Evaluation of VX-121/Tezacaftor/Deutivacaftor in Cystic Fibrosis Subjects 1 Through 11 Years of Age

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vertex Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

6 Mar 2023 → ongoing

Decision date (initial)

2024-09-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Vertex Pharmaceuticals Inc.

External identifiers

EU CT number

2024-513754-29-00

EudraCT number

2021-005930-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

Part A
• To evaluate the PK of VX-121, tezacaftor (TEZ), deutivacaftor (D-IVA), and relevant metabolites when dosed in triple combination (TC)
• To evaluate the safety and tolerability of VX-121/TEZ/D-IVA

Part B
• To evaluate the safety and tolerability of VX-121/TEZ/D-IVA through Week 24

Secondary objectives 2

1. To evaluate the efficacy of VX-121/TEZ/D-IVA through Week 24
2. To evaluate the PK of VX-121, TEZ, D-IVA, and relevant metabolites

Conditions and MedDRA coding

Cystic Fibrosis

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003052-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 28

1. 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.
2. 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.
3. 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.
4. Confirmed diagnosis of CF as determined by the investigator.
5. 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.
6. 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.
7. Subjects with stable CF disease at the start of the Treatment Period as deemed by the investigator.
8. 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.
9. Subjects who are able to swallow tablets.
10. Female subjects of childbearing potential (defined in Section 11.5.7.1) must have a negative serum pregnancy test at the Screening Visit.
11. Subjects of childbearing potential and who are sexually active must meet the contraception requirements outlined in Section 11.5.7.1.
12. 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.
13. Cohorts A2 and B2 (ID 13-20): Subject’s legally appointed and authorized representative will sign and date an ICF.
14. 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.
15. Subjects whose weight (without shoes) is ≥5th percentile for weight-for-age at the Screening Visit based on current CDC growth charts.
16. Confirmed diagnosis of CF as determined by the investigator.
17. 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.
18. 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.
19. 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.
20. 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.
21. Cohorts A3 and B3 (ID 21-28): Subject’s legally appointed and authorized representative will sign and date an ICF.
22. 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.
23. 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.
24. Confirmed diagnosis of CF as determined by the investigator.
25. 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.
26. Subjects with stable CF disease at the start of the Treatment Period as deemed by the investigator.
27. 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.
28. 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 10

1. 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
2. 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).
3. 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).
4. 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)
5. 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).
6. 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.
7. 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).
8. 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.
9. Use of restricted medication within specified duration before the first dose of study drug as defined in Table 9 3.
10. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part A: PK parameters of VX-121, TEZ, D-IVA, and relevant metabolites
2. Part A: Safety and tolerability as determined by adverse events (AEs), clinical laboratory values, standard 12 lead ECGs, vital signs, and pulse oximetry
3. Part B: Safety and tolerability as determined by AEs, clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse oximetry

Secondary endpoints 11

1. Part B (ID 1-11): Absolute change in SwCl from baseline through Week 24
2. PK parameters of VX 121, TEZ, D-IVA, and relevant metabolites
3. Drug acceptability assessment using Modified Facial Hedonic Scale
4. Absolute change in ppFEV1 from baseline through Week 24
5. Number of PEx and CF-related hospitalizations through Week 24
6. Absolute change in CFQ-R RD score from baseline through Week 24
7. Absolute change in BMI and BMI-for-age z-score from baseline at Week 24
8. Absolute change in weight and weight-for-age z-score from baseline at Week 24
9. Absolute change in height and height-for-age z-score from baseline at Week 24
10. Proportion of subjects with SwCl <60 mmol/L through Week 24
11. Proportion of subjects with SwCl <30 mmol/L through Week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 13

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vertex Pharmaceuticals Inc.

Sponsor organisation

Vertex Pharmaceuticals Inc.

Address

50 Northern Avenue

City

Boston

Postcode

02210-1862

Country

United States

Scientific contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Public contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications