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Trial registered on ANZCTR


Registration number
ACTRN12619001347156
Ethics application status
Approved
Date submitted
11/09/2019
Date registered
1/10/2019
Date last updated
6/02/2023
Date data sharing statement initially provided
1/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Orkambi in Patients with Cystic Fibrosis and Severe Liver Disease
Scientific title
Orkambi in Patients with Cystic Fibrosis and Severe Liver Disease
Secondary ID [1] 299257 0
Nil known
Universal Trial Number (UTN)
U1111-1240-0507
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cystic Fibrosis 314392 0
Cystic Fibrosis Related Liver Disease 314393 0
Condition category
Condition code
Respiratory 312729 312729 0 0
Other respiratory disorders / diseases
Oral and Gastrointestinal 312853 312853 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Human Genetics and Inherited Disorders 312854 312854 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 1
Participants between 6 years and 18 years will receive Lumacaftor/Ivacaftor (Orkambi) oral tablet at half dose for four days.
- 6 – 11 years = Lumacaftor 100mg/ Ivacaftor 125mg twice a day
- 12 years and older = Lumacaftor 200mg/ Ivacaftor 125mg twice a day

Pharmacokinetic studies will be performed from blood sampling during the 4 days and liver function monitoring will be performed.

Based on these results, a Phase 2a study or Phase 2b study may be performed on the same participants. If the area under the curve (AUC) in the Phase 1 pharmacokinetic studies is similar to previous data in these participants, the Phase 2a study (prolonged half dose study) will be performed. However, should the AUC be low compared to previous data, the Phase 2b (full dose study) will be performed.

Phase 2
Patients included in the study will be aged between 2 years and 18 years old, homozygous for Phe508del and have severe liver disease. Patients will receive two weeks of half dose Orkambi (Week 1–2), followed by two weeks of full dose Orkambi (Week 3–4).

Half dose Orkambi will be administered as follows:
- 2 to 5 years and less than 14kg (lumacaftor 100mg/ivacaftor 125mg granules) once a day;
- 2 to 5 years and greater or equal to 14kg (lumacaftor 150mg/ivacaftor 188mg granules) once a day;
- 6 to 11 years (lumacaftor 100mg/ivacaftor 125mg tablet) twice a day;
- 12 years or older (lumacaftor 200mg/ivacaftor 125mg tablets) twice a day.

• Full dose Orkambi will be administered as follows:
- 2 to 5 years and less than 14kg (lumacaftor 100mg/ivacaftor 125mg granules) twice a day;
- 2 to 5 years and greater or equal to 14kg (lumacaftor 150mg/ivacaftor 188mg granules) twice a day;
- 6 to 11 years (lumacaftor 200mg/ivacaftor 250mg tablet) twice a day;
- 12 years or older (lumacaftor 400mg/ivacaftor 250mg tablet) twice a day.

Investigations:
- In Week 1 (between day 6-8), patients will collect a faecal sample and have a blood
test for liver function tests and pharmacokinetic level.
- In Week 2 (Day 13-14), patients will have blood tests, a lung function test, faecal sample collection as well as have vital signs, growth measurements and a physical exam conducted. Liver function tests will be performed and pharmacokinetic sampling will occur at 0, 2, 4, 6, 8- and 24-hours post morning half-dose Orkambi.
- In Week 3 (between day 20-22), patients will collect a faecal sample and have a blood test for liver function tests and pharmacokinetic sampling.
- In Week 4 (Day 27-28), patients will have blood tests, a lung function test, faecal sample collection as well as have vital signs, growth measurements and a physical exam conducted. Liver function tests will be performed and pharmacokinetic sampling will occur at 0, 2, 4, 6, 8- and 24-hours post morning full-dose Orkambi.
- At Week 8, four weeks after the last dose of Orkambi, safety bloods for liver function tests, a repeat lung function test and liver elastography will be performed. A repeat optometry review will also occur three to four months post the last dose of Orkambi.
Intervention code [1] 315545 0
Treatment: Drugs
Comparator / control treatment
Comparator group:
Patients aged between 2 years and 18 years old, homozygous for Phe508del, without severe liver disease, who must already be receiving full dose Orkambi for a period of at least two weeks prior to enrolment to this group.

Dosing:
- 2 to 5 years and less than 14kg (lumacaftor 100mg/ivacaftor 125mg granules) twice a day;
- 2 to 5 years and greater or equal to 14kg (lumacaftor 150mg/ivacaftor 188mg granules) twice a day;
- 6 to 11 years (lumacaftor 200mg/ivacaftor 250mg tablet) twice a day;
- 12 years or older (lumacaftor 400mg/ivacaftor 250mg tablet) twice a day.

Investigations:
- For patients with available intravenous access (i.e. a portacath or peripherally inserted central catheter [PICC]), a full pharmacokinetic profile will be obtained at 0, 2, 4, 6, 8 and 24 hours post the first Orkambi dose of the day. One to two faecal samples will also be collected. Liver function tests may be collected, or retrospective results recorded.
- For patients without available intravenous access, a single faecal sample will be obtained. A single blood test will be also obtained if able, between 1 to 12 hours, post the first Orkambi dose of the day. Liver function tests may be collected, or retrospective results recorded.
Control group
Active

Outcomes
Primary outcome [1] 321365 0
Pharmacokinetics of Ivacaftor in patients with cystic fibrosis with and without severe liver disease. The pharmacokinetic study, assessing AUC, will be performed on the participants' serum for Phase 1 (half dose Orkambi), Phase 2 (full dose Orkambi) and patients without severe cystic fibrosis related liver disease on full dose Orkambi.
Timepoint [1] 321365 0
Phase 1
Sampling at day 1 (predose, 2h, 4h, 6h, 8h, 24h post dose) and day 4 (0h pre dose, 2h and 8h post dose)

Phase 2
- One sample the end of week 1 (day 6 -8)
- Week 2 (day 13-14), samples at predose, 2h, 4h, 6h, 8h, 24h post dose,
- One sample the end of week 3 (day 20-22)
- Week 4 (day 27-28) at predose, 2h, 4h, 6h, 8h, 24h post dose.

In patients without severe liver disease on full dose Orkambi with ready intravenous access, sampling will be obtained predose, 2h, 4h, 6h, 8h, 24h post dose. For patients without ready intravenous access, a single blood sample will be obtained between 1 and 12 hours post dose.
Primary outcome [2] 321460 0
Pharmacokinetics of Lumacaftor in patients with cystic fibrosis with and without severe liver disease. The pharmacokinetic study, assessing AUC, will be performed on the participants' serum for Phase 1 (half dose Orkambi), Phase 2 (full dose Orkambi) and patients without severe cystic fibrosis related liver disease on full dose Orkambi.
Timepoint [2] 321460 0
Phase 1
Sampling at day 1 (predose, 2h, 4h, 6h, 8h, 24h post dose) and day 4 (0h pre dose, 2h and 8h post dose)

Phase 2
- One sample the end of week 1 (day 6 -8)
- Week 2 (day 13-14), samples at predose, 2h, 4h, 6h, 8h, 24h post dose,
- One sample the end of week 3 (day 20-22)
- Week 4 (day 27-28) at predose, 2h, 4h, 6h, 8h, 24h post dose.

In patients without severe liver disease on full dose Orkambi with ready intravenous access, sampling will be obtained predose, 2h, 4h, 6h, 8h, 24h post dose. For patients without ready intravenous access, a single blood sample will be obtained between 1 and 12 hours post dose.
Secondary outcome [1] 374777 0
To assess the safety of Orkambi in patients with cystic fibrosis and severe liver disease. This will be assessed on participants' serum samples including liver function test, coagulation test and ammonia levels. Liver elastography will also be assessed at baseline and also 8 weeks after the final dose of Orkambi.
Timepoint [1] 374777 0
Phase 1
Liver function tests and coagulation tests at baseline, 24h, day 4 (8h post dose) and at week 4. Ammonia levels at baseline, day 4 (8h post dose) and at week 4. Liver elastography will also be assessed at baseline and at 4 weeks.

Phase 2
Liver function tests, coagulation tests, full blood counts and ammonia levels will be performed at baseline, and weekly for four weeks. Liver elastography will also be assessed at baseline and at 8 weeks after the final dose of Orkambi.
Secondary outcome [2] 402487 0
To assess the absorption of Ivacaftor via analysing the participant's faecal sample (Phase 2 participants and patients without severe liver disease). Patients without severe liver disease are recruited prospectively and the patients must be receiving full dose Orkambi for two weeks prior to enrolment to this group.
Timepoint [2] 402487 0
Patients with severe liver disease - Faecal samples will be performed at baseline and weekly for a total of four weeks. Faecal concentrations of Ivacaftor will be assessed.

Patients without severe liver disease - One to two faecal samples will be collected, if possible, coinciding with the day of the blood collection for the pharmacokinetic study. The first faecal sample of the day will be collected.
Secondary outcome [3] 402488 0
To assess the absorption of Lumacaftor via analysing the participant's faecal sample (Phase 2 participants and patients without severe liver disease). Patients without severe liver disease must be receiving full dose Orkambi for two weeks prior to enrolment to this group.
Timepoint [3] 402488 0
Patients with severe liver disease - Faecal samples will be performed at baseline and weekly for a total of four weeks. Faecal concentrations of Ivacaftor will be assessed.

Patients without severe liver disease - One to two faecal samples will be collected, if possible, coinciding with the day of the blood collection for the pharmacokinetic study. The first faecal sample of the day will be collected.

Eligibility
Key inclusion criteria
Phase 1
1. Children between 6 years old and 18 years of age homozygous for Phe508del-CFTR
2. Severe cystic fibrosis related liver disease

Phase 2
1. Children between 2 years old and 18 years of age homozygous for Phe508del-CFTR
2. Severe cystic fibrosis related liver disease

Patients without severe cystic fibrosis related liver disease
1. Children between 2 years old and 18 years of age homozygous for Phe508del-CFTR
2. On full dose Orkambi for at least two weeks prior to enrolment to the study
Minimum age
2 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Cystic fibrosis without severe liver disease
Exclusion criteria - presence of cirrhosis and portal hypertension

These patients must already be receiving full dose Orkambi for at least two weeks prior to enrolment to this group.

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



Intervention assignment
Parallel
Other design features
Not applicable
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
This will be a pharmacokinetic study. The sample size will be small due to patient population characteristics.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/10/2019
Actual
26/11/2019
Date of last participant enrolment
Anticipated
30/06/2023
Actual
Date of last data collection
Anticipated
25/08/2023
Actual
Sample size
Target
30
Accrual to date
28
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 14767 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 28000 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 303791 0
Self funded/Unfunded
Name [1] 303791 0
Professor Claire Wainwright
Country [1] 303791 0
Australia
Primary sponsor type
Individual
Name
Dr Adeline Lim
Address
Queensland Children's Hospital
501 Stanley Street
South Brisbane
QLD 4101
Country
Australia
Secondary sponsor category [1] 303914 0
Individual
Name [1] 303914 0
Professor Claire Wainwright
Address [1] 303914 0
Queensland Children's Hospital
501 Stanley Street
South Brisbane
QLD 4101
Country [1] 303914 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304312 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 304312 0
Level 7, Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
62 Graham Street, South Brisbane QLD 4101
Ethics committee country [1] 304312 0
Australia
Date submitted for ethics approval [1] 304312 0
14/08/2019
Approval date [1] 304312 0
28/08/2019
Ethics approval number [1] 304312 0
HREC/1 9 / QCHQ/5 3788

Summary
Brief summary
This is a pharmacokinetic study of Lumacaftor/Ivacaftor (Orkambi) in children between 2 years and 18 years of age who are homozygous for Phe508del-CFTR with severe cystic fibrosis related liver disease, in comparison to those without severe liver disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96494 0
Dr Adeline Lim
Address 96494 0
Queensland Children's Hospital
501 Stanley Street
South Brisbane
QLD 4101
Country 96494 0
Australia
Phone 96494 0
+61 730681111
Fax 96494 0
Email 96494 0
adeline.lim@health.qld.gov.au
Contact person for public queries
Name 96495 0
Dr Adeline Lim
Address 96495 0
Queensland Children's Hospital
501 Stanley Street
South Brisbane
QLD 4101
Country 96495 0
Australia
Phone 96495 0
+61 730681111
Fax 96495 0
Email 96495 0
adeline.lim@health.qld.gov.au
Contact person for scientific queries
Name 96496 0
Dr Adeline Lim
Address 96496 0
Queensland Children's Hospital
501 Stanley Street
South Brisbane
QLD 4101
Country 96496 0
Australia
Phone 96496 0
+61 730681111
Fax 96496 0
Email 96496 0
adeline.lim@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Analysed data will be published post de-identification.


What supporting documents are/will be available?



Results publications and other study-related documents

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