Restarting Triple Therapy With Robust Monitoring for Adverse Events (RETRIAL)

October 30, 2025 updated by: Gregory Sawicki, Boston Children's Hospital
RETRIAL is a multi-site observational study of people with Cystic Fibrosis (PWCF) ages 6 and up starting the new triple-therapy modulator (vanzacaftor/tezacaftor/deutivacaftor (VTD)), after having experienced neuropsychiatric events and/or liver injury while taking elexacaftor/tezacaftor/ivacaftor (ETI) that resulted in a modification or discontinuation of standard ETI dosing.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

RETRIAL is a prospective, longitudinal, observational, multi-site study of people with Cystic Fibrosis (PWCF) ages 6 and up who had to either change how they took or stop taking elexacaftor/tezacaftor/ivacaftor (ETI) due to new or worsening mental health/cognitive symptoms (such as depression, anxiety, mood, sleep, and/or brain fog/memory problems) and/or liver issues (elevated liver enzymes) while taking the standard dose, and who plan to start taking vanzacaftor/tezacaftor/deutivacaftor (VTD).

Study Type

Observational

Enrollment (Estimated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • Recruiting
        • University of Alabama at Birmingham
        • Contact:
        • Contact:
          • James Fowler
    • Colorado
      • Aurora, Colorado, United States, 80045
      • Denver, Colorado, United States, 80206
        • Recruiting
        • National Jewish Health
        • Contact:
        • Principal Investigator:
          • CJ Bathgate, PhD
    • Delaware
      • Wilmington, Delaware, United States, 19803
        • Recruiting
        • Nemours Children's
        • Contact:
        • Principal Investigator:
          • Kimberly Canter, PhD
        • Principal Investigator:
          • David Fedele, PhD
    • Florida
      • Jacksonville, Florida, United States, 32207
        • Recruiting
        • Nemours Children's
        • Principal Investigator:
          • Kimberly Canter, PhD
        • Principal Investigator:
          • David Fedele, PhD
        • Contact:
      • Orlando, Florida, United States, 32827
        • Recruiting
        • Nemours Children's
        • Contact:
        • Principal Investigator:
          • Kimberly Canter, PhD
        • Principal Investigator:
          • David Fedele, PhD
      • Pensacola, Florida, United States, 32514
        • Recruiting
        • Nemours Children's
        • Contact:
        • Principal Investigator:
          • Kimberly Canter, PhD
        • Principal Investigator:
          • David Fedele, PhD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory University
        • Contact:
        • Contact:
          • Eric Hunter
        • Principal Investigator:
          • Kimberly Dickinson, MD
    • Indiana
      • Bloomington, Indiana, United States, 47405
        • Recruiting
        • Indiana University
        • Contact:
        • Contact:
          • Mary Heskett
        • Principal Investigator:
          • Emma Tillman, PhD PharmD
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Recruiting
        • Kansas University Medical Center
        • Principal Investigator:
          • Amanda Bruce, PhD
        • Contact:
        • Contact:
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Recruiting
        • Johns Hopkins University
        • Principal Investigator:
          • Noah Lechtzin, MD
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Not yet recruiting
        • Massachusetts General Hospital
        • Contact:
        • Principal Investigator:
          • Isabel Neuringer, MD
        • Contact:
          • Ruobin Wei
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Boston Children's Hospital
        • Contact:
        • Principal Investigator:
          • Carolyn Snell, PhD
        • Principal Investigator:
          • Mimi Stotsky, PhD
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Recruiting
        • University of Michigan
        • Contact:
        • Contact:
          • Jessica Carey
        • Principal Investigator:
          • Hanna Phan, PharmD
    • Missouri
      • St Louis, Missouri, United States, 63130
        • Not yet recruiting
        • Washington University at St. Louis
        • Contact:
        • Contact:
          • Stacy Postma
        • Principal Investigator:
          • Andrea Coverston, MD
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15224
        • Recruiting
        • University of Pittsburgh Medical Center
        • Contact:
        • Principal Investigator:
          • Traci Kazmerski, MD
    • Texas
      • Dallas, Texas, United States, 75235
        • Recruiting
        • University of Texas Southwestern Medical Center
        • Principal Investigator:
          • Meghana Sathe, MD
        • Contact:
        • Principal Investigator:
          • David Finklea, MD
    • Washington
      • Seattle, Washington, United States, 98105

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Female and male people with CF ages 6 and older who are not able to tolerate the standard dose of ETI due to either new/worsening mental health symptoms and/or drug-induced liver injury.

Description

Inclusion Criteria:

RETRIAL-Mental Health:

  • PWCF age 6 years and up (if age is < 12 years old, the PWCF's caregiver will complete daily diaries and surveys; see "Caregiver Participant Inclusion Criteria" below)
  • Eligible for VTD and intending to take it

  • Experienced new or worsening mental health symptoms after initiating ETI, which led to one of the following changes in treatment to currently taking:

    1. No modulators
    2. A modulator other than ETI
    3. A flipped dose of ETI
    4. A reduced dose of ETI
  • Willing to delay first VTD dose for short period of time to complete the Baseline assessments
  • Has access to a smart device (phone, tablet, etc.) capable of receiving messages with survey links
  • Is English-speaking.

RETRIAL-LIVER:

  • A person with CF age 6 years and up
  • Eligible for VTD and intending to take it

  • Experienced drug-induced liver injury (as defined by local care team) after initiating ETI, which led to one of the following changes in treatment to currently taking:

    1. no modulators; or
    2. a modulator other than ETI; or
    3. a reduced or altered dose of ETI;
  • Willing to delay first VTD dose for short period of time to complete the Baseline assessments
  • Has access to a smart device (phone, tablet, etc.) capable of receiving messages with survey links
  • Is English-speaking.

Exclusion Criteria:

RETRIAL-Mental Health:

  • Cannot access VTD
  • Currently, or prior history of, taking VTD
  • Unable or unwilling to follow protocol
  • If <12 years old, having another <12-year-old person in the same household consented into the study
  • Is actively listed on any transplant list, or within 3 months post-transplant surgery
  • Is currently pregnant (test not required)
  • Anticipated change in CF Care Centers in the next 6 months
  • Any situation that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.

RETRIAL-LIVER:

  • Cannot access VTD
  • Currently, or prior history of, taking VTD
  • Unable or unwilling to follow protocol
  • If <12 years old, having another <12-year-old person in the same household consented into the study
  • Any severe, decompensated liver disease (e.g. Child-Pugh, Class C)
  • Is actively listed on any transplant list, or within 3 months post-transplant surgery (any organ), or history of liver transplant
  • Is currently pregnant (test not required)
  • Anticipated change in CF Care Centers in the next 6 months
  • Any situation that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.

Caregiver Participant:

Inclusion Criteria:

  • Is a primary, daily caregiver of a person with CF under the age of 12 enrolled in the study
  • Has access to smart device (phone, tablet, etc.) capable of receiving messages with survey links
  • Is able to read and complete surveys and Daily Diary in English.

Exclusion Criteria:

- Any situation that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
RETRIAL-Mental Health
People with CF ages 6 and up with a history of new or worsening mental health symptoms (such as depression, anxiety, mood, sleep) while on elexacaftor/tezacaftor/ivacaftor (ETI) requiring discontinuation or change from standard dosing who start taking vanzacaftor/tezacaftor/deutivacaftor (VTD).
Other: RETRIAL-Mental Health
Participants will complete: daily diaries for 6 weeks, from about 2 weeks prior to starting VTD to about 4 weeks after; biweekly surveys, from about 2 weeks prior to starting VTD to 6 months after, and 2 quarterly surveys (at 9mo and 12mo post-initiation of VTD).
RETRIAL-Neuro
People with CF from RETRIAL-Mental Health who experienced new/worsening neurocognitive symptoms (such as brain fog or memory problems) while taking elexacaftor/tezacaftor/ivacaftor (ETI).
Other: RETRIAL-Neuro
Participants will complete a neurocognitive assessment prior to starting VTD and 28 days after.
RETRIAL-Liver
People with Cystic Fibrosis ages 6 and up with a history of drug-induced liver injury (such as elevated liver enzymes) attributed to elexacaftor/tezacaftor/ivacaftor (ETI) requiring dose modification or discontinuation who start taking vanzacaftor/tezacaftor/deutivacaftor (VTD).
Other: RETRIAL-Liver

Participants may have a research liver function test done prior to starting VTD and 28 days after, if not done clinically.

Participants will complete surveys: before starting VTD, a month after, and quarterly (at about 3, 6, 9, and 12 months) following VTD initiation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
RETRIAL-Mental Health (1st objective - discontinuation): one-year incidence of discontinuation or change from VTD standard dosing due to new/worsening mental health symptoms.
Time Frame: Baseline to Month 12
Discontinuation or change from VTD standard dosing due to mental health symptoms at any time during the one-year follow-up as reported in either: daily diaries, biweekly or quarterly surveys, or chart review.
Baseline to Month 12
RETRIAL-Mental Health (2nd objective - symptoms): proportion of participants that experience any worsening in mental health symptoms during the 6-month follow-up
Time Frame: Baseline to Month 6
Change from baseline that exceeds the minimally-important difference (MID) / minimally-important change (MIC) within the first 6 months after starting VTD in any of the following patient-reported outcome measures: (1) depression (PHQ-8 or PROMIS depression parent proxy), (2) anxiety (GAD-7 or PROMIS anxiety parent proxy), (3) anger and irritability (PROMIS-anger or PROMIS-anger parent proxy), (4) cognitive functioning (PROMIS- cognitive function or PROMIS-cognitive function parent proxy), (5) sleep disturbance (PROMIS-sleep disturbance or PROMIS-sleep disturbance parent proxy).
Baseline to Month 6
RETRIAL-Mental Health (3rd objective - RETRIAL-Neuro): proportion of participants that have a worsening on the NIH Toolbox's Fluid Cognition Composite score at 1 month follow-up.
Time Frame: Baseline to Day 30
Decrease in age-adjusted standard score from baseline to 1 month on the NIH Toolbox's Fluid Cognition Composite Score (a performance-based neurocognitive measure) that exceeds MIC ≥ 7.5 points, signifying a worsening in function.
Baseline to Day 30
RETRIAL-Liver: one-year incidence of drug-induced liver injury (DILI) with VTD, defined by expert consensus after review of clinical and laboratory data.
Time Frame: Baseline to Month 12
Positive DILI diagnosis, including those characterized as "likely," "probable," and "highly probable," as reviewed by a hepatology panel of three experts who assign these likelihood scores based upon review of case report forms, including a specific clinical narrative and laboratory values assessing for other potential etiologies.
Baseline to Month 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
RETRIAL-Mental Health (1st objective - discontinuation): one-year incidence of discontinuation or change from VTD standard dosing due to any reason.
Time Frame: Baseline to Month 12
Reported discontinuation or change from VTD standard dosing due to any reason during the one-year follow-up as reported in either: daily diaries, biweekly or quarterly surveys, or chart review.
Baseline to Month 12
RETRIAL-Mental Health (2nd objective - symptoms): proportion of participants that experience worsening of _each_ mental health symptom during the 6-month follow-up.
Time Frame: Baseline to Month 6
Change from baseline that exceeds the MID/MIC of new/worsening symptoms within the first 6 months after starting VTD for _each_ of the following patient-reported outcomes: (1) depression (PHQ-8 or PROMIS depression parent proxy), (2) anxiety (GAD-7 or PROMIS anxiety parent proxy), (3) anger and irritability (PROMIS-anger or PROMIS-anger parent proxy), (4) cognitive functioning (PROMIS- cognitive function or PROMIS-cognitive function parent proxy), (5) sleep disturbance (PROMIS-sleep disturbance or PROMIS-sleep disturbance parent proxy).
Baseline to Month 6
RETRIAL-Mental Health (3rd objective - RETRIAL-Neuro): proportion of participants that have a worsening of _each_ of the NIH Toolbox's cognition domain score at 1 month follow-up.
Time Frame: Baseline to Month 1
Decrease in age-adjusted standard score from baseline to 1-month that exceeds MIC ≥ 7.5 points for _each_ of the following domains: (1) Flanker, (2) Dimensional Change Card Sort (DCCS), (3) Picture Sequence Memory Test (PSMT), (4) List Sorting, (5) Pattern Comparison.
Baseline to Month 1
RETRIAL-Liver: one-year incidence of discontinuation or change from VTD standard dosing due to patient-reported or medical team-documented concerns for liver injury.
Time Frame: Baseline to Month 12
Reported discontinuation or change from VTD standard dosing due to concerns for liver injury during the one-year follow-up as reported in either: 28-day or quarterly surveys, chart review, or case report forms.
Baseline to Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Boston Children's Hospital

Collaborators

Johns Hopkins University
Massachusetts General Hospital
Washington University School of Medicine
Children's Hospital Colorado
University of Kansas Medical Center
Indiana University
Cystic Fibrosis Foundation
National Jewish Health

Investigators

  • Principal Investigator: Anna Georgiopoulos, MD, Massachusetts General Hospital
  • Principal Investigator: CJ Bathgate, PhD, National Jewish Health
  • Principal Investigator: Janis Stoll, MD, Washington University at St. Louis

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2025

Primary Completion (Estimated)

March 1, 2028

Study Completion (Estimated)

June 1, 2028

Study Registration Dates

First Submitted

November 8, 2024

First Submitted That Met QC Criteria

November 8, 2024

First Posted (Actual)

November 12, 2024

Study Record Updates

Last Update Posted (Estimated)

November 3, 2025

Last Update Submitted That Met QC Criteria

October 30, 2025

Last Verified

October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-P00050262

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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