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1 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: Minniti CP, Gorbach AM, Xu D, et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol 2014; published online Nov org/ /s (14)

2 SUPPLEMENTAL DATA FOR: A phase 1 trial of topical sodium nitrite for chronic leg ulcers in patients with sickle cell anemia Caterina P. Minniti, MD a, Alexander M. Gorbach, PhD b, Dihua Xu, PhD a, Yuen Yi Hon, PharmD c, Kara-Marie Delaney, MD a, Miles Seidel, BS b, Nitin Malik, BS b, Marlene Peters-Lawrence, RN a, Carly Cantilena, BS a, James S. Nichols, RN a, Laurel Mendelsohn, BS a, Anna Conrey, NP a, George Grimes, PharmD c, and Gregory J. Kato, MD a a National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD;; b Infrared Imaging & Thermometry Unit, NIBIB, National Institutes of Health, Bethesda, MD; c Pharmaceutical Development Services, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD; Short title: Sodium nitrite for leg ulcers in sickle cell Key words: leg ulcer, sickle cell, blood flow, sodium nitrite Corresponding author: Gregory J. Kato, MD Department of Medicine, Division of Hematology-Oncology Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh 200 Lothrop Street, BST E1240, Pittsburgh, PA katogj@upmc.edu Office Phone: Fax:

3 SUPPLEMENTAL METHODS Patient exclusion criteria Exposure to therapeutic nitric oxide, L-arginine, nitroprusside or nitroglycerine within the past 1 week. Patients presenting with clinically diagnosed bacterial infection (e.g., osteomyelitis, pneumonia, sepsis or meningitis). Patients who have a pre-existing methemoglobinemia (more than 2.5%) Patients who are currently enrolled in any other investigational drug study (this does not include observational or natural history protocols). Use of PDE5 inhibitors, such as sildenafil, 4 days prior to screening. Pregnant women (urine or serum HCG +) or nursing mothers. Wound care The following was the prospectively defined procedure used in all protocol patients: Cleanse leg with skin cleanser Cleanse ulcer with normal saline and gauze removing any debris from wound bed Apply petrolatum-based ointment to moisturize under wrap Cover ulcer with Mepilex white foam Apply two-layer compression wrap to leg (depending on the condition of the ulcer) Change dressing twice weekly 2

4 Figure 1: Pharmacokinetic analysis during treatment of leg ulcers with topical sodium nitrite. (A) Pharmacokinetics analysis of methemoglobin by dose level cohort. (B) Pharmacokinetics of plasma nitrite concentrations during the entire trial. (C) Whole blood nitrite concentrations in relation to hydroxycarbamide use. (D) Observed dose response of whole blood nitrite to hydroxycarbamide dose during the first 24 h after sodium nitrite application. 3

5 Supplemental Table 1. Clinical details of each patient. Study wound size (cm 2 ) Active ulcers (number) Duration of study ulcer (months) Age Age at first Trauma prior to Vaso-occlusive Pain Crisis Analgesic used at beginning Sex (years) ulcer (years) ulcer opening (previous 12 months) of trial Prior Wound therapies M childhood N 3 severe, 5 moderate Ibuprofen 400 mg PRN Bedside debridement, honey M Y 30+ moderate F Y (immobililty s/p hip surgery) 1 severe, 36 moderate F N No pain except ulcer pain F Y (scratch from bicycle pedal) No pain except ulcer pain Percocet 5/325 4 daily, OxyContin 80 mg TID MS-Contin mg daily, Dilaudid 8 mg daily Methadone 25 mg daily, Oxycodone mg daily MS-Contin 60 mg daily, MSIR mg daily Hyperbaric oxygen, surgical debridement, skin graft, whirlpool debridement, bedside debridement, MIST, Maggot therapy Bedside debridement, Pulsatile High- Pressure Lavage Hyperbaric oxygen, surgical debridement, bedside debridement, MIST, Maggot twicw22therapyx2 Surgical sharp debridement, skin graft, whirlpool debridement, negative pressure wound therapy, hyperbaric oxygen F Y (scratch) 36 moderate OxyContin 60 mg BID M N 2 severe, 15 moderate Oxycodone 60 mg daily Surgical sharp debridement, skin graft, bedside debridement, negative pressure wound therapy, MIST, pulsatile high- pressure lavage Hyperbaric oxygen, bedside debridement, negative pressure wound therapy M N 5 moderate Percocet 10/325 6 daily Bedside debridement, MIST low- frequency ultrasound F Y No pain except ulcer pain Tramadol mg daily Bedside debridement, Negative Pressure wound Therapy F N F N (urticaria at first site) 3 severe 2 severe M N 10 mild Percocet 5/ daily Bedside debridement, Skin graft, whirlpool debridement Fentanyl patch + Dilaudid 2 mg (2-3x daily) Bedside debridement Dilaudid 2 mg 1-2 daily x 6 days Bedside debridement, Surgical sharp debridement, MIST low- frequency ultrasound F N 1 moderate Vicodin 5/500mg 4-6 daily Hyperbaric oxygen, Surgical sharp debridement, Skin graft, conservative sharp wound F N 10 mild, 1 extreme severe M Y 14 mild, 5 moderate, 1 severe, 1 extremely severe MS-Contin & Dilaudid (also Lyrica, gabapentin, & namubetone) Oxycodone 5mg PRN Surgical sharp debridement, Conservative sharp wound debridement, Topical enzymes, sclerotherapy of great saphenous vein Conservative sharp wound debridement (bedside), M N 1 extremely severe Ibuprofen 400 mg PRN Hyperbaric oxygen, Surgical sharp debridement, Conservative sharp wound debridement, Collagen graft, Negative pressure therapy, Topical enzymes F N 30 mild, 2 severe, 1 extremely severe M Y (Dog scratch) 10 moderate,3 severe MS-Contin 30 mg BID/TID PRN, Dilaudid 4-8mg q4 hours PRN Methadone 40 mg TID, Dilaudid 16 mg q 4-6 hours PRN Conservative sharp wound debridement (bedside), Pulsatile High-Pressure lavage, Topical enzymes Conservative Sharp Wound Debridement (bedside), Topical enzymes 4

6 Supplemental Table 2: Laboratory values in the 18 subjects at baseline and at the end of study. Values that were statistically significantly lower at the end of study are in bold. Laboratory Variable Baseline End of study p Value Methemoglobin (%) 1.4 ± ± White Blood Cell (K/uL) 9.9 ± ± Hemoglobin (g/dl) 8.1 ± 1 8 ± Hematocrit (%) 23.4 ± ± Mean corpuscular volume (fl) 93.8 ± ± Platelet count (K/uL) ± ± Absolute neutrophil (K/uL) 5.1 ± ± Reticulocyte (%) 8.9 ± ± Absolute reticulocyte count (K/uL) ± ± Sodium (mmol/l) ± ± Potassium (mmol/l) 4.5 ± ± Chloride (mmol/l) ± ± Total CO2 (mmol/l) 25.3 ± ± Creatinine (mg/dl) 0.7 ± ± Glucose (mg/dl) 93.5 ± ± Blood urea nitrogen (BUN) (mg/dl) 11.7 ± ± Albumin (g/dl) 4 ± ± Calcium (mmol/l) 2.2 ± ± Magnesium (mmol/l) 0.8 ± ± Phosphorus (mg/dl) 3.8 ± ± Alkaline phosphatase (U/L) ± ± Alanine aminotransferase (U/L) 34.2 ± ± Aspartate aminotransferase (U/L) 46.6 ± ± Total bilirubin (mg/dl) 2.5 ± ± Direct bilirubin (mg/dl) 0.5 ± ± Lactate dehydrogenase (U/L) ± ± Total protein (g/dl) 8 ± ± Creatine kinase (U/L) 91.4 ± ± Uric acid (mg/dl) 7.9 ± ±

7 Supplemental Table 3: Results of bacterial and fungal cultures of ulcers before and at end of study in each of the subjects. Results are qualitative. Cultures were obtained by the wound care nurse, with a cotton swab, in the center of the study ulcer. Before sodium nitrite cream application Moderate Staphylococcus aureus, moderate Klebsiella pneumoniae Heavy Staphylococcus aureus, heavy Enterococcus faecalis, scant Candida albicans Heavy Corynebacterium species 1 colony Coagulase-Negative Staphylococcus Heavy Methicillin Sensitive Staphylococcus aureus & Corynebacterium striatum Moderate Group B Streptococcus Moderate Staphylococcus aureus/heavy Pseudomonas/Moderate Coagulase-Negative Staphylococcus Moderate Staphylococcus aureus Moderate Corynebacterium, moderate Staphylococcus aureus Enterococcus faecalis, moderate Candida albicans, light No growth Streptococcus species Moderate MRSA, scant Escherichia coli, Moderate Streptococcus Moderate Staphylococcus agalactiae (Group aureus B) Light Pantoea calida End of Study Moderate Staphylococcus aureus, moderate Klebsiella pneumoniae, light Streptococcus agalactiae (Group B) Heavy Staphylococcus aureus, heavy Enterococcus faecalis Not collected Heavy Staphylococcus aureus, Streptococcus agalactiae Moderate Methicillin Sensitive Staphylococcus aureus & Corynebacterium species Heavy Group B Streptococcus, Moderate Coagulase-Negative Staphylococcus, 1 colony Candida albicans Moderate Staphylococcus aureus Heavy Staphylococcus aureus, Group B Streptococcus Heavy Staphylococcus aureus No growth Moderate Methicillin Resistant Staphylococcus aureus, light Corynebacterium species (consistent with skin flora) Moderate Staphylococcus aureus, light Corynebacterium jeikeium 6

Supplementary materials

Supplementary materials Table S Adverse events identified by participants diary logs and blood hematologic and biochemical tests (n=2) group (n=) Placebo group (n=) P value for chi-squared test Asthma