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Trial registered on ANZCTR


Registration number
ACTRN12620001354976
Ethics application status
Approved
Date submitted
27/09/2020
Date registered
15/12/2020
Date last updated
15/12/2020
Date data sharing statement initially provided
15/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of efficacy, tolerability and safety of tobramycin inhalation powder using Orbital™ dry powder inhaler (DPI) device vs TOBI Podhaler for lung infections in cystic fibrosis (CF) patients (Tobra Orbital TOBI Trial-TOTT).
Scientific title
Multi-centre, open-label, parallel, randomized trial to compare efficacy, tolerability and safety of tobramycin inhalation powder using Orbital™ DPI device vs TOBI Podhaler for lung infections in CF patients (Tobra Orbital TOBI Trial-TOTT)
Secondary ID [1] 302416 0
None
Universal Trial Number (UTN)
U1111-1258-8088
Trial acronym
TOTT
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Cystic Fibrosis 319211 0
Condition category
Condition code
Respiratory 317180 317180 0 0
Other respiratory disorders / diseases
Infection 317181 317181 0 0
Other infectious diseases
Human Genetics and Inherited Disorders 317554 317554 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tobramycin Inhalation Powder using Orbital DPI inhaler in Cystic Fibrosis patients.
All patients will commence 4 weeks treatment with TOBI Podhaler PulmosphereTM (Treatment A - Comparator), followed by 4 weeks with no inhalation treatment. Study participants will then be randomised in week 8 into one of the three study arms:
- TOBI Podhaler PulmosphereTM (Treatment A): control group (Comparator)
- Tobramycin-Orbital Puck B (Treatment B)*
- Tobramycin-Orbital Puck C (Treatment C)*
*The difference between Treatments B & C is only in the puck (hole) size and number of breaths. Treatment B has a puck hole of 0.9 mm and Treatment C has a puck hole of 0.6 mm.
The inhaled tobramycin dose is the same between the 3 groups.
Treatment A: 4 capsules (28mg each) twice daily for 4 weeks using TOBI Podhaler device.
Treatment B: 150 mg to be administered twice daily for 4 weeks using Orbital device (puck hole of 0.9 mm)
Treatment C: 150 mg to be administered twice daily for 4 weeks (puck hole of 0.6 mm).

Strategies used to monitor adherence to the intervention:
For Treatment A: Participants will be instructed to keep their used capsules in the bag provided (grouped per week) and bring them back to their visits so that compliance can be determined based on the number of capsules used.
For treatments B& C: Orbital devices will have serial numbers and patients will be instructed to keep their used devices (grouped per week) and bring them back to their visits so that compliance can be determined. Devices to be assessed for residual drug as an indication for adherence.

A subset of participants will be asked to complete additional safety assessments. This will be the first 10 participants consenting to do the additional safety assessments.
Intervention code [1] 318698 0
Treatment: Other
Intervention code [2] 318978 0
Treatment: Devices
Comparator / control treatment
TOBI Podhaler PulmosphereTM control group (Comparator)
Dose; 4 capsules (28mg each) twice daily for 4 weeks using TOBI Podhaler device
Control group
Active

Outcomes
Primary outcome [1] 325256 0
Efficacy:
To achieve comparable efficacy of tobramycin administered using the Orbital device compared to the TOBI Podhaler Pulmospheres, defined as reaching a comparable FEV1 change by spirometry.

Timepoint [1] 325256 0

All 4 visits. Week 0 (with first Treatment A dose) , 4 (with last Treatment A dose), 8 (with first dose of intervention) and 12 (with the final intervention dose).
Primary outcome [2] 325257 0
Tolerability (composite):
-Compare the tolerability of the Orbital device to TOBI Podhaler Pulmospheres using the tolerability questionnaire (specifically designed for this study) & Cough questionnaire.
-Compare the tolerability and number of breaths required to empty the pucks between the two puck hole sizes in the study assessed by the administering clinician at the first visit the intervention is introduced.
Timepoint [2] 325257 0
Tolerability: End of week 4 & end of week 12
Cough: Week 0 (with first Treatment A dose) , 4 (with last Treatment A dose), 8 (with first dose of intervention) and 12 (with the final intervention dose).
Primary outcome [3] 325603 0
Efficacy:
Quantitative microbiology (by measuring Pseudomonas density in sputum).
Timepoint [3] 325603 0
All 4 visits. Week 0 (with first Treatment A dose) , 4 (with last Treatment A dose), 8 (with first dose of intervention) and 12 (with the final intervention dose).
Secondary outcome [1] 387353 0
Safety (composite):
To monitor PK parameters (Tmax and Cmax) of tobramycin in blood and auditory activity (high frequency audiometry) in a subset of patients to ascertain if this tobramycin formulation delivered via the Orbital device has a comparable safety to using TOBI Podhaler Pulmospheres.
Timepoint [1] 387353 0
PK: Week 0 and same day of of intervention administration in week 8 at time 0 baseline-before treatment), 30 min, 1h, 2h, 4h and 6h (post treatment).
Audiometry: Week 0 and same day of intervention administration in week 8.
Secondary outcome [2] 387354 0
Usability:
To assess patient usability of the Orbital device following training from the clinician administering the first dose of medication as measured by the Human Factor Assessment checklist
Timepoint [2] 387354 0
Week 8 after intervention administration only (treatments B & C).

Eligibility
Key inclusion criteria
Inclusion criteria, which must be met at the time of study screening, are:
A stable history of chronic CF disease with a FEV1 of greater than or equal to 30% predicted.
Clinical stability, as determined by the clinician’s evaluation, with no pulmonary exacerbation in the past month determined by the patient’s records (e.g. need for IV antibiotics).
Proven previous tolerability to TobiPodhaler.
Chronic Pseudomonas aeruginosa infection as determined by the patient’s records.
Aged equal to or greater than 18 years
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria are:
• CF patients with severe unstable conditions.
• CF patients with chronic Mycobacterium abscessus and Burkholderia cepacia complex (B. cepacia) colonisation.
• CF patients who are on continuous tobramycin therapy (not on alternate month tobramycin therapy)
• Pregnant or lactating females or females who intend to fall pregnant within the study period.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
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 in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 17657 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 17658 0
The Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 31503 0
2050 - Camperdown
Recruitment postcode(s) [2] 31504 0
4032 - Chermside

Funding & Sponsors
Funding source category [1] 306837 0
Government body
Name [1] 306837 0
NHMRC National Health and Medical Research Council DevelopmentGrant
Address [1] 306837 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 306837 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Woolcock Institute of Medical Research
Address
Woolcock Institute of Medical Research,
431 Glebe Point RD
Glebe 2037
NSW, Australia
Country
Australia
Secondary sponsor category [1] 307399 0
None
Name [1] 307399 0
None
Address [1] 307399 0
Country [1] 307399 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306998 0
Sydney Local Health District- Royal Prince Alfred Hospital
Ethics committee address [1] 306998 0
50 Missenden RD, RPA
Camperdown NSW 2050
Australia
Ethics committee country [1] 306998 0
Australia
Date submitted for ethics approval [1] 306998 0
Approval date [1] 306998 0
21/08/2020
Ethics approval number [1] 306998 0

Summary
Brief summary
Aims:
The aim of this study is to demonstrate clinical proof of concept of tobramycin inhaled dry powder formulation using the Orbital device in a Phase I clinical trial.
Tolerability, safety (including pharmacokinetic (PK) assessments) and efficacy will be evaluated and compared to inhaled tobramycin using the standard care capsule-based TOBI Podhaler Pulmosphere therapy.
Specifically, the study aims to collect information about the efficacy, tolerability and safety, of the Orbital DPI in comparison to the TOBI Podhaler.
The results of this study will be used to inform a larger trial in the future.

Hypotheses:
It is hypothesised that the use of the Orbital Device with multi-breath inhalation manoeuvres of the same dose will be better tolerated in terms of decreased coughing generally associated with DPIs, and overall convenience in device use when compared to the TOBI Podhaler.
The single dose disposable Orbital DPI device is expected to be as effective (comparable FEV1 change and decrease in Pseudomonas density), safe (maximum blood concentration – Cmax not exceeding 2µg/mL) as well as more tolerable for patients (Cough Severity Scale and Tolerability Questionnaire) which will lead to improved adherence.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105694 0
Prof Paul Young
Address 105694 0
Woolcock Institute of Medical Research
431 Glebe Point Road,
GLEBE NSW 2037
Australia

Country 105694 0
Australia
Phone 105694 0
+61 2 9114 0350
Fax 105694 0
Email 105694 0
paul.young@sydney.edu.au
Contact person for public queries
Name 105695 0
Dr Rania Salama
Address 105695 0
Woolcock Institute of Medical Research
431 Glebe Point Road,
GLEBE NSW 2037
Australia
Country 105695 0
Australia
Phone 105695 0
+61 2 9114 0317
Fax 105695 0
Email 105695 0
rania.salama@sydney.edu.au
Contact person for scientific queries
Name 105696 0
Dr Rania Salama
Address 105696 0
Woolcock Institute of Medical Research
431 Glebe Point Road,
GLEBE NSW 2037
Australia
Country 105696 0
Australia
Phone 105696 0
+61 2 9114 0317
Fax 105696 0
Email 105696 0
rania.salama@sydney.edu.au

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?
No other documents available
Summary results
No Results