Clinical trial NCT04585009: Safety, Tolerability and Pharmacokinetics of GSK3923868 Inhalation Powder in Healthy Participants and Stable Asthmatics
Official title: A Randomised Double-blind, Placebo Controlled, Single Ascending and Repeat Dose, First Time in Human Study in Healthy Participants and Stable Asthmatics to Assess Safety, Tolerability and Pharmacokinetics of GSK3923868 Inhalation Powder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: First time in human
Stable asthmatics
GSK3923868
Inhalation powder
Phosphatidylinositol 4-kinase beta
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2020-10-14
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part A will be a single ascending dose escalation study consisting of two sequential cross-over cohorts (Cohorts 1 and 2) in healthy participants. Part B is a repeat dose study consisting of two parallel cohorts (Cohort 3 and 4) in healthy participants. Part C is a repeat dose study consisting of one cohort (Cohort 5) in participants with asthma.
Primary purpose: TREATMENT

Brief summary: This is a first time in human (FTIH) study designed to evaluate the safety, tolerability and pharmacokinetic (PK) profile of single and repeat doses of GSK3923868 inhalation powder in both healthy participants and asthmatics. This is a 3-part, randomized, double blind, placebo controlled study of GSK3923868, administered as an inhalation powder blend (GSK3923868 capsules for inhalation) via Mono-dose inhaler in healthy participants (Parts A and B) and in participants with asthma (Part C). The duration of study participation for each part A, B and C will be 11, 9 and 8 weeks, respectively.


Eligibility criteria: Inclusion Criteria: For Parts A and B

* Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
* Participants who are generally healthy as determined by medical evaluation based on screening medical history, physical examination, vital signs, ECG assessment, pulmonary function testing, laboratory tests and cardiac monitoring.
* Body weight at least 50.0 kilograms (kg) (110 pounds \[lbs\]) and body mass index (BMI) within the range 18.5 to 32.0 kilograms per meter square (kg/m\^2) (inclusive).
* Male Participants: A male participant is eligible to participate if they agree to the following during the intervention period and for at least 10 days after the last dose of study intervention: Refrain from donating sperm. Plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remaining abstinent OR must agree to use contraception as detailed below when having sexual intercourse with a woman of childbearing potential who is not currently pregnant: Agree to use a male condom AND female partner to use an additional highly effective contraceptive method with a failure rate of \< 1 percent per year. The participant should also be advised of the benefit for a female partner as a condom may break or leak.
* Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding and is a woman of non-childbearing potential (WONCBP).
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

Inclusion Criteria: Part C

* Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
* Participants who are otherwise healthy (other than the acceptable condition of asthma and other mild atopic diseases, including allergic rhinitis and atopic dermatitis) as determined by medical evaluation based on screening medical history, physical examination, vital signs, ECG assessment, pulmonary function testing, laboratory tests and cardiac monitoring.
* A physician diagnosis of asthma (as defined by the Global Initiative for Asthma \[GINA\], 2020 guidelines) at least 6 months before screening. The reason for diagnosis of asthma should be documented in the participant's source data, including relevant history.
* A screening pre-bronchodilator FEV1 \>= 65 percent predicted normal value.
* Positive bronchodilator reversibility test defined as an increase in FEV1 of \> 12 percent and \> 200 milliliter (mL) from Baseline, 10 to 15 minutes after administration of 400 micrograms (μg) salbutamol (or equivalent).
* Participants with maintained control of their asthma using the permitted medications: short-acting beta agonist (SABA) use only (n=8 participants) and regular treatment with inhaled corticosteroid (ICS) or ICS/long-acting beta agonist (LABA) (including use of Leukotriene Receptor Agonist \[LTRA\]) (n=8 participants).
* Body weight at least 50.0 kg (110 lbs) and BMI within the range 18.5 to 32.0 kg/m\^2 (inclusive).
* Male Participants: A male participant is eligible to participate if they agree to the following during the intervention period and for at least 10 days after the last dose of study intervention: Refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remaining abstinent OR must agree to use contraception as detailed below when having sexual intercourse with a woman of childbearing potential who is not currently pregnant: Agree to use a male condom AND female partner to use an additional highly effective contraceptive method with a failure rate of \< 1 percent per year. The participant should also be advised of the benefit for a female partner as a condom may break or leak.
* Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding and is a WONCBP.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria: Part A and B

* History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
* Alanine transaminase (ALT) and Aspartate Aminotransferase (AST) above upper limit of normal (ULN).
* Total Bilirubin above ULN (isolated bilirubin above ULN is acceptable if total bilirubin is fractionated and direct bilirubin \<35 percent).
* Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* QTcF \> 450 milliseconds (msec) at screening visit based on the average of triplicate ECGs.
* Screening ECG measurements meets the following criteria for exclusion: heart rate: males- \<45 or \> 100 beats per minute (bpm); females- \<50 or \> 100 bpm; PR interval: \<120 or \>220 msec; QRS duration: \<70 or \>120 msec; QTcF: \>450 msec.
* Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
* Evidence of previous myocardial infarction (does not include ST segment changes associated with re-polarization).
* Signs and symptoms suggestive of COVID-19.
* Past or intended use of over-the-counter or prescription medication, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days before the first dose of study intervention, unless in the opinion of the Investigator and the GlaxoSmithKline (GSK) Medical Monitor, the medication will not interfere with the study procedures or compromise participant safety.
* Participation in this study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days.
* Exposure to more than 4 new chemical entities within 12 months before the first dosing day.
* Current enrolment or past participation in a clinical trial and has received an investigational product within the following time period before the first dosing day in this study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* FEV1 and FVC is \< 80 percent predicted normal value.
* Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
* Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
* Positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
* Positive pre-study drug/alcohol screen.
* Positive human immunodeficiency virus (HIV) antibody test.
* Positive test for COVID-19 infection.
* Current or history of drug abuse.
* Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular (AV) block \[2nd degree or higher\], Wolff-Parkinson-White (WPW) syndrome).
* Sinus Pauses \> 3 seconds.
* Any significant arrhythmia which, in the opinion of the Investigator or GSK Medical monitor, will interfere with the safety for the individual participant.
* Non-sustained or sustained ventricular tachycardia (with more than 3 consecutive ventricular ectopic beats).
* Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of \> 14 units for both males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Current or previous use of tobacco- or nicotine-containing products (e.g. cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of \> 5 pack years.
* Positive breath carbon monoxide test indicative of recent smoking at screening or each in-house admission to the clinical research unit.
* Sensitivity to any of the study interventions, or components thereof (including lactose and magnesium stearate \[MgSt\]), or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* Participants with known COVID-19 positive contacts in the past 14 days.

Exclusion criteria: Part C

* Any asthma exacerbation requiring systemic corticosteroids within 8 weeks of screening, or that resulted in overnight hospitalization requiring additional treatment for asthma within 3 months of screening.
* A history of life-threatening asthma, defined as an any asthma episode that required admission to a high-dependency or intensive therapy unit.
* Significant pulmonary diseases, other than asthma, including (but not limited to): pneumonia previously requiring hospital admission, bronchiectasis, pulmonary fibrosis, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other significant respiratory abnormalities.
* ALT and AST above ULN.
* Bilirubin above ULN (isolated bilirubin above ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent).
* Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* QTcF \> 450 msec at screening visit based on the average of triplicate ECGs.
* Signs and symptoms suggestive of COVID-19.
* Past or intended use of over-the-counter or prescription medication, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days before the first dose of study intervention, unless in the opinion of the Investigator and the GSK Medical Monitor, the medication will not interfere with the study procedures or compromise participant safety.
* Participation in this study would result in loss of blood or blood products in excess of 500 mL within 56 days.
* Exposure to more than 4 new chemical entities within 12 months before the first dosing day.
* Current enrolment or past participation in a clinical trial and has received an investigational product within the following time period before the first dosing day in this study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Presence of HBsAg at screening or within 3 months prior to first dose of study intervention.
* Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
* Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.
* Positive pre-study drug/alcohol screen.
* Positive HIV antibody test.
* Positive test for COVID-19 infection.
* Current or history of drug abuse.
* Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of \> 14 units for males and females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Current or previous use of tobacco- or nicotine-containing products (e.g. cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of \> 5 pack years.
* Positive breath carbon monoxide test indicative of recent smoking at screening or each in-house admission to the clinical research unit.
* Sensitivity to any of the study interventions, or components thereof (including lactose and MgSt), or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* Participants with known COVID-19 positive contacts in the past 14 days.

Primary outcomes:
measure: Part A, Cohort-1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 43
measure: Part A, Cohort 2: Number of Participants With AEs and SAEs
timeFrame: Up to Day 43
measure: Part B: Number of Participants With AEs and SAEs
timeFrame: Up to Day 28
measure: Part C: Number of Participants With AEs and SAEs
timeFrame: Up to Day 21
measure: Part A, Cohort-1: Number of Participants With Clinically Significant Changes in Clinical Chemistry and Hematology Laboratory Parameters
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part A, Cohort-2: Number of Participants With Clinically Significant Changes in Clinical Chemistry and Hematology Lab Parameters
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part B: Number of Participants With Clinically Significant Changes in Clinical Chemistry and Hematology Lab Parameters
timeFrame: From start of the treatment (Day 1) to Day 18
measure: Part C: Number of Participants With Clinically Significant Changes in Clinical Chemistry and Hematology Lab Parameters
timeFrame: From start of the treatment (Day 1) to Day 8
measure: Part A, Cohort-1: Number of Participants With Clinically Significant Changes in Vital Signs and 12-Lead Electrocardiogram (ECG) Findings
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part A, Cohort-2: Number of Participants With Clinically Significant Changes in Vital Signs and 12-Lead ECG Findings
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part B: Number of Participants With Clinically Significant Changes in Vital Signs and 12-Lead ECG Findings
timeFrame: From start of the treatment (Day 1) to Day 18
measure: Part C: Number of Participants With Clinically Significant Changes in Vital Signs and 12-Lead ECG Findings
timeFrame: From start of the treatment (Day 1) to Day 8
measure: Part A, Cohort-1: Number of Participants With Clinically Significant Changes in Spirometry Measurements
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part A, Cohort-2: Number of Participants With Clinically Significant Changes in Spirometry Measurements
timeFrame: From start of the treatment (Day 1) to Day 2 in each treatment period
measure: Part B: Number of Participants With Clinically Significant Changes in Spirometry Measurements
timeFrame: From start of the treatment (Day 1) up to Day 18
measure: Part C: Number of Participants With Clinically Significant Changes in Spirometry Measurements
timeFrame: From start of the treatment (Day 1) to Day 8
Secondary outcomes:
measure: Part A, Cohort 1 and 2: Area Under the Plasma GSK3923868 Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-t])
timeFrame: Up to Day 2 in each treatment period
measure: Part A, Cohort 1 and 2: Area Under the Plasma GSK3923868 Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-inf])
timeFrame: Up to Day 2 in each treatment period
measure: Part A, Cohort 1 and 2: Maximum Observed GSK3923868 Plasma Concentration (Cmax)
timeFrame: Up to Day 2 in each treatment period
measure: Part A, Cohort 1 and 2: Time to Maximum Observed Plasma Drug Concentration (Tmax)
timeFrame: Up to Day 2 in each treatment period
measure: Part B, Cohort 3 and 4: AUC From Time Zero (Predose) to Time Tau (AUC [0-tau]) (Tau=24hours for Once a Day Dosing Regimen) of GSK3923868
timeFrame: Up to Day 14
measure: Part B, Cohort 3 and 4: Cmax of GSK3923868
timeFrame: Up to Day 14
measure: Part B, Cohort 3 and 4: Tmax of GSK3923868
timeFrame: Up to Day 14
measure: Part C: AUC (0-tau) (Tau=24 Hours for Once a Day Dosing Regimen) of GSK3923868
timeFrame: Up to Day 7
measure: Part C: Cmax of GSK3923868
timeFrame: Up to Day 7
measure: Part C: Tmax of GSK3923868
timeFrame: Up to Day 7
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: