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1 Supplementary Online Content Khanna D, Denton CP, Merkel PA, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA. doi: /jama etable 1. List of the Independent Data Monitoring Committee Members and International Liver Safety Board Members etable 2. Schedule of Visits and Assessments for DUAL-1 and DUAL-2 Study Endpoints emethod. Development of the HDISS-DU Patient-Reported Outcome Questionnaire efigure. Distribution of Randomized Patients by Country in A) DUAL-1 and B) DUAL-2 etable 3. Imputation Rules for the Primary Endpoint Analysis etable 4. Sensitivity Analyses of the Primary Endpoint for A) DUAL-1 and B) DUAL-2 etable 5. Missing Data for the Primary Endpoint Analysis in A) DUAL-1 and B) DUAL-2 etable 6. Summary of Digital Ulcer Complications up to End of Treatment in A) DUAL-1 and B) DUAL-2 etable 7. Adverse Events and Laboratory Abnormalities This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. List of the Independent Data Monitoring Committee Members and International Liver Safety Board Members Independent Data Monitoring Committee Members Name Jerry Molitor, MD, PhD David DeMets, PhD Björn Nashan, MD, PhD Affiliation Professor of Medicine, University of Minnesota Minneapolis, Minnesota, USA Professor of Biostatistics and Medical Informatics University of Wisconsin, Madison, Wisconsin, USA Professor of Surgery, University Medical Center Hamburg- Eppendorf, Hamburg, Germany International Liver Safety Board Members Name Willis Maddrey, MD Paul Watkins, MD James Freston, MD Affiliation Professor of internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Professor of Medicine, The University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA Independent Pharmaceutical Consultant, Council member of the National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA

3 etable 2. Schedule of Visits and Assessments for DUAL-1 and DUAL-2 Study Endpoints Time Days -14 to -1 (Screeni ng) Day 1 (Randomizati on) Wee k 4 Wee k 8 Wee k 12 Week 16 (Primary Endpoint Assessme nt) Visit s Ever y Mont h Visits Every 3 Mont hs End-of- Treatment Assessm ent Evaluation of digital X X X X X X X X ulcers a SHAQ, X X X X HAQ-DI b HDISS- DU TM, b X X X X X Xc X Patient and physicianreported global assessme nt Overall hand pain related to digital ulcers Digital ulcer complicati ons Adverse events Vital signs (BP,HR) 12-lead ECG Laboratory tests d X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Pregnancy test e X X f X X X X Hb LT Hb LT Hb LT X Monthly (+/-7 days) X Hb/LT Monthly (+/-7 days) and up to at least 30 days after end of treatment Abbreviations: BP, blood pressure; ECG, electrocardiogram; ecrf, electronic Case Report Form;, Hb, hemoglobin; HDISS-DU, Hand Disability in Systemic Sclerosis-Digital Ulcers; HR, heart rate; LT, liver test; SHAQ, Scleroderma Health Assessment Questionnaire; SSc, systemic sclerosis; wk, week. a Total number of digital ulcers, occurrence of new digital ulcers, healing of all digital ulcers, baseline and new digital ulcers, and location of digital ulcers were recorded at each visit. b During a given visit, the HDISS-DU should have been performed before any other assessment(s), followed by the SHAQ. c Performed at the first 2 quarterly visits only. d Blood chemistry and hematology, unless otherwise indicated. LTs included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin (direct and indirect). e Women of childbearing potential only. Serum β-human chorionic gonadrotropin was assessed unless otherwise indicated. f A urine pregnancy test was to be performed if visit 1 was done more than 5 days before visit 2.

4 emethod. Development of the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU ) patient-reported outcome questionnaire The HDISS-DU was developed in accordance with the 2009 guidance from the US Food and Drug Administration. 1 The concepts and items comprising the HDISS-DU were developed based on an initial phase of interviews of digital ulcer patients that included concept elicitation and cognitive debriefing on the Cochin Hand Function Scale (an 18-item functional disability questionnaire that uses tasks of daily living to assess function 2-4 ), and a second phase of patient cognitive debriefing interviews on a revised instrument. Results from the cognitive debriefing interviews suggest that the draft HDISS-DU is a comprehensive measure assessing the impact of digital ulcers on hand functioning that asks patients to rate their ability to complete common activities over the past 7 days. 5 The psychometric evaluation, including final validation of the HDISS-DU and derivation of a scoring algorithm, is under development based on blinded data from the DUAL studies. References 1. US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. US FDA website. Accessed October 5, Duruöz MT, Poiraudeau S, Fermanian J, et al. Development and validation of a rheumatoid hand functional disability scale that assess functional handicap. J Rheumatol. 1996:23(7): Mouthon L, Mestre-Stanislas C, Bérezné A, et al. Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis. Ann Rheum Dis. 2010;69(1): Rannou F, Poiraudeau S, Bérezné A, et al. assessing disability and quality of life in systemic sclerosis: construct validities of the Cochin Hand Function Scale, Health Assessment Questionnaire (HAQ), Systemic Sclerosis HAQ, and Medical Outcomes Study 36-Item Short Form Health Survey. Arthritis Rheum. 2007;57(1): Khanna D, Poiraudeau S, Gelhorn H, et al. Development and content validity of the Hand Disability in Systemic Sclerosis Digital Ulcers (HDISS-DU) Scale. Arthritis Rheum. 2011;63(10):S726.

5 efigure. Distribution of Randomized Patients by Country in A) DUAL-1 and B) DUAL-2 a) DUAL-1 b) DUAL-2

6 etable 3. Imputation Rules for the Primary Endpoint Analysis Rule 1 Rule 2 Rule 3 Imputation of digital ulcer in the event of monotone pattern of missing data Imputation of digital ulcers in the event of missing intermediate visit Imputation of digital ulcers in the event of missing postbaseline digital ulcer assessment Missing values for the primary endpoint were imputed using rules 1 to 3. For each individual with nonmissing digital ulcer assessment up to a certain time point and missing afterward up to week 16, the cumulative number of new digital ulcers at week 16 was not imputed. In this event, the rate of new digital ulcers up to week 16 was estimated from the NB-2 model assuming a constant rate of occurrence of new digital ulcers over time For each individual, missing values of digital ulcers due to intermediate missing visits were replaced by the mean number of digital ulcers between the closest nonmissing visits, ie, before and after the intermediate missing visit. In the special case where the assessment at week 4 was missing but that at week 8 was not, the cumulative number of new digital ulcers was imputed as the mean between the number of new digital ulcers at week 8 and the number of digital ulcers that the individual developed between 4 weeks prior to randomization and randomization (based on the onset dates of digital ulcers present at screening and baseline) For each individual with no postbaseline digital ulcer assessment, the cumulative number of new digital ulcers at week 16 was imputed with the number of digital ulcers that the individual developed between 16 weeks prior to randomization and randomization (based on the onset dates of digital ulcers present at screening and baseline)

7 etable 4. Sensitivity Analyses of the Primary Endpoint for A) DUAL-1 and B) DUAL-2 A) DUAL-1 Analysis Placebo 3mg Multiple imputation analysis using variables treatment group, number of digital ulcers at randomization and the count of new digital ulcers at each visit up to week 16 Pitman's permutation test 1 (ITT set) (applying Rule 1, 2 and 3 for missing data from etable 3) Binomial regression model (mitt set) applying only Rule 1 and Rule 2 from etable 3 Binomial regression model (per protocol set) applying only Rule 1 and Rule 2 from etable 3 unadjusted (applying Rule 1, 2 and 3 for missing data from etable 3) standardizing the number of digital ulcers over 16 weeks (112 days) for each patient instead of using the offset variable in the primary model (applying Rule 1, 2 and 3 for missing data from etable 3) including sex as a covariate (applying Rule 1, 2 and 3 for missing data from etable 3) including treatment, sex, and time to digital ulcer diagnosis as covariates (applying Rule 1, 2 and 3 for missing data from etable 3) Estimated mean number of new digital ulcers over 16 weeks 0.86 (0.59 to 1.27) 0.91 (0.62 to 1.33) 10mg 1.02 (0.69 to 1.52) 1.05 (0.61 to 1.80) 1.18 (0.69 to 2.03) P value Mean number of 0.8 ( (0.6 to 0.9 (0.6 to new digital ulcers to 1.1) 1.2) 1.2) over 16 weeks P Value Estimated mean (0.59 number of new (0.57 to to 1.27) digital ulcers over 1.23) 16 weeks 1.05 (0.70 to 1.56) 1.03 (0.60 to 1.76) 1.24 (0.72 to 2.14) P Value Estimated mean ( (0.77 number of new (0.59 to to 1.34) to 1.68) digital ulcers over 1.26) 16 weeks 1.06 (0.62 to 1.80) 1.31 (0.77 to 2.24) P Value Estimated mean ( (0.69 number of new (0.56 to to 1.26) to 1.41) digital ulcers over 1.15) 16 weeks 1.10 (0.66 to 1.84) 1.23 (0.74 to 2.06) P Value Estimated mean ( (0.79 number of new (0.53 to to 1.25) to 1.75) digital ulcers over 1.20) 16 weeks 1.04 (0.59 to 1.85) 1.48 (0.85 to 2.60) P Value Estimated mean ( (0.57 number of new (0.44 to to 1.15) to 1.35) digital ulcers over 1.06) 16 weeks 1.07 ( (0.78 to 1.78) to 2.13) P Value Estimated mean (0.48 number of new (0.45 to to 1.16) digital ulcers over 1.06) 16 weeks 0.85 (0.55 to 1.29)

8 etable 4. (Continued) Sensitivity Analyses of the Primary Endpoint for A) DUAL-1 and B) DUAL-2 Analysis Placebo 3mg 10mg 1.08 (0.65 to 1.78) 1.22 (0.74 to 2.02) P Value applying Rule 1 and 3 for missing data Estimated mean number of new 0.81 (0.56 to 0.93 (0.64 to 1.34) 1.07 (0.74 to 1.54) from etable 3, and imputing 0 digital ulcers for missing intermediate visits instead of Rule 2 digital ulcers over 16 weeks 1.18) 1.14 (0.68 to 1.90) 1.31 (0.79 to 2.18) Binomial regression model (mitt set) applying Rule 1 for missing data from etable 3 and imputing 0 digital ulcers for missing intermediate visits instead of Rule 2, up to end of double-blind treatment (applying Rule 1, 2 and 3 for missing data from etable 3) P Value Estimated mean (0.58 number of new (0.55 to to 1.25) digital ulcers over 1.18) 16 weeks 1.03 (0.69 to 1.54) 1.06 (0.62 to 1.82) 1.29 (0.75 to 2.22) P Value Estimated mean ( (1.90 number of new (1.85 to to 3.17) to 3.97) digital ulcers up to 3.64) end of double-blind treatment 0.86 (0.53 to 1.39) 1.06 (0.65 to 1.72) P Value Neuhauser M. Nonparametric Statistical Tests: A Computational Approach. CRC Press, mitt, modified intent-to-treat (all randomized patients who had at least one post-baseline digital ulcer assessment during the first 16 weeks); ITT, intent-to-treat

9 etable 4. (Continued) Sensitivity Analyses of the Primary Endpoint for A) DUAL-1 and B) DUAL-2 B) DUAL-2 Analysis Placebo 3mg Multiple imputation analysis using variables treatment group, number of digital ulcers at randomization and the count of new digital ulcers at each visit up to week 16 Pitman's permutation test 1 (ITT set) (applying Rule 1, 2 and 3 for missing data from etable 3) Binomial regression model (mitt set) applying only Rule 1 and Rule 2 from etable 3 Binomial regression model (per protocol set) applying only Rule 1 and Rule 2 from etable 3 unadjusted (applying Rule 1, 2 and 3 for missing data from etable 3) standardizing the number of digital ulcers over 16 weeks (112 days) for each patient instead of using the offset variable in the primary model (applying Rule 1, 2 and 3 for missing data from etable 3) including sex as a covariate (applying Rule 1, 2 and 3 for missing data from etable 3) including treatment, sex, and time to digital ulcer diagnosis as covariates (applying Rule 1, 2 and 3 for missing data from etable 3) Estimated mean number of new digital ulcers over 16 weeks 1.14 (0.81 to 1.61) 1.41 (1.01 to 1.95) 10mg 1.50 (1.07 to 2.08) 1.23 (0.77 to 1.97) 1.31 (0.82 to 2.10) P value Mean number of 1.0 ( (0.9 to 1.3 (0.9 to new digital ulcers to 1.4) 1.8) 1.6) over 16 weeks P Value Estimated mean (1.01 number of new (0.80 to to 1.93) digital ulcers over 1.57) 16 weeks 1.43 (1.03 to 1.99) 1.25 (0.78 to 1.99) 1.29 (0.80 to 2.05) P Value Estimated mean ( (1.15 number of new (0.97 to to 2.17) to 2.16) digital ulcers over 1.83) 16 weeks 1.19 (0.77 to 1.86) 1.18 (0.76 to 1.84) P Value Estimated mean ( (0.97 number of new (0.79 to to 1.94) to 1.88 digital ulcers over 1.56) 16 weeks 1.26 (0.79 to 2.03) 1.22 (0.76 to 1.97) P Value Estimated mean ( (1.01 number of new (0.78 to to 1.82) to 2.01) digital ulcers over 1.59) 16 weeks 1.15 (0.71 to 1.89) 1.28 (0.78 to 2.08) P Value Estimated mean ( (1.06 number of new (0.87 to to 2.10) to 2.09) digital ulcers over 1.73) 16 weeks 1.20 ( (0.78 to 1.88) to 1.89) P Value Estimated mean (0.99 number of new (0.85 to to 1.99) digital ulcers over 1.66) 16 weeks 1.18 (0.76 to 1.83) 1.49 (1.07 to 2.07) 1.25 (0.81 to 1.94)

10 etable 4. (Continued) Sensitivity Analyses of the Primary Endpoint for A) DUAL-1 and B) DUAL-2 Analysis Placebo 3mg 10mg P Value applying Rule 1 and 3 for missing data Estimated mean number of new 1.20 (0.87 to 1.40 (1.03 to 1.91) 1.46 (1.07 to 1.99) from etable 3, and imputing 0 digital ulcers for missing intermediate visits instead of Rule 2 digital ulcers over 16 weeks 1.67) 1.16 (0.75 to 1.82) 1.21 (0.78 to 1.90) Binomial regression model (mitt set) applying Rule 1 for missing data from etable 3 and imputing 0 digital ulcers for missing intermediate visits instead of Rule 2, up to end of double-blind treatment (applying Rule 1, 2 and 3 for missing data from etable 3) P Value Estimated mean (0.98 number of new (0.79 to to 1.87) digital ulcers over 1.56) 16 weeks 1.44 (1.03 to (0.76 to 1.94) 1.29 (0.81 to 2.07) P Value Estimated mean ( (2.51 number of new (2.02 to to 4.60) to 4.58) digital ulcers up to 3.74) end of double-blind treatment 1.25 (0.82 to 1.91) 1.23 (0.81 to 1.89) P Value Neuhauser M. Nonparametric Statistical Tests: A Computational Approach. CRC Press, mitt, modified intent-to-treat (all randomized patients who had at least one post-baseline digital ulcer assessment during the first 16 weeks); ITT, intent-to-treat

11 etable 5. Missing Data for the Primary Endpoint Analysis in A) DUAL-1 and B) DUAL-2 A. DUAL-1 Placebo N = 97 3mg N = 95 10mg N = 97 Complete profile 77 (79.4%) 72 (75.8%) 72 (74.2%) At least one missing 20 (20.6%) 23 (24.2%) 25 (25.8%) assessment Monotone pattern of 9 (9.3%) 11 (11.6%) 15 (15.5%) missing data a Intermediate missing data b 8 (8.2%) 9 (9.5%) 4 (4.1%) Only baseline data 3 (3.1%) 3 (3.7%) 6 (6.2%) a data available up to a certain visit, after which, all data are missing (i.e. data available at baseline, week 4, week 8 and week 12; or at baseline, week 4 and week 8; or at baseline and week 4) b most of those patients (17/21) have only data missing from one intermediate visit, while data are available for all other visits B. DUAL-2 Placebo N = 89 3mg N = 88 10mg N = 88 Complete profile 66 (74.2%) 68 (77.3%) 65 (73.9%) At least one missing 23 (25.8%) 20 (22.7%) 23 (26.1%) assessment Monotone pattern of missing 15 (16.9%) 11 (12.5%) 18 (20.5%) data a Intermediate missing data b 6 (6.7%) 4 (4.5%) 1 (1.1%) Only baseline data 2 (2.2%) 5 (5.7%) 4 (4.5%) a data available up to a certain visit, after which, all data are missing (i.e. data available at baseline, week 4, week 8 and week 12; or at baseline, week 4 and week 8; or at baseline and week 4) b most of those patients (8/11) have only data missing from one intermediate visit, while data are available for all other visits

12 etable 6. Summary of Digital Ulcer Complications up to End of Treatment in A) DUAL-1 and B) DUAL-2 A. DUAL-1 Digital Ulcer Complication a Placebo N = 94 3mg N = 92 10mg N = 92 Total patients with at least 1 digital ulcer 18 (19.1) 13 (14.1) 18 (19.6) complication Total number of digital ulcer complications Initiation of systemic antibiotics for digital ulcer 12 (12.8) 6 (6.5) 16 (17.4) Required class II-IV narcotics or dose 6 (6.4) 5 (5.4) 7 (7.6) increase >50% compared with baseline Use of parenteral prostanoids 4 (4.3) 4 (4.3) 2 (2.2) Ischemic crisis necessitating hospitalization 1 (1.1) 3 (3.3) 1 (1.1) Gangrene - 2 (2.2) - Use of ERAs (1.1) B. DUAL-2 Digital Ulcer Complication a Placebo N = 87 3mg N = 84 10mg N = 84 Total patients with at least 1 digital ulcer 18 (20.7) 18 (21.4) 18 (21.4) complication Total number of digital ulcer complications Initiation of systemic antibiotics for digital ulcer 15 (17.2) 15 (17.9) 12 (14.3) Required class II-IV narcotics or dose 4 (4.6) 4 (4.8) 11 (13.1) increase >50% as compared to baseline Use of parenteral prostanoids 3 (3.4) - 4 (4.8) Failure of conservative management 2 (2.3) 1 (1.2) 2 (2.4) Ischemic crisis necessitating hospitalization 2 (2.3) 1 (1.2) 1 (1.2) (Auto) amputation 1 (1.1) - 1 (1.2) Use of ERAs (1.2) Abbreviations: ERA, endothelin receptor antagonist. a Defined as either initiation of systemic antibiotics for digital ulcer, required class II-IV narcotics or dose increase >50% compared with baseline, use of parenteral prostanoids, ischemic crisis necessitating hospitalization, gangrene, or use of ERAs.

13 etable 7. Adverse Events and Laboratory Abnormalities Placebo (n = 97) DUAL-1 3 mg (n = 94) 41.4 (22.1, 59.9) 10 mg (n = 97) 37.4 (18.3, 63.5) Placebo (n = 89) DUAL-2 3 mg (n = 88) 40.5 (17.7, 61.7) 10 mg (n = 87) 38.6 (15.0, 62.1) Treatment exposure (weeks), median (Q1, Q3) 43.1 (22.9, 65.1) 37.4 (17.0, 58.1) Patients with 1 13 (13.4) 17 (18.1) 14 (14.4) 13 (14.6) 10 (11.4) 21 (24.1) serious adverse event, Total number of serious adverse events Patients with 1 71 (73.2) 67 (71.3) 74 (76.3) 70 (78.7) 73 (83.0) 74 (85.1) adverse event, n (%) Total number of adverse events Total number of individual adverse events a, Headache 12 (12.4) 14 (14.9) 19 (19.6) 19 (21.3) 17 (19.3) 15 (17.2) Infected skin 12 (12.4) 7 (7.4) 14 (14.4) 14 (15.7) 15 (17.0) 12 (13.8) ulcer Peripheral edema 6 (6.2) 7 (7.4) 13 (13.4) 4 (4.5) 10 (11.4) 14 (16.1) Skin ulcer 11 (11.3) 9 (9.6) 10 (10.3) 10 (11.2) 14 (15.9) 10 (11.5) Anemia 7 (7.2) 5 (5.3) 8 (8.2) 5 (5.6) 6 (6.8) 11 (12.6) URTI 4 (4.1) 3 (3.2) 7 (7.2) 6 (6.7) 11 (12.5) 8 (9.2) ALT increase 1 (1.0) 2 (2.1) 6 (6.2) 2 (2.2) 5 (5.7) 3 (3.4) GERD 5 (5.2) 0 (0.0) 6 (6.2) 2 (2.2) 4 (4.5) 2 (2.3) Diarrhea 7 (7.2) 6 (6.4) 5 (5.2) 6 (6.7) 10 (11.4) 10 (11.5) Dizziness 2 (2.1) 4 (4.3) 5 (5.2) 3 (3.4) 5 (5.7) 7 (8.0) Pain in extremity 7 (7.2) 4 (4.3) 5 (5.2) 13 (14.6) 8 (9.1) 9 (10.3) AST increase 1 (1.0) 3 (3.2) 5 (5.2) 1 (1.1) 5 (5.7) 2 (2.3) Back pain 3 (3.1) 3 (3.2) 5 (5.2) 6 (6.7) 8 (9.1) 2 (2.3) Arthralgia 7 (7.2) 6 (6.4) 4 (4.1) 4 (4.5) 7 (8.0) 3 (3.4) Nausea 6 (6.2) 5 (5.3) 4 (4.1) 2 (2.2) 5 (5.7) 5 (5.7) Bronchitis 5 (5.2) 7 (7.4) 1 (1.0) 3 (3.4) 4 (4.5) 1 (1.1) Sinusitis 2 (2.1) 5 (5.3) 1 (1.0) 2 (2.2) Nasopharyngitis 2 (2.1) 3 (3.2) 4 (4.1) 5 (5.6) 7 (8.0) 10 (11.5) Fatigue 1 (1.0) 4 (4.3) 3 (3.1) 4 (4.5) 2 (2.3) 7 (8.0) Influenza 2 (2.1) 4 (4.3) 3 (3.1) 3 (3.4) 2 (2.3) 5 (5.7)

14 etable 7. (Continued) Adverse Events and Laboratory Abnormalities (Continued) Myalgia -- 1 (1.1) -- 3 (3.4) 5 (5.7) 4 (4.6) Dyspepsia 3 (3.1) -- 2 (2.1) 6 (6.7) 1 (1.1) 3 (3.4) Constipation 3 (3.1) 2 (2.1) 3 (3.1) 3 (3.4) 7 (8.0) 2 (2.3) Dermatitis (3.1) 1 (1.1) 5 (5.7) 2 (2.3) Bursitis (5.6) 2 (2.3) 2 (2.3) Oropharyngeal pain 1 (1.0) -- 1 (1.0) 6 (6.7) 3 (3.4) 1 (1.1) Pharyngitis 1 (1.0) (0.0) 5 (5.7) 0 (0.0) Laboratory findings, total patients with at least one finding, no. (%) ALT or AST >3 3/96 (3.1) 2/94 (2.1) 5/94 (5.3%) 2/88 (2.3) 2/88 (2.3) 4/86 (4.7) ULN ALT or AST >3 ULN and bilirubin >2 ULN 0/96 (0.0) 0/94 (0.0) 0/94 (0.0) 1/88 (1.1) 0/88 (0.0) 1/86 (1.2) Hemoglobin <10 g/dl and decrease from baseline of 1.6 g/dl 3/93 (3.2) 5/93 (5.4) 9/93 (9.7) 4/88 (4.5) 10/88 (11.4) Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GERD, gastroesophageal reflux disease; URTI, upper respiratory tract infection. a Includes adverse events that occurred in 5% or more of patients in either macitentan groups. The empty cells (--) correspond to the absence of this particular adverse event in a treatment group. 11/86 (12.8)