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Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Boyle MP, Bell SC, Konstan MW, et al, on behalf of the VX09-809-102
study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for
treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a
phase 2 randomised controlled trial. Lancet Respir Med 2014; published online June 25.
http://dx.doi.org/10.1016/S2213-2600(14)70132-8.
VX09-‐809-‐102 clinical trial Web Appendix SUPPLEMENTAL APPENDIX
1. VX10-809-102 Study Group
2. Additional Acknowledgements
3. Supplemental Methodology
4. Supplemental Results
5. Supplemental Table 1. Changes in sweat chloride concentration in Cohort 1
6. Supplemental Table 2. Changes in percent-predicted FEV1 from baseline in Cohort 1
7. Supplemental Table 3. Adverse event summary for Cohort 1
8. Supplemental Table 4. Changes in patient-reported respiratory symptoms using the
CFQ-R Respiratory domain in Cohort 2
9. Supplemental Table 5. Genotypes of the 27 F508del-CFTR heterozygous patients
randomized and dosed in Cohort 2
10. Supplemental Figure 1. Changes in percent-predicted FEV1 from baseline for Cohort 2
heterozygote patients
11. Appendix Bibliography
1 VX09-‐809-‐102 clinical trial Web Appendix 1) VX09-809-102 Study Group
Michael Anstead, M.D., University of Kentucky, Lexington, Kentucky, USA; Drucy S.
Borowitz, M.D., Women and Children’s Hospital of Buffalo, Buffalo, New York, USA; Michael
P. Boyle, M.D., Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Scott H.
Donaldson, M.D., University of North Carolina School of Medicine, Chapel Hill, North
Carolina, USA; Henry L. Dorkin, M.D., Children’s Hospital Boston, Boston, Massachusetts,
USA; Jordon M. Dunitz, M.D., University of Minnesota, Minneapolis, Minnesota, USA; Patrick
A. Flume, M.D., Medical University of South Carolina, Charleston, South Carolina, USA; Floyd
R. Livingston, M.D., Nemours Children’s Clinic, Orlando, Florida, USA; Michael W. Konstan,
M.D., Rainbow Babies and Children’s Hospital and Case Western Reserve University School of
Medicine, Cleveland, Ohio, USA; Nathan Kraynack, M.D., Akron Children’s Hospital, Akron,
Ohio, USA; Susanna McColley, M.D., Ann & Robert H Lurie Children's Hospital of Chicago,
Chicago, Illinois, USA; Richard B. Moss, M.D., Stanford University School of Medicine, Palo
Alto, California, USA; Clement Ren, M.D., University of Rochester Strong Memorial Hospital,
Rochester, New York, USA; Steven M. Rowe, M.D., University of Alabama at Birmingham,
Birmingham, Alabama, USA; Michael S. Schechter, Emory University and Children’s
Healthcare of Atlanta, Atlanta, Georgia, USA; Scott C. Bell, M.B., M.D., Prince Charles
Hospital and Queensland Children’s Medical Research Institute, Brisbane, Australia; Barry
Clements, M.D.., Princess Margaret Hospital, Perth, Australia; Philip Thompson, M.B., Lung
Institute of Western Australia, Perth, Australia; John Kolbe, M.B.B.S., Auckland Clinical
Studies, Auckland, New Zealand; Christopher Wynne, M.B., ChB, Christchurch Clinical Studies
Trust, Christchurch, New Zealand; Lieven Dupont, MD, PhD. University Hospital, Gasthuisberg,
Leuven, Belgium; Ernst Rietschel, MD, University Hospital Cologne, Cologne, Germany.
2 VX09-‐809-‐102 clinical trial Web Appendix 2) Additional Acknowledgments
The authors would like to thank the Study Coordinators at participating sites, including:
Jameelah Ali, Carol Barlow-Woody, Karen Callahan, Catherine Correia, Diana Diaz, Erin
Felling, Nathalie Feyaerts, Brittany Fulle, Carolyn Harris, Nancy Jenks, Terri Johnson, Kenneth
Kesser, Bobbi Ksenich, Clair Lee, Angela Leung, Sue Melbourne, Petra Nahbein-Uhlherr,
Deborah Ouellette, Ginger Reeves, Noopur Singh, Denise Stacklie, Emily Stevens, Ashley
Warden, and Michelle Wood.
This project was supported by: MPB supported by Johns Hopkins Institute for Clinical and
Translational Research (ICTR) (NIH UL1 TR 000424-06) and Cystic Fibrosis Foundation
Therapeutics (CFFT) (ZEITLI09Y0), SCB supported by Qld Health, Health Research
Fellowship, SMR supported by the UAB Center for Clinical and Translational Science (NIH
UL1TR000165), the UAB CF Research Center (NIH P30 DK072482), and CFFT (ROWE14Y0).
MWK supported by the Case Western Reserve University Clinical and Translational Science
Collaborative (NIH UL1 RR024989), the CWRU CF Research Center (NIH P30 DK027651),
and by CFFT (KONSTAN09Y0). SM was supported by the Cystic Fibrosis Foundation
Therapeutics Inc (MCCOLL09Y0).
3) Supplemental Methodology
For Cohort 2, patients who were heterozygous for F508del-CFTR had to have a second CFTR
allele mutation that was either predicted to result in the lack of CFTR protein production or is
known not to respond to ivacaftor based on in-vitro testing1. The list of eligible mutations is
included in Appendix B of the protocol and selection of mutations predicted to result in lack of
3 VX09-‐809-‐102 clinical trial Web Appendix CFTR protein production was based on data available at www.CFTR2.org under “mutation
characteristics” for each specific mutation.
Safety was evaluated by assessment of adverse events, clinical laboratory tests, standard digital
electrocardiograms (ECG), vital signs, and physical examinations. Twenty-four or 48 hour
ambulatory ECG monitoring was included in Cohort 1 only.
Sweat testing was performed by pilocarpine iontophoresis. Samples were collected using an
approved Macroduct® (Wescor, Logan UT) collection device as described previously.2 Sweat
samples were sent to a central laboratory for testing and interpretation of results. The sweat test
was to be conducted before patients received the morning dose of study drug, except for the first
study day when the test could be performed on the previous day. Two sweat samples, one from
each arm, were to be collected at each study visit.
Spirometry was performed according to American Thoracic Society guidelines.3 Assessments
were to be performed prior to the use of bronchodilators (at least 4 hours since last short-acting
β-agonist or anticholinergic, 12 hours since last long-acting treatment, and 24 hours since the last
once-daily treatment) and prior to study drug administration on the day of the visit. FEV1, forced
vital capacity (FVC), and forced midexpiratory flow rate (FEF25-75%) were determined. Values
were recorded as volumes (L) for FEV1 and FVC or rate (L/s) for FEF25-75% and as percent
predicted for age, gender, height and ethnicity.3,4
All sweat samples for sweat chloride analyses had to have a minimum volume of 15 µL to be
considered valid. For patients with valid sweat samples from both arms at a time point, the
4 VX09-‐809-‐102 clinical trial Web Appendix average of the results for the left and right arms were used for analysis. For patients with only 1
valid sample, the value of that sample alone was used. Sweat chloride values outside of the
physiologic range, defined as <10 mmol/L or >160 mmol/L, were not included in the analyses.
Study Blinding and Randomisation
Due to concerns that sweat chloride data might lead to unblinding of study personnel, the
sponsor study team members did not have access to sweat chloride results during the conduct of
the trial. Patients and their caregivers were also not to be informed of their study-related
spirometry results during the trial.
Safety interim analyses by the non-sponsor, independent Data Monitoring Committee (DMC)
occurred after approximately 50% and 100% of subjects completed 21 days of treatment in
Cohort 1, and approximately 33%, 50% and 100% of subjects completed 56 days of treatment in
Cohort 2.
4) Results
Study Participants
The genotypes of the 27 F508del-CFTR compound heterozygous patients randomized and dosed
in Cohort 2 are provided in Supplemental Table 5.
Study Drug Compliance
For Cohort 1, the mean rate of adherence to the study drugs was 100% in both active treatment
and placebo arms. For Cohort 2, mean rates of adherence to study drug ranged between 90% and
99%. For Cohort 3, mean rates of adherence during monotherapy and combination periods were
5 VX09-‐809-‐102 clinical trial Web Appendix 99% and 97%, respectively, for the 400 mg q12h lumacaftor treatment arm, and 100% and 93%,
respectively, for the placebo arm.
Sweat Chloride Concentration
Sensitivity analyses revealed that in Cohort 1, the observed reduction in sweat chloride
concentration in the placebo arm was driven by a single patient who had a -35·5 mmol/L change
from baseline value. At the follow-up visit after withdrawal of study drug, mean sweat chloride
levels increased in both the active treatment arms, but did not change in the placebo arm (Figure
3).
Clinical Endpoints
In Cohort 2, among the twenty F508del homozygotes receiving combination therapy with
lumacaftor 600mg and ivacaftor 250mg, five (25%) experienced at least a 10 percentage point
improvement in absolute FEV1 during combination therapy, compared to 0/21 in the placebo
arm (Figure 5C).
6 VX09-‐809-‐102 clinical trial Web Appendix 5) Supplemental Table 1. Changes in sweat chloride concentration in Cohort 1.
Lumacaftor 200mg qd Ivacaftor 150mg q12h Lumacaftor 200mg qd Ivacaftor 250mg q12h Placebo Monotherapy (Day 1 – Day 14); Change from Day 1 Baseline N* 19 17 17 Change from baseline, mean (95%CI), †
mmol/L -‐4·8 (-‐8·6, 1·0) -‐4·1 (-‐8·1, -‐0·1) -‐1·7 (-‐5·6, 2·3) P value, within-‐treatment arm change 0·015 0·046 0·406 -‐3·1 (-‐8·7, 2·4) -‐2·4 (-‐8·0, 3·2) n/a 0·264 0·393 n/a Treatment difference vs placebo (95%CI), mmol/L P value, between-‐group Combination therapy (Day 14 – Day 21); Change from Day 14 Baseline N* 19 14 17 Change from baseline, mean (95%CI), †
mmol/L -‐2·1 (-‐5·4, 0·9) -‐9·1 (-‐12·9, -‐5·4) 0·5 (-‐3·0, 4·1) P value, within-‐treatment arm change 0·193 < 0·001 0·754 -‐2·7 (-‐7·5, 2·1) -‐9·7 (-‐14·8, -‐4·6) < 0·001 Treatment difference vs placebo (95%CI), mmol/L P value, between-‐group 0·267 n/a n/a Total Change: Monotherapy + Combination therapy (Day 1 – Day 21); Change from Day 1 Baseline N* 20 17 16 Change from baseline, mean (95%CI), †
mmol/L -‐6·7 (-‐11·1, -‐2·4) -‐12·6 (-‐17·2, -‐7·9) -‐1·7 -‐6·5, 3·1) P value, within-‐treatment arm change 0·003 <0·001 0·482 Treatment difference vs placebo (95%CI), mmol/L P value, between-‐group -‐5·0 (-‐11·6, 1·5) 0·126 -‐10·9 (-‐17·6, -‐4·2) 0·002 n/a n/a * Individuals with sweat quantity not sufficient for analysis, or with sweat values reported as <10mmol/L or >160 mmol/L not
included in N
† Reported means are least-square means. Results were based on an ANCOVA model: change adjusted for treatment, baseline,
and baseline age. Baseline for monotherapy is pre-dose value at study start (Day 1). Baseline for combination therapy period
is pre-dose value at start of combination period (Day 14).
n/a, not applicable; 95% CI, 95% confidence interval
7 VX09-‐809-‐102 clinical trial Web Appendix 6) Supplemental Table 2. Absolute change in percent-predicted FEV1 from baseline in Cohort 1
for monotherapy and combination therapy.
Lumacaftor 200 mg qd Ivacaftor 150mg q12h Lumacaftor 200 mg Ivacaftor 250mg q12h Placebo Monotherapy (Day 1 – Day 14); Change from Day 1 Baseline N 20 20 21 Change from baseline, mean (95%CI)* -‐0·3 (-‐2·4, 1·7) -‐0·1 (-‐2·1, 2·0) 1·7 (-‐0·2, 3·6) P value, within-‐treatment arm change 0·736 0·964 0·076 -‐2·1 (-‐4·8, 1·7) -‐2·2 (-‐4·7, 1·1) n/a 0·137 0·123 n/a Treatment difference vs placebo (95%CI) P value, between-‐group Combination therapy (Day 14 – Day 21); Change from Day 14 Baseline N 20 18 21 Change from baseline, mean (95%CI)* 3·5 (0·9, 6·1) 0·6 (-‐2·2, 3·5) -‐1·4 (-‐3·9, 1·1) P value, within-‐treatment arm change 0·010 0·657 0·244 4·9 (1·4, 8·4) 2·1 (-‐1·8, 5·9) n/a 0·007 0·282 n/a Treatment difference vs placebo (95%CI) P value, between-‐group Total Change: Monotherapy + Combination therapy (Day 1 – Day 21); Change from Day 1 Baseline N* 20 18 21 Change from baseline, mean (95%CI), 3·1 (0·1, 6·1) 0·5 (-‐2·8, 3·8) 0·3 (-‐2·6, 3·1) P value, within-‐treatment arm change 0·047 0·756 0·858 2·8 (-‐1·3, 7·0) 0·3 (-‐4·2, 4·7) n/a 0·176 0·908 n/a Treatment difference vs placebo (95%CI), mmol/L P value, between-‐group *Reported means are least-square means. Results were based on an ANCOVA model: change adjusted for treatment + baseline +
baseline age. Baseline for monotherapy is pre-dose value at study start (Day 1). Baseline for combination therapy period is predose value at start of combination period (Day 14).
n/a, not applicable; 95% CI, 95% confidence interval
8 VX09-‐809-‐102 clinical trial Web Appendix 7) Supplemental Table 3: Adverse event summary for Cohort 1
N Number of adverse events, n Number of serious adverse events, n Patients reporting any adverse event, n (%) Monotherapy (Day 1 – Day 14) Combination therapy (Day 14 – Day 21) Lumacaftor 200 mg qd* Placebo Lumacaftor 200 mg qd Ivacaftor 250 mg q12h 20 31 Placebo Lumacaftor 200 mg qd Ivacaftor 150 mg q12h 20 43 41 75 21 31 0 0 0 0 0 29 (71) 12 (57) 14 (70) 12 (60) 15 (71) 21 55 Adverse events occurring in ≥10% of VX-‐809 and/or ivacaftor-‐treated patients Cough Pulmonary exacerbation† Oropharyngeal pain Nasal congestion Dizziness Prothrombin time prolonged Upper respiratory tract infection 6 (15) 2 (5) 2 (5) 0 0 1 (2) 1 (5) 0 0 0 0 0 4 (20) 2 (10) 1 (5) 1 (5) 2 (10) 2 (10) 1 (5) 1 (5) 2 (10) 3 (15) 1 (5) 0 4 (19) 1 (5) 2 (10) 2 (10) 0 0 0 0 2 (10) 0 0 Reported adverse events are treatment-emergent adverse events
*Combines lumacaftor treatment arms.
†Coded as cystic fibrosis lung per MedDRA (Medical Dictionary for Regulatory Activities).
9 VX09-‐809-‐102 clinical trial Web Appendix 8) Supplemental Table 4. Changes in patient-reported respiratory symptoms using the CFQ-R
Respiratory domain in Cohorts 2 and 3.
F508del-‐CFTR genotype Change from baseline‡, mean (95% CI) P value, within-‐treat arm change Treatment difference vs placebo (95% CI) P value, between-‐
group Placebo Lumacaftor 600 mg qd Ivacaftor 250 mg q12h homozygous homozygous homozygous* Mixed† heterozygous homozygous 21 20 20 11 27 18 5·2 (-‐1·5, 12·0) -‐2·3 (-‐9·3, 4·6) -‐9·5 (-‐16·4, -‐2·6) -‐8·8 (-‐18·1, 0·5) 2·9 (-‐3·1, 8·9) -‐9·9 (-‐17·2, -‐2·7) 0·128 0·505 0·007 0·065 0·335 0·008 2·3 (-‐6·7, 11·3) -‐5·3 (-‐14·4, 3·9) -‐12·4 (-‐21·6, -‐3·3) -‐11·7 (-‐22·8, -‐0·6) n/a -‐12·8 (-‐22·3, -‐3·4) 0·613 0·255 0·008 0·040 n/a 0·008 Combination therapy (Day 28 – Day 56) N Change from baseline‡, mean (95% CI) P value, within-‐treat arm change Treatment difference vs placebo (95% CI) P value, between-‐
group Lumacaftor 400 mg q12h Ivacaftor 250 mg q12h Monotherapy (Day 1 – Day 28) N Lumacaftor Lumacaftor Lumacaftor 200 mg qd 400 mg qd 600 mg qd ivacaftor 250 Ivacaftor 250 Ivacaftor 250 mg q12h mg q12h mg q12h 21 20 20 10 25 17 3·3 (-‐3·6, 10·2) 7·9 (0·8, 14·9) 8·9 (1·9, 15·9) 11·2 (1·3, 21·1) -‐8·6 (-‐14·9, -‐
2·2) 5·5 (-‐2·1, 13·1) 0·347 0·030 0·014 0·028 0·009 0·154 11·8 (2·5, 21·2) 16·4 (6·9, 26·0) 17·4 (7·9, 27·0) 19·8 (7·9, 31·6) n/a 14·1 (4·1, 24·1) 0·013 <0·001 <0·001 0·001 n/a 0·006 Total Change Monotherapy + Combination therapy (Day 1 – Day 56) N Change from baseline, mean (95% CI) P value, within-‐treat arm change Treatment difference vs 21 20 20 10 25 17 7·9 (0·5, 15·3) 5·5 (-‐2·2, 13·2) -‐0·9 (-‐8·5, 6·7) 4·0 (-‐6·8, 14·8) -‐8·0 (-‐14·9, -‐
1·1) -‐4·9 (-‐13·2, 3·4) 0·037 0·157 0·812 0·462 0·023 0·242 15·9 (5·8, 26·0) 13·5 (3·2, 23·9) 7·1 (-‐3·3, 17·4) 12·0 (-‐0·8, 24·9) n/a 3·1 (-‐7·7, 13·9) 10 VX09-‐809-‐102 clinical trial Web Appendix placebo (95% CI) P value, between-‐
group 0·002 0·011 0·177 0·066 n/a 0·570 * One patient was later identified to be heterozygous
† Mixed placebo population included patients homozygous or heterozygous for F508del-CFTR; Cohorts 2 and 3 pooled
‡Baseline for monotherapy is pre-dose value at study start (Day 1). Baseline for combination therapy period is pre-dose value at start of
combination period (Day 28).
n/a, not applicable; 95% CI, 95% confidence interval
11 VX09-‐809-‐102 clinical trial Web Appendix 9) Supplemental Table 5: Genotypes of the 27 F508del-CFTR compound heterozygous patients
randomized and dosed in Cohort 2
Genotype of non-‐F508del-‐CFTR allele Number of Patients R334W 1 Q493X 1 I507del 1 G542X 3 R560T 2 621+1G>T 5 R1066C 1 W1282X 3 N1303K 4 1717-‐1G>A 2 1898+1G>A 2 A2184del 1 3120+1G>A 1 12 VX09-‐809-‐102 clinical trial Web Appendix Supplemental Figures
12) Supplemental Figure 1. Changes in percent-predicted FEV1 from baseline in Cohort 2 heterozygote patients
Placebo population included patients homozygous or heterozygous for F508del-CFTR
*P<0·05 for within-treatment arm change from baseline
†P<0·05 versus placebo
14) Appendix Bibliography
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