VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

Toward evidence-based communication on overweight body mass index and mortality.

BACKGROUND: Reducing overweight and obesity has been a longstanding focus of public health messaging and physician-patient interactions. Clinical guidelines by major public health organizations describe both overweight and obesity as risk factors for mortality and other health conditions. Accordingly, a majority of primary care physicians believe that overweight BMI (even without obesity) strongly increases mortality risk. MAIN POINTS: The current evidence base suggests that although both obese BMI and underweight BMI are consistently associated with increased all-cause mortality, overweight BMI (without obesity) is not meaningfully associated with increased mortality. In fact, a number of studies suggest modest protective, rather than detrimental, associations of overweight BMI with all-cause mortality. Given this current evidence base, clinical guidelines and physician perceptions substantially overstate all-cause mortality risks associated with the range of BMIs classified as "overweight" but not "obese." Discrepancies between evidence and communication regarding mortality raise the question of whether similar discrepancies exist for other health outcomes. CONCLUSIONS: Health communication that inaccurately conveys current evidence may do more harm than good; this applies to communication from health authorities to health practitioners as well as to communication from health practitioners to individual patients. We give three recommendations to better align health communication with the current evidence. First, recommendations to the public and health practitioners should distinguish overweight from obese BMI and at this time should not describe overweight BMI as a risk factor for all-cause mortality. Second, primary care physicians' widespread misconceptions about overweight BMI should be rectified. Third, the evidence basis for other potential risks or benefits of overweight BMI should be rigorously examined and incorporated appropriately into health communication.

Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis.

BACKGROUND: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. METHODS: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. RESULTS: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. CONCLUSIONS: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

Metabolic Basis and Pathogenesis of Skeletal Muscle Dysfunction as Cause of Frailty in Chronic Kidney Disease.

BACKGROUND: Frailty is common in patients with chronic kidney disease (CKD), as is its physical component, phenotypic frailty, and each contributes to CKD-related disability and are associated with increased mortality. Chronic kidney disease has been described as a model of premature aging and its phenotypic frailty shares features with that which has been better characterized for aging. SUMMARY: Decreased skeletal muscle function contributes to the phenotypic frailty of CKD and aging and potentially remediable metabolic derangements appear to mediate both. KEY MESSAGES: Metabolic derangements of skeletal muscle dysfunction shared by CKD-related and aging-related phenotypic frailty offer potential research avenues to help identify additional preventive and treatment strategies. Those derangements distinctive for CKD provide potential treatment targets for the kidney care community to enhance the quality and quantity of life for patients with CKD.

Factors Affecting the Decision to Initiate Dialysis: A National Survey of United States Nephrologists.

INTRODUCTION: The percentage of patients initiating dialysis at an estimated glomerular filtration rate (eGFR) ≤9 mL/min/1.73 m2 decreased between 2000 and 2018 in the USA. Clinical practice guidelines recommend basing the decision to initiate dialysis primarily on uremic signs and symptoms rather than on a particular level of kidney function. However, what signs and symptoms currently practicing nephrologists consider "uremic," how they weigh eGFR and other factors in the decision to initiate dialysis have not been reported. METHODS: The study was an online survey of 255 US nephrologists, conducted between August and October 2021. RESULTS: Nearly half of respondents (49.8%) had an absolute lower eGFR (8.4 [95% CI: 7.6, 9.2] mL/min/1.73 m2) at which they would initiate dialysis in an asymptomatic patient. The top 5 symptoms that would trigger a recommendation to initiate dialysis were loss of appetite/nausea/vomiting (17%), low eGFR (10%), shortness of breath (10%), declining physical ability/function (9%), and generalized weakness (9%). Poor nutritional status and physical function decline were considered very important in the decision to initiate dialysis by 64% and 55% of respondents, respectively. Nephrologists surveyed significantly shortened the time to dialysis initiation in response to declining physical function in an otherwise asymptomatic (hypothetical) patient. CONCLUSIONS: Nearly half of nephrologists sometimes based their decision to initiate dialysis on eGFR alone. The eGFR threshold at which they did so was lower than has been examined in randomized controlled trials of dialysis initiation. Initiatives designed to safely delay dialysis through aggressive medical management could focus on modifiable factors that are the most important drivers of the decision to initiate dialysis.

Relationship between Metabolic Acidosis and Chronic Kidney Disease Progression across Racial and Ethnic Groups: An Observational, Retrospective Cohort Study.

INTRODUCTION: Metabolic acidosis is associated with chronic kidney disease (CKD) progression and mortality, but the association of race/ethnicity with incident metabolic acidosis and/or its adverse outcomes in patients with CKD is unknown. METHODS: We used deidentified medical records data (2007-2019) to generate a cohort of 136,067 patients with nondialysis-dependent CKD stages 3-5 and ≥2 years' postindex data or death within 2 years. We grouped participants into those with and without metabolic acidosis (serum bicarbonate 12 to <22 mEq/L vs. 22 to <30 mEq/L) as Asian, Black, Hispanic, non-Hispanic White individuals, or unknown. Cox proportional hazards models examined factors associated with (1) incident metabolic acidosis; and (2) time to the composite outcome of death, dialysis, transplant, or ≥40% decline from baseline eGFR (DD40) within each race/ethnic group. RESULTS: Metabolic acidosis incidence was higher for Asian, Black, and Hispanic versus non-Hispanic White individuals (p values for adjusted hazard ratios [HR] all <0.001), but this higher hazard was mitigated in all groups with increasing community education. During the median follow-up of 4.2 years, 47,032 of 136,607 (34.6%) experienced a DD40 event. There was an independent association of metabolic acidosis with DD40 within each race/ethnic group. Adjusted HRs (95% confidence interval) for DD40 were 1.806 (1.312, 2.486), 1.420 (1.313, 1.536), 1.409 (1.211, 1.641), and 1.561 (1.498, 1.626) in Asian, Black, Hispanic, and non-Hispanic White groups, respectively (all p < 0.0001), for metabolic acidosis versus normal serum bicarbonate. DISCUSSION/CONCLUSION: The higher incidence of metabolic acidosis observed in Asian, Black, and Hispanic individuals was mitigated by residing in higher education zip codes. Once established, metabolic acidosis was independently associated with DD40 in patients with CKD in all racial/ethnic groups examined.

Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial.

BACKGROUND: Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes. METHODS: This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. RESULTS: At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001). CONCLUSIONS: Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.

Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.

BACKGROUND: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study.

BACKGROUND: Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort. METHODS: In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years. RESULTS: A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001). CONCLUSIONS: In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.

BACKGROUND: Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS: We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (≤18 mmol/L vs >18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS: Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0·0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION: Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING: Tricida.

Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.

BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus.

BACKGROUND: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at µ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a µ-opioid antagonist and κ-opioid agonist. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. RESULTS: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. CONCLUSIONS: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Serum Bicarbonate and Graft and Patient Outcomes Among Kidney Transplant Recipients: A Retrospective Cohort Study Evaluating Changes in Serum Bicarbonate Over Time.

Rationale & Objective: Identification of treatable risk factors for kidney allograft failure is necessary to improve graft longevity. Metabolic acidosis with either low serum bicarbonate or normal serum bicarbonate (eubicarbonatemic metabolic acidosis) is implicated in native kidney disease progression but its effects in kidney transplant recipients are unclear. Study Design: Retrospective cohort study. Setting & Participants: An Integrated Claims-Clinical dataset of US patients with chronic kidney disease (estimated glomerular filtration rates <60 mL/min/1.73 m2) and serum bicarbonate data were used to generate a cohort of kidney transplant recipients with data from ≥1 year before and after transplantation. Primary Predictor: The primary independent variable was a change in serum bicarbonate from baseline. Outcomes: The primary outcomes were graft failure and all-cause mortality. The secondary outcomes were major adverse cardiac events and all-cause hospitalization. Analytical Approach: We used adjusted time-dependent Cox proportional hazards models to assess the risk of graft failure, all-cause mortality, major adverse cardiac events, and time to first hospitalization. Results: In this US community-based cohort of 1,915 kidney transplant recipients with a median follow-up of ∼2.5 years, each 1-mEq/L increase in serum bicarbonate was associated with significantly lower hazard of graft loss, death, major adverse cardiac events, and hospitalization by 10%, 8%, 4%, and 8%, respectively. Limitations: Possible residual confounding. Conclusions: In a US community-based population of kidney transplant recipients, even small incremental increases in serum bicarbonate (1 mEq/L) were significantly associated with reduced hazard of graft loss, all-cause mortality, cardiovascular events, and hospitalization. Interventional trials evaluating the potential benefits of treating metabolic acidosis in kidney transplant recipients are warranted.

Metabolic Acidosis and Adverse Outcomes and Costs in CKD: An Observational Cohort Study.

Rationale & Objective: Metabolic acidosis is a risk factor for progression of chronic kidney disease (CKD), but little is known about its effect on health care costs and resource utilization. We describe the associations between metabolic acidosis, adverse kidney outcomes, and health care costs in patients with CKD stages G3-G5 and not receiving dialysis. Study Design: Retrospective cohort study. Setting & Participants: An integrated claims-clinical data set of US patients with CKD stages G3-G5, with serum bicarbonate values of 12 to <22 mEq/L (metabolic acidosis group) or 22 to 29 mEq/L (normal serum bicarbonate level group). Predictor: The primary exposure variable was the baseline serum bicarbonate level. Outcomes: The primary clinical outcome was the composite of all-cause mortality, maintenance dialysis, kidney transplant, or a decline in the estimated glomerular filtration rate of ≥40% (DD40). The primary cost outcome was all-cause predicted per-patient per-year cost, assessed over a 2-year outcome period. Analytical Approach: Logistic and generalized linear regression models, adjusted for key covariates such as age, sex, race, kidney function, comorbidities, and pharmacy insurance coverage, were used to assess serum bicarbonate levels as a predictor of DD40 and health care costs, respectively. Results: 51,558 patients qualified. The metabolic acidosis group experienced higher rates of DD40 (48.3% vs. 16.7%, P < 0.001) and higher all-cause yearly costs ($65,172 vs. $24,681, P < 0.001). Two-year adjusted odds ratio of DD40 per 1-mEq/L increase in serum bicarbonate levels was 0.873 (95% CI, 0.866-0.879); the parameter estimate (±SE) for costs was -0.070 ± 0.0075 (P < 0.001). Limitations: Possible residual confounding. Conclusions: Patients with CKD and metabolic acidosis had higher costs and rates of adverse kidney outcomes compared with patients with normal serum bicarbonate levels. Each 1-mEq/L increase in serum bicarbonate levels was associated with a 13% decrease in 2-year DD40 events and a 7% decrease in per-patient per-year cost.