ICM to Evaluate the Activation of p.Phe508del-CFTR by Lumacaftor in Combination With Ivacaftor

NCT02807415 | Completed DMC

• 1 other identifier: 2846-2015 82DZLE12A1
• Study Type: observational
• Target: 104
• Locations: 1 country
• Sites: 3

Brief Summary

The academic investigator - initiated trial will evaluate in a postapproval setting whether, and if yes, to what extent and variability, the treatment with lumacaftor in combination with ivacaftor reverses the p.Phe508del CFTR - mediated basic defect in p.Phe508del homozygous subjects with cystic fibrosis under real life conditions.

Conditions

Cystic Fibrosis

Keywords

cystic fibrosis; CFTR; CFTR modulation; sweat test; intestinal current measurement, ICM; nasal transepithelial potential difference measurement, NPD

Outcome Measures

Primary Outcomes (1)

• ICM Absolute change from baseline of the cumulative chloride secretory ion current response to forskolin/IBMX and carbachol in rectal tissue as a CFTR biomarker

  ICM will be performed according to the Standard Operating Procedure ICM\_EU001, version 2.7 (October 2011) 'Ion Transport in Rectal Biopsies for Diagnosis and Clinical Trials in Cystic Fibrosis of the European Cystic Fibrosis Society (ECFS) Diagnostic Working Group \& Clinical Trials Network modified by in-house protocol adjustments at the CF electrophysiology laboratories in Hannover and Heidelberg as described by Graeber et al. (2015) \[39\]. Electronic files of the tracings will be evaluated on-site and at the CF Electrophysiology Laboratory at the University of Heidelberg.

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

Secondary Outcomes (3)

• Spirometry Absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1)

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

• NPD Absolute change from baseline of the Sermet score of nasal transepithelial potential difference measurements (NPD) as a CFTR biomarker

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

• Sweat chloride testing Absolute change from baseline of the chloride concentration in Gibson-Cooke pilocarpine iontophoresis sweat test as a CFTR biomarker

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

Other Outcomes (2)

• Drug testing Plasma concentrations of lumacaftor, ivacaftor, and their metabolites

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

• Safety Issues assessed by Liver-related events, respiratory events and elevation of blood creatine phosphokinase

  Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor

Interventions

Lumacaftor plus Ivacaftor DRUG

Oral treatment with lumacaftor/ivacaftor tablets according to the prescribing information

Also known as: Orkambi; VX-770; VX-809

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Subjects with cystic fibrosis aged 6 years and older, homozygous for the p.Phe508del-CFTR mutation

You may qualify if:

• p.Phe508del homozygous subjects aged 6 years and older with cystic fibrosis
• FEV1 ≥ 40% of predicted normal for age, gender and height (Knudson standards) or FEV1 \> 35% of predicted normal for age, gender and height at baseline, stable lung function during the preceding three months and no acute upper or lower respiratory infection or pulmonary exacerbation during the preceding four weeks
• Hematology, serum chemistry, coagulation results at baseline with no clinically significant abnormalities that would interfere with the oral treatment with Orkambi® and with the study assessments, as judged by the investigator
• Able to understand and comply with protocol requirements, restrictions, and instructions and likely to complete the study as planned, as judged by the investigator
• Willing to remain on a stable medication regimen and administration of Orkambi® according to the FDA-approved patient labeling and the prescribing information for the duration of study participation -

You may not qualify if:

• History of any illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering Orkambi®
• An acute upper or lower respiratory infection or pulmonary exacerbation at baseline
• Advanced liver disease as documented by sonography
• Abnormal liver function at baseline, defined as ≥ 3 upper limit of normal in minimum 3 of the following: serum aspartate transaminase, serum alanine transaminase, gamma-glutamyl transpeptidase, or total bilirubin
• Abnormal blood creatine phosphokinase at baseline
• Abnormal renal function at baseline, defined as creatinine clearance \< 60 mL/min
• Co-medication with strong Cytochrome P450, Family 3, subfamily A (CYP3A) inhibitors and inducers
• Non-congenital lens opacities
• Haemorrhoids (bleeding risk when taking rectal suction biopsies for ICM)
• History of nasal surgery that removed the respiratory epithelium
• Topical treatment of nostrils in the 3 days prior to baseline
• Disturbing nasal aspects of secretions, erythema, crustae, ulcera, edema at baseline
• Participation in a clinical study involving administration of a CFTR modulator
• History of solid organ or haematological transplantation

Sponsors & Collaborators

• Hannover Medical School: lead
• Heidelberg University: collaborator
• University of Giessen: collaborator

Study Sites (3)

Justus-Liebig-University

Giessen, 35385, Germany

Location

Hannover Medical School

Hanover, 30625, Germany

Location

University of Heidelberg

Heidelberg, 69120, Germany

Location

Related Publications (5)

• Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17.

  PMID: 25981758 BACKGROUND

• Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang X, Marigowda G, Waltz D, Wainwright CE; VX-809 TRAFFIC and TRANSPORT study groups. Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. Lancet Respir Med. 2016 Aug;4(8):617-626. doi: 10.1016/S2213-2600(16)30121-7. Epub 2016 Jun 10.

  PMID: 27298017 BACKGROUND

• Graeber SY, Hug MJ, Sommerburg O, Hirtz S, Hentschel J, Heinzmann A, Dopfer C, Schulz A, Mainz JG, Tummler B, Mall MA. Intestinal Current Measurements Detect Activation of Mutant CFTR in Patients with Cystic Fibrosis with the G551D Mutation Treated with Ivacaftor. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1252-5. doi: 10.1164/rccm.201507-1271LE. No abstract available.

  PMID: 26568242 BACKGROUND

• Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, Wege S, Mairbaurl H, Dorda M, Hyde R, Bagheri-Hanson A, Rueckes-Nilges C, Fischer S, Mall MA, Tummler B. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018 Jun 1;197(11):1433-1442. doi: 10.1164/rccm.201710-1983OC.

  PMID: 29327948 RESULT

• Graeber SY, Boutin S, Wielputz MO, Joachim C, Frey DL, Wege S, Sommerburg O, Kauczor HU, Stahl M, Dalpke AH, Mall MA. Effects of Lumacaftor-Ivacaftor on Lung Clearance Index, Magnetic Resonance Imaging, and Airway Microbiome in Phe508del Homozygous Patients with Cystic Fibrosis. Ann Am Thorac Soc. 2021 Jun;18(6):971-980. doi: 10.1513/AnnalsATS.202008-1054OC.

  PMID: 33600745 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

plasma samples

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

lumacaftor; ivacaftor; lumacaftor, ivacaftor drug combination

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Study Officials

• Burkhard Tümmler, MD PhD

  Hannover Medical School

  PRINCIPAL INVESTIGATOR

• Marcus Mall, MD

  Heidelberg University

  PRINCIPAL INVESTIGATOR

• Lutz Nährlich, MD

  University of Giessen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2016
• First Posted: June 21, 2016
• Study Start: June 1, 2016
• Primary Completion: December 31, 2019
• Study Completion: February 10, 2020
• Last Updated: July 30, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: IPD data are made available in a written summary report to the physician treating the study participant within 4 weeks after study day 2
• Access Criteria: access criterion: - the individual study participant gains access to printouts of sweat chloride concentration, NPD and ICM tracings upon request. \- the physician treating the study participant receives a written report for this subject that summarizes the findings of spirometry, sweat chloride concentration, NPD and ICM tracings.

Locations

DE (3)