Phase 3 Evaluation of Pharmacokinetics, Safety, and Tolerability of VX-121/Tezacaftor/Deutivacaftor Combination in Pediatric Cystic Fibrosis Patients
- Trial ID
- 2024-513754-29-00
- Protocol
- VX21-121-105
- Sponsor
- Vertex Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to evaluate the **pharmacokinetics** (PK), safety, and tolerability of the VX-121/Tezacaftor/Deutivacaftor triple combination therapy in pediatric subjects aged 1 through 11 years with **Cystic Fibrosis**. This is clinically relevant as it aims to determine the appropriate dosing and safety profile of this combination therapy in a younger population, which is crucial for optimizing treatment outcomes and minimizing adverse effects in this age group.
Secondary objectives include:
- Evaluating the efficacy of VX-121/TEZ/D-IVA through Week 24, which is important for assessing the therapeutic benefits over a sustained period.
- Evaluating the PK of VX-121, TEZ, D-IVA, and relevant metabolites, which provides insights into the drug's absorption, distribution, metabolism, and excretion, further informing dosing strategies.
Participants
The clinical trial involves a total of **50 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects, with an age range spanning from 12 months to 11 years. Participants are required to have a confirmed diagnosis of Cystic Fibrosis and at least one TCR mutation, including the F508del mutation, in the CFTR gene. The trial population was selected based on specific criteria, including stable CF disease and the ability to maintain a stable CF medication regimen, excluding CFTR modulators, throughout the study duration. Participants are expected to have a weight within the 5th percentile for their age according to CDC growth charts. The trial includes vulnerable populations, and subjects must be able to swallow tablets. The selection process ensures that participants have a stable health status at the start of the treatment period, as determined by the investigator. Lifestyle considerations such as diet and physical activity are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the pharmacokinetics, safety, and tolerability of a triple combination therapy consisting of **VX-121**, tezacaftor, and deutivacaftor in subjects with **cystic fibrosis** aged 1 through 11 years. This is a Phase 3, randomized, double-blind, controlled study. The trial is divided into two parts: Part A focuses on pharmacokinetics and initial safety, while Part B extends the evaluation of safety and tolerability over a 24-week period. The estimated duration of the trial is from February 2023 to August 2027.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, weight, and genotype. The screening visit will also include a negative serum pregnancy test for female subjects of childbearing potential. Following the screening, eligible participants will be randomized into cohorts and will attend regular follow-up visits to monitor safety, tolerability, and pharmacokinetic parameters. The end-of-study visit will conclude the trial, assessing the overall outcomes and any adverse events experienced by the participants.
The expected length of participant involvement varies depending on the cohort, with some participants involved for up to 24 weeks. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or if the participant's screening genotype does not confirm study eligibility. The trial aims to provide comprehensive data on the safety and efficacy of the triple combination therapy in the pediatric population with cystic fibrosis.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific formulations, dosages, and administration routes. **Kalydeco 59.5 mg granules in sachet** is an oral solution containing the active substance **ivacaftor**. It is administered orally with a maximum daily dose of 59.5 mg, and the treatment period is limited to 4 weeks. The granules are provided by Vertex Pharmaceuticals (Ireland) Limited and are of chemical origin.
Another experimental medication is **VX-121/VX-661/VX-561 granules**, which contain the active substances **tezacaftor, deutivacaftor, and vanzacaftor**. These granules are administered orally with a maximum daily dose of 8 mg, and the treatment period extends up to 24 weeks. The granules are produced by Vertex Pharmaceuticals, Incorporated, and are also of chemical origin.
**Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets** are administered orally and contain the active substances **tezacaftor, elexacaftor, and ivacaftor**. The maximum daily dose is 50 mg, with a treatment period of 4 weeks. These tablets are manufactured by Vertex Pharmaceuticals (Ireland) Limited and are of chemical origin.
**VX-445/VX-661/VX-770 fixed-dose combination granules** are another formulation used in the trial. These granules contain **tezacaftor, elexacaftor, and ivacaftor** and are administered orally with a maximum daily dose of 80 mg over a 4-week treatment period. The granules are provided by Vertex Pharmaceuticals, Incorporated, and are of chemical origin.
**VX-121/VX-661/VX-561 Film-coated tablet** is an oral formulation containing **tezacaftor, deutivacaftor, and vanzacaftor**. The maximum daily dose is 10 mg, and the treatment period is 24 weeks. These tablets are produced by Vertex Pharmaceuticals, Incorporated, and are of chemical origin.
**Kalydeco 75 mg film-coated tablets** are administered orally and contain the active substance **ivacaftor**. The maximum daily dose is 75 mg, with a treatment period of 4 weeks. These tablets are manufactured by Vertex Pharmaceuticals (Ireland) Limited and are of chemical origin.
**Kalydeco 75 mg granules in sachet** is another oral formulation containing **ivacaftor**. The maximum daily dose is 75 mg, and the treatment period is 4 weeks. These granules are provided by Vertex Pharmaceuticals (Ireland) Limited and are of chemical origin.
**VX-445/VX-661/VX-770 film-coated fixed-dose combination tablet** is an oral formulation containing **tezacaftor, elexacaftor, and ivacaftor**. The maximum daily dose is 100 mg, with a treatment period of 4 weeks. These tablets are produced by Vertex Pharmaceuticals, Incorporated, and are of chemical origin.
**Kalydeco 150 mg film-coated tablets** are administered orally and contain the active substance **ivacaftor**. The maximum daily dose is 150 mg, with a treatment period of 4 weeks. These tablets are manufactured by Vertex Pharmaceuticals (Ireland) Limited and are of chemical origin.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data provided.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part A include the pharmacokinetic (PK) parameters of VX-121, tezacaftor (TEZ), deutivacaftor (D-IVA), and relevant metabolites, as well as safety and tolerability determined by adverse events (AEs), clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse oximetry. For Part B, the primary endpoints focus on safety and tolerability, assessed similarly through AEs, clinical laboratory values, ECGs, vital signs, and pulse oximetry.
Secondary endpoints for Part B include the absolute change in sweat chloride (SwCl) from baseline through Week 24, PK parameters of VX-121, TEZ, D-IVA, and relevant metabolites, and drug acceptability assessment using the Modified Facial Hedonic Scale. Additional secondary endpoints involve the absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Week 24, the number of pulmonary exacerbations (PEx) and cystic fibrosis (CF)-related hospitalizations through Week 24, and the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain (RD) score from baseline through Week 24. Other measures include changes in body mass index (BMI) and BMI-for-age z-score, weight and weight-for-age z-score, and height and height-for-age z-score from baseline at Week 24. The proportion of subjects with SwCl <60 mmol/L and <30 mmol/L through Week 24 will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Cohorts A1 and B1 (ID 1-12): Subject (or subject’s legally appointed and authorized representative) will sign and date an informed consent form (ICF), and an assent form.
- Subjects 6 through 11 years of age (inclusive), on the date of informed consent; subjects who completed Cohort A1 but are ≥12 years of age on the date of informed consent in Cohort B1 are not eligible to enroll in Cohort B1.
- Subjects whose weight (without shoes) is between the 5th and 95th percentile (inclusive) for weight-for-age at the Screening Visit based on current CDC growth charts.
- Confirmed diagnosis of CF as determined by the investigator.
- Subjects who have at least 1 TCR mutation (including F508del) in the CFTR gene • This assessment does not need to be repeated for confirmed subjects in Part A who participate in Cohort B1. • Genotype should be confirmed at the Screening Visit. If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility. • Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study.
- Subjects with forced expiratory volume in 1 second (FEV1) ≥60% of predicted normal for age, sex, and height using equations of the Global Lung Function Initiative (GLI) at the Screening Visit (Section 11.4.1). Spirometry measurements used to confirm eligibility must meet American Thoracic Society/European Respiratory Society criteria for acceptability and repeatability, as judged by the investigator.
- Subjects with stable CF disease at the start of the Treatment Period as deemed by the investigator.
- Subjects who are willing to remain on a stable CF medication regimen (other than CFTR modulators) through Day 22 (Cohort A1) or through Week 24 (Cohort B1) or, if applicable, through the Safety Follow-up Visit.
- Subjects who are able to swallow tablets.
- Female subjects of childbearing potential (defined in Section 11.5.7.1) must have a negative serum pregnancy test at the Screening Visit.
- Subjects of childbearing potential and who are sexually active must meet the contraception requirements outlined in Section 11.5.7.1.
- As deemed by the investigator, the subject’s legally appointed and authorized representative (e.g., parent or legal guardian) AND the subject must be able to understand protocol requirements, restrictions, and instructions. The subject’s legally appointed and authorized representative should be able to ensure that the subject will comply with and is likely to complete the study as planned.
- Cohorts A2 and B2 (ID 13-20): Subject’s legally appointed and authorized representative will sign and date an ICF.
- Subjects 2 through 5 years of age (inclusive) at the Day 1 Visit; subjects who completed Cohort A2 but would be ≥6 years of age at the Day 1 Visit in Cohort B2 are not eligible to enroll in Cohort B2.
- Subjects whose weight (without shoes) is ≥5th percentile for weight-for-age at the Screening Visit based on current CDC growth charts.
- Confirmed diagnosis of CF as determined by the investigator.
- Subjects who have at least 1 TCR mutation (including F508del) in the CFTR gene. • This assessment does not need to be repeated for confirmed subjects in Part A who participate in Cohort B2. • Genotype should be confirmed at the Screening Visit. If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility. • Subjects who have been enrolled and whose screening 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. 7. Subjects who are willing to remain on a stable CF medication regimen (other than CFTR modulators) through Day 22 (Cohort A2) or through Week 24 (Cohort B2) or, if applicable, through the Safety Follow up Visit.
- Subjects who are willing to remain on a stable CF medication regimen (other than CFTR modulators) through Day 22 (Cohort A2) or through Week 24 (Cohort B2) 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.
- Cohorts A3 and B3 (ID 21-28): Subject’s legally appointed and authorized representative will sign and date an ICF.
- Subjects 12 to <24 months of age (inclusive) at the Day 1 Visit; subjects who completed Cohort A3 but would be ≥24 months of age at the Day 1 Visit in Cohort B3 are not eligible to enroll in Cohort B3.
- Subjects whose weight (in a dry diaper or dry underclothes only) is ≥5th percentile for weight-for-age at the Screening Visit based on current CDC growth charts.
- Confirmed diagnosis of CF as determined by the investigator.
- Subjects who have at least 1 TCR mutation (including F508del) in the CFTR gene • This assessment does not need to be repeated for confirmed subjects in Part A who participate in Cohort B3. • Genotype should be confirmed at the Screening Visit. If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility. • Subjects who have been enrolled and whose screening 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 who are willing to remain on a stable CF medication regimen (other than CFTR modulators) through Day 22 (Cohort A3) or through Week 24 (Cohort B3) or, if applicable, through the Safety Follow-up Visit.
- As judged by the investigator, the parent or legal guardian signing the informed consent on behalf of the subject must be able to understand the protocol requirements, restrictions, and instructions and 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 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: • Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15) • Chronic kidney disease of Stage 3 or above • Solid organ or hematological transplantation • Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator • Cancer
- Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (as deemed by the investigator).
- History of intolerance to study drug that would pose an additional risk to the subject in the opinion of the investigator (e.g., subjects with a history of liver function test [LFT] elevations requiring treatment interruption or discontinuation, allergy or hypersensitivity to the study drug).
- Any of the following abnormal laboratory values at screening: • Hemoglobin <10 g/dL • Total bilirubin ≥2 × upper limit of normal (ULN) • Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN • Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)
- An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of VX 121/TEZ/D-IVA).
- Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms: • The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent and assent. • The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 36. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms: • The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent and assent. • The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent one within the 6 months before the date of informed consent and assent. months, and the most recent one within the 6 months before the date of informed consent and assent.
- An acute illness not related to CF (e.g., gastroenteritis) within 14 days before Day 1 (the first dose of VX-121/TEZ/D-IVA).
- Ongoing or prior participation in a study of an investigational treatment other than a Vertex CFTR modulator within 28 days or 5 terminal half-lives (whichever is longer) before screening, or participation in an interventional study of a non-investigational treatment from screening through end of study participation. 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.
- Use of restricted medication within specified duration before the first dose of study drug as defined in Table 9 3.
- The subject or 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 |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 01 Feb 2023 | 2 |
 Denmark | Not Yet Recruiting | 01 Feb 2023 | 2 |
 France | Recruiting | 01 Feb 2023 | 4 |
 Germany | Recruiting | 01 Feb 2023 | 8 |
 Ireland | Not Yet Recruiting | 01 Feb 2023 | 4 |
 The Netherlands | Recruiting | 01 Feb 2023 | — |
 Sweden | Recruiting | 01 Feb 2023 | 1 |
| Netherlands | — | — | 2 |
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-121/VX-661/VX-561 Film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 10 | 24 | PRD8903755 |
VX-445/VX-661/VX-770 film-coated fixed-dose combination tablet | Test | FILM-COATED TABLET | ORAL USE | 100 | 4 | PRD7400755 |
VX-445/VX-661/VX-770 fixed-dose combination granules | Test | GRANULES | ORAL USE | 80 | 4 | PRD8170957 |
VX-121/VX-661/VX-561 granules | Test | GRANULES | ORAL USE | 12 | 24 | PRD11906849 |
Kalydeco 75 mg granules in sachet | Test | GRANULES IN SACHET | ORAL USE | 75 | 4 | PRD11210353 |
VX-121/VX-661/VX-561 Film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 4 | 24 | PRD9725716 |
Kalydeco 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 150 | 4 | PRD6728158 |
VX-445/VX-661/VX-770 fixed-dose combination granules | Test | GRANULES | ORAL USE | 100 | 4 | PRD8315183 |
Kalydeco 59.5 mg granules in sachet | Test | GRANULES IN SACHET | ORAL USE | 59.5 | 4 | PRD10980411 |
VX-445/VX-661/VX-770 fixed-dose combination tablet | Test | FILM-COATED TABLET | ORAL USE | 50 | 4 | PRD7975086 |