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

Overview

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.

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).

Interventions

• 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).
• 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.
• Other RETRIAL-Neuro
  Participants will complete a neurocognitive assessment prior to starting VTD and 28 days after.

Primary outcome measures

• 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]
• 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]
• 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]
• 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]

Secondary outcome measures (4)

• 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]
• 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]
• 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]
• 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]

Eligibility criteria

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:

• No modulators
• A modulator other than ETI
• A flipped dose of ETI
• 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:

• no modulators; or
• a modulator other than ETI; or
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 18 centers

• University of Alabama at Birmingham — Birmingham
• Children's Hospital Colorado — Aurora
• National Jewish Health — Denver
• Nemours Children's — Wilmington
• Nemours Children's — Jacksonville
• Nemours Children's — Orlando
• Nemours Children's — Pensacola
• Emory University — Atlanta
• … and 10 more centers

Identifiers

NCT: NCT06683092 · IRB-P00050262

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗