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Trial registered on ANZCTR


Registration number
ACTRN12616000496415
Ethics application status
Approved
Date submitted
12/04/2016
Date registered
15/04/2016
Date last updated
7/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I study of inhaled PB01 in healthy male volunteers to assess the anti-inflammatory effects of PB01 on lung inflammation.
Scientific title
A Phase I, double-blind, placebo-controlled, randomised, crossover study to assess the anti-inflammatory effects of orally inhaled PB01 following an inhaled lipopolysaccharide (LPS) challenge in healthy male volunteers.
Secondary ID [1] 288940 0
PAR_002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Airway inflammation and fibrosis 298297 0
Condition category
Condition code
Respiratory 298423 298423 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
PB01 solution for oral inhalation is administered using a nebuliser and consists of PB01 in 20mM sodium phosphate buffer and 500mM sodium chloride, pH7.

A randomised, double blind, placebo-controlled, two period crossover study in healthy male participants. Over the two Treatment Periods, all participants will be randomised to receive a single orally inhaled dose of either 30mg PB01 or Placebo (in either sequence) at each Treatment Period. Investigational Medicinal Product (IMP) will be administered by an Aerogen Aeroneb Go vibrating mesh nebuliser for a duration of 15 minutes. Participants will be trained on the use of the Aeroneb Go nebuliser. An inhaled lipopolysaccharide (LPS) challenge (30 microgram) will be administered 1 hour post commencement of the IMP dose administration. The total dose of 30 microgram LPS (from Escherichia coli 026:B6 (Sigma)) will be delivered by a total of 5 inhalations using a calibrated breath activated nebuliser.

Following Screening, eligible participants will be admitted to the study unit on Treatment Period 1 Day 1 and will be randomised in a 1:1 ratio to receive either PB01 followed by Placebo or Placebo followed by PB01 in a two period crossover design. IMP will be administered on Treatment Period 1 Day 1 followed by the LPS challenge. Administration of the IMP and LPS will be performed at the study unit under the supervision of the clinical site personnel and participants will be confined to the study unit overnight (i.e. 24 hours) and discharged from the study unit after completion of all study procedures on Treatment Period 1 Day 2.

There will be a minimum of 24 days and a maximum of 65 days wash-out between dosing on Treatment Period 1 Day 1 and Treatment Period 2 Day 1.

At least 72 hrs and no more than 10 days prior to Treatment Period 2 Day 1 participants will attend a Baseline Visit which will include sputum sampling to determine eligibility to continue to Treatment Period 2.

On Treatment Period 2 Day 1, participants will be admitted to the study unit for IMP administration followed by the LPS challenge under the supervision of the clinical site personnel and participants will be confined to the study unit overnight (i.e. 24 hours) and discharged from the study unit after completion of all study procedures on Treatment Period 2 Day 2.

An End of Study visit will be performed 7 days (+ 5 days) after the last dose of IMP (i.e on Day 8 (+5)).

The maximum planned study duration will be 99 days per participant.

The investigator is responsible for maintaining accurate IMP accountability records throughout the study. Drug accountability will be performed by the monitor during monitoring visits to reconcile the number of IMP vials dispensed with that used/returned.
Intervention code [1] 294415 0
Treatment: Drugs
Comparator / control treatment
Placebo solution for oral inhalation contains vehicle only, which consists of 20mM sodium phosphate buffer and 500mM sodium chloride, pH 7.

Participants will be randomised in a ratio of 1:1 to either PB01 followed by Placebo or Placebo followed by PB01 in a two period crossover design. Over the two treatment periods, all participants will receive a single orally inhaled dose of either 30mg PB01 or Placebo (in either sequence) at each Treatment Period.
Control group
Placebo

Outcomes
Primary outcome [1] 297909 0
Change in neutrophil content of an induced sputum sample collected 6 hours post LPS challenge compared with the baseline neutrophil content of an induced sputum sample collected at least 72 hours prior to dosing with IMP.
Timepoint [1] 297909 0
The change in neutrophil content will consist of the level of neutrophils in sputum at Screening (baseline for Treatment Period 1), 7 hours post IMP dose administration in Treatment Period 1, Baseline Visit (baseline for Treatment Period 2) and 7 hours post IMP dose administration in Treatment Period 2.
Secondary outcome [1] 322595 0
To evaluate the safety and tolerability of orally inhaled PB01 in healthy male participants.
Timepoint [1] 322595 0
A single dose of 30mg PB01, will be administered via oral inhalation, one hour prior to an orally inhaled lipopolysaccharide (LPS) challenge in a two period cross over study. Participants will make 5 visits to the study unit for Screening (baseline for Treatment Period 1), Day 1 and 2 of Treatment Period 1, Baseline Visit (baseline for Treatment Period 2), Day 1 and 2 of Treatment Period 2 and End of Study Evaluation. During each visit (with the exception of the Treatment Period 2 Baseline visit) vital signs, physical examination, clinical laboratory determinations (haematology, clinical chemistry, liver function tests, coagulation, urinalysis), 12 lead electrocardiogram (ECG) reading and spirometry will be performed.
At the Treatment Period 2 Baseline visit, clinical laboratory determinations will be performed.
All participants will be monitored for adverse events and concomitant medications for the duration of the study and all information received between consent and End of Study Evaluation will be recorded in the case report form.
Secondary outcome [2] 322659 0
Sputum concentrations of PB01 measured at 7 hours post commencement of PB01 dose administration.
Timepoint [2] 322659 0
The pharmacokinetic data will consist of the concentration of PB01 in sputum at Screening (baseline for Treatment Period 1), 7 hours post IMP dose administration in Treatment Period 1, Baseline Visit (baseline for Treatment Period 2) and 7 hours post IMP dose administration in Treatment Period 2.
Secondary outcome [3] 322660 0
Changes in blood inflammatory cell counts (neutrophils, monocytes, eosinophils).
Timepoint [3] 322660 0
In both Treatment Periods 1 and 2, blood samples will be collected prior to IMP administration and following LPS challenge. Samples will be collected on Day 1, pre-dose (of IMP) and at 6 and 24 (Day 2) hours after commencement of LPS challenge.
Secondary outcome [4] 322661 0
Changes in sputum inflammatory cell counts (total cells, macrophages, eosinophils).
Timepoint [4] 322661 0
In both Treatment Periods 1 and 2, induced-sputum samples will be collected for biomarker analysis during Screening period prior to Treatment Period 1 (baseline for Treatment Period 1) and Treatment Period 2 Baseline Visit prior to Treatment Period 2 (baseline for Treatment Period 2) and on Day 1, 6 hours after LPS challenge at each Treatment Period (i.e. 7 hours after commencement of dosing with IMP).
Secondary outcome [5] 322822 0
Change in serum levels of C-reactive protein.
Timepoint [5] 322822 0
In both Treatment Periods 1 and 2, blood samples will be collected prior to IMP administration and following LPS challenge. Samples will be collected on Day 1, pre-dose (of IMP) and at 6 and 24 (Day 2) hours after commencement of LPS challenge.

Eligibility
Key inclusion criteria
Able to speak, read and understand English sufficiently to understand the purposes and risks of the study and to provide written informed consent.

Healthy males aged 18 to 55 years inclusive at the time of consent.

Body Mass Index (BMI) of greater than or equal to 18 to less than or equal to 32.0 kg/m2.

Normal pulmonary function and performance on pulmonary function tests, defined as Forced expiratory volume measured in one second, expressed in litres (FEV1), and Forced vital capacity, expressed in litres (FVC) both greater than or equal to 80% of their predicted value for age, ethnicity, sex and height.

Participants must be willing and able to comply with scheduled visits, study restrictions, treatment plan, laboratory tests and other study procedures.

Participants must be willing not to donate sperm and to comply with the medically acceptable contraceptive requirements of the study from first dose of IMP to 30 days after the last IMP administration.

Ability to produce a sputum sample, sufficient to produce at least 50 mg sputum plugs with a viability factor of not less than 40%, total cell count range greater than or equal to 0.50 to less than or equal to 14 x 106 cells per gram, comprising less than or equal to 55% neutrophils, less than or equal to 20% squamous epithelial cells and less than or equal to 3% eosinophils.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants will not be eligible to participate in the study if they meet any of the following criteria:
Clinically significant respiratory disease including airway inflammation, haemoptysis or other respiratory disease (except for completely-resolved childhood asthma and symptom free for greater than 5 years).
Current smokers or ex-smokers who have given up smoking for less than 12 months and/or have a smoking pack history of greater than 5 pack years (1 pack year equals 20 cigarettes per day for 1 year or 5 cigarettes per day for 4 years).
Participants with any currently active infection, or who have a previous respiratory tract infection that resolved less than 4 weeks prior to screening or to randomisation, or any other previous infection that resolved less than 7 days prior to screening or to randomisation.
Any clinically significant abnormalities on physical examination, medical history, 12-lead electrocardiogram (ECG), or vital signs as judged by the investigator and in consultation with the sponsor if required.
Any clinically significant abnormalities on clinical laboratory tests (clinical chemistry, liver function, haematology, coagulation profile and urinalysis) at screening. Note: These screening laboratory samples must be obtained no more than 7 days prior to randomisation.
Clinically significant abnormality of renal function, defined as Cockcroft Gault creatinine clearance less than 70 ml/min. Note: These screening laboratory samples must be obtained no more than 7 days prior to randomisation.
Clinically significant abnormality of hepatic function defined as AST or ALT greater than 1.5 times the upper limit of normal. Note: These screening laboratory samples must be obtained no more than 7 days prior to randomisation.
History or evidence of, or positive test for Hepatitis B, Hepatitis C and HIV.
Positive urine drug screen, urine cotinine test or alcohol breath test at screening or prior to randomisation, or a history of drug or alcohol abuse and/or dependence within the past year prior to screening.
Administration of any investigational agent within 8 weeks or 5 half-lives (whichever is longer) prior to screening.
History of clinically significant allergic disease requiring medical treatment with medications as judged by the investigator and in consultation with the sponsor if required.
History of hypersensitivity to follistatin or drugs of the same pharmacological class.
Surgical or medical conditions which could significantly alter drug absorption, distribution, metabolism or excretion.
Major surgery within 3 months prior to screening or anticipated surgery in the study period.
Blood or plasma donation of more than 500 mL during the 3 months prior to screening or randomisation.
History of or current clinically-significant gastrointestinal, hepatic, renal, cardiovascular, respiratory, endocrine, oncological, immunological, neurological, ophthalmological, haematological or psychiatric disorder or any other condition, which in the opinion of the investigator and in consultation with the sponsor if required would jeopardize the safety of the participant or the validity of the study results.
History of significant drug hypersensitivity, milk protein allergy, hypersensitivity to inhalation challenges, or any history of anaphylactic reactions.
Participants who have undergone an lipopolysaccharide (LPS) challenge within the previous month prior to screening or a history of significant adverse reaction to LPS challenge.
Unable to use nebuliser.
An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 7785 0
United Kingdom
State/province [1] 7785 0
Manchester

Funding & Sponsors
Funding source category [1] 293296 0
Commercial sector/Industry
Name [1] 293296 0
Paranta Biosciences Ltd
Address [1] 293296 0
189-191 Balaclava Road, Caulfield North, Victoria 3161
Country [1] 293296 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Paranta Biosciences Ltd
Address
189-191 Balaclava Road, Caulfield North, Victoria 3161
Country
Australia
Secondary sponsor category [1] 292098 0
None
Name [1] 292098 0
Address [1] 292098 0
Country [1] 292098 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294771 0
North West - Greater Manchester Central Research Ethics Committee
Ethics committee address [1] 294771 0
3rd Floor
Barlow House
4 Minshull Street
Manchester
M1 3DZ
Ethics committee country [1] 294771 0
United Kingdom
Date submitted for ethics approval [1] 294771 0
04/12/2015
Approval date [1] 294771 0
19/02/2016
Ethics approval number [1] 294771 0

Summary
Brief summary
This study is designed to evaluate the anti-inflammatory effect of orally inhaled PB01 as a single dose (30mg) on lung inflammation produced by an orally inhaled LPS challenge in healthy male participants aged 18 and 55 years.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64978 0
Prof Dave Singh
Address 64978 0
Medicines Evaluation Unit Ltd
The Langley Building
Wythenshawe Hospital
Southmoor Road
Manchester
M23 9QZ
Country 64978 0
United Kingdom
Phone 64978 0
+44 161 946 4050
Fax 64978 0
+44 161 946 1459
Email 64978 0
dsingh@meu.org.uk
Contact person for public queries
Name 64979 0
Mr Ross Barrow
Address 64979 0
Paranta Biosciences Ltd, 189-191 Balaclava Road, Caulfield North, Victoria 3161
Country 64979 0
Australia
Phone 64979 0
+61 3 9526 0021
Fax 64979 0
Email 64979 0
ross.barrow@parantabio.com
Contact person for scientific queries
Name 64980 0
Ms Nuket Desem
Address 64980 0
Paranta Biosciences Ltd, 189-191 Balaclava Road, Caulfield North, Victoria 3161
Country 64980 0
Australia
Phone 64980 0
+61 3 9526 0021
Fax 64980 0
Email 64980 0
nuket.desem@parantabio.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary