Safety and Efficacy Established in Two Phase 3 Studies in Patients Age 12 Years and Older1,2
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
ORKAMBI Improved and Sustained Lung Function and Other Key Clinical Outcomes1,2
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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
POOLED DATA FROM TRIALS 1 AND 21
Discontinuation Due to Adverse Events1
ORKAMBI 5%; placebo 2%
Serious Adverse Reactions1
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Whether considered by investigators to be drug-related or not, serious adverse reactions that occurred more frequently in patients treated with ORKAMBI included the following (these occurred in ≤1% of patients):
- Pneumonia
- Hemoptysis
- Increased blood creatine phosphokinase
- Cough
- Transaminase elevations
Liver-Related Adverse Reactions1
- In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was similar between patients who received ORKAMBI vs placebo
-
3 patients who received ORKAMBI had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy vs none in the placebo group
- 1 of the 3 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
-
1 of the 6 patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI experienced worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy
- The event occurred within 5 days of the start of dosing and resolved following discontinuation of ORKAMBI
Respiratory Adverse Events1,2
-
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%) compared to 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 adverse reactions 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, Phase 3b 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 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65%1
Menstrual Abnormalities1
- In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (eg, amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%)
- These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%)
Increased Blood Pressure1
- In Trials 1 and 2, adverse reactions 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
COMMON ADVERSE REACTIONS
Adverse Reactions in ≥5% of Patients Treated With ORKAMBI and at a Higher Rate Than Placebo1
Adverse Reactions
(Preferred Term)
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
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; 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.