Inhalation of Leukotriene B4 (LTB4) in patients suffering from Bronchiectasis
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
LTB4 Sweden AB
30 participants
May 1, 2013
Interventional
Conditions
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).
Eligibility
Inclusion Criteria15
- Males or females 18 – 70 years of age (inclusive).
- Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
- Willing and able to comply with the Protocol, including availability for all scheduled study visits.
- 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.
- Body Mass Index (BMI) of 18 to 30 kg/m2 inclusive and weight up to a maximum of 90 kg inclusive.
- Negative urine screen for drugs of abuse and negative alcohol breath test at screening and prior to dosing.
- 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.
- Males or females 18 - 75 years of age (inclusive) with a clinical diagnosis of bronchiectasis.
- Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
- Willing and able to comply with the Protocol, including availability for all scheduled study visits.
- 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.
- Negative urine screen for drugs of abuse and negative alcohol breath test at screening and prior to dosing
- 25% less than FEV1less than 75% of predicted at screening
- “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).
- Oxygen saturation on room air higher than 92% at screening
Exclusion Criteria28
- Participation in another experimental/interventional protocol within 30 days prior to screening.
- 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.
- 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.
- Positive human immunodeficiency virus (HIV), Hepatitis B (HBV), Hepatitis C (HCV) and tuberculosis (TB) screening test results.
- Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the Investigational Product administration).
- 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).
- Donation of blood or plasma within one month of Investigational Product administration.
- Subjects who in the opinion of the Investigator are in poor medical or psychiatric risk for therapy with an investigational drug.
- 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.
- 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)
- Participation in another experimental/interventional protocol within the past 30 days prior to screening.
- 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.
- 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.
- Positive HIV, HBV, HCV and TB screening test results.
- Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the study drug administration).
- Donation of blood or plasma within one month of Investigational Product administration.
- Subjects who in the opinion of the Investigator are in poor medical or psychiatric risk for therapy with an investigational drug.
- Under treatment for cancer within the previous year.
- 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.
- Active cholecystitis, gall bladder symptoms or any hepatobiliary abnormalities.
- 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.
- Have Diabetes.
- Acute bacterial, fungal or viral infection.
- Have New York Heart Association Class III or IV heart failure.
- Ventricular arrhythmias requiring chronic drug treatment.
- Changes in antipseudomonal antibiotics or supporting medications within 30 days before screening.
- Use of oral corticosteroids in the past 30 days before screening.
- Concurrent use of montelukast
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Interventions
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.
Locations(1)
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ACTRN12614001199606