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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.1,2
Download the Clinical Brochure, including information for studies in patients age 6 through 11 years.
Potentially Clinically Significant (PCS) Laboratory Tests
Parameter PCS/Categorical Criteria
TRIAL 3: 24 Weeks
n/Na (%)
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
TRIAL 3: 24 Weeks
n/N (%)
ORKAMBI
Total Incidence
4/58 (6.9)
Wheezing
2/58 (3.4)
Dyspnea
1/58 (1.7)
Respiration abnormal
1/58 (1.7)
Most Frequently Observed Treatment-Emergent Adverse Events in ≥10% of Patients
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.
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 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 24.1,3
Download the Clinical Brochure, including information for studies in patients age 6 through 11 years.
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
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)
Potentially Clinically Significant (PCS) Laboratory Tests
Parameter PCS/Categorical Criteria
TRIAL 4: 24 Weeks
n/N (%)
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)
TRIAL 4: 24 Weeks
n/N (%)
ORKAMBI
Placebo
Total Incidencec
19/103 (18)
13/101 (13)
Dyspnea
5/103 (5)
5/101 (5)
Respiration abnormal
6/103 (6)
4/101 (4)
Wheezing
5/103 (5)
3/101 (3)
Asthma
4/103 (4)
1/101 (1)
Chest discomfort
0/103 (0)
1/101 (1)
Some patients had more than one respiratory event.
cSome patients had more than one respiratory event.
Treatment Emergent Adverse Events With Incidence >10% in Any Treatment Group
TRIAL 4d: 24 Weeks
ORKAMBI
n=103
Placebo
n=101
Patients with any adverse event
n (%)
98 (95)
98 (97)
Cough
46 (45)
47 (47)
Infective pulmonary exacerbation of cystic fibrosis
20 (19)
18 (18)
Productive cough
18 (17)
6 (6)
Nasal congestion
17 (17)
8 (8)
Oropharyngeal pain
15 (15)
10 (10)
Pyrexia
15 (15)
20 (20)
Upper abdominal pain
13 (13)
7 (7)
Headache
13 (13)
9 (9)
Upper respiratory tract infection
13 (13)
10 (10)
Sputum increased
11 (11)
2 (2)
Abdominal pain
10 (10)
10 (10)
Nausea
10 (10)
9 (9)
Rhinorrhea
10 (10)
5 (5)
Vomiting
10 (10)
10 (10)
Fatigue
9 (9)
11 (11)
dTrial 4 Safety Set.
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.
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.
ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 2 years 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.
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
Substrates of CYP3A
Strong CYP3A Inducers
Click here to access full Prescribing Information.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Milla CE, Ratjen F, Marigowda G, et al.; On behalf of the VX13-809-011 Part B Investigator Group. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. doi: 10.1164/rccm.201608-1754OC 3. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557-567. doi: 10.1016/S2213-2600(17)30215-1 4. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138. doi: 10.1016/j.jcf.2013.09.005
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Milla CE, Ratjen F, Marigowda G, et al.; On behalf of the VX13-809-011 Part B Investigator Group. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. doi: 10.1164/rccm.201608-1754OC 3. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557-567. doi: 10.1016/S2213-2600(17)30215-1 4. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138. doi: 10.1016/j.jcf.2013.09.005
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4):325-335. doi:10.1016/S2213-2600(18)30460-0 3. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4)(suppl):1-13. doi:10.1016/S2213-2600(18)30460-0 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00179(1); 2019.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 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.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston. MA. VXR-HQ-88-00201; 2018.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-10745 (v2.0); 2021. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed November 1, 2021.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019