Effect of Lumacaftor-ivacaftor on Glucose Handling and Tolerance in Cystic Fibrosis Phe508del (LIGHT-CF)

A Study of the Effect of Combination Lumacaftor and Ivacaftor on Glucose Tolerance in Persons With Cystic Fibrosis Who Are Homozygous for the Phe508del Cystic Fibrosis Transmembrane Conductance Regulator Mutation.

The purpose of this research study is to find out if the combined therapy lumacaftor-ivacaftor effects how people with cystic fibrosis respond to an oral glucose tolerance test, a test for diabetes.

Study Overview

• Status: Withdrawn
• Conditions: Diabetes; Cystic Fibrosis
• Intervention / Treatment: Drug: Lumacaftor-ivacaftor; Other: OGTT

Detailed Description

This is a single center, open label study with crossover in patients with Cystic Fibrosis (CF). Patients will have 2-3 visits at the Diabetes Center at Massachusetts General Hospital (MGH).

The participants will have been previously screened clinically to make sure they are candidates for starting the combination drug, lumacaftor-ivacaftor. These patients will be contacted prior to their first visit to discuss enrollment in the study.

At the first study visit (Visit 1), the participant will come to the Diabetes Center after an overnight fast of at least 8 hours. The following will occur at this study visit: informed consent; brief medical history; weight and height; vital signs and blood pressure; blood draw for DNA extraction, and an extra research tube for storage; administration of 75g Glucola load as per a standard oral glucose tolerance test (OGTT) protocol; and blood work for glucose and insulin at 30, 60, 90 and 120 minutes after the glucose load. This will be scheduled at a time that is convenient to the patient, with an attempt to coordinate with the patient's visit to the CF clinic prior to starting lumacaftor-ivacaftor combination drug.

At the 2nd study visit (Visit 2), which will take place 3 months after starting the combination drug, the participant will again come to the Diabetes Center after an overnight fast of at least 8 hours. The participant will undergo a second OGTT as in the first visit. The 3rd study visit (Visit 3) will be 6 months after initiation of the drug, and will have a repeat administration of an OGTT. If a participant starts the combination drug before enrolling in the study, he/she can still participate in the study as long as he or she has had a clinical OGTT performed within 6 months of starting the combination drug. In these cases, the informed consent, brief medical history, weight and height and vital signs and blood pressure, as well as blood draw for DNA will occur on the Visit 2, which will be the first study visit for these participants. If a clinical OGTT had been performed prior to but within 6 months of starting the combination therapy, this OGTT can be used in analysis of the data, although will not have the full amount of data as the study OGTT.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years old or greater
2. Patients diagnosed with CF, genotype homozygous PheDel508

3. Subject is planning on starting lumacaftor-ivacaftor for clinical reasons, with no contraindication for starting the drug* OR subject is taking combination drug and had an OGTT done at a partners facility in the 6 months prior to initiating the drug.

   • Contraindications for taking drug include abnormal liver enzyme tests, renal dysfunction, pregnancy or nursing mothers

Exclusion Criteria:

1. Currently taking any medications for diabetes (including oral or injectable antihyperglycemic agents and/or insulin).
2. Had an admission for CF exacerbation less than 2 weeks prior to staring the medication. This will be defined as requiring new IV or PO antibiotics different than those used in maintenance therapy.
3. Is currently taking oral glucocorticoids or has been on oral or IV glucocorticoids in the past 2 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lumacaftor Ivacaftor; Subjects will get an OGTT before and after starting the combination therapy lumacaftor-ivacaftor.	Drug: Lumacaftor-ivacaftor; Subjects who are planning on starting the combination therapy (lumacaftor-ivacaftor) will participate in OGTTs before and after starting the medication.; Other Names: Orkambi; Other: OGTT; A subject is given an oral glucose load and insulin and glucose measurements are taken at specified time periods.; Other Names: Oral Glucose tolerance test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fasting Glucose	This will be compared from baseline to 3 months after starting the medication	3 months
Change in Fasting Glucose	This will compare baseline to 6 months after starting the medication	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic risk score	We will examine how the OGTT data is dependent on genotype at variants associated with type 2 diabetes using a genetic risk score	6 months
Pulmonary function test (PFT) FEV1 measurements	We will compare how PFT measurement of FEV1 are related to changes in OGTT	6 months
Change in Fasting Insulin	This will be compared from baseline to 3 months after starting the medication	3 months
Change in Fasting Insulin	This will be compared from baseline to 6 months after starting the medication	6 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Jose Florez, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• 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.
• Bellin MD, Laguna T, Leschyshyn J, Regelmann W, Dunitz J, Billings J, Moran A. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes. 2013 Sep;14(6):417-21. doi: 10.1111/pedi.12026. Epub 2013 Mar 13.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Anticipated): February 1, 2018
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: January 7, 2016
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimate): January 12, 2016

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 29, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Genetics
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: 2015P001811

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No