Studied in Over 250 Patients Age 6 Through 11 Years
Trial 3 | Phase 3, Open-Label Safety Study
Trial 3 was a 24-week, Phase 3, open-label study (N=58) assessing the safety, tolerability, and pharmacokinetics of ORKAMBI in patients age 6 through 11 years with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, and had a percent predicted FEV1 of ≥40%. Patients received ORKAMBI tablets (lumacaftor 200 mg/ivacaftor 250 mg q12h) with fat-containing food and continued to take their prescribed CF therapies (including during the 2-week washout period). Primary endpoints were safety and tolerability, including assessments of adverse events, clinical laboratory values, and spirometry (FEV1) up to 24 weeks.1-3
Trial 3 | Limitations
- The study was open-label and not placebo controlled2; therefore, causality cannot be attributed to drug effect
Download the Clinical Brochure, including information for studies in patients age 6 through 11 years.
Safety Profile in Trial 3 Was Similar to That Observed in Patients Age 12 Years and Older1
Primary Endpoints Were Safety and Tolerability, Including Assessments of Adverse Events, Clinical Laboratory Values, and Spirometry (FEV1) Up To 24 Weeks.
Discontinuations Due to Serious Adverse Events1
- Trial 3: 3.4% (n=2); due to elevated liver transaminases (1) and rash (1)2
Serious Adverse Reactions
- Trial 3: 6.9% (n=4); included infective pulmonary exacerbation (2), ileus (1), and elevated liver transaminase levels (1)2
Liver-Related Adverse Reactions2
Potentially Clinically Significant (PCS) Laboratory Tests
Parameter PCS/Categorical Criteria
TRIAL 3: 24 Weeks
n/Na (%)2
ALT or AST
ORKAMBI
>8 x ULN
3/57 (5.3)
>5 x ULN
5/57 (8.8)
>3 x ULN
11/57 (19.3)
Discontinuation due to transaminase elevations
1/57 (1.8)
aNumber of subjects with at least one measurement during the period from initiation of study drug to 28 days following last dose.2
- In Trial 3, no patients had an increase in total bilirubin levels >2 x ULN1,4,5
Respiratory Symptom-Related Adverse Reactions1,2
TRIAL 3: 24 Weeks
n/Na (%)1,2
ORKAMBI
Total Incidence
2/58 (3.0)
Dyspnea
1/58 (1.7)
Respiration abnormal
1/58 (1.7)
Chest discomfort
0/58 (0)
aNumber of subjects with at least one measurement during the period from initiation of study drug to 28 days following last dose.2
Common Adverse Reactions in Trial 36
Most Frequently Observed Treatment-Emergent Adverse Events in ≥10% of Patients6
TRIAL 3b: 24 Weeks
ORKAMBI
n=58
Any TEAEs, n (%)
55 (94.8)
Cough
29 (50.0)
Infective pulmonary exacerbation
12 (20.7)
Nasal congestion
12 (20.7)
Headache
12 (20.7)
Abdominal pain upper
8 (13.8)
Sputum increased
8 (13.8)
ALT increased
7 (12.1)
Pyrexia
6 (10.3)
Vomiting
6 (10.3)
Abdominal pain
6 (10.3)
Fatigue
6 (10.3)
Nausea
6 (10.3)
bTrial 3 Safety Set.
Lung Function Through 24 Weeks
Trial 3: Percent Predicted FEV1 at Week 24 (Part of the Safety Assessment)
- +2.5% point LS mean within-group improvement2,7
- -3.2% point LS mean within-group decrease from Week 24 at Week 26 (washout)2
Trial 3: Sweat Chloride Was Reduced at Week 242
- -24.8 mmol/L LS mean within-group improvement at Week 242
- Washout: +21.3 mmol/L LS mean within-group absolute change from Week 24 at Week 262
- There was no direct correlation between changes in sweat chloride levels and improvement in lung function (percent predicted FEV1)1
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; CI, confidence interval; FEV1, forced expiratory volume in 1 second; LS, least squares; q12h, every 12 hours; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.
Trial 4 | Phase 3, Double-Blind, Placebo-Controlled Efficacy and Safety Study
Trial 4 was a 24-week, Phase 3, double-blind, placebo-controlled study assessing the efficacy and safety of ORKAMBI in patients age 6 through 11 years with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, with an LCI2.5 score of ≥7.5, and a percent predicted FEV1 of ≥70%. Patients received either ORKAMBI tablets (lumacaftor 200 mg/ivacaftor 250 mg q12h) or placebo with fat-containing food and continued to take their prescribed CF therapies. Primary endpoint was an absolute change in LCI2.5 from baseline through Week 24.8,9
Additional Disclosure
- The Trial 4 efficacy results are not included in the approved full Prescribing Information, and the FDA did not consider either study in approving ORKAMBI
Download the Clinical Brochure, including information for studies in patients age 6 through 11 years.
Safety Profile in Trial 4 Was Similar to That Observed in Patients Age 12 Years and Older1
Discontinuations Due to Adverse Events8
-
Trial 4: 3% (n=3) in the ORKAMBI group vs 2% (n=2) in the placebo group discontinued treatment due to adverse events. These events included
-
1 case of abnormal respiration and 2 cases of elevated transaminases in the ORKAMBI group
-
2 cases of elevated transaminases in the placebo group
-
Serious Adverse Reactions8
-
Trial 4: 13% (n=13) in the ORKAMBI group vs 11% (n=11) in the placebo group experienced serious adverse events. Of these,
-
2 were treatment related for ORKAMBI (1 drug interaction and 1 obstructive airway disorder)
-
3 were treatment related for placebo (1 distal intestinal obstruction disorder and 2 elevated aminotransferases)
-
Liver-Related Adverse Reactions4
Potentially Clinically Significant (PCS) Laboratory Tests
Parameter PCS/Categorical Criteria
TRIAL 4: 24 Weeks
n/N (%)4
ALT or AST
ORKAMBI
Placebo
>8 x ULN
1/103 (1.0)
2/101 (2.0)
>5 x ULN
5/103 (4.9)
3/101 (3.0)
>3 x ULN
13/103 (12.6)
8/101 (7.9)
Discontinuation due to transaminase elevations
2/103 (1.9)
2/101 (2.0)
- In Trial 4, no patients had an increase in total bilirubin levels >2 x ULN1,4,5
Respiratory Symptom-Related Adverse Reactions4,8
TRIAL 4: 24 Weeks
n/N (%)4,8
ORKAMBI
Placebo
Total Incidence
11/103 (11)
9/101 (9)
Dyspnea
5/103 (5)
5/101 (5)
Respiration abnormal
6/103 (6)
4/101 (4)
Chest discomfort
0/103 (0)
1/101 (1)
Common Adverse Reactions in Trial 44
Most Frequently Observed Treatment-Emergent Adverse Events in ≥5% of Patients in the ORKAMBI Arm and ≥3% Higher than Placebo4
TRIAL 4c: 24 Weeks
ORKAMBI
n=103
Placebo
n=101
Any TEAEs, n (%)
98 (95.1)
98 (97.0)
Productive cough
18 (17.5)
6 (5.9)
Nasal congestion
17 (16.5)
8 (7.9)
Oropharyngeal pain
15 (14.6)
10 (9.9)
Headache
13 (12.6)
9 (8.9)
Abdominal pain upper
13 (12.6)
7 (6.9)
Sputum increased
11 (10.7)
2 (2.0)
Rhinorrhea
10 (9.7)
5 (5.0)
Rash
6 (5.8)
1 (1.0)
cTrial 4 Safety Set.
Lung Function Through 24 Weeks
Trial 4 | Statistically Significant Improvement Through Week 24 vs Placebo8
Adapted from Ratjen F et al. Lancet Respir Med. 2017;5(7):557-567, with permission from Elsevier.
Improvements in lung function are represented by a negative change in LCI.
- Within-group LS mean absolute change in LCI2.5 from baseline through Week 24 was -1.0 (95% CI -1.3 to -0.8) for ORKAMBI vs 0.1 (95% CI -0.2 to 0.3) for placebo. Treatment difference vs placebo is -1.1 (95% CI -1.4 to -0.8; P<0.0001)8
- LCI is still considered an exploratory endpoint in clinical trials10
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; CI, confidence interval; FEV1, forced expiratory volume in 1 second; LCI, lung clearance index; LS, least squares; q12h, every 12 hours; TEAE, treatment emergent adverse event; ULN, upper limit of normal.
