Orkambi in Patients with Cystic Fibrosis and Severe Liver Disease

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.