: TRANSITION: An Observational Study of Transition From Lumacaftor/Ivacaftor to Tezacaftor/Ivacaftor (Tez/Iva)

• Sponsor: National Jewish Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT03445793
• Collaborator: (none)
• Enrollment: 5
• Location: 1
• Actual Duration (Months): 20
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is a single center study of clinical and laboratory outcomes in patients ≥ 12 who transition from use of Orkambi to tez/iva. Clinical and laboratory measurements will be measured at baseline, 1 month, 3 months, and 6 months after initiation of tez/iva. Change from baseline at 6 months pre-specified will be reported. The length of study participation will be approximately 6 months.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis (CF)

Detailed Description

While cystic fibrosis (CF) therapeutic development previously targeted the signs and symptoms of the disease, in the last 5 years, two drugs that treat the basic defect in CF have been approved, ivacaftor (iva) and lumacaftor/ivacaftor (lum/iva). This class of drugs, deemed cystic fibrosis transmembrance conductance regulator (CFTR) modulators, variably improve CFTR function as measured by pilocarpine iontophoresis and sweat collection, and clinical outcomes including lung function, body mass index (BMI), rate of exacerbations and patient reported quality of life.

In patients with the G551D mutation who received iva, there was a marked decrease in sweat chloride and marked improvement in lung function as measured by absolute change from baseline of percent predicted expiratory volume in 1 second (ppFEV1). The clinical outcomes assessed in the phase III studies of lum/iva and tez/iva were similar, and included lung function, rate of pulmonary exacerbations, BMI, and CFQ-R scores. While the correlation between improvement in sweat chloride and lung function is poor, and a minimum threshold for change in sweat chloride that correlates with clinical outcomes has yet to be defined, it has also not been determined if an increase in sweat chloride caused by a transition from one drug to another would adversely impact clinical outcomes. Outcomes between the phase III studies of lum/iva and tez/iva were similar, tez/iva has three advantages that are likely to make it more appealing to patients and providers than lum/iva including positive clinical efficacy data, fewer drug-drug interactions, and an improved tolerance profile.

Following tez/iva approval, a rapid uptake of tez/iva for patients homozygous for F508del CFTR is expected; as a result of the transition from lum/iva to tez/iva, sweat chloride will increase possibly resulting in an adverse impact on clinical outcomes. This study aims to determine the rationale for patient transition from lum/iva to tez/iva, in addition to evaluate the impact of transition on CFTR function, pulmonary health, gastrointestinal health, and general health. While it is possible that there will be no change in sweat chloride or small changes that are without clinical significance, systematic collection of data as patients transition from lum/iva to tez/iva would permit rapid identification of any safety issues. Because the U.S. always leads the way with approval and reimbursement of new therapeutics, our experience with this transition will help guide its conduct for physicians and patients in the rest of the world.

Study Design

• Study Type: Observational
• Actual Enrollment: 5 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: : TRANSITION: An Observational Study of the Effects on Sweat Chloride and Clinical Outcomes of Transition From Lumacaftor/Ivacaftor to Tezacaftor/Ivacaftor (Tez/Iva)
• Actual Study Start Date: Mar 1, 2018
• Actual Primary Completion Date: Nov 1, 2019
• Actual Study Completion Date: Nov 1, 2019

Outcome Measures

Primary Outcome Measures

1. Change in Sweat Chloride Concentration in Millimoles/Liter From Baseline at 6 Months Pre-specified to be Reported [Baseline to 6 months]

   Sweat chloride is a measure of CFTR function. The calculations represent the average change from baseline to the average change at 6 months.

Secondary Outcome Measures

1. Rationale for Transition Per Physician Questionnaire [1 day (the questionnaire is done once at visit 1)]

   Questionnaire to determine the treating physician's reason for transition to tezacaftor/ivacaftor from lumacaftor/ivacaftor

2. Rationale for Transition Per Subject Questionnaire [1 day (the questionnaire is done once at visit 1)]

   Questionnaire to determine the subject's reason for transition to tezacaftor/ivacaftor from lumacaftor/ivacaftor

3. Pulmonary Exacerbations [One year prior to study entry (time of consent) and during study participation]

   Number of pulmonary exacerbations requiring oral or IV antibiotics

4. Change in Percent Predicted (ppFEV1) Value From Baseline at 6 Months Pre-specified to be Reported [Baseline to 6 months]

   Pulmonary function by spirometry, percent predicted forced expiratory volume in 1 second. The calculations represent the average change from baseline to the average change at 6 months.

5. Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline at 6 Months [Baseline to 6 months]

   CF-related quality of life measure is a validated, CF specific, patient reported outcome (PRO). This portion of the PRO is specific to respiratory symptoms. The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition), with higher scores indicating better health in respiratory domain.

6. Change in Weight in Kilograms From Baseline at 6 Months Pre-specified to be Reported [Baseline to 6 months]

   Weight is a reflection of nutrition status in CF and is expected to improve with CFTR modulation. The calculations represent the average change from baseline to the average change at 6 months.

7. Change in BMI in kg/m^2 From Baseline at 6 Months Pre-specified to be Reported [Baseline to 6 months]

   BMI is a reflection of nutrition status in CF and is expected to improve with CFTR modulation. The calculations represent the average change from baseline to the average change at 6 months.

8. Number of People With Undetectable or Normal Fecal Elastase Measurements at 6 Months Pre-specified to be Reported [6 months]

   Fecal elastase in micrograms/gram. Fecal elastase is a measure of pancreatic function: Less than 100 mcg/g indicates severe exocrine pancreatic insufficiency, 100-200 mcg/g indicates moderate to mild insufficiency, greater than 200 indicates normal pancreatic function. The count represents the number of participants with either an undetectable fecal elastase level or normal level at 6 months, indicating change in pancreatic function at 6 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of CF

• Male or female subjects greater than or equal to 12 years of age

• Ability to reproducibly perform spirometry testing

• Physician decision to treat with tezacaftor/ivacaftor (Smydeko)

• Ability to understand and sign a written informed consent or assent and comply with the requirements of the study

• Continuous use of orkambi for at least 1 month prior to visit 1

Exclusion Criteria:

• History of hypersensitivity to tezacaftor and/or ivacaftor

• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data

• Any acute lower respiratory symptoms treated with oral, inhaled or intravenous antibiotics (IV) or systemic corticosteroids within the 2 weeks prior to Visit 1

• Major or traumatic surgery within 12 weeks prior to Visit 1

• For women of child-bearing potential: a positive pregnancy test at Visit 1

• Unable or unwilling to fast (including no enteric tube feedings) for at least 6 hours prior each visit

• Initiation of any new chronic therapy within 4 weeks prior to Visit 1

• Use of an investigational agent within 28 days prior to Visit 1

• Use of chronic oral corticosteroids within 28 days prior to Visit 1

• Treatment for nontuberculous mycobacterial (NTM) infection, consisting of greater than or equal to two antibiotics (oral, IV, and/or inhaled) within 28 days prior to Visit 1

• History of lung or liver transplantation, or listing for organ transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Heatlh	Denver	Colorado	United States	80206

Sponsors and Collaborators

• National Jewish Health

Investigators

• Principal Investigator: Jennifer Taylor-Cousar, MD, MSCS, National Jewish Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 26, 2018
• Informed Consent Form - Feb 19, 2019

More Information

Publications

None provided.

• Responsible Party: Jennifer Taylor-Cousar, MD, Principal Investigator, Co-Director/CF TDN Director, Adult CF Program, National Jewish Health
• ClinicalTrials.gov Identifier: NCT03445793
• Other Study ID Numbers: HS-3145
• First Posted: Feb 26, 2018
• Last Update Posted: Oct 1, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jennifer Taylor-Cousar, MD, Principal Investigator, Co-Director/CF TDN Director, Adult CF Program, National Jewish Health: DeltaF508deletion (F508del) mutation in 2 copies
• Additional relevant MeSH terms: Cystic Fibrosis

Study Results

Participant Flow

Recruitment Details	Single center recruitment from March 2018 until November 2019.
Pre-assignment Detail	Participant must complete baseline visit while on lumacaftor/ivacaftor prior to transition to tezacaftor/ivacaftor.

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Overall Participants	5
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.4 (1.14)
Sex: Female, Male (Count of Participants)
Female	2 40%
Male	3 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Cystic Fibrosis Mutation Type (Count of Participants)
Homozygous for F508del	5 100%
Heterozygous for F508del	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.3 (1.50)

Outcome Measures

1. Primary Outcome

Title	Change in Sweat Chloride Concentration in Millimoles/Liter From Baseline at 6 Months Pre-specified to be Reported
Description	Sweat chloride is a measure of CFTR function. The calculations represent the average change from baseline to the average change at 6 months.
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (95% Confidence Interval) [mmol/L]	10.2

2. Secondary Outcome

Title	Rationale for Transition Per Physician Questionnaire
Description	Questionnaire to determine the treating physician's reason for transition to tezacaftor/ivacaftor from lumacaftor/ivacaftor
Time Frame	1 day (the questionnaire is done once at visit 1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Side Effects/Intolerance of Orkambi	4 80%
No benefit on Orkambi	1 20%

3. Secondary Outcome

Title	Rationale for Transition Per Subject Questionnaire
Description	Questionnaire to determine the subject's reason for transition to tezacaftor/ivacaftor from lumacaftor/ivacaftor
Time Frame	1 day (the questionnaire is done once at visit 1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
"Orkambi is no longer working for me"	1 20%
No benefit on Orkambi	1 20%
Side effects/Intolerance on Orkambi	2 40%
Personal desire to try new therapy	1 20%

4. Secondary Outcome

Title	Pulmonary Exacerbations
Description	Number of pulmonary exacerbations requiring oral or IV antibiotics
Time Frame	One year prior to study entry (time of consent) and during study participation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (Standard Deviation) [Pulmonary Exacerbations]	3.2 (3.96)

5. Secondary Outcome

Title	Change in Percent Predicted (ppFEV1) Value From Baseline at 6 Months Pre-specified to be Reported
Description	Pulmonary function by spirometry, percent predicted forced expiratory volume in 1 second. The calculations represent the average change from baseline to the average change at 6 months.
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (95% Confidence Interval) [percent predicted (ppFEV1)]	-2.0

6. Secondary Outcome

Title	Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline at 6 Months
Description	CF-related quality of life measure is a validated, CF specific, patient reported outcome (PRO). This portion of the PRO is specific to respiratory symptoms. The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition), with higher scores indicating better health in respiratory domain.
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (95% Confidence Interval) [score on a scale]	-11.3

7. Secondary Outcome

Title	Change in Weight in Kilograms From Baseline at 6 Months Pre-specified to be Reported
Description	Weight is a reflection of nutrition status in CF and is expected to improve with CFTR modulation. The calculations represent the average change from baseline to the average change at 6 months.
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (Standard Deviation) [kg]	2.0 (2.68)

8. Secondary Outcome

Title	Change in BMI in kg/m^2 From Baseline at 6 Months Pre-specified to be Reported
Description	BMI is a reflection of nutrition status in CF and is expected to improve with CFTR modulation. The calculations represent the average change from baseline to the average change at 6 months.
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Mean (95% Confidence Interval) [kg/m^2]	-0.67

9. Secondary Outcome

Title	Number of People With Undetectable or Normal Fecal Elastase Measurements at 6 Months Pre-specified to be Reported
Description	Fecal elastase in micrograms/gram. Fecal elastase is a measure of pancreatic function: Less than 100 mcg/g indicates severe exocrine pancreatic insufficiency, 100-200 mcg/g indicates moderate to mild insufficiency, greater than 200 indicates normal pancreatic function. The count represents the number of participants with either an undetectable fecal elastase level or normal level at 6 months, indicating change in pancreatic function at 6 months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
Measure Participants	5
Undetectable <15	5 100%
Normal Result	0 0%

Adverse Events

Time Frame	6 months
Arm/Group Title	Observational
Arm/Group Description	Participants who have cystic fibrosis and are clinically stable at time of transition from Lumacaftor/Ivacaftor to tezacaftor/ivacaftor as a continuous treatment as determined by their clinical physician.
All Cause Mortality
	Observational
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Observational
	Affected / at Risk (%)	# Events
Total	3/5 (60%)
Respiratory, thoracic and mediastinal disorders
Hospitalization due to pulmonary exacerbation	3/5 (60%)	16
Other (Not Including Serious) Adverse Events
	Observational
	Affected / at Risk (%)	# Events
Total	2/5 (40%)
Respiratory, thoracic and mediastinal disorders
Increased cough after stopping Tezacaftor/Ivacaftor	1/5 (20%)	1
Exacerbation of Chronic Sinusitis	1/5 (20%)	1

Limitations/Caveats

The limitation is the small sample size. Less patients with cystic fibrosis transitioned from lumacaftor/ivacaftor to tezacaftor/ivacaftor than expected. The enrolled number of patients left the study underpowered to detect differences.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.