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Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis.The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373.Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p0·0001; treatment difference 22%, 95% CI 12-32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment.Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis.AbbVie.

Background/Aims Upadacitinib (UPA), an oral Janus kinase (JAK) inhibitor, demonstrated efficacy and safety in patients (pts) with psoriatic arthritis (PsA) and prior inadequate response or intolerance to ≥ 1 biologic disease-modifying antirheumatic drug (bDMARD) at week (wk) 56 in the phase 3 SELECT-PsA 2 study. We aimed to evaluate the efficacy and safety of UPA at wk 104 from the ongoing long-term extension of SELECT-PsA 2. Methods Pts were randomized to UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) for 24 wks; PBO pts were then switched to UPA15 or UPA30. For continuous UPA treatment groups, efficacy endpoints at wk 104 were analyzed using non-responder imputation (NRI) and as observed (AO) (binary endpoints) or mixed-effect model repeated measures (MMRM) and AO (continuous endpoints). Treatment-emergent adverse events (TEAEs) were summarized for pts who received ≥1 dose of study drug using visit-based cut-off at wk 104. Results A total of 641 pts received ≥1 dose of study drug. At wk 104, 38.4% of all patients had discontinued study drug, with the highest discontinuation observed in patients randomized to PBO at baseline (all PBO: 46.7%). The most common reasons for discontinuation were lack of efficacy (UPA15: 12.3%, UPA30: 8.7%, all PBO: 21.7%) and adverse event (UPA15: 10.9%, UPA30: 13.3%, all PBO: 12.7%). The proportion of UPA pts that achieved ACR20/50/70, MDA, PASI75/90/100, and resolution of dactylitis and enthesitis were generally similar, or further improved, with 104 wks of treatment vs 56 wks. Similarly, mean change from baseline in HAQ-DI, patient’s assessment of pain, BASDAI, and ASDAS was improved with UPA treatment. At 104 wks of therapy, clinical responses were largely similar with UPA15 and UPA30. Generally, safety data at wk 104 were consistent with that reported at wk 56. Rates of serious infection, herpes zoster, hepatic disorder, anemia, neutropenia, lymphopenia, and CPK elevation remained numerically higher with UPA30 vs UPA15, while rates of malignancies, MACE, and VTE were similar for both UPA groups. One death was reported with UPA15 (unexplained due to lack of information; however, the patient had recently been diagnosed with ovarian cancer) and two with UPA30 (pancytopenia and COVID-19 pneumonia). Conclusion In PsA pts with prior inadequate response or intolerance to ≥ 1 bDMARD, clinical responses were maintained with UPA15 and UPA30 up to two years of treatment. No new safety signals were identified in this long-term extension. Disclosure P.J. Mease: Consultancies; Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squib, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, GSK, Janssen, Novartis, Pfizer, Sun Pharma, and UCB. Member of speakers’ bureau; Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squib, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, GSK, Janssen, Novartis, Pfizer, Sun Pharma, and UCB. Grants/research support; Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squib, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, GSK, Janssen, Novartis, Pfizer, Sun Pharma, and UCB. A. Setty: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. K. Papp: Consultancies; Consultant of: AbbVie, Akros, Allergan, Almirall, Amgen, Arcutis, Avillion, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, Genentech/Roche. Member of speakers’ bureau; Speakers bureau: AbbVie, Akros, Allergan, Almirall, Amgen, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, Genentech/Roche, Janssen, Kyowa. Grants/research support; Grant/research support from: AbbVie, Akros, Allergan, Almirall, Amgen, Arcutis, Avillion, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, G. F. Van den Bosch: Consultancies; Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, and UCB. Member of speakers’ bureau; Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, and UCB. S. Tsuji: Consultancies; Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, and UCB. Member of speakers’ bureau; Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, and UCB. Grants/research support; Grant/research support from: AbbVie, Eli Lilly, Janssen, Novartis, and UCB. M. Keiserman: Consultancies; Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB. Member of speakers’ bureau; Speakers bureau: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB. Grants/research support; Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB. X. Bu: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. L. Chen: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. R. Mccaskill: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. E. Mcdearmon-Blondell: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. P. Wung: Shareholder/stock ownership; Financial Disclosures: Employee of AbbVie and may hold stock or options. W. Tillett: Consultancies; Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, MSD, Novartis, Pfizer, and UCB. Member of speakers’ bureau; Speakers bureau: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB. Grants/research support; Grant/research support from: AbbVie, Celgene, Eli Lilly, and Janssen.

ObjectivesRecent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis.MethodsPatients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24.ResultsNinety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was –4.76 (0.86) for romilkimab versus –2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of –2.31 (1.21) (–4.32 to –0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab.ConclusionThis study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance.Trial registration numberNCT02921971.

SummaryBackgroundElevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.MethodsThis was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to ≥2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered withClinicalTrials.gov(NCT04327388).FindingsBetween March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to ≥2-point improvement between placebo (12·0 [9·0–15·0] days) and sarilumab groups (200 mg: 10·0 [9·0–12·0] days, p=0.96, log-rank test; 400 mg: 10·0 [9·0–13·0] days, p=0.34) or in proportions of patients alive (placebo, 91·7%; sarilumab 200 mg, 89·9%, p=0·63; sarilumab 400 mg, 91·9%, p=0·85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI −7·7 to 25·5, p=0·25) for critical patients. There were no unexpected safety signals.InterpretationThis trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.FundingSanofi and Regeneron Pharmaceuticals, Inc.

Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Background:Systemic sclerosis (SSc) is a progressive, multi-organ disease with limited treatment options. Interleukin-4 (IL-4) and IL-13 have been implicated in the fibrotic pathway and pathogenesis of SSc and are promising targets. Romilkimab (RKB) is an engineered humanized bispecific Ig-G4 antibody that binds and neutralizes both IL-4/IL-13. We report a Phase IIa randomized, double-blind, placebo-controlled trial (NCT02921971, Sanofi funded) employing RKB in SSc.Objectives:To evaluate the efficacy and safety of RKB in dcSSc.Methods:Patients with dcSSc duration ≤36 months, mRSS 10-35, with or without immunosuppressive background therapy were randomized (1:1) to subcutaneous RKB 200mg or placebo (PBO) for 24 weeks and stratified on history of SSc-ILD. Primary endpoint was mean change in mRSS at Week 24 and FVC/DLco and HAQ-DI were secondary endpoints. All analyses used a 1-sided p-value Results:Ninety-seven patients with similar baseline characteristics between arms, including use of background therapy (RKB 59.2% vs. PBO 52.1%) were randomized. Six (12.2%) and 4 (8.3%) patients discontinued study treatment early in the PBO and RKB arms, respectively. Primary endpoint showed an absolute change in mRSS of -2.45 (0.85) and -4.76 (0.86) for PBO and RKB groups, respectively with a difference of -2.31 (1.21) favoring RKB (p=0.029). Subgroup analysis based on background therapy showed a similar treatment effect with a PBO subtracted difference in mRSS of -2.69 (1.83) and -2.38 (1.59), suggesting an additive effect between background therapy and RKB. Secondary endpoints did not show a statistically significant difference between RKB vs. PBO arms, although there was numerically less decline in FVC with RKB with a PBO subtracted difference of 70ml (p=0.06). Exploratory endpoints suggested possible effect of RKB on overall pain, Raynaud’s, digital ulcers, and EQ-5D-5L. Post-hoc analysis was undertaken to determine time to progression (first event defined as death, ≥10% relative decline in % predicted FVC, ≥15% relative decline in % predicted DLCO, ≥20% increase or +5 in mRSS, or other events: cardiac, SRC, PAH development) and showed a benefit for RKB (HR: 0.47 p=0.04). Adverse events were balanced between the two groups (RKB 83.3% vs. PBO 83.7%). There were 5 and 4 SAEs in the PBO and RKB arms, respectively. One death occurred in each arm (SRC – RKB, cardiomyopathy – PBO).Conclusion:Patients with dcSSc who were treated with RKB showed a statistically significant reduction in mRSS compared to those receiving PBO. Secondary outcomes were not met, although RKB was associated with a smaller decline in FVC than PBO. Post-hoc analysis showed a possible reduction on time to progression with RKB. RKB was well tolerated with no major safety concerns.References:None.Disclosure of Interests:Yannick Allanore Grant/research support from: Yannick Allanore has received grants from Inventiva, Roche and Sanofi, Consultant of: Yannick Allanore has received fees from Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Curzion, Inventiva, Roche, Sanofi, Peter Wung Shareholder of: I own Sanofi stock, Employee of: I work for Sanofi, Christina Soubrane Employee of: I work for Sanofi., Corinne Esperet Employee of: I work for Sanofi., MARRACHE Frederic Employee of: I work for Sanofi, Raphael Bejuit Employee of: I work for Sanofi., Amel Lahmar Employee of: I work for Sanofi., Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer

Rationale: Prevalence of ANA is not very well characterized in idiopathic pulmonary fibrosis (IPF). While ANA is used in the evaluation of patients with suspected IPF to exclude mimickers of fibrotic lung disease, its clinical significance in patients with confirmed IPF remains to be elucidated. The aim of this study is to address these deficiencies by examining the data from a large IPF cohort. Method: We analyzed the data from the recently completed ESTAIR study (NCT02345070), a phase 2b trial assessing the safety and efficacy of SAR156597 in IPF. The diagnosis of IPF was confirmed by central review of chest HRCT and lung biopsy (if performed) and ANA was obtained at baseline. Prevalence of ANA with its associated baseline demographics and disease characteristics were analyzed from the mITT population. Results: A total of 325 patients were included in the mITT population. Of the 325 patients, 171 (52.6%) were ANA negative while 105 (32.3%) had low titer ANA (1:40 or 1:80) and 48 (14.7%) had high titer ANA (≥1:160) at baseline. Patients who had a high titer ANA were more likely to be female (35.4% vs. 23.4%) and white (100% vs. 91.8%), have earlier diagnosis (1.68±1.46 vs. 1.82±1.27 yrs) and symptoms of IPF, have never smoked (56.3% vs. 32.3%), have greater history of acute exacerbations (12.5% vs. 4.7%) and require supplemental oxygen (22.9% vs. 11.7%) and show more definite features of UIP on HRCT (41.7% vs. 31.0%) compared to those who were ANA negative. Conclusions: Circulating ANA is prevalent in the IPF population. Its overall clinical significance remains to be determined but IPF patients with a high titer ANA likely represent a unique subset of the overall population.

A phase 2b trial (NCT02345070) was conducted to evaluate the efficacy and safety of two dose levels/regimens of SAR156597 (a bispecific IgG4 antibody that binds and neutralises both circulating interleukin-4 and interleukin-13), in comparison with placebo, administered to patients with idiopathic pulmonary fibrosis (IPF) over 52 weeks.DRI11772 was a multinational randomised double-blind placebo-controlled phase 2b trial. Patients aged >40 years with a documented diagnosis of IPF received SAR156597 200 mg once every week (QW), SAR156597 200 mg once every 2 weeks (Q2W) or placebo, over 52 weeks. The primary efficacy end-point was absolute change from baseline in forced vital capacity (FVC) % predicted at 52 weeks.Of 327 randomised patients, 325 received treatment with placebo (n=109), SAR156597 Q2W (n=108) or SAR156597 QW (n=108). The mean change from baseline in FVC % pred at 52 weeks was –5.8%, –5.2% and –6.3% for the placebo, Q2W and QW arms, respectively (Q2W versus placebo, p=0.59; QW versus placebo, p=0.63). The safety profile observed in the three treatment arms was generally similar, although serious adverse events were more common in the QW arm than in the other arms.The DRI11772 study failed to demonstrate benefit of SAR156597 in the treatment of IPF.

The effects of low-dose oral spironolactone (SPIRO) in a rat model of hypertensive heart failure (spontaneously hypertensive heart failure rat) were compared with its effects when combined with captopril (CAP). Twenty-six spontaneously rats with hypertensive heart failure were treated with either placebo (CON), SPIRO (20 mg/kg/d by mouth), CAP (100 mg/kg/d by mouth), or both SPIRO and CAP for 12 weeks. This dose of oral SPIRO did not affect blood pressure, left ventricular end-diastolic diameter, left ventricular ejection fraction, plasma atrial natriuretic peptide concentration, or cardiac fibrosis; however, in combination with CAP, it exerted a significant depressor effect after 12 weeks of treatment that was accompanied by increased urine output and decreased urinary protein excretion. These effects were significantly greater than those with CAP treatment alone. A significant increase in plasma aldosterone level was observed only in CON (174 ± 21%). These data suggest that the addition of low-dose SPIRO to angiotensin I–converting enzyme inhibitor treatment may prevent progression into end-stage congestive heart failure through synergistic effects on diuresis and renoprotection.