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Trial registered on ANZCTR


Registration number
ACTRN12614001199606
Ethics application status
Approved
Date submitted
3/11/2014
Date registered
14/11/2014
Date last updated
14/11/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Inhalation of Leukotriene B4 (LTB4) in patients suffering from Bronchiectasis
Scientific title
A Phase I study to evaluate the safety, tolerability and pharmacodynamics of inhaled Leukotriene B4 (LTB4) in healthy subjects and in chronically infected bronchiectasis patients
Secondary ID [1] 285589 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Suppurative Lung Disease 293427 0
Bronchiectasis 293428 0
Condition category
Condition code
Respiratory 293702 293702 0 0
Other respiratory disorders / diseases
Infection 293745 293745 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A: This part of the study is a single dose escalating design to examine the safety and tolerability of respirable doses of approximately 10 microgram, 50 microgram and 250 microgram of inhaled LTB4 and select a safe and biologically active dose for Part B.
Three treatment groups (six subjects per group) will be administered a single dose of LTB4 (IP in liquid form, inhaled via nebulizer) in a dose escalation design.
Part B: The second part of the study is a multiple dose design to examine the safety and tolerability of the dose selected in Part A in bronchiectasis patients chronically infected with Pseudomonas aeruginosa (PA). In addition, this part of the study will evaluate the effect of inhaled LTB4 on neutrophil recruitment, C-reactive protein (CRP) levels and bacterial load in chronically infected patients.
The dose selected will be administered to 12 chronically infected bronchiectasis patients, twice-daily, for 15 days (Day 15 morning dose only).
Subjects in Part A of the study were monitored during their single IP inhalation, Patients in Part B were trained on the correct use of the PARI nebulizer and then continued to inhale the IP at home. A diary as well as the number of returned IP vials was used to confirm correct inhalation at home.
Intervention code [1] 290539 0
Treatment: Drugs
Comparator / control treatment
not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293509 0
1)To assess the safety and tolerability of inhaled LTB4 in healthy subjects administered as a single respirable dose which has an estimated lung exposure of 10 microgram, 50 microgram and 250 microgram.
Safety and tolerability was assessed by direct questioning of the subjects to monitor any side effects and adverse events , by conducting spirometries to monitor FEV1 and by evaluation of blood samples obtained at pre-defined timepoints throughout the subjects study participation.
Timepoint [1] 293509 0
1)Neutrophil counts in blood will be determined from samples collected on Day 1 and Day 15 pre-dose and then at 1, 2, 4 and 8 hours post-dose. DSubjects will be monitored for side effects and adverse events up to 48 hours (Day 17) post final dose.
Primary outcome [2] 293510 0
To assess the safety and tolerability of inhaled LTB4 in patients with bronchiectasis when administered as multiple doses at a dose level determined by Part A
Timepoint [2] 293510 0
Neutrophil counts in blood will be determined from samples collected on Day 1 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose) and Day 15 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose).
CRP levels in blood will be determined, using the high sensitivity CRP assay, from samples collected on Day 1 (prior to the morning dose) and 2 hours post–dose on Day 15 (or at Early Termination for subjects who withdraw from Day 7 to Day 15)
Bacterial load in sputum samples will be determined from samples collected on Day 1 (prior to the morning dose) and 5 hours post-dose on Day 15 (or at Early Termination for subjects who withdraw from Day 7 to Day 15).
Secondary outcome [1] 311202 0
To evaluate if systemic neutrophilia occurs after inhalation of LTB4
Timepoint [1] 311202 0
Neutrophil counts in blood will be determined from samples collected on Day 1 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose) and Day 15 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose)
Secondary outcome [2] 311203 0
To evaluate if inhaled LTB4 causes neutrophil recruitment in patients with bronchiectasis
Timepoint [2] 311203 0
Neutrophil counts in blood will be determined from samples collected on Day 1 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose) and Day 15 (prior to the morning dose and then at 1, 2, 4 and 8 hours post-dose)
Secondary outcome [3] 311204 0
To evaluate if inhaled LTB4 reduces bacterial load in patients with bronchiectasis
Timepoint [3] 311204 0
Bacterial load in sputum samples will be determined from samples collected on Day 1 (prior to the morning dose) and 5 hours post-dose on Day 15 (or at Early Termination for subjects who withdraw from Day 7 to Day 15).
Secondary outcome [4] 311205 0
To evaluate if LTB4 reduces systemic low grade inflammation (as measured by changes in CRP levels in serum) in patients with bronchiectasis
Timepoint [4] 311205 0
CRP levels in blood will be determined, using the high sensitivity CRP assay, from samples collected on Day 1 (prior to the morning dose) and 2 hours post–dose on Day 15 (or at Early Termination for subjects who withdraw from Day 7 to Day 15)

Eligibility
Key inclusion criteria
PART A – INCLUSION CRITERIA
1. Males or females 18 – 70 years of age (inclusive).
2.Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
3.Willing and able to comply with the Protocol, including availability for all scheduled study visits.
4.Use of effective contraception (A highly effective method of birth control is defined as those which result in a low failure rate(i.e. less than 1 percent per year) when used consistently and correctly), if procreative potential exists.
5.Body Mass Index (BMI) of 18 to 30 kg/m2 inclusive and weight up to a maximum of 90 kg inclusive.
6.Negative urine screen for drugs of abuse and negative alcohol breath test at screening and prior to dosing.
7.In good general health with no clinically significant abnormalities at screening determined by medical history, vital signs, physical examination, serum chemistry, hematology, urinalysis, and 12-lead ECG.

PART B – INCLUSION CRITERIA
2.Males or females 18 - 75 years of age (inclusive) with a clinical diagnosis of bronchiectasis.
3.Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
4.Willing and able to comply with the Protocol, including availability for all scheduled study visits.
5.Use of effective contraception (A highly effective method of birth control is defined as those which result in a low failure rate(i.e. less than 1 percent per year) when used consistently and correctly), if procreative potential exists.
6.Negative urine screen for drugs of abuse and negative alcohol breath test at screening and prior to dosing
7.25% less than FEV1less than 75% of predicted at screening
8.“Stable” PA present in sputum at screening. Culture proven colonization by PA for at least 3 months prior to screening (i.e. documentation of PA on two or more cultures more than one month apart, including PA at the time of entry into the study).
9.Oxygen saturation on room air higher than 92% at screening
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
PART A – EXCLUSION CRITERIA
1.Participation in another experimental/interventional protocol within 30 days prior to screening.
2.Females who are nursing, pregnant or intend to become pregnant or females of childbearing potential who have had a positive pregnancy test during screening evaluation.
3.A history of drug or alcohol abuse within one year of study entry. Alcohol abuse is defined as consumption of more than 3 standard drinks per day and not able to abstain from alcohol totally within 24 hours of dose administration until the end of the treatment period.
4.Positive human immunodeficiency virus (HIV), Hepatitis B (HBV), Hepatitis C (HCV) and tuberculosis (TB) screening test results.
5.Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the Investigational Product administration).
6.Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
7.Donation of blood or plasma within one month of Investigational Product administration.
8.Subjects who in the opinion of the Investigator are in poor medical or psychiatric risk for therapy with an investigational drug.
9.History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past five years, regardless of whether there is evidence of local recurrence or metastases.
10.Treatment with any prescription medication and/or non-prescription products including vitamins or mineral supplements within 14 days before Investigational Product administration (with the exception of birth control medications)
PART B – EXCLUSION CRITERIA
1.Participation in another experimental/interventional protocol within the past 30 days prior to screening.
2.Females who are nursing, pregnant or intend to become pregnant or females of childbearing potential who have had a positive pregnancy test during screening evaluation.
3.A history of alcohol or drug abuse within one year of study entry. Alcohol abuse is defined as consumption of more than 3 standard drinks per day and not able to abstain from alcohol totally within 24 hours of dose administration until the end of the treatment period.
4.Positive HIV, HBV, HCV and TB screening test results.
5.Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the study drug administration).
6.Donation of blood or plasma within one month of Investigational Product administration.
7.Subjects who in the opinion of the Investigator are in poor medical or psychiatric risk for therapy with an investigational drug.
8.Under treatment for cancer within the previous year.
9.Presence of any severe liver disease with cirrhosis, active hepatitis, active chronic hepatitis, alanine transaminase (ALT) or aspartate transaminase (AST) higher than 3 x Upper Limit of Normal (ULN), biliary obstruction with hyperbilirubinemia higher than 2 x ULN.
10.Active cholecystitis, gall bladder symptoms or any hepatobiliary abnormalities.
11.The presence of severe renal impairment, creatinine clearance (CrCl) less than 30 ml/min or creatinine higher than 3 x ULN, or subjects undergoing dialysis.
12.Have Diabetes.
13.Acute bacterial, fungal or viral infection.
14.Have New York Heart Association Class III or IV heart failure.
15.Ventricular arrhythmias requiring chronic drug treatment.
16.Changes in antipseudomonal antibiotics or supporting medications within 30 days before screening.
17.Use of oral corticosteroids in the past 30 days before screening.
18.Concurrent use of montelukast

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Part A - 3 cohorts (3 different doses), 6 patients each, all healthy volunteers
Part B - treatment of patients in single group
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Safety: Safety parameters will be summarized, using descriptive statistics where appropriate, and presented by time point and treatment group/dose level. All safety parameters will be presented for individual subjects in data listings.
Pharmacodynamics: All pharmacodynamic parameters will be summarized by time point and treatment group/dose level. Pre- and post- dose values will be compared using an applicable statistical method (e.g. Wilcoxons signed rank test). All pharmacodynamic parameters will be presented in individual subjects in data listings

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2013
Actual
1/05/2013
Date of last participant enrolment
Anticipated
31/07/2014
Actual
24/06/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 8861 0
6009 - Broadway Nedlands

Funding & Sponsors
Funding source category [1] 290182 0
Commercial sector/Industry
Name [1] 290182 0
LTB4 Sweden AB
Country [1] 290182 0
Sweden
Primary sponsor type
Commercial sector/Industry
Name
LTB4 Sweden AB
Address
LTB4 Sweden AB
Kornhamstorg 53
SE-111 27 Stockholm
Sweden
Country
Sweden
Secondary sponsor category [1] 288894 0
Commercial sector/Industry
Name [1] 288894 0
INCResearch Australia
Address [1] 288894 0
159 Port Road
Hindmarsh SA 5007
Country [1] 288894 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291892 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 291892 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 291892 0
Australia
Date submitted for ethics approval [1] 291892 0
28/11/2011
Approval date [1] 291892 0
08/04/2013
Ethics approval number [1] 291892 0
2012-11-1205

Summary
Brief summary
The purpose of this study is to test the safety, tolerability and Pharmacodynamics (what the study drug does to thebody) of LTB4. This study is conducted in healthy men and women to find out what is a safe, tolerable dose of the study drug and to determine its effect on blood cells. The results of this part of the study will lead to a second part in which we will test the safe, tolerable dose determined in this study in patients with the lung disease bronchiectasis (a condition in which damage to the airways causes them to widen and become flabby and scarred) who are chronically infected with Pseudomonas aeruginosa (a bacterial infection).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52406 0
Dr Janakan Krishnarajah
Address 52406 0
Linear Clinical Research Ltd
First Floor, B Block, QEII Medical Centre
Hospital Ave
Nedlands WA 6009
Country 52406 0
Australia
Phone 52406 0
+61 8 6382 5100
Fax 52406 0
Email 52406 0
[email protected]
Contact person for public queries
Name 52407 0
Janakan Krishnarajah
Address 52407 0
Linear Clinical Research Ltd
First Floor, B Block, QEII Medical Centre
Hospital Ave
Nedlands WA 6009
Country 52407 0
Australia
Phone 52407 0
+61 8 6382 5100
Fax 52407 0
Email 52407 0
[email protected]
Contact person for scientific queries
Name 52408 0
Carl-Johan Darlsgaard
Address 52408 0
LTB4 Sweden AB
Kornhamstorg 53
SE-111 27 Stockholm
Sweden
Country 52408 0
Sweden
Phone 52408 0
+46 8 566 301 73
Fax 52408 0
Email 52408 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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