Testing drug effectiveness for cystic fibrosis using personalized medicine

Testing Drug Efficacy in Cystic Fibrosis Through N-of-1 Trials

This study is testing if personalized medicine can help find the best CF treatments for people with rare cystic fibrosis gene mutations by using their own nasal cells.

Quick facts

• Phase: NA
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 6 Years and up
• Sex: All
• Sponsor: Children's Hospital Medical Center, Cincinnati (other)
• Drugs / interventions: prednisone
• Locations: 1 site (Cincinnati, Ohio)
• Trial ID: NCT04580368 on ClinicalTrials.gov

What this trial studies

This study aims to validate a personalized medicine approach for identifying effective treatments using FDA-approved CFTR modulators for patients with rare cystic fibrosis gene mutations. It involves ex vivo testing of CFTR function on nasal cells at the Cincinnati Children's Human Nasal Epithelium Core Laboratory. The results will inform N-of-1 trials to assess the therapeutic benefit of these treatments in individual patients. The study will continuously incorporate newly approved CF drug therapies as they become available.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 6 years and older with a documented diagnosis of cystic fibrosis and at least one rare CFTR variant.

Not a fit: Patients without a rare CFTR variant or those not prescribed a CFTR modulator may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to more effective personalized treatments for patients with rare cystic fibrosis mutations.

How similar studies have performed: Other studies have shown promise in using personalized medicine approaches for cystic fibrosis, but this specific N-of-1 trial methodology is relatively novel.

Eligibility criteria

Inclusion Criteria:

* Signed informed consent (and assent when applicable)
* Willing and able to adhere to the study visit schedule and protocol requirements
* Male or Female ≥6 years old and within the FDA-approved range for the proposed modulator drug

  * Ivacaftor: ≥4 months old
  * Lumacaftor/Ivacaftor: 2 years old
  * Tezacaftor/Ivacaftor: 12 years old
  * Elexacaftor/Tezacaftor/Ivacaftor: ≥12 years old
* At least one rare CFTR variant (incidence of \<5% of the CF population)
* Documentation of a CF diagnosis as evidenced by one or more clinical features of CF plus at least one of the following:

  * Sweat Chloride ≥60mmol/L by quantitative pilocarpine iontophoresis
  * Two mutations in the CFTR gene
  * Abnormal nasal potential difference (NPD) testing supportive of a CF diagnosis
* FEV1 \> 50% predicted for age
* Stable chronic CF therapies with no changes in \>28 days (except for chronic cycled inhaled antibiotics such as tobramycin)
* Prescribed CFTR modulator by a licensed physician
* No contraindication to treatment with the selected drug at the time of treatment initiation

Exclusion Criteria:

* Presence of any condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the patient and/or quality of the data
* For women of child bearing potential:

  * Positive pregnancy test or known pregnancy at Visit 1
  * Lactating
  * Unwilling to practice a medically acceptable form of contraception (acceptable forms include abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or postmenopausal during the study
* BMI \< 10th percentile for age (if \<18 years old) or \< 20kg/m2 (if ≥18 years old)
* FEV1 ≤ 50% predicted for age
* Growth of CF pathogens from sputum cultures that are associated with unstable disease (e.g., nontuberculous mycobacteria, Burkholderia spp) within six months of enrollment
* Concomitant use of CYP3A inducers or inhibitors (e.g., voriconazole, fluconazole, rifampin) or prednisone (\>20mg daily)
* Concomitant conditions:

  * Poorly controlled diabetes mellitus (HbA1c \>8.5 or glucosuria as noted below)
  * Advanced CF liver disease (cirrhosis with portal hypertension, ascites, or abnormal liver laboratory testing as noted below)
  * End stage renal disease
  * History of organ transplantation
  * Additional medical conditions that in the opinion of the Investigator place the patient at risk of participation or may impact the patient's ability to complete the trial (e.g., uncontrolled depression, anxiety disorder, poor adherence to CF therapies, active ABPA)
* Any of the following abnormal laboratory values at the Screening Visit:

  * CBC
  * WBC \>15,000 K/mcL or ANC \<1,500 K/mcL
  * Hemoglobin \<10 gm/dL
  * Platelets \<50,000 K/mcL
  * Chemistries
  * \>2+ Glucosuria
  * Clinically significant abnormalities as assessed by the Investigator
  * Glomerular filtration rate ≤50 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)
  * Hepatic Function Testing / Coagulation Testing
  * ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)
  * ≥3 × ULN alanine aminotransferase (ALT)
  * ≥3 × ULN gamma-glutamyl transpeptidase
  * Total or direct bilirubin \>2 × ULN
  * INR \> 1.5 x ULN
  * Positive pregnancy test

Where this trial is running

Cincinnati, Ohio

• CCHMC — Cincinnati, Ohio, United States (RECRUITING)

Study contacts

• Study coordinator: John Brewington, MD

Conditions: Cystic Fibrosis, CFTR modulators, cystic fibrosis, HNE, human nasal epithelial cells, NPD, nasal potential difference, air-liquid interface