondary objectives are the exploration of the pharmacokinetics (PK) including dose proportionality (only for Part 1) as well as attainment of steady state. This includes exploration of a therapeutic exposure range, a range not adequately achieved in the single-rising dose trial 1405-0001.


Eligibility criteria: Inclusion criteria:

* Healthy subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), PR), 12-lead Electrocardiogram (ECG), and clinical laboratory tests
* Age of 18 to 70 years (inclusive)
* BMI of 18.5 to 29.9 kg/m2 (inclusive)
* Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation
* For Part I: Subjects genotyped as UGT2B17 extensive metabolizers, i.e., carrying at least one functional allele of the UGT2B17 gene (\*1/\*1 or \*1/\*2).

For Part II: Subjects genotyped as UGT2B17 poor metabolizers, i.e., carrying no functional allele of the UGT2B17 gene (\*2/\*2)

-Male or female subjects:

* For 'female subjects not of childbearing potential' at least one of the following criteria must be fulfilled:
* Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy)
* Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)
* Female subjects of childbearing potential must use a highly effective contraception method from at least 30 days before the first administration of trial medication until 14 days after trial completion

Exclusion criteria:

* Any finding in the medical examination (including Blood Pressure (BP), PR, or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator. In particular a marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) at screening
* Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm
* Any laboratory value outside the reference range that the investigator considers to be of clinical relevance; safety laboratory screening evaluation can be repeated a maximum of two times
* Any evidence of a concomitant disease assessed as clinically relevant by the investigator or at risk of requiring concomitant drug therapy, e.g., gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorder, diseases of the central nervous system (including, but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders
* History of cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
* History of relevant orthostatic hypotension, fainting spells, or blackouts
* History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients); mild seasonal allergy adequately managed by topic administration of drugs to eyes or nose is not excluded
* Subjects with a documented active malignancy, or malignancy for which the subject has undergone resection, radiation therapy, or drug therapy (e.g., cytostatic, protein kinase inhibitor, or immune checkpoint inhibitor therapy), within the last 5 years.
* Subjects who have been previously randomised in this study.
* Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation)
* Intake of an investigational drug in another clinical trial within 60 days, or within 5 half-lives of the investigational drug (whichever is longer), of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered
* Major surgery (major according to the investigator's assessment) performed within 6 weeks prior to randomisation or planned within 3 months after screening, e.g. hip replacement.
* Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day), also inability to refrain from smoking during in-house confinement
* Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) or any other drug abuse or positive drug screening
* Blood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trial
* Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial
* Inability to comply with the dietary regimen of the trial site
* A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)
* Subjects with veins unsuited for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator.
* Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
* Male subjects with 'women of childbearing potential' (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from the first administration of trial medication until 30 days after the last administration of trial medication
* Known relevant immunodeficiency, as judged by the investigator
* Chronic or relevant acute infections
* History and/or presence of tuberculosis; positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), or history of pneumococcal infection
* Positive results for Hepatitis B antigen, Hepatitis C antibodies, and/or human immunodeficiency virus (HIV) 1 antigen or HIV1/2 antibodies, at screening
* Aural body temperature of more than 37.7°C on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing.
* Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosing
* C-reactive protein above upper limit of laboratory reference range at screening and/or on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing.
* Subjects with signs of current gingivitis/periodontitis. Inspection of the oral cavity will be performed by the investigator.
* Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure), according to investigator.
* Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula \< 80 mL/min at screening.
* Known clinically relevant impairment of liver function or clinically relevant laboratory abnormality at the screening visit (V1) regarding liver aminotransferases, alkaline phosphatase, gamma glutamyl transferase, bilirubin, serum albumin, as judged by the investigator.
* Subjects with a known coagulopathy or abnormal coagulation laboratory parameters at screening, or subjects who, within 10 days prior to administration of trial medication, used any drug that could reasonably inhibit coagulation
* Females with a positive pregnancy test or breastfeeding

Primary outcomes:
measure: Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs)
timeFrame: Midazolam alone: From administration of midazolam on Day -1 until first administration of BI 1323495 on Day 1, up to 24 hours. All others: From first administration until 7 days after the last administration of BI 1323495, up to 18 days.
Secondary outcomes:
measure: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12)
timeFrame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, and 12h after the first administration of BI 1323495 on Day 1.
measure: Only for Once Daily (qd) Dosing Group: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Uniform Dosing Interval of 24 h After Administration of the First Dose (AUC0-24)
timeFrame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24 h after administration of BI 1323495 on Day 1.
measure: Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax)
timeFrame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the first administration of BI 1323495 on Day 1. * Applicable only for the 120 mg BI 1323495 qd EM arm.
measure: Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)
timeFrame: Within 3 hours before and 20 minutes (min), 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm.
measure: Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)
timeFrame: Within 3 hours before and 20 min, 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last drug administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm.
Other outcomes:
Locations:
city: Hannover
country: Germany
facility: Fraunhofer ITEM
Study officials:
References: