Phase 1A Safety Trial of Inhaled PK10571 (GB002) | NCT03473236

Name	Class
Pulmokine Inc.	INDUSTRY
Worldwide Clinical Trials	OTHER

Description Module

Detailed Description

This is a first-in-human, single-center, randomized, double-blind, placebo-controlled, two-part study in healthy adult males and females of non-childbearing potential. "Double-Blind" means neither the study subject nor the investigator knows if PK10571 or placebo is being given. "Placebo" means a capsule filled with a powder that does not contain the active drug, PK10571. Because the safety profile of PK10571 in humans is unknown and this is the first clinical study to assess PK10571 in humans, a single-ascending dose design will be used in Part A of the study going from a low dose to higher doses based on safety. Part B will be a multiple-ascending dose design to be run only after review of safety and measurement of drug levels in the blood from Part A.

In the single ascending dose study (Part A) up to five doses may be given to different groups of study subjects based on safety and measurement of drug levels in the blood. Subjects will be randomized into one dose cohort to receive either PK10571 or placebo. Within each cohort, 6 subjects will receive active drug and 2 subjects will receive placebo.

In the multiple ascending dose study (Part B), up to three doses of PK10571 will be tested. The daily dose will be administered daily for 7 days with close clinical monitoring. The dose for the first cohort of Part B will be determined by review of the safety and drug levels from Part A by the Safety Review Committee. The dose interval for the first cohort of Part B (i.e., once daily, twice daily, or up to three times daily) will be determined by review of the safety and drug levels in the blood from Part A by the Safety Review committee. Subsequent doses and dosing intervals will be determined by review of the safety and drug levels from the prior cohort.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1A	Experimental	Dose 1 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.	Drug: GB002 Device: Generic Dry Powder Inhaler Drug: Placebo
Cohort 2A	Experimental	Dose 2 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.	Drug: GB002 Device: Generic Dry Powder Inhaler Drug: Placebo
Cohort 3A	Experimental	Dose 3 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.	Drug: GB002 Device: Generic Dry Powder Inhaler Drug: Placebo
Cohort 4A	Experimental	Dose 4 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.	Drug: GB002 Device: Generic Dry Powder Inhaler Drug: Placebo
Cohort 5A	Experimental	Dose 5 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.

Name	Type	Description	Arm Group Labels	Other Names
GB002	Drug	Inhaled GB002	Cohort 1A Cohort 1B Cohort 2A Cohort 2B Cohort 3A Cohort 3B Cohort 4A

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A serious AE (SAE) is one that, in the view of either the investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. A TEAE is defined as any AE that has an onset on or after the first dose of study drug and before the end of study/end of treatment (EoS/ET) visit, or any pre-existing condition that has worsened in severity on or after the first dose of study drug and before the EoS/ET visit.	SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days
Number of Participants With Vital Sign Findings Reported as TEAEs	Vital signs evaluated included blood pressure, pulse oximetry, respiratory rate, and temperature.	SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days
Number of Participants With Clinically Significant Findings in Physical Examinations	Physical examination assessments included: physical exam for general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back and neck; heart; chest; lungs; abdomen; skin; and extremities, musculoskeletal and neurological.	SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days
Number of Participants With Clinically Significant Changes From Baseline in ECG Data (Overall Interpretation)	12-lead electrocardiograms (ECG) assessments included heart rate, PR interval, QRS duration, QT interval, QTc interval, QTc interval corrected using Bazett's formula (QTcB), QTc interval corrected using Fridericia's formula (QTcF), RR interval.

Other Outcomes

Measure	Description	Time Frame
Change From Baseline in White Blood Cell Count	Measurement of white blood cell count	SAD: from baseline to 11 days, MAD: from baseline to 35 days
Change From Baseline in Hemoglobin	Measurement of hemoglobin

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Males and females (if unable to become pregnant)
Age 18-55
Body mass index (BMI) 18-32 kg/m^2 and minimum weight of 50 kg (110 lbs)
Non-smoker
Ability to give informed consent
Ability to remain in study unit for duration of study and return for outpatient visits
Ability to use dry powder inhaler (DPI) effectively

(See full protocol for additional details.)

Exclusion Criteria:

Hospitalization within the 6 months prior to the first dose of study treatment
History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results
History or presence of active lung disease (i.e., asthma, chronic obstructive pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) or prior intubation
Currently uses an inhaler
History or presence of heart disease (i.e., prior myocardial infarction [MI], coronary artery disease, heart failure, hypertension, pulmonary hypertension, valve disease, atrial fibrillation, other arrhythmia, or prolonged QT syndrome)
History or presence of cancer (with the exception of basal cell skin cancer that has been effectively treated)
History of diabetes mellitus
History of thyroid disease other than hypothyroidism control with levothyroxine and documented normal thyroid-stimulating hormone (TSH)
History of tuberculosis, Lyme disease, or other chronic or opportunistic infection.
History of positive purified protein derivative (PPD) skin test, or positive PPD test at screening
Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at screening or has been previously treated for hepatitis B, hepatitis C, or HIV infection
History of smoking within the past 15 years
Is a female with a positive pregnancy test result, or who has the ability to become pregnant, or who is lactating
Has forced expiratory volume in 1 second (FEV1) less than 80% predicted, forced vital capacity (FVC) ˂80% predicted, or resting oxygen saturation less than 97% on room air at screening or baseline
Upper respiratory infection within the 3 months prior to the first dose of medication
History of major bleeding or major surgical procedure of any type within 6 months prior to the first dose of medication
History of minor bleeding disorders such as epistaxis, rectal bleeding (spots of blood on toilet paper), and gingival bleeding within 3 months before the study treatment
History of bleeding disorder or coagulopathy
Females with history of dysfunctional uterine bleeding, including history of menorrhagia or metrorrhagia, unless subject has had a hysterectomy.
History of GI bleed
Has used any over-the-counter (OTC) medication, nutritional or dietary supplements, herbal preparations, or vitamins within 7 days prior to the first dose of medication
Has used any antiplatelet agents such as acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel (or similar agent) or anti-coagulants within 7 days prior to the first dose of medication
Has used any prescription medication, except female hormonal replacement therapy, within 14 days prior to the first dose of study medication
Has been treated with any known drugs that are moderate or strong inhibitors/inducers of CYP enzymes such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication and that in the Investigator's judgment may impact subject safety or the validity of the study results
History of peripheral vascular disease
History of autoimmune or collagen vascular disease
History of sleep apnea
History of clinically significant allergy to medications
History of anaphylaxis
History of liver disease
History of alcohol or drug abuse
Prolonged QTc on 12-lead ECG (i.e., QTc corrected using Fridericia's formula [QTcF] ˃450 msec), PR >210 msec, or QRS >110 msec at screening.
Evidence of prior MI on ECG; presence of atrial fibrillation on ECG; presence of pre-excitation, 2nd or 3rd degree heart block, or abnormal waveform morphology that would preclude accurate measurement of the QT interval duration or other clinically significant abnormalities
Chest x-ray reveals presence of infiltrate or other abnormality (mass, granuloma, fibrosis, pulmonary thickening, pleural effusion, pulmonary edema, wide mediastinum, cardiomegaly, or clinically significant increased interstitial markings)
History of neurologic disorder (i.e., multiple sclerosis, amyotrophic lateral sclerosis [ALS], cerebrovascular accident [CVA], transient ischemic attach [TIA])
History of deep vein thrombosis or pulmonary embolus
History of clotting disorder
History of mental illness requiring drug treatment or hospitalization
History of renal failure or proteinuria (defined as 1+ proteinuria: ≥75 mg/dL on isolated urinalysis)
Test results greater than the upper limit of normal (ULN) for AST, ALT, or total bilirubin
Out of range results on the following coagulation tests: INR, prothrombin time (PT), or partial thromboplastin time (PTT)
Total cholesterol >250 mg/dL or triglycerides >300 mg/dL at screening (based on fasting lipid profile)
Estimated creatinine clearance less than 60 mL/min
Hemoglobin at screening of <11.5 g/dl (if female subject) or <12.5 g/dl (if male subject)
Has a clinically significant abnormal finding on the physical exam, medical history, electrocardiogram (ECG), or clinical laboratory results at screening. Note: Subjects with abnormal laboratory results not specifically excluded by this protocol may be enrolled if the Investigator deems the out-of-range values as not clinically significant
History of treatment with a kinase inhibitor
Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication
Has donated blood or plasma within 30 days prior to the first dose of study medication
Has participated in another clinical trial (randomized subjects only) within 30 days prior to the first dose of study medication
Has a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates) or cotinine
Vital signs (measured sitting after 3 minutes rest) at screening that are not within the following ranges (inclusive): heart rate: 40-100 beats per minute [bpm]; systolic blood pressure (BP): 90-145 mmHg; diastolic BP: 50-95 mmHg. Out-of-range vital signs may be repeated once. Blood pressure will be measured in both arms at screening, with a 3-minute rest between each measurement. Predose vital signs will be assessed by the Principal Investigator or designee (e.g., a medically qualified sub-investigator) prior to study drug administration. The Principal Investigator or designee will verify the eligibility of each subject with out-of-range vital signs and document approval prior to dosing
Significant difference (i.e., greater than 15 mmHg) between the systolic blood pressure in each arm at screening
History of lactose intolerance

ID	Title	Description
FG000	SAD PK10571 (GB002) Placebo QD	A placebo single ascending dose (SAD) inhaled once a day (QD) over 11 days in healthy volunteers
FG001	SAD GB002 3.75 mg QD	GB002 SAD 3.75 mg inhaled QD over 11 days in healthy volunteers
FG002	SAD GB002 7.5 mg QD	GB002 SAD 7.5 mg inhaled QD over 11 days in healthy volunteers
FG003	SAD GB002 15 mg QD	GB002 SAD 15 mg inhaled QD over 11 days in healthy volunteers
FG004	SAD GB002 30 mg QD	GB002 SAD 30 mg inhaled QD over 11 days in healthy volunteers
FG005	SAD GB002 48 mg QD	GB002 SAD 48 mg inhaled QD over 11 days in healthy volunteers
FG006	MAD GB002 Placebo BID/TID	A placebo multiple ascending dose (MAD) inhaled either twice daily (BID) or thrice daily (TID) over 35 days in healthy volunteers
FG007	MAD GB002 18 mg BID	GB002 MAD 18 mg inhaled BID over 35 days in healthy volunteers
FG008	MAD GB002 24 mg TID	GB002 MAD 24 mg inhaled TID over 35 days in healthy volunteers
FG009	MAD GB002 48 mg TID	GB002 MAD 48 mg inhaled TID over 35 days in healthy volunteers

ID	Title	Description
BG000	SAD GB002 Placebo QD	A placebo SAD inhaled QD over 11 days in healthy volunteers
BG001	SAD GB002 3.75 mg QD	GB002 SAD 3.75 mg inhaled QD over 11 days in healthy volunteers

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 31, 2018	Nov 18, 2019	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Aug 16, 2018	Nov 18, 2019	SAP_001.pdf