Safety of Stopping Pancreatic Enzyme Replacement Therapy in Children With Improved Pancreatic Function After Highly Effective Modulator Therapy

The Return of the Pancreas: Evaluating Impact of CFTR Modulators on Pancreatic Function

The goal of this clinical trial is to evaluate the safety of stopping pancreatic enzyme replacement therapy (PERT) in children with cystic fibrosis (CF) receiving CFTR modulator therapy (CFTRm) who have regained pancreatic sufficiency. The main questions it aims to answer are:

1. Does discontinuation of PERT affect gastrointestinal symptoms, nutritional status, pancreatic function, or body composition over 6 months?
2. Does stopping PERT increase gastrointestinal symptoms or affect nutritional status, pancreatic function, or body composition compared with continuing PERT?

Researchers will evaluate changes in growth, gastrointestinal symptoms, vitamin levels, pancreatic function, and body composition following PERT discontinuation.

Participants will:

• Complete study visits and assessments over 6 months
• Continue or discontinue PERT based on study assignment
• Undergo anthropometric measurements
• Complete questionnaires about gastrointestinal symptoms
• Provide blood samples to assess vitamin levels and coagulation markers
• Provide stool samples to measure fecal elastase-1 (FE-1) and evaluate pancreatic function

This prospective clinical trial will evaluate the safety and feasibility of discontinuing pancreatic enzyme replacement therapy (PERT) in children with cystic fibrosis (CF) who regain pancreatic sufficiency after treatment with cystic fibrosis transmembrane conductance regulator modulators (CFTRm).

Pancreatic insufficiency is a common complication of CF and is typically treated with lifelong PERT. Recent studies and case reports have shown that some individuals receiving CFTR modulators experience improvement or normalization of pancreatic function, as measured by fecal elastase-1 (FE-1) levels. However, there is limited evidence regarding the safety of stopping PERT after pancreatic function recovery. This study aims to address this knowledge gap by prospectively evaluating growth, gastrointestinal symptoms, nutritional status, and pancreatic function after PERT withdrawal.

Eligible participants are children and adolescents aged 18 years or younger with cystic fibrosis and a history of pancreatic insufficiency who are receiving CFTR modulator therapy. Participants will undergo fecal elastase testing at enrollment and will be assigned to study groups based on pancreatic function status. Participants with FE-1 levels ≥200 µg/g will discontinue PERT under medical supervision, while participants with FE-1 levels <200 µg/g will continue standard therapy.

Study assessments will include growth measurements, gastrointestinal symptom questionnaires, laboratory monitoring of fat-soluble vitamins and liver function, CFTR modulator trough levels, and repeat fecal elastase testing. Body composition will also be evaluated. Participants who discontinue PERT will undergo close clinical monitoring throughout the study period for signs of malabsorption, poor weight gain, recurrent pancreatic insufficiency, or pancreatitis. PERT may be restarted if clinically indicated.

The study will also explore factors associated with successful recovery of pancreatic function and sustained pancreatic sufficiency, including demographic characteristics, nutritional status, medication history, and laboratory markers. In addition, optional biospecimen storage will allow future analyses of the metabolome and microbiome related to pancreatic function and CFTR modulator response.

This study is intended to provide feasibility and safety data to support future larger multicenter trials and to improve individualized treatment strategies for children with CF who experience recovery of pancreatic function after CFTR modulator therapy.

Inclusion Criteria:

• Diagnosis of cystic fibrosis.
• History of pancreatic insufficiency, documented by a prior fecal elastase-1 (FE-1) concentration <200 µg/g stool.
• Current pancreatic sufficiency at study entry, defined as fecal elastase-1 (FE-1) concentration ≥200 µg/g stool after treatment with a CFTR modulator.
• Age ≤18 years.
• Current use of a CFTR modulator, including ivacaftor, elexacaftor/tezacaftor/ivacaftor, or vanzacaftor/tezacaftor/deutivacaftor.

Exclusion Criteria:

• CF-related diabetes requiring current insulin use
• Advanced CF liver disease as defined by nodular liver, advanced fibrosis (F4), multi-lobular cirrhosis with or without portal hypertension, non-cirrhotic portal hypertension
• Short gut syndrome as defined by need for surgical bowel resection and subsequent need for parenteral nutrition for > 60 days or bowel length less than 25%
• Moderate to severe malnutrition, defined as a BMI-for-age z score ≤ -2 for participants aged ≥2 years or a weight-for-length z score ≤ -2 for participants aged <2 years