Clinical Trials for Age 12 Years and Older
Safety and Efficacy Established in Two Phase 3 Studies in Patients Age 12 Years and Older1,2
STUDY DESIGN
Trials 1 and 2 | Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Studies
Trials 1 and 2 were 24-week, Phase 3, randomized, double-blind, placebo-controlled studies of patients age 12 years and older with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, and had a percent predicted FEV1 (ppFEV1) of 40-90 at screening. Patients received either ORKAMBI tablets (lumacaftor 400 mg/ivacaftor 250 mg q12h) or placebo with fat-containing food and continued to take their prescribed CF therapies. The primary endpoint in both trials was an absolute change in ppFEV1 from baseline at Week 24 assessed as the average of the treatment effects at Week 16 and at Week 24.1,2
SUMMARY OF RESULTS
ORKAMBI Improved and Sustained Lung Function and Other Key Clinical Outcomes1,2
-
In each trial, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary endpoints vs placebo. For an endpoint to be significant, both it and all previous tests had to achieve P≤0.02502
- Statistically significant endpoints are indicated by the shaded boxes in the table below
- The safety of ORKAMBI was evaluated based on a pre-specified pooled analysis
- A separate pooled analysis for efficacy was not pre-specified and did not correct for multiple comparisons.1,2 Secondary analyses of Trials 1 and 2 were conducted to evaluate efficacy
| TRIAL 11,2 | TRIAL 21,2 | POOLED2 | |||||
|---|---|---|---|---|---|---|---|
| ORKAMBI (n=182) |
Placebo (n=184) |
ORKAMBI (n=187) |
Placebo (n=187) |
ORKAMBI (n=369) |
Placebo (n=371) |
||
| PRIMARY ENDPOINTS | |||||||
| Absolute change in percent predicted FEV₁ at Week 24 (percentage points)a |
Treatment difference (95% CI) | 2.6 (1.2, 4.0) (P=0.0003) |
- | 3.0 (1.6, 4.4) (P<0.0001) |
- | 2.8 (1.8, 3.8) |
- |
| KEY SECONDARY ENDPOINTS | |||||||
| Relative change in percent predicted FEV₁ at Week 24 (percentage)a |
Treatment difference (95% CI) | 4.3 (1.9, 6.8) (P=0.0006) |
- | 5.3 (2.7, 7.8) (P<0.0001) |
- | 4.8 (3.0, 6.6) |
- |
| Absolute change in BMI at Week 24 (kg/m2) | Treatment difference (95% CI) | 0.1 (-0.1, 0.3) |
- | 0.4 (0.2, 0.5) (P=0.0001) |
- | 0.2 (0.1, 0.4) |
- |
| Absolute change in CFQ-R Respiratory Domain score at Week 24 (points) | Treatment difference (95% CI) | 1.5 (-1.7, 4.7) |
- | 2.9 (-0.3, 6.0) |
- | 2.2 (0.0, 4.5) |
- |
| Proportion of patients with ≥5% relative change in percent predicted FEV₁ at Week 24a |
% | 37% | 22% | 41% | 23% | 39% | 22% |
| Odds ratio (95% CI) | 2.1 (1.3, 3.3) |
- | 2.4 (1.5, 3.7) |
- | 2.2 (1.6, 3.1) |
- | |
| Number of pulmonary exacerbations through Week 24b |
No. of events (rate per 48 weeks) |
73 (0.7) |
112 (1.1) |
79 (0.7) |
139 (1.2) |
152 (0.7) |
251 (1.1) |
| Rate ratio (95% CI) | 0.7 (0.5, 0.9) |
- | 0.6 (0.4, 0.8) |
- | 0.6 (0.5, 0.8) |
- | |
| TRIAL 11,2 | |||
| ORKAMBI (n=182) |
Placebo (n=184) |
||
| PRIMARY ENDPOINTS | |||
| Absolute change in percent predicted FEV₁ at Week 24 (percentage points)a |
Treatment difference (95% CI) | 2.6 (1.2, 4.0) (P=0.0003) |
- |
| KEY SECONDARY ENDPOINTS | |||
| Absolute change in BMI at Week 24 (kg/m2) | Treatment difference (95% CI) | 0.1 (-0.1, 0.3) |
- |
| Absolute change in CFQ-R Respiratory Domain score at Week 24 (points) | Treatment difference (95% CI) | 1.5 (-1.7, 4.7) |
- |
| Proportion of patients with ≥5% relative change in percent predicted FEV₁ at Week 24a |
% | 37% | 22% |
| Odds ratio (95% CI) |
2.1 (1.3, 3.3) |
- | |
| Number of pulmonary exacerbations through Week 24b |
No. of events (rate per 48 weeks) |
73 (0.7) |
112 (1.1) |
| Rate ratio (95% CI) | 0.7 (0.5, 0.9) |
- | |
| TRIAL 21,2 | |||
| ORKAMBI (n=187) |
Placebo (n=187) |
||
| PRIMARY ENDPOINTS | |||
| Absolute change in percent predicted FEV₁ at Week 24 (percentage points)a |
Treatment difference (95% CI) | 3.0 (1.6, 4.4) (P<0.0001) |
- |
| KEY SECONDARY ENDPOINTS | |||
| Relative change in percent predicted FEV₁ at Week 24 (percentage)a |
Treatment difference (95% CI) | 5.3 (2.7, 7.8) (P<0.0001) |
- |
| Absolute change in BMI at Week 24 (kg/m2) | Treatment difference (95% CI) | 0.4 (0.2, 0.5) (P=0.0001) |
- |
| Absolute change in CFQ-R Respiratory Domain score at Week 24 (points) | Treatment difference (95% CI) | 2.9 (-0.3, 6.0) |
- |
| Proportion of patients with ≥5% relative change in percent predicted FEV₁ at Week 24a |
% | 41% | 23% |
| Odds ratio (95% CI) | 2.4 (1.5, 3.7) |
- | |
| Number of pulmonary exacerbations through Week 24b |
No. of events (rate per 48 weeks) |
79 (0.7) |
139 (1.2) |
| Rate ratio (95% CI) | 0.6 (0.4, 0.8) |
- | |
| POOLED5 | |||
| ORKAMBI (n=369) |
Placebo (n=371) |
||
| PRIMARY ENDPOINTS | |||
| Absolute change in percent predicted FEV₁ at Week 24 (percentage points)a |
Treatment difference (95% CI) | 2.8 (1.8, 3.8) |
- |
| KEY SECONDARY ENDPOINTS | |||
| Relative change in percent predicted FEV₁ at Week 24 (percentage)a |
Treatment difference (95% CI) | 4.8 (3.0, 6.6) |
- |
| Absolute change in BMI at Week 24 (kg/m2) | Treatment difference (95% CI) | 0.2 (0.1, 0.4) (P=0.0001) |
- |
| Absolute change in CFQ-R Respiratory Domain score at Week 24 (points) | Treatment difference (95% CI) | 2.2 (0.0, 4.5) |
- |
| Proportion of patients with ≥5% relative change in percent predicted FEV₁ at Week 24a |
% | 39% | 22% |
| Odds ratio (95% CI) | 2.2 (1.6, 3.1) |
- | |
| Number of pulmonary exacerbations through Week 24b |
No. of events (rate per 48 weeks) |
152 (0.7) |
251 (1.1) |
| Rate ratio (95% CI) | 0.6 (0.5, 0.8) |
- | |
IV, intravenous.
aAssessed as the average of the treatment effects at the Week 16 and Week 24 time points.1
bA pulmonary exacerbation was defined as a new or change in antibiotic therapy (IV, inhaled, or oral) associated with 4 or more of the following 12 pre-specified sinopulmonary signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature >38°C (100.4°F); anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical chest exam; decrease in pulmonary function by 10%; radiographic changes indicative of pulmonary infection.2
Download the Clinical Brochure, including adverse events information for patients 12 years of age and older.
THE OVERALL SAFETY PROFILE OF ORKAMBI IS BASED ON
POOLED DATA FROM TRIALS 1 AND 21
Discontinuation Due to AEs1
ORKAMBI 5%; placebo 2%
Serious AEs1
- Serious AEs, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included those below. These occurred in 1% or less of patients:
- Pneumonia
- Hemoptysis
- Increased blood creatine phosphokinase
- Cough
- Transaminase elevations
Liver-Related AEs1
- In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was similar between patients treated with ORKAMBI and those who received placebo
- Three patients who received ORKAMBI had liver-related serious AEs, including two reported as transaminase elevations and one as hepatic encephalopathy, compared to none in the placebo group
- Of these three patients, one had elevated transaminases (>3 x ULN) associated with bilirubin elevation >2 x ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 x ULN
- Among six patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient
- The event occurred within 5 days of the start of dosing and resolved following discontinuation of ORKAMBI
Respiratory AEs1,2
- In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (eg, chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) than in patients who received placebo (14%)1
- Respiration abnormal (chest tightness): ORKAMBI (9%) vs placebo (6%)
- Dyspnea: ORKAMBI (13%) vs placebo (8%)
- The incidence of these AEs was more common in patients treated with ORKAMBI with lower pretreatment FEV1
- Most respiratory symptom-related adverse events occurred within the first week of treatment and resolved within 2 to 3 weeks2
- During a 24-week, open-label clinical trial in 46 patients age 12 years and older (Trial 5) with advanced lung disease (ppFEV1 <40) [mean ppFEV1: 29.1 at baseline (range: 18.3-42.0)], the incidence of respiratory symptom-related AEs was 65%1
Menstrual Abnormalities1
- In Trials 1 and 2, menstrual abnormalities (eg, amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) were more common in female patients treated with ORKAMBI (10%) than in patients receiving placebo (2%)
- These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared with those not using hormonal contraceptives (3%)
Increased Blood Pressure1
- In Trials 1 and 2, AEs related to increases in blood pressure (eg, hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo
- The proportion of patients who experienced a systolic blood pressure value >140 mm Hg or a diastolic blood pressure >90 mm Hg on at least two occasions was 3.6% and 2.2%, respectively, in patients treated with ORKAMBI compared with 1.6% and 0.5% in patients who received placebo
TRIALS 1 AND 2 IN PATIENTS AGE 12 YEARS AND OLDER:
COMMON AE
Adverse Events in ≥ 5% of Patients Treated With ORKAMBI and at a Higher Rate Than Placebo1
| Adverse Event | ORKAMBI n=369 (%) | Placebo n=370(%) |
|---|---|---|
| Dyspnea | 48 (13) | 29 (8) |
| Nasopharyngitis | 48 (13) | 40 (11) |
| Nausea | 46 (13) | 28 (8) |
| Diarrhea | 45 (12) | 31 (8) |
| Upper respiratory tract infection | 37 (10) | 20 (5) |
| Fatigue | 34 (9) | 29 (8) |
Respiration abnormalc | 32 (9) | 22 (6) |
| Blood creatine phosphokinase increased | 27 (7) | 20 (5) |
| Rash | 25 (7) | 7 (2) |
| Flatulence | 24 (7) | 11 (3) |
| Rhinorrhea | 21 (6) | 15 (4) |
| Influenza | 19 (5) | 8 (2) |
cReported as chest tightness.2
The safety profile from 2 pediatric trials in patients with CF aged 6 through 11 years who were homozygous for the F508del-CFTR mutation—a 24-week, open-label, multicenter safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo)—was similar to that observed in Trials 1 and 2.
Adverse reactions that are not listed in the table above and that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%).
In a 24-week, open-label, multicenter study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6), the safety profile was similar to that observed in studies in patients aged 6 years and older.
Download the Clinical Brochure, including adverse events information for patients 12 years of age and older.
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; AE, adverse event; BMI, body mass index; CFQ-R, cystic fibrosis questionnaire-revised; CI, confidence interval; IV, intravenous; LS, least squares; q12h, every 12 hours; ppFEV1, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Use in Patients With Advanced Liver Disease
- Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced
INDICATION AND USAGE
ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
INDICATION AND USAGE
ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Use in Patients With Advanced Liver Disease
- Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced
Liver-related Events
- Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
- It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
- Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing
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 ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI
Respiratory Events
- Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy
Effect on Blood Pressure
- Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI
Drug Interactions
Substrates of CYP3A
- Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
Strong CYP3A Inducers
- Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co‑administration with strong CYP3A inducers is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
Most Common Adverse Reactions
- The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
- The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased
- The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established
Click here to access full Prescribing Information.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Wainwright CE, Elborn JS, Ramsey BW, et al. for the TRAFFIC and TRANSPORT Study Groups. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231.