Dataset Information

Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease.

ABSTRACT:

Context

The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown.

Objective

This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies.

Participants and methods

Women age 60 to 90 years with a bone mineral density (BMD) T-score of less than -2.5 to greater than -4.0 at the total hip or lumbar spine were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months (long-term arm) or placebo (cross-over arm) in FREEDOM; eligible participants could enroll in the extension to receive denosumab 60 mg subcutaneously every 6 months. Change in estimated glomerular filtration rate (eGFR) from study baseline and annualized rates of fracture and adverse events (AEs) were the main outcome measures.

Results

Most participants (1259/1969 [64%] long-term arm; 1173/1781 [66%] crossover arm) with baseline CKD stage 2 or 3 remained within the same CKD subgroup at study completion; less than 3% progressed to CKD stage 4. Participants in all eGFR subgroups showed similar, persistent BMD gains over time and a low incidence of fractures. The percentage of participants reporting serious AEs was similar among renal subgroups (normal, CKD stage 2, CKD stage 3a, CKD stage 3b) both for the long-term (54% vs 52% vs 57% vs 58%) and crossover (43% vs 42% vs 43% vs 68%) arms, except CKD stage 3b subgroup, crossover arm.

Conclusion

The safety and efficacy of denosumab did not differ among participants with mild to moderate CKD.

SUBMITTER: Broadwell A

PROVIDER: S-EPMC7823314 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease.

Broadwell Aaron A Chines Arkadi A Ebeling Peter R PR Franek Edward E Huang Shuang S Smith Shawna S Kendler David D Messina Osvaldo O Miller Paul D PD

The Journal of clinical endocrinology and metabolism 20210101 2

<h4>Context</h4>The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown.<h4>Objective</h4>This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies.<h4>Participants and methods</h4>Women age 60 to 90 years with a bone ...[more]

PMID: 33211870

Similar Datasets

Project description:Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (-28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Project description:It is uncertain whether the risk of vertebral fracture (VF) and multiple vertebral fractures (MVFs; ≥2 VFs) after denosumab (DMAb) discontinuation is related to treatment duration. A prior analysis of Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) and FREEDOM Extension trials did not find a relationship with DMAb duration and may have underreported MVF incidence because it included women who did not have radiographs. In this post hoc exploratory analysis, the crude incidence and annualized rates of VF and MVF were determined in patients with ≥7 months' follow-up and ≥1 spine radiograph after discontinuing placebo or DMAb. A multivariate analysis was performed to identify predictors of MVF. Clinical characteristics of patients with ≥4 VFs were explored. This analysis included women who discontinued after placebo (n = 327) or DMAb either from FREEDOM or FREEDOM Extension (n = 425). The DMAb discontinuation group was subsequently dichotomized by treatment duration: short-term (≤3 years; n = 262) and long-term (>3 years; n = 213) treatment. For any VF, exposure-adjusted annualized rates per 100 patient-years (95% confidence interval [CI]) were 9.4 (95% CI, 6.4-13.4) for placebo, 6.7 (95% CI, 4.2-10.1) for short-term DMAb, and 10.7 (95% CI, 7.4-15) for long-term DMAb. Annualized rates for MVF were 3.6 (95% CI, 1.9-6.3), 2.9 (95% CI, 1.4-5.4), and 7.5 (95% CI, 4.8-11.1), respectively. Annualized rates for ≥4 VFs were 0.59 (95% CI, 0.1-2.1), 0.57 (95% CI, 0.1-2.1), and 3.34 (95% CI, 1.7-6.0), respectively. In a multivariate regression model, DMAb duration was significantly associated with MVF risk (odds ratio 3.0; 95% CI, 1.4-6.5). Of 15 patients with ≥4 VFs, 13 had DMAb exposure (mean ± standard deviation [SD], 4.9 ± 2.2 years). The risk of MVF after DMAb discontinuation increases with increased duration of DMAb treatment. Patients transitioning off DMAb after 3 years may warrant more frequent administration of zoledronic acid or another bisphosphonate to maintain bone turnover and bone mineral density (BMD) and prevent MVF. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Project description:Background and objectivesAccumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD.MethodsThe phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated.ResultsBetween December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated.DiscussionBased on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD.Classification of evidenceThis study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD.Trial registration informationThe Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

Project description:The 3-year placebo-controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7-year open-label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long-term control group, thus limiting the ability to fully evaluate long-term efficacy. This analysis provides a quantitative estimate of the long-term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®- (Fracture Risk Assessment Tool-) and virtual twin-estimated 10-year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10-year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (n = 1278) were included in the analysis. The 10-year observed cumulative incidence of major osteoporotic fracture (MOF) and hip fractures was compared with the 10-year fracture probability predicted at baseline by FRAX, a computer-based fracture risk algorithm, and with that estimated for a hypothetical cohort of 10-year placebo controls (virtual twins). The observed 10-year fracture incidence was lower than the 10-year probability predicted by FRAX for both MOF (10.75% [95% CI, 9.05 to 12.46] versus 15.63% [95% CI, 15.08 to 16.18], respectively), and hip fractures (1.17% [95% CI, 0.58 to 1.76] versus 5.62% [95% CI, 5.28 to 5.97], respectively). The observed fracture incidence was also lower than the fracture rate estimated in a hypothetical cohort of 10-year placebo controls for MOF (23.13% [95% CI, 17.76 to 28.87]; relative risk 0.49 [95% CI, 0.36 to 0.64]). These data support the long-term efficacy of denosumab in reducing MOF and hip fractures in postmenopausal women with osteoporosis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Project description:BackgroundMolidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat.MethodsBoth studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs).ResultsIn patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group.ConclusionsMolidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

Project description:This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.IntroductionThis analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment.MethodsIn FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM.ResultsDuring FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43-0.81]; P = 0.0012).ConclusionsThese data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

Dataset Information

Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease.

Context

Objective

Participants and methods

Results

Conclusion

Publications

Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets