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Trial registered on ANZCTR


Registration number
ACTRN12620000531910
Ethics application status
Approved
Date submitted
23/03/2020
Date registered
30/04/2020
Date last updated
30/04/2020
Date data sharing statement initially provided
30/04/2020
Date results provided
30/04/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of adding calcium salt of ethylene diamine tetra-acetate (CaEDTA) to nebulised tobramycin on bacterial clearance and lung function in patients with cystic fibrosis with chronic Pseudomonas aeruginosa lung infections: a randomised controlled trial..
Scientific title
A Phase IIb, Single-Centre, Randomised, Double-Blind, Comparator-Controlled, Parallel-Group, Pilot Study to evaluate the safety and tolerability of CaEDTA added to Inhaled Tobramycin vs Tobramycin Alone as Adjunctive therapy to a Course of Standard Treatment for Cystic Fibrosis patients Admitted to Hospital with a Pseudomonas aeruginosa Pulmonary Exacerbation.
Secondary ID [1] 300826 0
TGA2013/0576
Universal Trial Number (UTN)
Trial acronym
The TEDIV study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cystic fibrosis 316714 0
Pseudomonas aeruginosa 316715 0
Condition category
Condition code
Respiratory 314959 314959 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 315092 315092 0 0
Cystic fibrosis
Infection 315093 315093 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We tested if disrupting iron utilisation by Pseudomonas aeruginosa by adding the chelating agent, calcium salt of Ethylene diamine-tetraacetate (CaEDTA) to nebulised tobramycin would enhance bacterial clearance and improve clinical outcomes in cystic fibrosis patients.

Study drug: The study drug (active drug or placebo) was supplied in blinded 1·5 ml prefilled syringes which when added to 250 mg tobramycin (Tobra-Day®) resulted in a 4 ml solution at pH 7·1. The active drug consisted of CaEDTA (75mg, 50mM final concentration) in Tris buffered solution, while the placebo consisted of Tris buffered saline.

Study design: All patients received standard treatment of their pulmonary exacerbation as per their treating physician. In addition, patients were randomised 1:1 to receive either active drug or placebo. First dose of the study drug was given within the first 72 hours of initiation of intravenous antibiotics. The study consisted of three phases: (i) The inpatient phase for first 2 weeks (while on intravenous antibiotics) when participants received study drug (active drug or placebo) four times daily – twice combined with 250 mg inhaled tobramycin, and twice with 0·9% normal saline; (ii) the 2-6 week outpatient phase during which the participants received study drug twice daily with 250 mg inhaled tobramycin. (iii) The safety phase between 6-10 weeks, when no study drug was given.
Intervention code [1] 317157 0
Treatment: Drugs
Comparator / control treatment
Tris buffered saline supplied in 1·5 ml prefilled syringes served as the comparator.

The study consisted of three phases: (i) The inpatient phase for first 2 weeks (while on intravenous antibiotics) when participants received study drug (active drug or placebo) four times daily – twice combined with 250 mg inhaled tobramycin, and twice with 0·9% normal saline; (ii) the 2-6 week outpatient phase during which the participants received study drug (active drug or placebo) twice daily with 250 mg inhaled tobramycin. (iii) The safety phase between 6-10 weeks, when no study drug was given.
Control group
Placebo

Outcomes
Primary outcome [1] 323269 0
The primary outcome was safety and tolerability of nebulised CaEDTA in Tris buffered saline vs placebo (Tris-buffered saline) in combination with 250 mg tobramycin,

Safety and tolerability of CaEDTA was assessed by both clinical and laboratory methods:
Clinically by screening for respiratory symptoms and signs through vital signs and systems assessment (pre- and post first dose of the study drug). Clinical evaluation was repeated at subsequent clinic visits at 2 weeks, 6 weeks and 10 weeks from commencement of the study drug. Additional telephone calls were made at one week and 4 weeks to check safety and adherence to therapy.

As the study drug was nebulised, patients were assessed for tolerability of the study drug by measuring lung function (percentage predicted FEV1) before the first dose of study drug and repeated again at 30 minutes, one hour and 2 hours after the first dose of the study drug during first visit.

Blood was collected at visit one before the administration of the study drug and repeated again at each clinic visit at 2 weeks, 6 weeks and 10 weeks. Blood was analysed for full blood count, electrolytes, urea, creatinine, liver function tests (alanine aminotransferase and aspartate aminotransferase), calcium, magnesium, phosphorus and iron indices (iron, ferritin, transferrin and transferrin saturation).

Patients were screened for any treatment emergent adverse events (AE’s) during each visit (clinic visit and phone call visits). Details of all concomitant medications for the duration of the study were also obtained at each clinic visit.



Timepoint [1] 323269 0
Clinic visits were conducted on day one of commencement of the study drug and repeated again at 2 weeks, 6 weeks and 10 weeks from commencement of the study drug. Telephone calls were made at week one and week four from commencement of intervention.
Primary outcome [2] 323270 0
The additional primary outcome was bacterial clearance of Pseudomonas aeruginosa from sputum in the CaEDTA group vs placebo group. Sputum was collected by induced sputum method before administration of the study drug and repeated at 2 weeks, 6 weeks and 10 weeks after commencement of the study drug. Sputum density of Pseudomonas aeruginosa was measured as colony factor unit/gram of sputum and change in sputum density of Pseudomonas aeruginosa relative to admission was analysed in CaEDTA group vs placebo group.
Timepoint [2] 323270 0
Primary time points were 2 weeks, 6 weeks and 10 weeks from the time of administration of the first dose of the study drug ((active drug or placebo).
Secondary outcome [1] 381378 0
The secondary outcome was change in lung function (percentage predicted FEV1) in the CaEDTA group vs placebo group. Lung function was measured before the administration of the first dose of study drug and repeated at 2 weeks, 6 weeks and 10 weeks after commencement of the study drug. Change in lung function at 2 weeks, 6 weeks and 10 weeks relative to admission was analysed in CaEDTA group vs placebo group.
Timepoint [1] 381378 0
Secondary time points were 2 weeks, 6 weeks and 10 weeks from the time of administration of the first dose of the study drug ((active drug or placebo).

Eligibility
Key inclusion criteria
• Male or female 6 years of age or older with a documented diagnosis of CF (positive sweat chloride test, genotype with two identifiable CF mutations) accompanied by one or more clinical features consistent with the CF phenotype.
• Current pulmonary exacerbation requiring antibiotic therapy.
• If older than 6 years, must be able to perform acceptable spirometric manoeuvres.
• FEV1 > 25% of predicted values (if older than 6 years of age).
• Positive sputum or bronchoalveolar lavage culture for Pseudomonas aeruginosa in the past 12 months.
• Must be able to give informed consent or have legally acceptable representative who can give informed consent in accordance with ICH/GCP.
• Females of child-bearing potential must agree to use an acceptable method of contraception for the duration of the trial.

Initially the study was planned to be conducted in children with cystic fibrosis, however due to slow recruitment, the study was extended to include adults with cystic fibrosis with all procedures remaining the same. We therefore obtained additional approval for inclusion of Sir Charles Gairdener Hospital adult patients to the study.
Minimum age
6 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Known hypersensitivity to the investigational product or its components or known relevant medication allergy.
• Participation in another study with an investigational drug within 2 months of the planned first dose of investigational product.
• Known relevant substance abuse.
• Female patients who are pregnant or lactating
• Clinically significant disease or other medical condition other than CF or CF related conditions that would, in the opinion or the Investigator, compromise the safety of the patient or quality of the data.
Please note: The presence of additional bacterial or fungal organisms on sputum culture and/or the prescription of additional antibiotics (oral, intravenous, anti-pseudomonal, or non-anti-pseudomonal) at any stage through the trial will NOT affect inclusion into the trial)

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)
The statistician held the full randomisation code so that all investigators, study staff and participants remained blinded. Access to a patient’s allocated treatment was available in a sealed envelope kept in the pharmacy with the investigational product in the event of a need for un-blinding.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The pharmacist prepared a permuted-block randomisation schedule prior to commencement of the study.

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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Efficacy analyses were reported in the per-protocol population, defined as participants who completed >75% of doses with not more than 3 consecutive missed doses. Test of normality was determined using Shapiro-Wilk test. When data is normally distributed, values were presented as means and standard deviations and student t test was used to determine statistical significance. When data were not normally distributed, results were presented as medians and interquartile ranges and Mann-Whitney test was applied to determine statistical significance. All data analysis was done in SPSS 24

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
6/03/2014
Date of last participant enrolment
Anticipated
Actual
23/11/2015
Date of last data collection
Anticipated
Actual
3/02/2016
Sample size
Target
32
Accrual to date
Final
26
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 16147 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [2] 16487 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 29676 0
6008 - Subiaco
Recruitment postcode(s) [2] 30037 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 305284 0
Hospital
Name [1] 305284 0
Princess Margaret Hospital
Country [1] 305284 0
Australia
Funding source category [2] 305285 0
Government body
Name [2] 305285 0
Telthon Kids Institute
Country [2] 305285 0
Australia
Primary sponsor type
Government body
Name
Telethon Kids Institute
Address
Roberts Road, Subiaco
Perth
Western Australia
Post code 6008
Country
Australia
Secondary sponsor category [1] 305644 0
Hospital
Name [1] 305644 0
Princess Margaret Hospital
Address [1] 305644 0
Roberts Road, Subiaco
Perth
Western Australia
Post code 6008
Country [1] 305644 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305623 0
Princess Margaret Hospital for Children's Ethics Committee
Ethics committee address [1] 305623 0
Ethics committee country [1] 305623 0
Australia
Date submitted for ethics approval [1] 305623 0
19/09/2013
Approval date [1] 305623 0
01/10/2013
Ethics approval number [1] 305623 0
2013073EP

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100994 0
Dr Barry Clements
Address 100994 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 100994 0
Australia
Phone 100994 0
+61 414930103
Fax 100994 0
Email 100994 0
[email protected]
Contact person for public queries
Name 100995 0
Barry Clements
Address 100995 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 100995 0
Australia
Phone 100995 0
+61 414930103
Fax 100995 0
Email 100995 0
[email protected]
Contact person for scientific queries
Name 100996 0
Barry Clements
Address 100996 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 100996 0
Australia
Phone 100996 0
+61 414930103
Fax 100996 0
Email 100996 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7407Study protocol    379484-(Uploaded-20-03-2020-17-34-10)-Study-related document.pdf
7408Informed consent form    379484-(Uploaded-20-03-2020-17-39-41)-Study-related document.pdf
7409Clinical study report    379484-(Uploaded-20-03-2020-18-11-18)-Study-related document.pdf
7410Ethical approval    379484-(Uploaded-20-03-2020-18-17-46)-Study-related document.pdf
7501Ethical approvalEthics approval for adding Sir Charles Gairdener Hospital to include adult CF patients in the study   379484-(Uploaded-02-04-2020-23-10-00)-Study-related document.pdf



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.