STUDY DESIGN
TRIAL 4: A phase 3, open-label safety study in patients aged 2 to <6 years1-3,a
- Phase 3, 24-week, open-label study evaluating the safety and tolerability of TRIKAFTA2,3,a,b,c
- 75 patients received TRIKAFTA
- Dosage was based on weight:
- ≥10 to <14 kg (n=16): elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg qam and ivacaftor 59.5 mg qpm2,3
- ≥10 to <14 kg (n=16): elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg qam and ivacaftor 59.5 mg qpm2,3
- ≥14 kg (n=59): elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg qam and ivacaftor 75 mg qpm2,3
- ≥14 kg (n=59): elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg qam and ivacaftor 75 mg qpm2,3
- Dosage was based on weight:
aPatients on CFTR modulators were asked to washout for 4 weeks prior to Day 1.
bAll patients who completed the last treatment period visit and did not permanently discontinue the study drug were enrolled in the open-label Extension Study.
cTrial 4 was a 2-part study: Part A was a pharmacokinetic and safety study while Part B evaluated safety, pharmacokinetics, pharmacodynamics, and efficacy.
Select Inclusion Criteria1-3
- Confirmed CF diagnosis
- Patients who had at least one F508del mutation or a mutation known to be responsive to TRIKAFTA were eligible for the study
- Stable CF as deemed by the investigator at screening
- Ages 2 to <6 years at Day 1 of the study
- Body weight ≥10 kg at screening
Key Exclusion Criteria
- Clinically significant cirrhosis with or without portal hypertension
- 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)
- Solid organ or hematologic transplantation
Primary Endpoint2
- Safety and tolerability as determined by adverse events and clinical laboratory assessments
Select Secondary Endpoints2
- Absolute change from baseline through Week 24 in sweat chloride concentration
- Absolute change from baseline through Week 24 in LCI2.5
Select Additional Endpoints2
- Absolute change from baseline at Week 24 in BMI
- Absolute change from baseline at Week 24 in BMI-for-age z-score
Baseline Characteristics2
| TRIKAFTA (N=75) | |
|---|---|
| Sex, female, n (%) | 41 (54.7) |
| Mean age, years (SD) | 4.1 (1.1) |
| Mean sweat chloride, mmol/L (SD) | 100.7 (11.2) |
| Mean BMI, kg/m2 (SD) | 15.79 (1.06) |
| Mean BMI-for-age z-score (SD) | 0.09 (0.85) |
| Mean LCI2.5, units (SD) | 8.41 (1.48) |
Trial 4 Limitations and Disclosures2
- Trial 4 was an open-label study with no placebo-control arm designed to assess safety as the primary endpoint. Therefore, causality cannot be attributed to TRIKAFTA. (All patients in the study knew they were on active treatment, which may have introduced a bias related to that awareness.)2
- Parts of this study overlapped with the COVID-19 pandemic; therefore, some patients were unable to complete in-person evaluations at all time points. For patients who were unable to complete in-person visits, data were collected remotely and those patients remained in the study2
- Only the absolute change in sweat chloride data are included in the approved full Prescribing Information, and the FDA did not consider the study in the initial approval of TRIKAFTA
SUMMARY OF RESULTS
Trial outcomes for patients aged 2 to <6 years2
Primary Endpoint2
SAFETY AND TOLERABILITY OF TRIKAFTA
The safety profile of TRIKAFTA in patients aged 2 to <6 years is consistent with the safety profile established in Trial 11,2
Discontinuations and serious adverse events
- 2 patients (2.7%) experienced serious adverse events2
- One patient experienced abnormal behavior that led to study drug discontinuation. The patient had a history of behavioral and developmental issues, and developed hyperactivity, aggression, increased urinary urgency, and enuresis, which resolved after treatment discontinuation. The investigator assessed the events as possibly related to treatment
- One patient had a pulmonary exacerbation, which was considered not related to treatment and resolved without change in treatment
- There were no deaths in Trial 44
| TRIKAFTA n (%) (N=75) | |
|---|---|
| Patients with any TEAEs | 74 (98.7) |
| Cough | 46 (61.3) |
| Pyrexia | 26 (34.7) |
| Rhinorrhea | 25 (33.3) |
| Vomiting | 21 (28.0) |
| COVID-19 | 14 (18.7) |
| Nasal congestion | 13 (17.3) |
| Rash | 12 (16.0) |
| Upper respiratory tract infection | 11 (14.7) |
| Decreased appetite | 9 (12.0) |
| ALT increased | 8 (10.7) |
| Infective PEx of CF | 8 (10.7) |
Liver-related adverse events2
| TRIKAFTA n (%) (N=75) | ||
|---|---|---|
| Elevated ALT or aspartate transaminase (AST), n (%) | >3x ULN | 6 (8.0) |
| >5x ULN | 2 (2.7) | |
| >8x ULN | 1 (1.3) | |
| ALT or AST >3x ULN and total bilirubin >2x ULN | 0 | |
| Adverse events of elevated ALT and/or AST | 8 (10.7) | |
- 1 patient required treatment interruption during Trial 4 and later discontinued TRIKAFTA during the open label extension due to transaminase elevations1
Rash events2,3
- 15 patients (20.0%) experienced rash eventsd
- 12 patients had rash events that were assessed as unlikely/not related to study drug and/or were confounded by concurrent viral symptoms
- No patients discontinued due to rash events, although 2 patients had interruptions and both resumed study drug without recurrence of rash
- Rash events were more frequent among males (32.4%) than females (9.8%)
dRash events were determined to be mild or moderate in severity. Includes rash, rash erythematous, rash maculopapular, rash papular, and urticaria.
Select Secondary Endpoints
LS-mean absolute change from baseline through Week 24 (95% CI: -61.3, -54.6)
Mean (SD) at baseline: 100.7 mmol/L (11.2)
- Subgroup analysis of absolute change in sweat chloride by genotype saw LS mean (95% CI) reductions of 52.6 mmol/L (-56.9, -48.4) in patients with F/MF genotype (n=47) and -70.0 mmol/L (-75.4, -64.5) in patients with F/F genotype (n=22)2
eIn Trial 4, mean baseline sweat chloride (SD) was 100.7 mmol/L (11.2) for all patients receiving TRIKAFTA in this study.
- 1 patient (1.4%) in the study, of F/MF genotype, had a sweat chloride concentration <60 mmol/L at baseline3
fPercentages were calculated by dividing n (the number of patients with sweat chloride concentration below the indicated threshold at week 24) by N1, where N1 is the number of patients with evaluable data. Patients with missing data were considered missing at random and were not counted in the denominator.
LS-mean absolute change from baseline through Week 24 (95% CI: -1.01, -0.66)
Mean (SD) at baseline: 8.41 units (1.48)
A Subgroup analysis of LCI2.5 by genotype indicates that results for patients with F/F genotype are consistent with those of patients with F/MF genotype3
Lung clearance index (LCI), derived from multiple breath washout tests, is an established research outcome for individuals with CF. It involves following an inert tracer gas washed out from the lungs during relaxed tidal breathing. Key advantages of LCI over ppFEV₁ include an increased sensitivity to early changes in airway obstruction and ability to be performed repeatedly even in very young children with growing lungs.5
gAt screening, LCI2.5 was assessed in patients ages 3 to 5 years only.
hIn Trial 4, mean baseline LCI2.5 was 8.41 units (SD, 1.48) for patients receiving TRIKAFTA.
iLCI represents a measure of the number of times the volume of a gas in the lung at the start of a washout must be turned over to wash out tracer gas to the predefined endpoint.5
Select Additional Trial Outcomes2
(95% CI: -0.10, 0.17)
Mean (SD) at baseline: 15.79 kg/m² (1.06)
(95% CI: 0.0, 0.20)
Mean (SD) at baseline: 0.09 (0.85)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; F/F, homozygous for the F508del mutation; F/MF, heterozygous for the F508del mutation and a minimal function mutation; GGT, gamma-glutamyl transferase; LS, least squares; PEx, pulmonary exacerbation; SE, standard error; TEAE, treatment-emergent adverse event; ULN, upper limit of normal; WK, week.
IMPORTANT SAFETY INFORMATION
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE
- TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA.
- Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA, then every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test (LFT) elevations at baseline.
- Interrupt TRIKAFTA for significant elevations in LFTs or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, resume treatment only if benefit is expected to outweigh risk. Closer monitoring is advised after resuming TRIKAFTA.
- TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B). If used, use with caution at a reduced dosage and monitor patients closely.
INDICATIONS AND USAGE
TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on clinical and/or in vitro data.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.
WARNINGS AND PRECAUTIONS
Drug-Induced Liver Injury and Liver Failure
- TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Liver failure leading to transplantation and death has been reported in patients with and without a history of liver disease taking TRIKAFTA. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA
- Assess LFTs (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA, then every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or LFT elevations at baseline
- Interrupt TRIKAFTA in the event of signs or symptoms of liver injury, which may include:
- Significant elevations in LFTs (e.g., ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN)
- Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
- Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, and if benefit is expected to outweigh risk, resume TRIKAFTA with close monitoring
- TRIKAFTA should not be used in patients with severe hepatic impairment. TRIKAFTA is not recommended in patients with moderate hepatic impairment and should only be considered when there is a clear medical need and benefit outweighs risk. If used, use with caution at a reduced dosage and monitor patients closely
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by concomitant use of strong CYP3A inducers, which may reduce therapeutic effectiveness of TRIKAFTA. Concomitant use with strong CYP3A inducers is not recommended
Concomitant Use With CYP3A Inhibitors
- Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors
Cataracts
- Non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow‑up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%)
Most Common Adverse Reactions
- The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA and higher than placebo by ≥1% were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, blood bilirubin increased and constipation
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of TRIKAFTA in patients with CF younger than 2 years of age have not been established
Please see full Prescribing Information, including Boxed WARNING.
References:
1. TRIKAFTA [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2024. 2. Goralski JL, Hoppe JE, Mall MA, et al. Phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children aged 2 to 5 years with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care Med. Final MS pp1-35, Feb. 27, 2023. 3. Goralski JL, Hoppe J, Mall MA, et al. Phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children aged 2 to 5 years with cystic fibrosis and at least one F508del allele. Online data supplement. Am J Respir Crit Care Med. pp1-35, Feb. 27, 2023. 4. A phase 3 study evaluating the safety, tolerability, and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor triple combination therapy in cystic fibrosis subjects 2 through 5 years of age. European Union Clinical Trials Register. Updated October 21, 2021. Accessed January 1, 2025. https://www.clinicaltrialsregister.eu/ctr-search/rest/download/result/zip/pdf/2020-002251-38/1 5. Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 2009;103(6):793-799. doi:10.1016/j.rmed.2009.01.025