A First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Immunogenicity of PMG1015

Study Overview
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Brief Summary
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This is a Phase 1A, first in human, randomized, double-blinded, placebo-controlled, dose escalation study of PMG1015 in healthy adult volunteers. PMG1015 is a monoclonal antibody, being developed as a novel therapeutic treatment for patients with Idiopathic Pulmonary fibrosis (IPF). This study aims to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of PMG1015 after Single ascending doses (SAD).

Detailed Description
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Participants will be enrolled and randomized into 1 of 7 cohorts in a double-blind manner.

Official Title
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A Phase 1A, First in Human, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Immunogenicity of PMG1015 in Healthy Volunteers

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: PMG1015 Dose 1
* Drug: PMG1015 Dose 2
* Drug: PMG1015 Dose 3
* Drug: PMG1015 Dose 4
* Drug: PMG1015 Dose 5
* Drug: PMG1015 Dose 6
* Drug: Placebo
* Drug: PMG1015 Dose 7


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or non-pregnant, non-lactating female volunteers, between 18 and 60 years of age, inclusive at the time of informed consent. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (inclusive) and body weight between 50 and 100 kg for males and between 45 and 100 kg for females. No clinically significant clinical laboratory values (Hematology, coagulation, biochemistry and urinalysis) at the discretion of the PI. Females of child bearing potential must use an acceptable, highly effective double contraception and have a negative pregnancy test at Screening and Day-1. Documented evidence of surgical sterilization at least 6 months prior to screening for women or vasectomy at least 90 days prior to screening. Women not of child bearing potential must be menopausal for >/= 12 months. Males must not donate sperms for at least 90 days after PMG1015 administration. Exclusion Criteria: History or evidence of clinically significant condition, including but not limited to any cardiovascular, gastrointestinal, endocrinologic, hematologic, psychiatric, renal disease, musculoskeletal, infectious, or neurological condition or any chronic medical condition and/or other major disease, as determined by the PI. A PR < 40 or > 100 beats per minute, mean systolic blood pressure (SBP) > 140 mmHg, or mean diastolic blood pressure (DBP) > 95 mmHg . A mean corrected QT interval using Fridericia's formula (QTcF) interval at Screening > 450 ms in males and > 470 ms in females. If the mean QTcF exceeds these limits, one additional triplicate ECG will be performed. Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, in the judgment of the PI, may interfere with the interpretation of QTc-interval changes, including abnormal ST-T wave morphology or left ventricular hypertrophy. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatinine > 1.5 × the upper limit of the normal range (ULN) or total bilirubin or lymphocyte counts > ULN. Participants with a positive toxicology screening panel or alcohol breath test on Screening/Day-1. Participants with a history of substance abuse or dependency or history of recreational IV drug use over the last 2 years. Plasma donation/Blood donation or significant blood loss within 60 days prior to the first IP administration. Use of any IP (including other investigational mAb products) or investigational medical device within 30 days prior to Screening or 5 half-lives of the product (whichever is the longest) or participation in more than 4 investigational drug studies within 1 year prior to screening. Major surgery (general anesthetic) within 3 months or minor surgery (local anesthetic) within 1 month prior to IP administration, or planned surgery during the study period, which is determined by the PI to be clinically relevant. Fever or symptomatic bacterial or viral infection. Participants who have received live vaccines or attenuated vaccines within 1 month before dosing. Participants with any active malignancy or history of malignancy within 5 years prior to enrolment. Use of any other prescription medications. History of anaphylaxis, allergic reactions to the excipients of IP, asthma. Positive blood screen for HIV1/2 antibody, Hepatitis B surface antigen, hepatitis C virus, or syphilis at screening. Participants with an inability to tolerate venous access. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the follow-up period. An employee of Pulmongene or Novotech (Australia) Pty Ltd. Participant is unwilling to abstain from alcohol beginning 48 hours prior to admission to the CRU and while resident at the CRU. Any other condition or finding that in the opinion of the PI or designee would put the participant or study conduct at risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Doses Cohort 1a<br>Subjects will receive either Dose level 1 of PMG1015 or Placebo | Drug: PMG1015 Dose 1<br>* Dose level 1 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1b<br>Subjects will receive either Dose level 2 of PMG1015 or Placebo | Drug: PMG1015 Dose 2<br>* Dose level 2 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1c<br>Subjects will receive either Dose level 3 of PMG1015 or Placebo | Drug: PMG1015 Dose 3<br>* Dose level 3 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1d<br>Subjects will receive either Dose level 4 of PMG1015 or Placebo | Drug: PMG1015 Dose 4<br>* Dose level 4 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1e<br>Subjects will receive either Dose level 5 of PMG1015 or Placebo | Drug: PMG1015 Dose 5<br>* Dose level 5 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1f<br>Subjects will receive either Dose level 6 of PMG1015 or Placebo | Drug: PMG1015 Dose 6<br>* Dose level 6 of PMG1015<br>* Other names: PMG1015;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Doses Cohort 1g<br>Subjects will receive either Dose level 7 of PMG1015 or Placebo | Drug: Placebo<br>* Placebo to match<br>Drug: PMG1015 Dose 7<br>* Dose level 7 of PMG1015<br>* Other names: PMG1015;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of Treatment-emergent adverse events (TEAEs) | An Adverse Event (AE) is any event, side-effect or any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are AEs that occur following the start of treatment. | Day 1-Day 85 | 
| The severity of Treatment-emergent adverse events (TEAEs) | TEAEs are AEs that occur following the start of treatment. | Day 1-Day 85 | 
| The incidence of Serious adverse events (SAEs) | A serious adverse event (SAE) is defined as an AE occurring during any study phase and at any dose of IP (active or placebo) that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect. | Day 1-Day 85 | 
| The severity of Serious adverse events (SAEs) | A serious adverse event (SAE) is defined as an AE occurring during any study phase and at any dose of IP (active or placebo) that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect. | Day 1- Day 85 | 
| Number of participants with abnormally clinical vital signs | Vital signs include pulse rate (PR), blood pressure (BP), respiratory rate (RR) and tympanic temperature (T) | Day 1- Day 85 | 
| Number of participants with abnormal clinically significant 12-lead electrocardiogram (ECG) parameters | All ECG tracings will be reviewed by the PI or designee and assessed for clinical significance. | Day 1-Day 85. | 
| Number of participants with abnormal clinically significant clinical laboratory results | Clinical laboratory test include hematology, coagulation, biochemistry, and urinalysis. | Day 1- Day 85 | 
| MTD of PMG1015 in healthy participants | Maximum tolerated dose of PMG1015 in healthy participants | Day 1- Day 85 | 
| Number of patients with abnormal clinically significant results from physical examination | Complete physical examination include, general appearance, head, eyes, ears, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes. | Day 1-Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum-concentration time curve (AUC) from time zero (from the start of infusion time) to the last time point with measurable analyte concentration (AUC0-t) | Area under the plasma concentration versus time curve (AUC) from time 0 to time of last quantifiable concentration | Day 1-Day 85. | 
| AUC from time zero to infinity (AUC0-∞) | Area under the plasma concentration versus time curve (AUC) from time 0 (from the start of infusion) extrapolated to infinity | Day 1-Day 85. | 
| To determine %AUCexp | The percentage of the AUC that has been extrapolated beyond the last observed data point | Day 1-Day 85. | 
| To determine Cmax | Maximum observed serum PMG1015 concentration | Day 1-Day 85. | 
| To determine Tmax, derived from serum concentration of each dose of PMG1015 | Time to maximum observed concentration | Day 1-Day 85. | 
| To determine t1/2 | Terminal elimination half life summarized by dosing regimen | Day 1-Day 85. | 
| Apparent total body clearance (CL) | CL is the measure of the rate at which a drug is metabolized or eliminated by normal biological processes | Day 1-Day 85. | 
| Apparent volume of distribution during the terminal phase (Vz) | Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Day 1-Day 85. | 
| Apparent terminal elimination rate constant (λz or kel) | λz is calculated using log-linear regression of the terminal portions of the plasma concentrations versus time curves. | Day 1-Day 85. | 
| Levels of ADA | Anti-drug antibody levels in blood | Day 1-Day 85 |