Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001136695
Ethics application status
Approved
Date submitted
7/09/2023
Date registered
3/11/2023
Date last updated
6/06/2024
Date data sharing statement initially provided
3/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
ORganoId GuIded N-of-1 (ORIGIN-1) Trial: A phase 4 study to investigate whether people with cystic fibrosis (CF) with rare cystic fibrosis transmembrane regulator (CFTR) mutations who have an in vitro response to Trikafta will also have a clinically meaningful response to Trikafta versus placebo
Scientific title
Organoid Guided N-of-1 (ORIGIN-1) Trial: A phase 4 study to investigate whether people with CF with rare CFTR mutations who have an in vitro response to Trikafta will also have a clinically meaningful response to Trikafta versus placebo
Secondary ID [1] 310538 0
CTN-02290-1
Universal Trial Number (UTN)
Trial acronym
ORIGIN-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cystic Fibrosis 331357 0
Condition category
Condition code
Respiratory 328105 328105 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 328538 328538 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a crossover study whereby participants will switch between a TGA-approved triple combination drug and matched placebo after each washout period.
For a treatment block, participants will take orally a film-coated tablet containing Elexacaftor 150mg, Tezacaftor 50mg and Ivacaftor 75mg in the morning, and a film-coated tablet containing Ivacaftor 150mg in the evening, or a matched placebo, for 14 days, followed by a 14 days washout period. Two treatment blocks constitute a treatment cycle. Participants will undergo at least two treatment cycles and up to four treatment cycles during the study, depending on the results of the Bayesian analysis from the first two cycles.

Intervention adherence will be assessed by reconciliation of number of tablets dispensed and number of tablets returned.
Intervention code [1] 326942 0
Treatment: Drugs
Comparator / control treatment
Matched placebo (prosolv tablet: mannitol; fructose; microcrystalline cellulose, colloidal silicon dioxide; crospovidone)
Control group
Placebo

Outcomes
Primary outcome [1] 336012 0
Changes in lung function characterized by absolute difference in ppFEV1 measured by spirometry
Timepoint [1] 336012 0
Absolute difference in ppFEV1 after 14 days of Elexacaftor / Tezacaftor / Ivacaftor (ETI) therapy, compared to the ppFEV1 after 14 days of no ETI therapy, after at least 2 and no more than 4 complete cycles of ETI and matched placebo (PBO).
Secondary outcome [1] 426461 0
Absolute difference in self-reported Sinonasal Outcome Test (SNOT-22)
Timepoint [1] 426461 0
Absolute difference in self-reported Sinonasal Outcome Test (SNOT-22) after approximately 14 days of ETI therapy, compared to the SNOT-22 after approximately 14 days of PBO therapy, after at least 2 and no more than 4 complete cycles of ETI and matched PBO.
Secondary outcome [2] 426462 0
Absolute difference in self-reported Cystic Fibrosis Abdominal symptom (CFAbd)
Timepoint [2] 426462 0
Absolute difference in self-reported Cystic Fibrosis Abdominal symptom (CFAbd) score after approximately 14 days of ETI therapy, compared to the CFAbd after approximately 14 days of PBO therapy, after at least 2 and no more than 4 complete cycles of ETI and matched PBO.
Secondary outcome [3] 426463 0
Absolute difference in the risk of pulmonary exacerbation measured by number of hospitalizations or intravenous antibiotic therapy assessed by review of medical records.
Timepoint [3] 426463 0
Absolute difference in the risk of pulmonary exacerbation in the first 14 days of ETI therapy, compared to the risk in the first 14 days of PBO therapy, after at least 2 and no more than 4 complete cycles of ETI and matched PBO.
Secondary outcome [4] 426464 0
Absolute difference in the composite risk of serious and non-serious adverse events assessed by self reporting, Possible adverse reactions include: rash, headache, diarrhea, stomach pain, raised liver function enzymes.
Timepoint [4] 426464 0
Absolute difference in the composite risk of serious and non-serious adverse events, and the risk of serious and non-serious adverse reactions, in the first 14 days of ETI therapy, compared to the risk in the first 14 days of PBO therapy, after at least 2 and no more than 4 complete cycles of ETI and matched PBO.

Eligibility
Key inclusion criteria
Patients with CF who are 6 years old without a F508del mutation, and with a best measured ppFEV1 in the preceding 6 months between 40% and 90%. Participants that have provided or are willing to provide a colonic/rectal biopsy for 3D organoid culture and have a demonstrated positive response to ETI in an in vitro assay.
Minimum age
6 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of lung transplantation

Receiving a CFTR modulator therapy in the 28 days prior to the screening visit

Any of the following abnormal laboratory values at screening:

Hemoglobin lower than10 g/dL

Total bilirubin 2 times upper limit of normal (ULN)

Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) 3 times ULN

An acute upper or lower respiratory infection, pulmonary exacerbation(s) (PEx), or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of study medication in the Run-in Period (Day -28).

An established contraindication the study medication i.e., ETI

Pregnant or nursing females. All female subjects must have a negative pregnancy test at Screening (urine test).

A life expectancy of less than 12 months

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
All outcomes for this trial will be analysed based on a statistical model within a Bayesian inference framework.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
10/11/2023
Actual
13/11/2023
Date of last participant enrolment
Anticipated
30/08/2024
Actual
Date of last data collection
Anticipated
28/02/2025
Actual
Sample size
Target
20
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25500 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 41311 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 314739 0
Government body
Name [1] 314739 0
Department of Health and Aged Care - Medical Research Future Fund (MRFF)
Country [1] 314739 0
Australia
Primary sponsor type
University
Name
The University of Newcastle
Address
University Drive Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 316744 0
None
Name [1] 316744 0
Address [1] 316744 0
Country [1] 316744 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313750 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 313750 0
Awabakal Country: Level 3 POD, Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton 2305 NSW
Ethics committee country [1] 313750 0
Australia
Date submitted for ethics approval [1] 313750 0
12/04/2023
Approval date [1] 313750 0
16/05/2023
Ethics approval number [1] 313750 0
2023/ETH00670

Summary
Brief summary
This study aims to evaluate whether an in vitro test enables identification of people with Cystic Fibrosis rare mutations who are clinically responsive to CFTR modulators.
Cystic Fibrosis patients with two non-F508del mutations with a positive response in the in vitro testing will undergo cycles of treatment with a triple combination -Elexacaftor/Tezacaftor/Ivacaftor (Trikafta) and matched placebo. Short term improvement in lung function (FEV1) and CF-related symptoms will be used to determine if they respond to the treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129234 0
Prof Peter Wark
Address 129234 0
AIRMED, Alfred Health. Level 5. PO Box 315. Prahran, Victoria 3181.
Country 129234 0
Australia
Phone 129234 0
+61 03 90763698
Fax 129234 0
Email 129234 0
peter.wark@alfred.org.au
Contact person for public queries
Name 129235 0
Prof Peter Wark
Address 129235 0
AIRMED, Alfred Health. Level 5. PO Box 315. Prahran, Victoria 3181.
Country 129235 0
Australia
Phone 129235 0
+61 03 90763698
Fax 129235 0
Email 129235 0
peter.wark@alfred.org.au
Contact person for scientific queries
Name 129236 0
Prof Gerard Kaiko
Address 129236 0
Hunter Medical Research Institute - HMRI. Lot 1 Kookaburra Ct, New lambton Heights, NSW 2305
Country 129236 0
Australia
Phone 129236 0
+61 40420184
Fax 129236 0
Email 129236 0
gerard.kaiko@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual de-identifiable data collected during the trial
When will data be available (start and end dates)?
Immediately following publication of the full trial results with no end date
Available to whom?
Researchers who provide a methodologically sound proposal
Available for what types of analyses?
Any
How or where can data be obtained?
Written request for data approved by Investigators. Requests by email to Prof Peter Wark peter.wark@newcastle.edu.au / Dr Gerard Kaiko gerard.kaiko@newcastle.edu.au / Dr Lorena Sabino lorena.rodriguessabino@newcastle.edu.au


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
No additional documents have been identified.