The Lancet



Supplemental TablesTable S1. Clinical and safety laboratory measures and serum inflammatory markers by ELISA before and after 3-weeks intermittent DQ administration. Pearson correlations (r) for baseline vs. follow-up.Clinical & SafetyBaselineFollow-UpDifferenceWithin-SubjectCorr.Mean ± SDMean ± SDΔ ± SDp-valuerBody weight (kg)88.3 ±14.288.0 ± 14-0.04 ± 0.60.7860.99BMI28.9 ± 3.428.4 ± 3.5-0.02 ± 0.20.7160.99SBP (mmHg)139 ± 13144 ± 104.7±170.3130.02DBP (mmHg)80.3 ± 10.780.8 ± 8.20.5 ± 7.80.8140.69HbA1C (%)5.93 ± 0.95.98 ± 0.90.05 ± 0.130.1870.99Glucose (mg/dL)106 ± 33102 ± 23-3.6 ± 13.30.3240.94LipidsTotal cholesterol (mg/dL)174 ± 30168 ± 29-5.8 ± 260.4280.61Triglycerides (mg/dL)162 ± 147146 ± 122-16.8 ± 490.2250.95HDL-C (mg/dL)49.6 ± 13.547.6 ± 13.2-1.9 ± 4.10.1020.95LDL-C (mg/dL)95.0 ± 29.693.6 ± 36.8-1.3 ± 27.30.8580.68Kidney/ LiverCreatinine (mg/dL)0.96 ± 0.170.96 ±0.150.01 ± 0.10.9360.82Bilirubin (mg/dL)0.66 ± 0.210.56 ± 0.22-0.10 ± 0.150.0240.77Albumin (g/dL)4.18 ± 0.184.14 ± 0.26-0.04 ± 0.180.4770.71ALT (IU/L)17.3 ± 8.019.6 ± 7.82.14 ± 4.90.1270.81AST (IU/L)20.4 ± 5.120.9 ± 6.20.43 ± 2.70.560.91Complete Blood CountsWhite blood cell count (x10e3/uL)7.44 ± 1.676.77 ± 1.74-0.66 ± 1.00.0240.84Neutrophils (absolute, x10e3/uL)4.95 ± 1.564.32 ± 1.59-0.63 ± 0.920.0240.83Lymphocytes (absolute, x10e3/uL)1.65 ± 0.611.64 ± 0.59-0.01 ± 0.290.8540.89Monocytes (absolute, x10e3/uL)0.56 ± 1.450.64 ± 0.170.07 ± 0.90.0120.85Red blood cell count (x10e6/uL)4.77 ± 0.594.60 ± 0.56-0.17 ± 0.30.0410.88Hemoglobin (g/dL)15.2 ± 1.514.9 ± 1.2-0.3 ± 0.80.1670.87Hematocrit (%)44.8 ± 4.143.7 ± 3.3-1.1 ± 2.40.1240.82RBC Distribution Width (%)14.1 ± 0.914.1 ± 1.00.05 ± 0.40.6550.91Mean Corpuscular Volume (fL)94.3 ± 5.894.9 ± 5.70.57 ± 1.40.1490.97Mean Corpuscular Hemoglobin (pg)31.9 ±1.932.2 ± 2.00.35 ± 0.50.0140.98Inflammation Markers (ELISA)C-Reactive Protein (mg/L)1.96 ± 4.81.76 ± 3.8-0.21 ± 1.10.5230.99Monocyte Chemoattr. Prot 1 (MCP1,ng/mL)212 ± 16207 ± 14-5.9 ± 270.4260.89Interleukin-6 (IL-6, pg/mL)*5.4 ± 1.44.4 ± 1.0-1.0 ± 3.70.3120.73Plasminogen Actv. Inhib.1 (PAI-1, ng/mL)*3.10 ± 0.72.85 ± 0.6-0.25 ± 2.30.6850.60Osteopontin (ng/mL)94.0 ± 4.896.2 ± 5.62.7 ± 170.5680.70Apelin (ng/mL)*0.72 ± 0.050.68 ± 0.04-0.04 ± 0.20.4010.52*9 of 14 improve, score or level decrease ≥5%Table S2. Changes in measures of physical and pulmonary function and frailty index derived from clinical chemistries before and after three-week intermittent DQ in 11 participants with stable IPF categorized as low-moderate severity (percent predicted FVC 50-90%).Functional MeasureBaselineFollow-UpDifferenceWithin- SubjectsCorrelationMean ±SDMean ±SDΔ ± SDp-valuerPulmonary FunctionFEV1 (L/s)2.3 ± 0.572.3 ± 0.56+0.009 ± 0.190.880.94*FVC (L)2.9 ±0.612.7 ± 0.97-0.24 ± 0.630.230.77*Physical Function6-min walk distance (m)474 ± 57498 ± 50+24.0 ± 290.019*0.87*4-m gait speed (m/s)1.14 ± 0.181.26 ± 0.16+0.12 ±0.170.046*0.48Timed chair-stands (s)14.0 ± 2.612.2 ± 2.1-1.8 ± 2.80.057^0.31SPPB score10.3 ± 1.111.2 ± 0.9+0.91 ± 1.00.016*0.49*Frailty IndexFI-LAB (score)*0.83 ± 0.040.06 ± 0.030.02 ± 0.040.1030.33*p ≤ 0.05, ^p<0.10, n=11. FEV1: forced expiratory volume in one second (liters per sec, L/s); FVC: forced vital capacity (liters, L); FI-LAB (lab-based frailty index score derived from analytes in/out of reference range for 34 blood-based clinical chemistries). Within-subjects, paired t-test (p-value) and Pearson correlations for baseline vs. follow-upTable S3. Log-transformed circulating matrix remodeling proteins and microRNA markers biological aging before and after 3-weeks intermittent DQ administration and associations with change in physical function, pulmonary function, and FI-LAB.MarkernBaselineFollow-UpWithin-SubjectsPre-Post CorrelationNo. ≥ 5% Change w. DQChange with DQ: SASP vs. FunctionMeanSDMeanSDp-valuePearson rPearson rMMP1112.630.322.750.270.0860.90--FEV1, r = 0.52FI-LAB Index, r= 0.59MMP2124.620.164.620.140.9390.84--MMP3124.040.143.980.170.0830.717 downFEV1, r = 0.74MMP7112.810.292.820.390.9330.918 downMMP8112.720.332.460.430.1420.54--4m Gaitspeed, r = 0.72MMP9124.780.234.730.260.4430.76--4m Gaitspeed, r = 0.61MMP10113.040.553.050.480.9670.16--MMP12122.230.412.170.220.5810.248 downMMP13123.320.243.140.150.04-0.138 downTIMP1124.760.064.750.060.8920.79--TIMP2124.920.084.930.080.0520.968 upFI-LAB Index, r = -0.72TIMP4123.080.183.070.130.5340.87--FEV1, r = 0.59mir146a14-0.260.67-0.110.420.503-0.18--mir12614-0.130.36-0.010.150.2410.37--mir34c10-0.770.90-0.470.660.1370.93--6MWD, r = -0.56Change with DQ evaluated by plots of pre-post correlation and number ≥ 5% improved, *indicates paired samples t-test p ≤ 0.10.Pre-Post Pearson r are correlations for log transformed microarray markers baseline vs. follow-up; all p<0.05.Change with DQ: SASP vs. Function (right most column) shows Pearson correlations between percent change in log transformed marker with percent change in physical function (6MWD, 4m Gaitspeed, and 5-repeat chair-stand time), pulmonary function (FEV1, FVC), and Fi-LAB r ≥ 0.50, which correspond to p ≤ 0.10.Table S4. Transformed (asinh) circulating multiplexed cytokines, chemokines, and growth factors with DQ and associations with change in physical function, pulmonary function, and FI-LAB.MarkerBaselineFollow-UpWithin-SubjectsPre-Post CorrelationChange with DQ:SASP vs. FunctionLUMINEXMeanSDMeanSDp-valuePearson rPearson rEGF4.730.924.650.650.5240.87FI-LAB, r = -0.54FGF24.370.334.340.260.6240.85Chair-Stands, r = -0.73Eotaxin6.670.636.610.550.3660.93Chair-Stands, r = -0.52TGFα4.120.314.100.340.6160.91GCSF4.510.574.460.270.6420.70GMCSF4.310.334.400.280.1550.81Fractaline3.880.383.910.370.6250.89FI-LAB, r = -0.75IFNA23.870.303.910.210.4940.61INFgamma4.180.234.150.220.670.57GROalpha8.651.118.740.720.5630.89Chair-Stands, r = -0.55IL104.370.454.410.310.7320.60Chair-Stands, r= -0.57MCP35.720.845.720.790.4690.98PDGFAA9.580.699.650.370.5990.75PDGFBB8.660.818.770.500.4810.90IL154.380.204.400.200.3580.78sCD40L6.981.016.940.960.610.816MWD, r = -0.54Chair-Stands, r =-0.53IL1RA4.700.564.690.540.8270.95IL1a4.720.354.690.270.8590.80IL94.110.314.150.270.5920.67FI-LAB, r = -0.53IL1β4.150.294.130.290.5180.84FI-LAB, r = -0.61IL24.310.244.330.210.5660.73FI-LAB, r = -0.52IL33.970.263.980.240.6220.67FI-LAB, r = -0.55IL44.120.374.120.320.9310.69FI-LAB, r = -0.83IL54.480.614.530.560.9610.96IL64.950.414.840.360.2720.80IL85.930.545.880.470.130.90IP108.780.648.830.400.4420.62MCP19.370.429.330.350.7320.91FEV1, r = -0.65FVC, r = -0.71MIP1a4.300.394.290.380.4690.87FI-LAB, r = -0.55MIP1b4.540.254.550.240.8280.82RANTES9.030.318.990.310.8090.864m Gaitspeed, r = -0.55TNFα5.820.275.810.230.4160.95IL185.780.515.780.360.1960.87Chair-Stands, r = -0.72Black: pro-inflammatory; Green: anti-inflammatory, Gray: undetermined.Quality control: samples with a proportion of null values (concentration below detection limits) exceeding 20% are omitted (FLT3L, MCP3, IL12p40, IL12p70, IL13, IL17a, IL7, TGFβ, VEGFα). One statistical outlier removed (>80% markers >3 SD). Median fluorescence intensity signals asinh transformed. No marker levels changed with DQ |≥ 5%|. *indicates paired samples t-test p ≤ 0.10.Pre-Post Pearson r are correlations for asinh baseline vs. follow-up; all p<0.05. Change with DQ: SASP vs. Function (right most column) shows Pearson correlations between percent change in asinh transformed multiplex analyte with percent change in physical function (6MWD, 4m Gait speed, and 5-repeat chair-stand time), pulmonary function (FEV1, FVC), and Fi-LAB r ≥ 0.50, which correspond to p ≤ 0.10.Table S5. Comparison of published most frequent adverse events reported in placebo arms of Phase III randomized control trials in IPF and events reported in the present single-arm, open-label pilot trial of senolytics in IPF.Number of Reported EventsPercent Patient Reporting EventNo. EventsPercent EventsA+CIN1IN2CombinedA+ CIN1IN2CombinedIPF PilotIPF PilotN (total)277204219700%%%Avg %14%Cough82263113929.612.714.218.8642.9Nausea3712166513.45.97.38.9642.9Headache646423.123.1535.7Diarrhea60384013821.718.618.319.5214.3Upper respiratory tract infection5618249820.28.81113.317.1Fatigue484817.317.3428.6Rash24248.78.700Dyspnea4923259717.711.311.413.5321.4Dizziness36361313321.4IPF Exacerbation50214011118.110.318.315.600Bronchitis362817811313.77.811.500Constipation383813.713.7214.3Back pain373713.413.4214.3Dyspepsia^17176.16.117.1Nasopharyngitis3034349810.816.715.514.3321.4Anorexia181410426.56.94.66214.3Vomiting2447358.723.24.617.1Decrease in weight22132377.96.40.95.100Gastroesophageal reflux186.56.517.1Insomnia186.56.517.1Severe adverse events37629918.128.323.2214.29Serious adverse events55721272732.930.017.14Fatal adverse events1021314.99.67.2500Adverse events leading to treatment discontinuation22335510.815.113.000A+C: Combined event data from placebo arms of ASCEND and CAPACITY Phase III Trials of Pirfenidone for IPF (aged 67.8±7.3 years, percent predicted FVC 68.6±10.9%). IN1 & IN2: Event data for INPULSIS1 (IN1) and INPULSIS2 (IN2) Phase III Trials of Nintedanib for IPF. IN1 participants were aged 66.9±8.2 years, and percent predicted FVC was 80.5±17.3% at baseline. IN2 patients aged 67.1±7.5 years, and percent predicted FVC was 78.1±19.0 % at baseline. Phase III trial events only reported as most frequent adverse events defined as those with an incidence of more than 10% in any study group; blank cells correspond to no published data due to infrequent event reporting.IPF Pilot Events and Percent Events transferred from Table 2, collapsed by severity. Red shading indicates higher percent patients reporting event type in the present study compared with IPF patients on placebo in Phase III trials (difference >10%); yellow shading moderately elevated percent reporting compared with Phase III (difference within 5-10% higher), green shading similar (<5% difference) or better reporting in present trial compared with Phase III.A+C reported in: King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England journal of medicine. 2014 May 29;370(22):2083-92. IN1 & IN2 reported in: Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England journal of medicine. 2014 May 29;370(22):2071-82. ................
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