Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.

BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression. METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods. RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001). CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.

BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

The societal economic burden of autosomal dominant polycystic kidney disease in the United States.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney diseases characterized by progressive development of renal cysts and numerous extra-renal manifestations, eventually leading to kidney failure. Given its chronic and progressive nature, ADPKD is expected to carry a substantial economic burden over the course of the disease. However, there is a paucity of evidence on the impact of ADPKD from a societal perspective. This study aimed to estimate the direct and indirect costs associated with ADPKD in the United States (US). METHODS: A prevalence-based approach using data from scientific literature, and governmental and non-governmental organizations was employed to estimate direct healthcare costs (i.e., medical services, prescription drugs), direct non-healthcare costs (i.e., research and advocacy, donors/recipients matching for kidney transplants, transportation to/from dialysis centers), and indirect costs (i.e., patient productivity loss from unemployment, reduced work productivity, and premature mortality, caregivers' productivity loss and healthcare costs). The incremental costs associated with ADPKD were calculated as the difference between costs incurred over a one-year period by individuals with ADPKD and the US population. Sensitivity analyses using different sources and assumptions were performed to assess robustness of estimates and account for variability in published estimates. RESULTS: The estimated total annual costs attributed to ADPKD in 2018 ranged from $7.3 to $9.6 billion in sensitivity analyses, equivalent to $51,970 to $68,091 per individual with ADPKD. In the base scenario, direct healthcare costs accounted for $5.7 billion (78.6%) of the total $7.3 billion costs, mostly driven by patients requiring renal replacement therapy ($3.2 billion; 43.3%). Indirect costs accounted for $1.4 billion (19.7%), mostly driven by productivity loss due to unemployment ($784 million; 10.7%) and reduced productivity at work ($390 million; 5.3%). Total excess direct non-healthcare costs were estimated at $125 million (1.7%). CONCLUSIONS: ADPKD carries a considerable economic burden, predominantly attributed to direct healthcare costs, the majority of which are incurred by public and private healthcare payers. Effective and timely interventions to slow down the progression of ADPKD could substantially reduce the economic burden of ADPKD.

Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument.

BACKGROUND: The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition. STUDY DESIGN: Content for a new self-administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity. SETTING & PARTICIPANTS: 1,674 adult patients with ADPKD participated in this research: 285 patients in focus groups to generate questionnaire content, 15 patients in debriefing interviews to refine the PRO questionnaire, and 1,374 patients to assess the performance and measurement properties of the PRO questionnaire. OUTCOME: A new PRO questionnaire. RESULTS: The ADPKD Impact Scale (ADPKD-IS), consisting of 14 items representing 3 conceptual domains (physical, emotional, and fatigue) plus 4 additional questions, was developed. The instrument's reliability (regarding internal consistency and test-retest consistency) and validity (content and construct) were supported. LIMITATIONS: Need for more responsiveness testing when more data from clinical use become available over time. Complex concepts such as ADPKD-related pain and impact on a patient's HRQoL need further evaluation. CONCLUSIONS: The ADPKD-IS is a new patient-centric tool that reliably and validly provides a standardized method for assessing HRQoL and overall disease burden in patients with ADPKD.

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function.

BACKGROUND: A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN: Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS: Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION: Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES: Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS: GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS: In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS: Limited sample size, no control group. CONCLUSIONS: In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.

Patient-Reported Outcomes Measures, Polycystic Kidney Disease Burden, and Outcomes in Autosomal Dominant Polycystic Kidney Disease.

Rationale & Objective: Using OVERTURE (NCT01430494) study data on patient-perceived health, health care utilization, and productivity in autosomal dominant polycystic kidney disease (ADPKD), this research was conducted to characterize the burden of illness in patients with ADPKD and assess whether patient-reported outcome (PRO) assessment scores predict clinical and health-economic outcomes. Study Design: Data were analyzed from a prospective, observational study. Setting & Participants: The study cohort comprised 3,409 individuals with ADPKD in 20 countries who were aged 12-78 years and were in chronic kidney disease (CKD) stages G1-G5 and Mayo risk subclasses 1A-1E. Predictors: Scores on PRO instruments, including disease-specific assessments [ADPKD-Impact Scale (ADPKD-IS), and ADPKD-Urinary Impact Scale (ADPKD-UIS)] and generic measures were assessed. Outcomes: Clinical variables [eg, height-adjusted total kidney volume (htTKV), estimated glomerular filtration rate (eGFR), and abdominal girth] and health-economic outcomes were assessed. Analytical Approach: Associations among variables were evaluated using Spearman correlations, logistic regression, and generalized linear mixed effects repeated measures models. Results: Baseline CKD stage and Mayo risk classification showed little correlation with baseline PRO scores; however, scores on disease-specific instruments and measures of physical functioning were worse at more severe CKD stages. PRO scores predicted hospitalizations and sick days at 6-18 months, with strongest associations noted for the ADPKD-IS. PRO scores were not associated with htTKV and eGFR, but worse PRO scores were associated with greater abdominal girth. Poor baseline ADPKD-IS scores were positively associated with occurrence of ADPKD-related symptoms up to 18 months, including kidney pain (OR, 5.30; 95% CI, 2.75-10.24), hematuria (OR, 4.58; 95% CI, 1.99-10.53), and urinary tract infection (OR, 4.41; 95% CI, 1.93-10.11; P < 0.001 for all). Limitations: A limitation of the study was the maximum 18 months of follow-up available to assess outcomes. Conclusions: PRO scores predicted clinical and health-economic outcomes, such as hospitalization and absence from work, underscoring the importance of quality of life assessment of individuals with ADPKD. Plain-Language Summary: Patient-reported outcomes (PROs) are increasingly recognized as important parameters for assessing the clinical and humanistic burden of autosomal dominant polycystic kidney disease (ADPKD). We analyzed data from the observational OVERTURE study to better characterize disease impact on quality of life and determine whether patient-perceived burden might predict outcomes. Scores on PRO assessment instruments predicted hospitalizations and sick days at 6-18 months, with associations strongest for the disease-specific ADPKD-Impact Scale. Compared to patients who rated their health-related quality of life as good, those with poor baseline scores were significantly more likely to report ADPKD-related signs and symptoms up to 18 months of follow-up. These findings support using disease-specific PRO assessment instruments to assess and predict the impact of ADPKD.

Care partner evaluation of the behaviors in the Cohen-Mansfield Agitation Inventory.

Introduction: Agitation is a common symptom in patients with Alzheimer's dementia. But agitation can be a heterogeneous symptom, encompassing a diverse array of behaviors exhibited by patients. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale that is used to systematically assess the frequency and severity of agitation in older adults as rated by a primary caregiver. The CMAI was originally designed for use by professional care givers in institutional care settings. Alzheimer's dementia, however, is associated with a significant burden on family members, who provide the majority of care, and other informal care partners. Methods: Our qualitative study aimed to assess the accuracy and applicability of the CMAI according to the needs and perceptions of non-professional care partners. Specifically, we wanted to determine if the behaviors included in the instrument reflect: (a) the care partner's experience with agitation in Alzheimer's dementia patients, (b) how the behaviors and their frequency are related to the perception of agitation severity, and (c) what changes in agitation behaviors are meaningful to care partners. We interviewed 30 care partners for patients with Alzheimer's dementia in the United States. Results: The care partners confirmed all behaviors listed in the CMAI as relevant. The behaviors reflect a spectrum of severity, with aggressive behaviors considered more severe than non-aggressive behaviors and physical behaviors generally considered more severe than verbal behaviors. Any reduction or increase in the frequency of a behavior was meaningful to care partners. Generally, a change from physical to verbal behaviors and aggressive to non-aggressive was considered a meaningful improvement while a change from verbal to physical and non-aggressive to aggressive was considered a meaningful worsening. Discussion: The CMAI appropriately captures relevant behaviors of agitation in Alzheimer's dementia and provides insight into the relative improvement or worsening of agitation symptoms.

Defining a clinically meaningful within-patient change threshold for the Cohen-Mansfield Agitation Inventory in Alzheimer's dementia.

Introduction: The Cohen-Mansfield Agitation Inventory (CMAI) quantifies the frequency of agitation behaviors in elderly persons. This post hoc analysis of data from the brexpiprazole clinical program aimed to determine a meaningful within-patient change (MWPC) threshold for CMAI Total score among patients with agitation associated with dementia due to Alzheimer's disease. Methods: Data were included from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584). Change in CMAI Total score (range 29-203; higher scores indicate higher frequency of agitation behaviors) from baseline to Week 12 was the primary endpoint in each trial. MWPC thresholds were estimated from anchor-based mean change analyses and receiver operating characteristic (ROC) curves. The Clinical Global Impression-Severity of illness (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales, both as related to agitation, were used as anchors. Empirical cumulative distribution functions (eCDFs) and probability density functions (PDFs) were plotted as supportive evidence. Distribution-based methods were also employed. Results: Data from 898 patients were analyzed (mean age, 73.7 years; mean baseline CMAI Total score, 73.8). The mean CMAI Total score change corresponding to a difference of small improvement vs. stable (CGI-S one-point decrease vs. no change), or minimally improved vs. no change (CGI-I rating of 3 vs. 4), ranged from -10.6 to -13.5 points. The mean CMAI Total score change corresponding to a difference of moderate improvement vs. stable (CGI-S two-point decrease vs. no change), or much improved vs. no change (CGI-I rating of 2 vs. 4), ranged from -20.2 to -25.7 points. ROC curve analyses generally produced smaller estimates of meaningful change. eCDFs and PDFs showed good distribution and separation of CMAI Total score change between CGI-S/CGI-I categories. In distribution-based analyses, the minimal detectable change for CMAI Total score (10.5-11.8 points) was generally lower than anchor-suggested thresholds. Conclusion: Triangulation of evidence from anchor- and distribution-based analyses supports an MWPC threshold for CMAI Total score of -20 points, with a threshold range of -15 to -25 points, in patients with agitation associated with dementia due to Alzheimer's disease.

Pain and Health-Related Quality of Life in Autosomal Dominant Polycystic Kidney Disease: Results from a National Patient-Powered Registry.

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) affects health-related quality of life (HRQoL) including pain, discomfort, fatigue, emotional distress, and impaired mobility. Stakeholders prioritized kidney cyst-related pain as an important core outcome domain in clinical trials, leading to the development of disease-specific assessment tools. Study Design: The ADPKD Registry is hosted online with multiple disease-specific patient-reported outcomes modules to characterize the patient experience in the United States. Setting & Participants: The ADPKD Registry allows consented participants access to a Core Questionnaire that includes demographics, comorbid conditions, current symptoms, and kidney function. Participants complete subsequent modules on a 3-month schedule, including 2 validated HRQoL tools, the ADPKD-Pain and Discomfort Scale (ADPKD-PDS), the ADPKD Impact Scale (ADPKD-IS) and a Healthcare Access and Utilization module. Exposures: Patient-reported latest estimated glomerular filtration rate or creatinine used to calculate stage of chronic kidney disease. Outcomes: Health-related quality of life, measured using validated ADPKD-specific tools; access to polycystic kidney disease-specific health care. Analytical Approach: For the 2 HRQoL tools, scores were calculated for physical, emotional, and fatigue domains; pain severity; and pain interference (based on the licensed user manuals). Associations to health care access were also assessed. Results: By July 2022, 1,086 individuals with ADPKD completed at least 1 of the HRQoL modules, and 319 completed 4 over a year. Participants were an average age of 53. In total, 71% were women, and 91% were White, with all chronic kidney disease (CKD) stages represented. In total, 2.5% reported being treated with dialysis, and 23% had a kidney transplant. CKD stage 4/5 participants reported the most dull kidney pain, whereas sharp kidney pain was evenly distributed across early CKD stages. Dull kidney pain had an impact on sleep regardless of CKD stage. There was a strong positive correlation between the ADPKD-PDS and ADPKD-IS. Patients with a neutral or positive HRQoL were less likely to have been denied access to imaging or other care. Limitations: Currently, all the information collected is patient reported without health record validation of clinical variables. Conclusions: Use of the HRQoL tools in the ADPKD Registry provided a broad cross-sectional assessment in the United States and provided granular information on the burden of pain across the CKD spectrum in ADPKD. The ADPKD Registry allowed assessment of ADPKD impact in a community that experiences decline in health and kidney function over decades.

The Autosomal Dominant Polycystic Kidney Disease Registry is a longitudinal, patient-powered research tool created with the goal to better understand the impacts of ADPKD on affected individuals in the United States. Here, we analyze pain and other health-related quality of life outcomes in 1,086 individuals using validated tools and comment on the utility of these tools for future use in clinical trials and observational studies. We found that sharp pain, dull pain, fullness discomfort, and other related impacts affected individuals across the disease spectrum, although some participants reported more dull pain in later stages (CKD stages 4 and 5). Future analysis of these trends over time will be valuable in understanding how to assess and address the burden of pain in autosomal dominant polycystic kidney disease.

Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease.

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: <30 ml/min per 1.73 m(2). Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30 mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR ((125)I-iothalamate clearance) was found that reached significance in groups A and B: -7.8 (interquartile range -13.7 to -1.3) and -4.3 (-9.7 to -0.9) ml/min per 1.73 m(2), respectively, but not in group C (GFR decrease -0.7 (-1.1 to 1.5) ml/min/1.73 m(2)). The percentage change in GFR, ERPF ((131)I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Understanding Patients' Experiences with Borderline Personality Disorder: Qualitative Interviews.

Background: Patient perspectives of living with borderline personality disorder (BPD) are not traditionally captured in the literature. To overcome this gap, we explored participants' experiences with BPD to gain a better understanding of symptoms and impacts related to the condition. Methods: Two experienced researchers conducted semistructured interviews with a subset of participants from a randomized controlled trial evaluating a BPD treatment. The interview study was independent from the trial. Interviews focused on participants' experiences with BPD prior to the trial, including the symptoms and impacts of BPD. Interview transcripts were analyzed to identify dominant trends and generate patterns in the way participants described their experiences with BPD. Results: A total of 50 adults with BPD participated in the interview study. The mean age of the participants was 28.5 years (range, 18-53 years) and 72.0% were female. All participants described having difficulties with extreme emotional responses and interpersonal relationships, and most participants reported experiencing issues with self-image, impulsivity, suspiciousness/distrust, feelings of emptiness, and anger. The symptoms that were most bothersome to participants were extreme moods or emotional responses and a pattern of unstable personal relationships. All participants remarked that their BPD-related symptoms negatively impacted their interpersonal relationships, and nearly two-thirds of the sample reported that the impact of BPD on their relationships was the most bothersome. Additionally, more than half of the participants discussed impacts on work or school, memory or thinking, self-care, and financial and legal issues. Conclusion: Participants reported that the most bothersome symptoms of BPD were those related to extreme moods or emotional responses and interpersonal relationships. Participants similarly described the impact of BPD on their interpersonal relationships as the most bothersome. Overall, participant perspectives from this study indicate that the burden of BPD is significant and new treatments tailored to patients' real-world needs are warranted.

Caregiver Burden of Autosomal Dominant Polycystic Kidney Disease: A Qualitative Study.

Rationale & Objective: There is limited published research on how autosomal dominant polycystic kidney disease (ADPKD) impacts caregivers. This study explored how caregivers of individuals with ADPKD perceive the burdens placed on them by the disease. Study Design: Qualitative study consisting of focus groups and interviews. Discussions were conducted by trained interviewers using semi-structured interview guides. Setting & Participants: The research was conducted in 14 countries in North America, South America, Asia, Australia, and Europe. Eligible participants were greater than or equal to 18 years old and caring for a child or adult diagnosed with ADPKD. Analytical Approach: The concepts reported were coded using qualitative research software. Data saturation was reached when subsequent discussions introduced no new key concepts. Results: Focus groups and interviews were held with 139 participants (mean age, 44.9 years; 66.9% female), including 25 participants who had a diagnosis of ADPKD themselves. Caregivers reported significant impact on their emotional (74.1%) and social life (38.1%), lost work productivity (26.6%), and reduced sleep (25.2%). Caregivers also reported worry about their financial situation (23.7%). In general, similar frequencies of impact were reported among caregivers with ADPKD versus caregivers without ADPKD, with the exception of sleep (8.0% vs 28.9%, respectively), leisure activities (28.0% vs 40.4% respectively), and work/employment (12.0% vs 29.8%, respectively). Limitations: The study was observational and designed to elicit concepts, and only descriptive analyses were conducted. Conclusions: These findings highlight the unique burden on caregivers in ADPKD, which results in substantial emotional, social, and professional/financial impact.

Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies.

Rationale & Objective: Tolvaptan is indicated for treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Participants aged 56-65 years constituted a small proportion of the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial population. We assessed effects of tolvaptan on estimated glomerular filtration rate (eGFR) decline in participants aged >55 years. Study Design: This was a pooled data analysis from 8 studies of tolvaptan or non-tolvaptan standard of care (SOC). Setting & Participants: Participants aged >55 years with ADPKD were included. Data on participants in >1 study were linked longitudinally for maximum follow-up duration, with matching for age, sex, eGFR, and chronic kidney disease (CKD) stage to minimize confounding. Interventions: Tolvaptan or non-tolvaptan SOC. Outcomes: Treatment effects on annualized eGFR decline were compared using mixed models with fixed effects for treatment, time, treatment-by-time interaction, and baseline eGFR. Results: In the pooled studies, 230 tolvaptan-treated and 907 SOC participants were aged >55 years at baseline. Ninety-five participant pairs from each treatment group were matched, all in CKD G3 or G4, ranging from 56.0 to 65.0 years (tolvaptan) or from 55.1 to 67.0 years (SOC). The eGFR annual decline rate was significantly reduced by 1.66 mL/min/1.73 m2 (95% CI, 0.43-2.90; P = 0.009) in the tolvaptan group compared with SOC (-2.33 versus -3.99 mL/min/1.73 m2) over 3 years. Limitations: Limitations include potential bias because of study population differences (bias risk was reduced through matching and multiple regression adjustment); vascular disease history data was not uniformly collected, and therefore not adjusted; and natural history of ADPKD precludes evaluating certain clinical endpoints within the study time frame. Conclusions: In individuals aged 56-65 years with CKD G3 or G4, compared to a SOC group with mean GFR rate of decline ≥3 mL/min/1.73 m2/year, tolvaptan was associated with efficacy similar to that observed in the overall indication. Funding: Otsuka Pharmaceutical Development & Commercialization, Inc (Rockville, MD). Trial Registration: TEMPO 2:4 (NCT00413777); phase 1 tolvaptan trial (no NCT number; trial number 156-06-260); phase 2 tolvaptan trial (NCT01336972); TEMPO 4:4 (NCT01214421); REPRISE (NCT02160145); long-term tolvaptan safety extension trial (NCT02251275); OVERTURE (NCT01430494); HALT Progression of Polycystic Kidney Disease (HALT-PKD) study B (NCT01885559).

Development of a Patient-Reported Outcomes Tool to Assess Pain and Discomfort in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Pain has been identified as a core outcome for individuals with autosomal dominant polycystic kidney disease (ADPKD), but no disease-specific pain assessment has been developed using current development methodology for patient-reported outcomes (PRO) instruments. We developed and validated an ADPKD-specific pain questionnaire: the ADPKD Pain and Discomfort Scale (ADPKD-PDS). METHODS: Conceptual underpinnings were drawn from literature review, concept elicitation, expert consultation, and measurement performance. In the qualitative analysis phase, concepts were elicited from focus groups of adults with ADPKD, and the resulting draft instrument was refined using cognitive debriefing interviews with individuals with ADPKD. For quantitative analysis, adults with ADPKD completed the draft instrument and other PRO tools in an online survey, and a follow-up survey was conducted 3-4 weeks later. Survey responses were analyzed for item-level descriptive statistics, latent model fit statistics, item discrimination, item- and domain-level psychometric statistics, test-retest reliability, responsiveness to change, and convergent validity. RESULTS: In the qualitative phase, 46 focus groups were conducted in 18 countries with 293 participants. Focus groups described three conceptually distinct types of ADPKD-related pain and discomfort (dull kidney pain, sharp kidney pain, and fullness/discomfort). In the quantitative phase, 298 adults with ADPKD completed the online survey, and 108 participants completed the follow-up survey. After iterative refinement of the instrument, latent variable measurement models showed very good fit (comparative fit and nonnormed fit indices both 0.99), as did item- and domain-level psychometric characteristics. The final ADPKD-PDS contains 20 items assessing pain severity and interference with activities over a 7-day recall period. CONCLUSIONS: The ADPKD-PDS is the first validated tool for systematically assessing pain and discomfort in ADPKD.

OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD.

Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD. Methods: This prospective study enrolled a large international population (N = 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity. Results: Most subjects (84.4%) completed ≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up. Conclusion: Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease.

INTRODUCTION: Insight into the relationship between concepts that matter to the people affected by Alzheimer's disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD. METHODS: We compared WMM concepts rated as "very important" or higher to items included in COAs used commonly in AD studies. RESULTS: Twenty COAs designed to assess signs, symptoms, and impacts across the spectrum of AD were selected for review. Among these 20 COAs, only 5 reflected 12 or more WMM concepts [Integrated Alzheimer's Disease Rating Scale (iADRS), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer's Disease Composite Scores (ADCOMS), and Clinical Dementia Rating; Clinical Dementia Rating-Sum of Boxes (CDR/CDR-SB)]. Multiple symptoms and impacts of AD identified as important and meaningful in the WMM studies map only indirectly at best to 7 of the 20 most widely used COAs. CONCLUSION: While many frequently used COAs in AD capture some concepts identified as important to AD populations and their care partners, overlap between any single measure and the concepts that matter to people affected by AD is limited. The highest singly matched COA reflects fewer than half (45%) of WMM concepts. Use of multiple COAs expands coverage of meaningful concepts. Future research should explore the content validity of AD COAs planned for AD trials based on further confirmation of the ecological validity of the WMM items. This research should inform development and use of core outcome sets that capture WMM items and selection or development of new companion tools to fully demonstrate clinically meaningful outcomes spanning WMM.

Developing a Conceptual Disease Model of Patient Experiences and Identifying Patient-Reported Clinical Outcome Assessments for Use in Trials of Treatments for Focal Onset Seizures.

Purpose: To identify concepts important to understanding the experiences of adults with focal onset seizures (FOS) and evaluate clinical outcome assessments (COAs) for measuring these concepts in clinical trials of treatments for FOS. Methods: A search of published qualitative research, clinical trials, and approved product labels for FOS treatments was performed to develop a conceptual disease model (CDM) of patients' experience of living with FOS. Concepts of interest (COI) were selected, and a second literature search was conducted to identify COAs measuring these concepts. Ten COAs were selected and reviewed to document their development process, evidence of measurement properties, and methods for interpreting change scores using criteria proposed in regulatory guidelines for patient-reported outcomes to support label claims. Results: Concepts identified from the published literature (13 articles, 1 conference abstract), 24 clinical trials, and 8 product labels were included in a novel CDM. Impacts on physical, cognitive, and social and emotional function were chosen as COI for evaluating treatment outcomes for FOS; the additional concept of social support and coping strategies was chosen to understand patients' lived experiences. From 51 unique COAs identified, 10 were selected based on their potential coverage of the COI; some symptom severity and health-related quality of life (HRQoL) COAs covered multiple COI. Of these 10, 8 COAs evaluated impacts/limitations on physical function, 8 measured social and emotional impacts, and 5 assessed social support and coping strategies. While most assessments had gaps in evidence validating their measurement properties, 2 COAs measuring symptom severity and 1 COA measuring HRQoL had evidence confirming their potential utility in clinical trials to support label claims. Conclusion: This research provides insights into the experience of patients with FOS and identifies COAs that measure concepts considered to support endpoints in clinical trials for FOS.

Polycystic Kidney Disease-Related Disease Burden in Adolescents With Autosomal Dominant Polycystic Kidney Disease: An International Qualitative Study.

Rationale & Objective: Little is known about symptoms and disease impacts in adolescents with autosomal dominant polycystic kidney disease (ADPKD). The objective of the study was to explore these issues from the adolescent patient's perspective. Study Design: Observational, qualitative study. Setting & Participants: Eligible participants were 12-17 years old and had a diagnosis of ADPKD. Semi-structured interviews were conducted in 18 cities in 13 countries to elicit participant experiences of ADPKD-related symptoms and physical, social, and emotional impacts. Analytical Approach: Interviews were recorded, transcribed, and coded. Symptom and impact frequencies from the interviews were calculated, and representative quotes concerning elicited concepts were collated. Results: Thirty-three participants (mean age, 14.6 years; 42.4% female) completed interviews. Frequently reported symptoms included urinary urgency (n = 10; 30.3%) and back pain (n = 9; 27.3%). Consistent with previous findings in adults, participants experienced 3 primary types of pain: dull kidney pain, severe or sharp kidney pain, and a feeling of fullness and/or discomfort. Reported disease impacts included avoiding sports and physical activity (n = 10; 30.3%), missing school (n = 6; 18.2%) and social activities (n = 6; 18.2%), and feeling worried (n = 6; 18.2%), sad (n = 4; 12.1%), or frustrated (n = 3; 9.1%) about the disease and their future. Approximately one-fifth of participants (n = 7; 21.2%) reported that they were bothered or impacted by dietary limitations (primarily the need for reduced sodium intake and increased water intake). Limitations: The study had a small sample size. The researchers were unable to conduct focus groups with participants because of parental preferences. Conclusions: The findings from this exploratory study indicate that a substantial proportion of adolescents with ADPKD experience physical, social, and emotional impacts from their disease.

Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD.

Introduction: In 1- and 3-year randomized trials, tolvaptan slowed kidney function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. The 3-year trial also evaluated effects on total kidney volume (TKV); slowing of TKV growth was demonstrated. Subjects were followed in open-label extension trials. To characterize longer-term effects of treatment, an analysis was conducted comparing tolvaptan-treated subjects with subjects from standard of care (SOC) ADPKD studies without tolvaptan. Methods: This was a pooled, longitudinal analysis of data from 8 tolvaptan clinical trials and 5 studies without tolvaptan (natural history or SOC) in ADPKD. Data from subjects who participated in multiple studies were linked for longer follow-up. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and TKV over 5.5 years. To control for heterogeneity in disease characteristics between tolvaptan and SOC treatment groups, analysis populations matched for baseline demographic and disease characteristics were constructed. Results: Matched analysis (n = 1186 in each treatment group) indicated that tolvaptan slowed annualized eGFR decline by 1.01 ml/min per 1.73 m2 (P < 0.001) versus SOC over 5.5 years. An analysis conducted on the full, unmatched data set (tolvaptan: n = 2928; SOC: n = 4189) confirmed significant reduction in annual eGFR decline. Among subjects with TKV data, TKV was significantly reduced at years 1, 3, and 5 for tolvaptan versus SOC in both matched and full data sets. Conclusion: Comparison of a pooled tolvaptan cohort to a pooled control cohort with ADPKD supports longer-term treatment effects of tolvaptan.

Excess healthcare costs in patients with autosomal dominant polycystic kidney disease by renal dysfunction stage.

AIM: To build upon previous outdated studies by comprehensively assessing the direct healthcare burden of autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: Patients with ≥2 diagnoses for ADPKD (ADPKD cohort) were identified in the US fee-for-use IBM Truven Health Analytics MarketScan Commercial Claims and Encounters and IBM Truven Health Analytics MarketScan Medicare Supplemental databases (01 January 2015-31 December 2017) and matched (1:3) to controls without ADPKD (non-ADPKD cohort). The index date was the last calendar date followed by 12 months continuous enrollment (study period). Patients with ADPKD were stratified into one of seven mutually exclusive groups based on chronic kidney disease (CKD) stages (I-V), end-stage renal disease requiring renal replacement therapy (ESRD-RRT), and unknown stage. RESULTS: During the 12-month study period, patients with ADPKD incurred significantly higher total healthcare costs than those without ADPKD (mean cost difference = $22,879 per patient per year [PPPY]; p < .001). Besides CKD stages I and II, total healthcare cost differences increased as patients progressed beyond CKD stage III, with the greatest difference observed among patients with ESRD-RRT. Total healthcare cost differences between cohorts were more pronounced in subgroups of patients with hypertension ($29,347) and with high risk of rapid progression ($39,976). Similar results were observed in the Medicare Supplemental population, with a total mean cost difference of $42,694 PPPY (p < .001); cost difference was also higher in the hypertension ($46,461 PPPY) and high risk of rapid progression ($45,708 PPPY) subgroups. LIMITATIONS: Results may not be representative of the overall ADPKD US population; CKD stage was based on diagnosis and procedure codes; criteria used to identify ADPKD at risk of rapid progression did not rely on laboratory values; there may be billing inaccuracies and omissions in health insurance claims data. CONCLUSIONS: This study demonstrated the substantial healthcare costs associated with ADPKD, which increased as patients progressed through more severe CKD stages.