Cystic Fibrosis in the Kidney: Monitoring the Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in Urine After a Short Pause of Therapy

Study Overview
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Brief Summary
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In cystic fibrosis (CF) renal base excretion is impaired, due to mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, since CFTR function is crucial in regulation of the kidney's HCO3- excretion. The investigators suggest that challenged urine HCO3- excretion is a biomarker of CFTR function, which can be used to evaluate the extent of CFTR dysfunction and the possible correcting effects of CFTR modulating therapy. This study aims to evaluate changes in challenged urine HCO3- excretion in CF patients, who are currently in treatment with the triple CFTR modulator combination therapy, Elexacaftor/tezacaftor/ivacaftor (ETI), before, during, and after a short treatment pause.

Official Title
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Cystic Fibrosis in the Kidney: Monitoring the Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in Urine After a Short Pause of Therapy

Conditions
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Cystic Fibrosis (CF), CFTR Gene Mutation

Intervention / Treatment
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* Other: 12 hours ETI pause
* Other: 36 hours ETI pause
* Other: 60 hours ETI pause


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (age >17 years) CF patients. Normal kidney function estimated by eGFR>90. Adults capable of understanding and voluntarily consenting. Exclusion Criteria: Critical acute illness. Severe lung disease (ppFEV1<40%). Adults not capable of understanding and voluntarily consenting.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: CF patients will perform a challenged urine bicarbonate test three times during this trial; 1) before, 2) during, and 3) after ETI therapy pause. Each test performance takes 90 min. and is accompanied by baseline blood sampling. First, a baseline urine sample is collected. Then the test person ingests 79 mg. NaHCO3/kg body weight dissolved in tap water (2,25 mL/kg body weight) together with the same amount of clean tap water. After 90 min. the test person delivers the second urine sample, and the test is completed. The test should preferably be performed between breakfast and lunch, at least one hour after intake of food. There should be at least three days between each test. CF patients will be randomly allocated to an ETI treatment pause for either 12, 36, or 60 hours. Treatment will be resumed immediately after the pause is finished.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 12 hours ETI pause<br> | Other: 12 hours ETI pause<br>* Patients with CF are randomly allocated to ETI pause lasting 12 hours.<br>|
| Other: 36 hours ETI pause<br> | Other: 36 hours ETI pause<br>* Patients with CF are randomly allocated to ETI pause lasting either 36 hours.<br>|
| Other: 60 hours ETI pause<br> | Other: 60 hours ETI pause<br>* Patients with CF are randomly allocated to ETI pause lasting either 60 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in cumulative urine bicarbonate excretion before, during, and after ETI pause. | Challenged urine HCO3- test: Quantification of urine bicarbonate excretion after an acute oral NaHCO3 challenge before, under, and after ETI pause. | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. | 
| Link between changes in ETI plasma concentration and changes in urine bicarbonate excretion. | Venous blood sampling: ETI plasma concentration measurement. Challenged urine HCO3- test: Quantification of urine bicarbonate excretion | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Link between plasma acid-base status and urine acid-base excretion. | Venous blood sampling: Venous acid-base measurements. | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. | 
| Changes in plasma concentration of ETI during the trial. | Venous blood sampling: ETI plasma concentration measurement. | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. | 
| Changes in acid-base and fluid status during the trial. | Venous blood sampling: Venous acid-base and fluid measurements. | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. | 
| Changes in electrolytes during the trial. | Venous blood sampling: Venous electrolyte measurements. Challenged HCO3- urine test: Urine electrolyte measurements. | At baseline, after 12/36/60 hours of therapy pause and after therapy is resumed. |