Healthy Volunteers
Conditions
Keywords
Phase 1, First in Human, Healthy Volunteers, Lipopolysaccharide Challenge
Brief summary
The purpose of this study is to examine the safety, tolerability, immunogenicity and the way the body absorbs, distributes, breaks down and excretes various increasing single and multiple subcutaneous doses of PA401 in healthy subjects. This study will also look at the effect of PA401 on inflammation in the lungs following an inhaled lipopolysaccharide (LPS) challenge (LPS is a bacterial cell wall fragment) and sputum induction (a procedure performed to help to cough up sputum (phlegm)) after a single subcutaneous dose of two dose levels.
Interventions
BIOLOGICALPA401
Part A of Study: Subcutaneous, 0.1mg to 50mg, single ascending doses Part B of Study: Subcutaneous, up to 17.1mg, single dose
OTHERPlacebo
Subcutaneous
Sponsors
ProtAffin Biotechnologie AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adult males aged 18 to 65 years
Exclusion criteria
* Subjects with a clinically relevant medical history
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Adverse Events | up to 14 days post dose | — |
| Immunogenicity | Up to 28 days post dose | Anti-drug antibody data |
| Assessment of the Effect of PA401 on Induced Sputum Total Neutrophils | 5.5 hours post dose | Induced sputum was collected 6 hours after lipopolysaccharide challenge (5.5 hours following dosing) and assessed for neutrophils |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity | Up to 12 time-points up to 48 hours post dose | — |
| Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | Up to 12 time-points up to 48 hours post dose | — |
| Assessment of the Effect of PA401 on Induced Sputum Percentage Neutrophils | 5.5 hours post dose | Induced sputum was collected 6 hours after lipopolysaccharide challenge (5.5 hours following dosing) and assessed for neutrophils |
| Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax) | Up to 12 time-points up to 48 hours post dose | — |
| Pharmacokinetic Parameters: Terminal Half-life (t1/2) | Up to 12 time-points up to 48 hours post dose | — |
Countries
United Kingdom
Participant flow
Recruitment details
The study was conducted from June 2012 (first subject dosed) to April 2013 (last subject visit). The study was conducted in 2 parts; Part A was a single ascending dose study, Part B was a randomised placebo-controlled study to investigate the effect of a single dose of PA401 on sputum neutrophils following inhaled lipopolysaccharide challenge
Pre-assignment details
In Part B, subjects were included at baseline if they had a baseline neutrophil level in induced sputum of ≤70%
Participants by arm
| Arm | Count |
|---|---|
| Part A | 27 |
| Part B | 22 |
| Total | 49 |
Baseline characteristics
| Characteristic | Part A | Part B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 22 Participants | 49 Participants |
| Region of Enrollment United Kingdom | 27 participants | 22 participants | 49 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 27 Participants | 22 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 3 / 4 | 4 / 4 | 2 / 4 | 2 / 2 | 3 / 9 | 7 / 10 | 5 / 5 | 4 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 2 | 0 / 9 | 0 / 10 | 0 / 5 | 0 / 7 |
Outcome results
Primary
Assessment of the Effect of PA401 on Induced Sputum Total Neutrophils
Induced sputum was collected 6 hours after lipopolysaccharide challenge (5.5 hours following dosing) and assessed for neutrophils
Time frame: 5.5 hours post dose
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A PA401 0.1 mg | Assessment of the Effect of PA401 on Induced Sputum Total Neutrophils | 11.6882 x10e6 cells/g |
| Part A PA401 0.3 mg | Assessment of the Effect of PA401 on Induced Sputum Total Neutrophils | 7.7274 x10e6 cells/g |
| Part A PA401 1.0 mg | Assessment of the Effect of PA401 on Induced Sputum Total Neutrophils | 12.7241 x10e6 cells/g |
Primary
Immunogenicity
Anti-drug antibody data
Time frame: Up to 28 days post dose
Population: Safety analyses were performed on all subjects who received a dose of PA401 or placebo and who had any post-dose assessments
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A PA401 0.1 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 1 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 1 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 1 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part A PA401 0.1 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 0.3 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 1.0 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A PA401 3.0 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A PA401 10 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A Placebo | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A Placebo | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A Placebo | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part A Placebo | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A Placebo | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part A Placebo | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A Placebo | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part A Placebo | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part A Placebo | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 1.0 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 15 ADA positive | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part B PA401 3.0 mg | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B Placebo | Immunogenicity | Day 29 ADA positive | 0 participants |
| Part B Placebo | Immunogenicity | Day 1 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B Placebo | Immunogenicity | Day 1 anti-drug antibody (ADA) positive | 0 participants |
| Part B Placebo | Immunogenicity | Day 29 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B Placebo | Immunogenicity | Day 15 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B Placebo | Immunogenicity | Day 1 ADA positive and cross-reactive with IL-8 | 0 participants |
| Part B Placebo | Immunogenicity | Day 15 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B Placebo | Immunogenicity | Day 29 Pre-existing IL-8 autoantibodies | 0 participants |
| Part B Placebo | Immunogenicity | Day 15 ADA positive | 0 participants |
Primary
Treatment Emergent Adverse Events
Time frame: up to 14 days post dose
Population: Safety analyses were performed on all subjects who receive a dose of PA401 or placebo and who had any post-dose measurements
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A PA401 0.1 mg | Treatment Emergent Adverse Events | 3 Participants |
| Part A PA401 0.3 mg | Treatment Emergent Adverse Events | 3 Participants |
| Part A PA401 1.0 mg | Treatment Emergent Adverse Events | 4 Participants |
| Part A PA401 3.0 mg | Treatment Emergent Adverse Events | 2 Participants |
| Part A PA401 10 mg | Treatment Emergent Adverse Events | 2 Participants |
| Part A Placebo | Treatment Emergent Adverse Events | 3 Participants |
| Part B PA401 1.0 mg | Treatment Emergent Adverse Events | 7 Participants |
| Part B PA401 3.0 mg | Treatment Emergent Adverse Events | 5 Participants |
| Part B Placebo | Treatment Emergent Adverse Events | 4 Participants |
Secondary
Assessment of the Effect of PA401 on Induced Sputum Percentage Neutrophils
Induced sputum was collected 6 hours after lipopolysaccharide challenge (5.5 hours following dosing) and assessed for neutrophils
Time frame: 5.5 hours post dose
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A PA401 0.1 mg | Assessment of the Effect of PA401 on Induced Sputum Percentage Neutrophils | 32.9429 percentage of total cells |
| Part A PA401 0.3 mg | Assessment of the Effect of PA401 on Induced Sputum Percentage Neutrophils | 36.7007 percentage of total cells |
| Part A PA401 1.0 mg | Assessment of the Effect of PA401 on Induced Sputum Percentage Neutrophils | 34.3856 percentage of total cells |
Secondary
Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity
Time frame: Up to 12 time-points up to 48 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A PA401 0.1 mg | Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity | 23.9 ng.h/mL | Standard Deviation 9.72 |
| Part A PA401 0.3 mg | Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity | 93.2 ng.h/mL | Standard Deviation 12.1 |
| Part A PA401 1.0 mg | Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity | 12.2 ng.h/mL | Standard Deviation 3.82 |
| Part A PA401 3.0 mg | Pharmacokinetic Parameters: Area Under the Plasma Concentration-time Curve From Zero to Infinity | 29.3 ng.h/mL | Standard Deviation 5.66 |
Secondary
Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax)
Time frame: Up to 12 time-points up to 48 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A PA401 0.1 mg | Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | 1.88 ng/mL | Standard Deviation 0.587 |
| Part A PA401 0.3 mg | Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | 7.51 ng/mL | Standard Deviation 2.64 |
| Part A PA401 1.0 mg | Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | 1.29 ng/mL | Standard Deviation 0.411 |
| Part A PA401 3.0 mg | Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | 2.85 ng/mL | Standard Deviation 0.805 |
Secondary
Pharmacokinetic Parameters: Terminal Half-life (t1/2)
Time frame: Up to 12 time-points up to 48 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A PA401 0.1 mg | Pharmacokinetic Parameters: Terminal Half-life (t1/2) | 9.26 hours | Standard Deviation 2.57 |
| Part A PA401 0.3 mg | Pharmacokinetic Parameters: Terminal Half-life (t1/2) | 8.44 hours | Standard Deviation 0.846 |
| Part A PA401 1.0 mg | Pharmacokinetic Parameters: Terminal Half-life (t1/2) | 6.17 hours | Standard Deviation 1.79 |
| Part A PA401 3.0 mg | Pharmacokinetic Parameters: Terminal Half-life (t1/2) | 10.1 hours | Standard Deviation 4.47 |
Secondary
Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax)
Time frame: Up to 12 time-points up to 48 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A PA401 0.1 mg | Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax) | 2.75 hours | Standard Deviation 0.87 |
| Part A PA401 0.3 mg | Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax) | 2.02 hours | Standard Deviation 0.4 |
| Part A PA401 1.0 mg | Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax) | 2.09 hours | Standard Deviation 0.53 |
| Part A PA401 3.0 mg | Pharmacokinetic Parameters: Time of Occurrence of the Maximum Observed Plasma Concentration (Tmax) | 2.20 hours | Standard Deviation 1.1 |