Phase 3 Open-Label Study on Pharmacokinetics, Safety, and Tolerability of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients Aged 12 to <24 Months
- Trial ID
- 2023-503230-49-00
- Protocol
- VX22-445-122
- Sponsor
- Vertex Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, open-label study is to evaluate the **safety** and **tolerability** of the combination therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) in subjects with **Cystic Fibrosis** aged 12 to less than 24 months. This is clinically relevant as it aims to ensure that the treatment is safe and well-tolerated in this young patient population, which is crucial for the management of Cystic Fibrosis at an early age.
Secondary objectives include:
- Evaluating the pharmacokinetics (PK) of ELX, TEZ, IVA, and relevant metabolites to understand the absorption, distribution, metabolism, and excretion of the drugs in this age group.
- Assessing the pharmacodynamics (PD) of ELX/TEZ/IVA to determine the biological effects and mechanism of action of the treatment.
- Evaluating the efficacy of ELX/TEZ/IVA to measure the therapeutic benefits and improvements in clinical outcomes for the subjects.
Participants
The clinical trial involves a total of **35 participants** diagnosed with **Cystic Fibrosis**. The study population consists of both male and female subjects aged between **12 to less than 24 months**. Participants were selected based on a confirmed diagnosis of cystic fibrosis and the presence of at least one F508del mutation in the CFTR gene or another ELX/TEZ/IVA-responsive CFTR mutation. The trial includes a vulnerable population, as it involves young children. Participants are required to have stable cystic fibrosis disease at the start of the treatment period and must maintain a stable CF medication regimen, excluding CFTR modulators, throughout the study duration. The selection process ensures that the parent or legal guardian of each participant is capable of understanding the protocol requirements and ensuring compliance with the study procedures.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of a combination therapy consisting of elexacaftor, tezacaftor, and ivacaftor in subjects with **cystic fibrosis** aged 12 to less than 24 months. This is a Phase 3, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to commence recruitment on May 14, 2024, and conclude by October 6, 2025, with a total duration of approximately 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of cystic fibrosis, and specific genetic mutations responsive to the study drugs. The treatment period will last up to 24 weeks, during which participants will receive the study medication orally in the form of granules. Follow-up visits will be scheduled to monitor safety and collect data on pharmacokinetics and changes in sweat chloride levels, a key indicator of treatment efficacy. The end-of-study visit will assess the overall safety and tolerability of the treatment.
Participant involvement is expected to last for the entire 24-week treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include adverse events, non-compliance with the study protocol, or if the participant's central laboratory genotype does not confirm eligibility. The primary endpoints focus on safety assessments, including adverse events, clinical laboratory values, and vital signs, while secondary endpoints include pharmacokinetic parameters and changes in sweat chloride levels from baseline through Week 24.
Treatment
The clinical trial involves the administration of several experimental medications, each formulated as **granules** for oral use. The first medication, **Kalydeco 25 mg granules in sachet**, contains the active substance **ivacaftor**. It is administered orally with a maximum daily dose of 25 mg. The treatment period for this medication is up to 24 weeks. The granules are provided in sachets, ensuring ease of administration and accurate dosing. Participant compliance is monitored through regular assessments and adherence checks.
Another experimental medication used in the trial is **VX-770 granules**, also containing **ivacaftor** as the active ingredient. This formulation is administered orally with a maximum daily dose of 59.5 mg. The treatment duration is consistent with the other medications, extending up to 24 weeks. The granules are designed for ease of use, and participant adherence is closely monitored throughout the study.
The trial also includes a fixed-dose combination of **VX-445/VX-661/VX-770 granules**, which contains the active substances **tezacaftor**, **elexacaftor**, and **ivacaftor**. This combination is administered orally with a maximum daily dose of 80 mg. The treatment period is up to 24 weeks. The granules are formulated to ensure consistent dosing and participant compliance is tracked through scheduled assessments.
Additionally, the study utilizes **VX-445/VX-661/VX-770 granules** in a different dosage, with a maximum daily dose of 40 mg. This formulation also contains **tezacaftor**, **elexacaftor**, and **ivacaftor**. The administration route is oral, and the treatment period is up to 24 weeks. Compliance is monitored to ensure adherence to the dosing schedule.
Another variant of the **VX-445/VX-661/VX-770 granules** is used, with a maximum daily dose of 60 mg. This formulation is identical in active substances and administration route, with the treatment period extending up to 24 weeks. Participant adherence is evaluated regularly to maintain dosing accuracy.
Lastly, the trial includes **Kalydeco 50 mg granules in sachet**, containing **ivacaftor**. This medication is administered orally with a maximum daily dose of 50 mg, and the treatment period is up to 24 weeks. The granules are provided in sachets for precise dosing, and participant compliance is monitored throughout the study.
Efficacy
The efficacy of the clinical trial will be assessed through several key parameters. The primary endpoints focus on safety and tolerability, which will be evaluated by monitoring adverse events (AEs), clinical laboratory values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry. Secondary endpoints include pharmacokinetic (PK) parameters of **Elexacaftor (ELX)**, **Tezacaftor (TEZ)**, **Ivacaftor (IVA)**, and their relevant metabolites, as well as the absolute change in sweat chloride (SwCl) from baseline through Week 24.
Data collection will occur at specified intervals throughout the trial, with particular attention to the change in sweat chloride levels, which will be measured from baseline to Week 24. The trial is designed to ensure comprehensive monitoring of the participants' response to the treatment regimen, with a focus on both the safety and efficacy of the drug combination. The trial will utilize validated laboratory tests and clinical assessments to gather data, ensuring the reliability and accuracy of the efficacy evaluations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) will sign and date an informed consent form (ICF).
- Subjects (male and female) 12 to <24 months of age on Day 1.
- Confirmed diagnosis of CF as determined by the investigator.
- Subjects who have at least one F508del mutation in the CFTR gene or another ELX/TEZ/IVA-responsive CFTR mutation. A previous CFTR genotype laboratory report may be used to establish eligibility, but the subject’s genotype must be approved by the Vertex medical monitor. • All subjects will have a central laboratory genotype obtained on Day 1 (Parts A and B). Subjects with a historical CFTR genotype report may initiate study drug dosing before confirmation on central laboratory testing. Subjects who do not have a historical CFTR genotype report available will have genotyping performed at Screening Visit 1 instead of Day 1 in the respective Part, and the eligible CFTR mutation must be confirmed by central laboratory testing before the first dose of study drug. This assessment does not need to be repeated in the case of rescreening or for confirmed subjects in Part A who wish to screen for participation in Part B. • Subjects who have been enrolled based on a historical CFTR genotype laboratory report and whose central laboratory genotype does not confirm study eligibility must be discontinued from the study.
- Subjects with stable CF disease at the start of the Treatment Period as deemed by the investigator.
- Subjects whose parent or legal guardian is willing to keep the subject on a stable CF medication regimen (other than CFTR modulators) through Week 24 (Part B) or, if applicable, through the Safety Follow-up Visit.
- As judged by the investigator, the parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should be able to ensure that the subject will comply with and is likely to complete the study as planned.
Exclusion Criteria
- History of any illness or any clinical condition that, in the opinion of the investigator, might either confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following: o Clinically significant cirrhosis with or without portal hypertension o Solid organ or hematological transplantation o Cancer o Any history of seizure
- Any clinically significant laboratory abnormalities at the Screening Visits that would interfere with the study assessments or pose an undue risk for the subject (as deemed by the investigator).
- Any of the following abnormal laboratory values at screening: o Hemoglobin <10 g/dL o Total bilirubin, aspartate transaminase (AST), or alanine transaminase (ALT) ≥2 × upper limit of normal (ULN) o Alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) ≥3 × ULN o Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Bedside Schwartz equation)
- Any history of elevated serum ALT or AST ≥3 × ULN or total bilirubin ≥2 × ULN, unless occurring before 3 months of corrected gestational age and due to an identified proximate cause, such as reversible post-hepatic biliary obstruction, meconium ileus, infection, or neonatal hyperbilirubinemia, in the judgment of the investigator.
- An acute upper or lower respiratory infection, PEx, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
- Any history of respiratory tract culture positive for an organism associated with more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus)
- An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1).
- Ongoing or prior participation in an investigational drug study (including studies investigating ELX with or without coadministration with other study drugs) within 28 days of Screening Visit 1 (or the concurrent Screening Visit 1 and 2, as applicable). o A washout period of 5 terminal half lives of the previous investigational study drug, or 28 days, whichever is longer, must elapse before the Screening Visit. o The duration of the elapsed time may be longer if required by local regulations. Note: Ongoing participation in a noninterventional study (including observational studies) is permitted.
- Ongoing breastfeeding (or consumption of expressed breastmilk) by a subject whose mother is taking any CFTR modulator. o If a mother chooses to stop their own CFTR modulator use, or to stop breastfeeding (and all other routes of feeding expressed breastmilk to the subject), so as to allow the subject to participate in this study, then a washout period of 28 days from last exposure must elapse before the Day 1 Visit.
- Use of restricted medication within specified duration before the first dose of study drug as defined in the Prohibited Medications table of the Protocol.
- A close relative of the subject is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 14 May 2024 | 3 |
 Germany | Not Recruiting | 14 May 2024 | 9 |
 The Netherlands | Not Recruiting | 14 May 2024 | — |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VX-770 granules | Test | GRANULES | ORAL | 59.5 | 24 | PRD9088744 |
VX-445/VX-661/VX-770 fixed-dose combination granules | Test | GRANULES | ORAL USE | 80 | 24 | PRD8170957 |
VX-445/VX-661/VX-770 granules | Test | GRANULES | ORAL | 40 | 24 | PRD9662148 |
Kalydeco 25 mg granules in sachet | Test | GRANULES IN SACHET | ORAL | 25 | 24 | PRD7765990 |
VX-445/VX-661/VX-770 granules | Test | GRANULES | ORAL USE | 60 | 24 | PRD9662149 |
Kalydeco 50 mg granules in sachet | Test | GRANULES IN SACHET | ORAL | 50 | 24 | PRD3450695 |