Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001442493
Ethics application status
Approved
Date submitted
23/09/2016
Date registered
14/10/2016
Date last updated
20/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to determine the safety and maximum tolerable dose of LTI-01 in patients who has pneumonia-like symptoms with a build up of fluid in their lungs
Scientific title
Phase 1a/1b Trial of LTI-01 (Single Chain Urokinase, scuPA) Intrapleural Fibrinolytic Therapy (IPFT) in Patients with Complicated Parapneumonic Effusions or Empyema
Secondary ID [1] 289944 0
Nil known
Universal Trial Number (UTN)
U1111-1186-5603
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
complicated parapneumonic effusions 299928 0
empyema 299929 0
Condition category
Condition code
Respiratory 299826 299826 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective, open-label, dose escalation safety trial. Patients who present with symptoms consistent with pneumonia along with CPE/empyema will be initially treated by standard of care, including placement of chest tube and initiation of antibiotics, and will be evaluated for participation in this study. Eligible subjects will be appropriately consented to the study and will begin treatment with intrapleural LTI-01 within 24 hr of enrolment.

Subjects will be treated according to their assigned dose level daily for up to 3 days. First treatment will begin within 24 hours from initial consent. The study treatment will be administered as a bolus dose through the chest tube into the pleural space and allowed to stay in the space for 3 hours. This treatment will occur once per day for up to 3 consecutive days.

Study treatment will occur in a dose escalation format, with up to 5 dose level cohorts. The first 3 subjects enrolled will be given an initial dose of 50,000 IU LTI-01 daily for up to three days. Assuming there are no safety issues in these 3 subjects after review of safety data by the Safety Review Committee (SRC), comprising of the Medical Monitor, Study Investigators and the Sponsor, the dose level will be escalated (doubled) in each consecutive group of three subjects with dosing for up to three days at all dose levels. If complete resolution of the pleural process occurs after one or two doses of LTI-01 in any subject, no further LTI-01 will be administered. This escalation (three per dose level) will continue to a maximum dose level of 800,000 IU unless a dose limiting toxicity (DLT) is observed,

Clinical activity will be defined as pleural density improvement of 25%, (determined by the reduction of the percentage of pleural density versus the area of the ipsilateral hemithorax) or >50% reduction of pleural density at Day 4 versus baseline randomization radiographic analysis, as confirmed by chest X-ray and via estimation of the volume of the pleural collection by chest CT scanning. Improvement by chest ultrasonographic scoring will also be used to assess efficacy.
Intervention code [1] 295626 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299303 0
To evaluate the safety and tolerability of escalating doses of intrapleural LTI01.
This will be assessed as follows;
vital signs at 3, 5, 12, 18, 21 hours post dose, chest ultrasonography at 23 hours post each of the 3 doses, haematology, blood chemistry and plural fluid will be assessed at 3, and 23 hours post dose, assessment of PF drainage at 3 and 23 hours post dose and assessment of AE's and concomitant meds daily.
Timepoint [1] 299303 0
Maximum tolerated dose (MTD) will be assessed on Day 1 (dosing) to day 28 or hospital discharge. Which ever comes first.
Patient safety will be monitored continuously as above and MTD will be reached when two or more patients at a given cohort experience a dose limiting toxicity defined as either an acute bleeding event with more than 2mg per dL drop on blood Hgb with or without haemodynamic instability, or development of melena or overt bleeding from the chest tube including development of haemothorax with a pleural fluid Hct more than 50% that of blood Hct or a grade 3 non-haematological adverse event.
Secondary outcome [1] 326787 0
To evaluate pharmacodynamic effects of escalating doses of intrapleural LTI-01 assessed using surrogate measures on pleural fluid samples by measuring scuPA antigen and activities, D-Dimer and fibrinogen levels.

Timepoint [1] 326787 0
These will be measured at 3 and 23 hours post each of the 3 doses of LTI-01
Secondary outcome [2] 326788 0
Pleural space drainage will be measured to assess efficacy this will be assessed by review of chest ultrasounds
Timepoint [2] 326788 0
This will be assessed at 23 hours post each of the 3 doses
Secondary outcome [3] 327996 0
To evaluate pharmacokinetic effects of escalating doses of intrapleural LTI-01 using surrogate measures on plasma samples by measuring scuPA antigen and activities, D-Dimer and fibrinogen levels.
Timepoint [3] 327996 0
This will be measured at 3 and 23 hours post each of the 3 doses
Secondary outcome [4] 327997 0
Efficacy assessment will include referral for surgery this will be assessed by review of the medical records
Timepoint [4] 327997 0
any time during this hospitalisation and at 3 and 12 months post hospital discharge for this episode of CPE/empyema
Secondary outcome [5] 327998 0
efficacy assessment will include assessment of mortality this will be assessed by review of medical records at 3 and 12 months post last dose
Timepoint [5] 327998 0
this will be assessed throughout this hospitalisation and at 3 and 12 months post hospital discharge for this episode of CPE/empyema
Secondary outcome [6] 327999 0
efficacy assessment will include assessment of length of this hospitalisation this will be assed via review of medical records post discharge
Timepoint [6] 327999 0
this will be assessed throughout this hospitalisation for this episode of CPE/empyema

Eligibility
Key inclusion criteria
1. Male or female greater than or equal to 21 years of age
2. A clinical presentation compatible with pneumonia and a parapneumonic effusion
3. Has pleural fluid requiring drainage that is loculated as determined by lateral decubitius or chest CT or by chest ultrasonography, and which is either:
* purulent or
* gram stain positive or
* culture positive or
* acidic with a pH <=7.2 or
* greater than half the volume of the thoracic cavity
.
4. Written informed consent
5. Failure to drain the pleural space within 3 h after tube thoracostomy
6. Hemodynamically stable and not requiring use of intravenous pressor therapy
7. Absence of severe metabolic derangements such as a serum potassium of <6 mEq/L or diabetic ketoacidosis
Minimum age
21 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous treatment with intra-pleural fibrinolytics for this CPE/empyema
2. Has a known sensitivity to urokinase plasminogen activator
3. Has had a coincidental stroke, a major hemorrhage or major trauma
4. Head trauma or previous stroke
5. History of previous intracranial hemorrhage or symptoms suggestive of possible current intracranial hemorrhage.
6. Vascular puncture at a non-compressible site in the previous 7 days (e.g. subclavian artery, subclavian vein or internal jugular puncture)
7. Elevated blood pressure (systolic >185 mm Hg) or diastolic mm Hg (>110)
8. Active bleeding on examination
9. Acute bleeding diathesis: platelets <100,000 mm3 or therapeutic doses of heparin received within 48h or history of current warfarin therapy; use of other oral anticoagulants including warfarin or Xa or thrombin inhibitors.
10. Known platelet functional disorder or use of antiplatelet therapy including clopidigrel or other antiplatelet agents other than aspirin at any dose.
11. Estimated creatinine clearance of <30 ml/minute or estimated GFR (glomerular filtration rate)<30 ml/minute.
12. PT/PTT> 1.7x control or PT>15 sec.
13. Has had major surgery in the previous 10 days
14. Has had a previous pneumonectomy on the side of infection
15. Patients who are pregnant or lactating (females of childbearing potential must have a negative pregnancy test before randomization)
16. Expected survival less than three months from a different pathology to this empyema (e.g. metastatic lung carcinoma)
17. Known prior ipsilateral fibrothorax
18. Plasma fibrinogen (FGN) level < 150 mg/L
19. Known allergy to rodents

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Expiry of investigational product
Date of first participant enrolment
Anticipated
10/03/2017
Actual
7/03/2017
Date of last participant enrolment
Anticipated
27/03/2018
Actual
22/03/2018
Date of last data collection
Anticipated
26/03/2019
Actual
Sample size
Target
21
Accrual to date
Final
14
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 7702 0
Footscray Hospital - Footscray
Recruitment postcode(s) [1] 15625 0
3011 - Footscray
Recruitment outside Australia
Country [1] 8102 0
New Zealand
State/province [1] 8102 0

Funding & Sponsors
Funding source category [1] 294319 0
Commercial sector/Industry
Name [1] 294319 0
Lung Therapeutics, Inc
Country [1] 294319 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
88 Jephson Street
Toowong, QLD 4066
Country
Australia
Secondary sponsor category [1] 293159 0
Commercial sector/Industry
Name [1] 293159 0
Lung Therapeutics, Inc
Address [1] 293159 0
7500 Rialto Blvd, Suite 250
Austin, TX 78735
Country [1] 293159 0
United States of America
Other collaborator category [1] 279233 0
Individual
Name [1] 279233 0
Dr John Kolbe
Address [1] 279233 0
Reception J, 1st Floor
Greenlane Clinical Centre

214 Greenlane West Road,
Auckland 1051
Country [1] 279233 0
New Zealand
Other collaborator category [2] 279234 0
Individual
Name [2] 279234 0
Dr Graham Simpson
Address [2] 279234 0
Cairns & Hinterland Hospital and Health Service
Ground Floor, B Block,
Cairns Hospital
PO BOX 902 Cairns
QLD 4870
Country [2] 279234 0
Australia
Other collaborator category [3] 279235 0
Individual
Name [3] 279235 0
Dr Lutz Beckert
Address [3] 279235 0
Research & Enterprise Office
Department of Medicine
University of Otago
87 St David Street, PO BOX 56
Dunedin 9054
Country [3] 279235 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295745 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 295745 0
Westmead Hospital Campus
Institute road, Westmead
NSW 2145
Ethics committee country [1] 295745 0
Australia
Date submitted for ethics approval [1] 295745 0
15/06/2016
Approval date [1] 295745 0
23/09/2016
Ethics approval number [1] 295745 0
Ethics committee name [2] 297263 0
Northern B Health and Disability Ethics Committee
Ethics committee address [2] 297263 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [2] 297263 0
New Zealand
Date submitted for ethics approval [2] 297263 0
20/07/2016
Approval date [2] 297263 0
05/09/2016
Ethics approval number [2] 297263 0
Ethics committee name [3] 300733 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [3] 300733 0
2nd Floor A Block
Hospital Avenue
NEDLANDS WA 6009
Ethics committee country [3] 300733 0
Australia
Date submitted for ethics approval [3] 300733 0
26/06/2017
Approval date [3] 300733 0
12/09/2017
Ethics approval number [3] 300733 0
RGS0000000460

Summary
Brief summary
LTI-01, the study drug being researched in this project, is an experimental treatment being developed by Lung Therapeutics, Inc. This means that it is not an approved treatment in Australia, and is not yet approved anywhere else in the world.


LTI-01 is a treatment that is intended to either prevent or remove the build-up in the pleural space around the lungs (called ‘loculation’) and so promoting drainage of the fluid with the goal of avoiding the need for surgery.

Study participants will be given 1 dose of LTI-01 a day for up to 3 days in a row. LTI-01 will be administered directly into the pleural or lung cavity through a chest tube. During and after treatment, participants will be assessed for the following:
* how safe and well tolerated the LTI-01 is at the dose they are given
* how much of the LTI-01 drug is in your blood at specific times to measure the way the body is processes it
* the effect of the LTI-01 drug has on your body
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68286 0
Prof John Wheatley
Address 68286 0
Ludwig Centre for Respiratory Research
Westmead Hospital
Corner of Darcy and Hawkesbury Roads
Westmead NSW 2145
Country 68286 0
Australia
Phone 68286 0
+61 02 98456797
Fax 68286 0
+61 02 98457286
Email 68286 0
[email protected]
Contact person for public queries
Name 68287 0
Mr Brian Windsor
Address 68287 0
Lung Therapeutics, Inc.
1515 S. Capital of Texas Highway,
Suite 402
Austin, Texas 78746
Country 68287 0
United States of America
Phone 68287 0
+1 737 802 1973
Fax 68287 0
Email 68287 0
[email protected]
Contact person for scientific queries
Name 68288 0
Dr Steven Idell
Address 68288 0
The University of Texas
Health Science Center at Tyler
11937 US HWY 271
Tyler, TX, 75708
Country 68288 0
United States of America
Phone 68288 0
+1 903-877-7556
Fax 68288 0
+1 903-877-7613
Email 68288 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe contribution of the Urokinase plasminogen activator and the urokinase receptor to pleural and parenchymal lung injury and repair: A narrative review.2021https://dx.doi.org/10.3390/ijms22031437
EmbasePhase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyema.2019https://dx.doi.org/10.1172/jci.insight.127470
Dimensions AIUpdate on Novel Targeted Therapy for Pleural Organization and Fibrosis2022https://doi.org/10.3390/ijms23031587
Dimensions AIBacteriology and clinical outcomes of patients with culture-positive pleural infection in Western Australia: A 6-year analysis2018https://doi.org/10.1111/resp.13395
N.B. These documents automatically identified may not have been verified by the study sponsor.