STUDY DESIGN
TRIAL 3: A phase 3, open-label safety study in patients aged 6 to <12 years1,a
- Phase 3, 24-week, open-label, multicenter study evaluating the safety and tolerability of TRIKAFTA
- 66 patients received TRIKAFTAb
- Dosage was based on weight:
- <30 kg (n=36): elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg qam and ivacaftor 75 mg qpm
- ≥30 kg (n=30): elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm
- Dosage was based on weight:
Trial 3 was an open-label study with no placebo-controlled arm; therefore, causality cannot be attributed to TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
aAll patients who completed the last treatment period visit and did not permanently discontinue the study drug were enrolled in the open-label Extension Study.1
bTrial 3 was a 2-part study: Part A was a pharmacokinetic and safety study, and Part B evaluated safety, tolerability, efficacy, and pharmacokinetics. Patients who completed Part A were automatically enrolled in Part B.
Key Inclusion Criteria1,c
- Confirmed CF diagnosis, clinically stable, aged 6 to <12 years
- Weight ≥15 kg without shoes at screening visit
- Patient genotype:
- Homozygous for the F508del mutation OR
- Heterozygous for the F508del mutation and one of the approximately 200 other mutations in the CFTR gene that resulted in either:
- No CFTR protein
- A CFTR protein that lacks baseline function and is not responsive to ivacaftor and tezacaftor/ivacaftor
cKey exclusion criteria included 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), and solid organ or hematologic transplantation.1
Primary Endpoint1
- Safety and tolerability as determined by adverse events and clinical laboratory assessmentsd
dSafety and tolerability assessments were based on AEs, clinical laboratory values, electrocardiograms, vital signs, pulse oximetry, and ophthalmologic examinations.1
Select Secondary Endpoints1
- Absolute change from baseline through week 24 in ppFEV1
- Absolute change from baseline through week 24 in sweat chloride concentration
- Absolute change from baseline through week 24 in CFQ-R Respiratory Domain Score
- Absolute change from baseline through week 24 in LCI2.5
- Absolute change from baseline at week 24 in BMI and BMI-for-age z-score
Study Disclosures and Impact of COVID-191
- Trial 3 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)
- This 24-week safety study was conducted between August 2019 and August 2020, and overlapped with the COVID-19 pandemic
- Due to the onset of the pandemic, 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 study
- Additional analyses were performed to evaluate data collected from unscheduled visits. The results of those analyses were consistent with the main analyses
Safety analyses (primary endpoint)1
- All patients (N=66) in the study were included in the safety analysis. If a patient was unable to complete an in-clinic visit, safety information was collected remotely with site personnel
- If a patient was unable to complete laboratory tests at the scheduled Week 24 time point, unscheduled visits were conducted after Week 24
- The main safety analyses were based on data collected up to Week 24. Additional analyses were conducted with data from unscheduled visits, and those results were consistent with the main analyses
Efficacy analyses (secondary endpoints)1
- N values declined over time for each efficacy endpoint, as some patients were unable to complete in-clinic visits due to the pandemic
- The N values differ across endpoints due to varying restrictions placed on data collection during the pandemic
- The main efficacy analyses were based on data collected in-clinic through Week 24. Additional analyses were performed to evaluate the impact of missing data and to evaluate home-based data. All analyses were consistent with the main analyses
Baseline Characteristics1
| TRIKAFTA (N=66) | |
|---|---|
| Sex, female, % | 59.1 |
| Mean age, years (SD) | 9.3 (1.9) |
| Mean ppFEV₁ (SD) | 88.8 (17.7) |
| Mean sweat chloride, mmol/L (SD) | 102.2 (9.1) |
| Mean BMI, kg/m2 (SD) | 16.39 (1.69) |
| Mean BMI-for-age z-score (SD) | -0.16 (0.74) |
| Mean LCI2.5, units (SD)e | 9.77 (2.68) |
| Mean CFQ-R Respiratory Domain score, points (SD) | 80.3 (15.2) |
eLung 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.
Summary of Results
Trial outcomes for patients aged 6 to <12 years1
Primary Endpoint2
SAFETY AND TOLERABILITY OF TRIKAFTA
Safety results from Trial 3 were similar to those observed in Trial 1 in patients 12 years and
older1
- A total of 66 patients with CF aged 6 to <12 years received at least one dose of TRIKAFTA
Serious adverse reactions1
- 1 patient (1.5%) experienced serious adverse reactions. These concurrent reactions were rhinovirus infection, metapneumovirus infection, and pneumonia
Most common adverse reactions in Trial 31
| TRIKAFTA n (%) (N=66) | |
|---|---|
| Cough | 28 (42.4) |
| Headache | 16 (24.2) |
| Pyrexia | 14 (21.2) |
| Oropharyngeal pain | 12 (18.2) |
| Upper respiratory tract infection | 11 (16.7) |
| Nasal congestion | 10 (15.2) |
| Rashf | 8 (12.1) |
| Abdominal pain | 8 (12.1) |
| Rhinorrhea | 8 (12.1) |
| Viral upper respiratory tract infection | 8 (12.1) |
| Alanine transaminase (ALT) increased | 7 (10.6) |
| Diarrhea | 7 (10.6) |
| Influenza | 7 (10.6) |
| Vomiting | 7 (10.6) |
fIncludes preferred term of rash only.
Liver function test elevations1
| TRIKAFTA n (%) (N=66) | ||
|---|---|---|
| Elevated ALT or aspartate transaminase (AST), n (%) | >3x ULN | 7 (10.6) |
| >5x ULN | 1 (1.5) | |
| >8x ULN | 0 | |
| ALT or AST >3x ULN and total bilirubin >2x ULN, % | 0 | |
- The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 10.6% in patients treated with TRIKAFTA. No patients discontinued due to transaminase elevations
- Maximum indirect bilirubin elevations >2x to ≤3X ULN occurred in 4.6% of patients treated with TRIKAFTA. Maximum direct bilirubin elevations >1.5x ULN occurred in 0%. No patients had transaminase elevations >3x ULN and total bilirubin >2x ULN
- No patients aged 6 to <12 years had creatine kinase levels >5x ULN
Rash events2,3
- Rash events occurred in 15 (22.7%) patients. All rash events were mild or moderate in severity as determined by the study investigatorg
- 1 patient (1.5%) discontinued due to rash erythematous; all other rash events resolved without interruption of study drug
gIncludes rash, rash erythematous, rash maculopapular, rash papular, skin exfoliation, and urticaria.
Select Secondary Endpoints
Efficacy analyses (secondary endpoints)1
- N values declined over time for each efficacy endpoint, as some patients were unable to complete in-clinic visits due to the pandemic
- The N values differ across endpoints due to varying restrictions placed on data collection during the pandemic
- The main efficacy analyses were based on data collected in-clinic through Week 24. Additional analyses were performed to evaluate the impact of missing data and to evaluate home-based data. All analyses were consistent with the main analyses
Please see study disclosures and impact of COVID-19.
The minimal clinically important difference threshold for CFQ-R Respiratory Domain score is 4 points in patients with CF with stable respiratory symptoms and represents the minimal change a patient can detect.3
CFQ-R Respiratory Domain score measured composite patient-/caregiver-reported outcomes in the following respiratory symptoms4:
LCI is a measure of lung physiology derived from multiple breath washout tests. LCI represents a measure of the number of times the volume of gas in the lung at the start of the washout must be turned over in order to wash out the tracer gas to the predefined endpoint. With increasing disease severity, LCI increases.5
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; LCI, lung clearance index; ppFEV1, percent predicted forced expiratory volume in 1 second; SD, standard deviation; ULN, upper limit of normal.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Elevated Transaminases and Hepatic Injury
- Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment
- Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease
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 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 F508del mutation or a mutation that is responsive based on in vitro data.
- Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
- In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
- For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered
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 the 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 the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended
Concomitant Use With CYP3A Inhibitors
- Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors
Cataracts
- Cases of 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 (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 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, and blood bilirubin increased
- The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
- The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=66) was similar to that observed in Trial 1. The safety profile in patients age 2 through 5 years from an open-label trial (Trial 4; N=75) was similar to that observed in Trial 1
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
Click here to access full Prescribing Information for TRIKAFTA.
References:
1. Zemanick ET, Taylor-Cousar JL, Davies J, et al. A phase 3 open-label study of ELX/TEZ/IVA in children 6 through 11 years of age with CF and at least one F508del allele. Am J Respir Crit Care Med. 2021;203(12):1522-1532. doi:10.1164/rccm.202102-0509OC. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-9151 (v1.0); 2021. 3. Quittner AL, Modi AC, Wainwright C, et al. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618. 4. CFQ-R Cystic Fibrosis Questionnaire-Revised. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. English version 2.0. 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