Dapagliflozin for peritoneal dialysis patients with chronic heart failure in Japan: study protocol for a multicenter, open-label randomized controlled trial (the jDAPA-PD study)

doi:10.21203/rs.3.rs-4913398/v1

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Dapagliflozin for peritoneal dialysis patients with chronic heart failure in Japan: study protocol for a multicenter, open-label randomized controlled trial (the jDAPA-PD study)

https://doi.org/10.21203/rs.3.rs-4913398/v1

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Background

The effects of dapagliflozin on patients with end-stage kidney disease (ESKD) and chronic heart failure (CHF) who are on peritoneal dialysis (PD) are not well understood. The jDAPA-PD is a proof-of-concept study designed to assess the efficacy and safety of dapagliflozin in such patients in Japan.

Methods/design

: This is a multicenter, open-label randomized controlled trial conducted on 40 patients with ESKD and CHF on maintenance PD, particularly those who have substantial residual kidney function. Patients who were recently on sodium–glucose cotransporter 2 inhibitors, hemodialysis, or treatment for peritonitis or those who have a daily urine volume of < 500 mL will be excluded from the study. Participants will be randomized in a 1:1 allocation to either the 10 mg dapagliflozin orally once daily or the standard treatment groups. The primary endpoint is the change in extracellular water from baseline to week 24, which will be measured by bioelectrical impedance analysis. The secondary endpoints are all-cause mortality, cardiovascular events, hospitalization, PD discontinuation, and changes in body composition, blood pressure, renal and cardiac function, brain natriuretic peptide, peritoneal function, PD regimen, and weekly fluid removal from baseline to week 24. The safety endpoints are adverse events and adverse drug reactions that occur during the study period.

Discussion

This study will determine whether the oral administration of 10 mg of dapagliflozin for 24 weeks is effective in fluid control for patients with CHF on PD. The study will also provide evidence of the safety data and multifaceted effects of dapagliflozin in patients on PD.

Trial registration

: jRCT1031230624 (registered on February 5, 2024)

body composition

efficacy

end-stage kidney disease

extracellular water

fluid overload

safety

SGLT2 inhibitor

Peritoneal dialysis (PD), a treatment modality for end-stage kidney disease (ESKD), removes excess fluid and solutes by instilling and exchanging a high-concentration glucose solution through a catheter placed in the abdominal cavity[1]. Although the prognosis of PD is thought to be similar to that of hemodialysis (HD) [2, 3], PD has several advantages over HD, including better preservation of the residual kidney function[4], higher social and role quality of life[5], and lower health care cost[6]. Recently, PD has been reevaluated as a home-based, individualized dialysis therapy for ESKD[1].

The management of chronic heart failure (CHF) is crucial in patients on PD because it has been shown to be a strong poor prognostic factor in patients with chronic kidney disease (CKD)[7]. Although we currently have many choices of medication for CHF, these therapies have not been established in patients on PD[8]. Fluid overload, a major complication of PD and the primary driver of CHF exacerbation[9], is associated with an increased risk of mortality in patients on PD[10]. Therefore, body fluid management is of paramount importance in patients with CHF on PD, and the standard of care includes salt and water restriction, diuretic administration, and PD regimen enhancement. However, even when treated with these combinations, bioelectrical impedance analyses (BIAs) revealed that 20–25% of patients on PD had fluid overload [11]. In a clinical trial evaluating the benefit of strict body fluid management with BIA, a one-year intervention resulted in a 1.1 kg reduction in extracellular water (ECW) in the BIA group compared with the non-BIA group, and improved fluid overload led to improved rates of all-cause mortality, cardiovascular mortality, and PD duration at three years[12].

Other unmet needs in patients on PD include the loss of residual kidney function and the risks associated with long-term dialysate exposure. Since the former is associated with an increase in morbidity and mortality in patients on PD[13, 14], renoprotective agents should be used continuously even after PD initiation. Furthermore, patients on PD are predisposed to metabolic disorders such as diabetes mellitus and hyperlipidemia due to glucose absorption from the dialysate and encapsulating peritoneal sclerosis due to long-term exposure to high-glucose-concentration solutions[15, 16]. Therefore, there is a need to develop new treatment options that improve body fluid management, exhibit cardiac/renal protection, and prevent complications caused by long-term glucose exposure in patients on PD.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors selectively and reversibly inhibit SGLT2 in the renal proximal tubules, thereby inhibiting glucose and sodium reabsorption in the proximal tubules and increasing urinary glucose and sodium excretion. Dapagliflozin, a selective SGLT2 inhibitor, demonstrated renoprotective and cardioprotective effects in 4,304 nondialysis CKD patients with estimated glomerular filtration (eGFR) rates of 25–75 mL/min/1.73 m² by significantly prolonging the time to the first event of the primary endpoint composite of a sustained eGFR decline of ≥ 50%, end-stage kidney failure, and cardiac- or renal-related death compared with placebo in the DAPA-CKD study[17]. Basic studies in rats have demonstrated that SGLT2 is found in peritoneal mesothelial cells and that SGLT2 inhibitors inhibit glucose reabsorption from the peritoneum[18–20]. In addition, according to a case report, dapagliflozin (5 mg) once daily increased ultrafiltration in four patients on PD[21]. Therefore, dapagliflozin is expected to improve fluid overload by increasing urine volume and ultrafiltration in patients on PD.

The primary objective of this study is to obtain proof-of-concept for the efficacy of dapagliflozin compared with standard treatment for body fluid management in patients with CHF on maintenance PD. The secondary objectives are to evaluate the safety and tolerability of dapagliflozin in patients on PD and the multifaceted effects of dapagliflozin on kidney function, cardiac function, cardiovascular events, PD discontinuation, and transperitoneal glucose absorption.

Study design and setting

This multicenter, open-label randomized controlled trial aims to evaluate the efficacy and safety of dapagliflozin in patients with CHF on PD in Japan (the jDAPA-PD study). It will be performed at Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Nagaoka Red Cross Hospital, and Niigata Prefectural Shibata Hospital, Niigata, Japan. This is an investigator-initiated study conducted without manufacturer funding.

Study population

Inclusion criteria

1) Age ≥ 18 years.

2) Undergoing PD for ESKD treatment for more than three months.

3) A diagnosis of CHF with ongoing standard treatment.

4) A PD regimen that has been stable for at least four weeks.

Exclusion criteria

1) Participation in other clinical studies.

2) Ongoing pregnancy or breastfeeding.

3) SGLT2 inhibitor therapy within the last four weeks.

4) HD therapy within the last four weeks.

5) Treatment for peritonitis within the last four weeks.

6) Daily urine volume of < 500 mL.

7) Difficulties with the infusion and drainage of the PD dialysate.

8) Consideration of PD discontinuation within eight weeks after enrollment.

9) Difficulties undergoing BIA tests (pacemakers and limb defects).

10) Dapagliflozin allergy.

11) Inappropriateness of participation in the study as determined by the investigators.

Recruitment and consent

Eligible patients on PD attending outpatient clinics at facilities participating in the study will be recruited. Written informed consent will be obtained before randomization (Table 1).

Intervention

Participants will be randomly assigned in a 1:1 ratio, stratified by age, sex, and diabetes status, to either the dapagliflozin or standard treatment group (Fig. 1). Participants in the dapagliflozin group will receive 10 mg of dapagliflozin orally once daily for 24 weeks at the dose approved in Japan for CHF treatment in addition to the standard treatment. The drug label for dapagliflozin in Japan notes that it is approved for the treatment of type 2 diabetes, type 1 diabetes, CHF (limited to patients receiving standard treatment), and CKD (excluding patients with ESKD or those on dialysis). However, since it is not expected to be effective for type 2 or type 1 diabetes in patients with ESKD or those on dialysis, it should not be prescribed for these patients. Among patients with severely impaired kidney function, dapagliflozin may thus be used only for CHF treatment in Japan; however, considering its pharmacological action, it can be expected to have some efficacy in patients on PD who have residual kidney function.

Relevant concomitant care prohibited or restricted during the study

The administration of other SGLT2 inhibitors is prohibited during the study. Concomitant HD is also prohibited; however, if necessary, participants may undergo HD after discontinuing their participation in the study. Changes in prescriptions of diuretics, antidiabetic/ antihyperlipidemic agents, and peritoneal dialysis are restricted; however, if necessary, it may be altered. The details of these changes with the reasonings will be recorded.

Withdrawal of participants

Participants can withdraw from the study at any time for any reason. Patients who are ineligible, who switch to HD or who undergo kidney transplantation, who are lost to follow-up, or who are judged inappropriate to continue participating in the study by the principal investigator will also be withdrawn automatically. The principal investigator will record the reason for any immature termination in the case report form and medical records. Data obtained before withdrawal will be analyzed if the participant’s consent is obtained. Participants who withdraw from the study are guaranteed reception of standard dialysis therapy.

Endpoint

Efficacy primary endpoint

Change in ECW from baseline to week 24.

Efficacy secondary endpoint

1) Death.

2) Cardiovascular event (cardiovascular death, myocardial infarction, unstable angina, stroke and transient ischemic attack, pulmonary thromboembolism, and acute leg ischemia).

3) Hospitalization (excluding hospitalization for social reasons).

4) PD discontinuation.

5) Change in body composition indices (body weight, body mass index, ECW, ECW/height, ECW/total body water) from baseline to week 24^*.

6) Change in systolic and diastolic blood pressure from baseline to week 24^*.

7) Change in Kt/V urea from baseline to week 24^*.

8) Change in brain natriuretic peptide (BNP) levels from baseline to week 24^*.

9) Change in echocardiographic parameters (left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left atrial diameter (LAD), early to late (atrial) diastolic transmural flow velocity (E/A)) from baseline to week 24^*.

10) Change in D/P cr and the glucose concentration of the dialysate at four hours by the frequently and short time peritoneal equilibration test (PET)[22] from baseline to week 24^*.

11) Change in PD regimen (up, down, no change) from baseline to week 24^*.

12) Weekly fluid removal (urine, PD, total) from baseline to week 24^*.

^*At each timepoint from baseline to week 24.

Safety endpoint

Adverse events and adverse drug reactions during the study period.

Adverse event reporting

All information regarding adverse events (including symptoms, signs, onset time, and severity) during the study will be recorded in the case report form and medical records. The principal investigator will report the “disease or the like” including any disease, disability, death or infection associated with study participation to the Niigata University Central Review Board of Clinical Research per the Clinical Trials Act in Japan.

Sample size calculation

The sample size for this study is 40 participants as administered cases. There are no reports of comparative studies investigating the efficacy and safety of dapagliflozin in patients on PD. Given that this is an exploratory study, the target number of participants was determined based on the feasibility of study implementation.

Data management and monitoring

Registration, randomization, and data collection are performed using UHCT ACReSS, a web-based electronic data capture system designed by data managers in the Clinical and Translational Research Center, Niigata University Medical and Dental Hospital. Stratified block randomization is performed centrally through the web-based system. The principal investigator designates monitors independent of study investigators. The monitors will perform source data verification and raise queries with the trial site staff. Missing data and discrepancies will be reviewed and queried by data managers to ensure data quality.

Statistical analysis

General principles

Statistical analyses will be performed using SAS® ver. 9.4 (SAS Institute Inc., Cary, NC). A two-sided p < 0.05 will be considered statistically significant. Because this is an exploratory study, statistical tests will be performed including secondary endpoints, and the multiplicity of tests will not be considered. Baseline values are defined as the last values that precede the administration of the study treatment.

Analysis sets

The full analysis set (FAS) includes all randomized participants who have at least one efficacy data set after enrollment. The per protocol set (PPS) is the set of all participants from the FAS who complete the study treatment and show no findings that may have affected efficacy. The safety analysis set (SAF) included all randomized participants whose data are collected during the treatment period.

Statistical methods for efficacy primary endpoint

The primary analysis will be performed using FAS. Changes in ECW from baseline to week 24 will be compared between groups using mixed-effects models for repeated measures (MMRM), adjusted for age, sex, and diabetes. As a sensitivity analysis, the MMRM will be used for the PPS to perform between-group comparisons.

Statistical methods for efficacy secondary endpoints

The secondary analysis will be performed in FAS. Descriptive analyses will be performed to compare the incidence of death, cardiovascular events, hospitalizations, or PD discontinuation. Changes in the following measurements from baseline to week 24 will be analyzed at each timepoint: body composition (body weight, body mass index, ECW, ECW/height, ECW/total body water), systolic and diastolic blood pressure, Kt/V urea, BNP, echocardiographic parameters (LVDd, LVDs, LVEF, LVMI, LAD, E/A), D/P cr and D/D₀ glucose concentration of dialysate at four hours, PD regimen (up, down, no change), and weekly fluid removal (urine, PD, total).

Statistical methods for safety endpoints

The safety analysis will be performed in SAF. Descriptive analyses will be performed to compare the incidence of adverse events and adverse drug reactions.

Methods for subgroup analysis

Descriptive and explorative subgroup analyses will be performed. The subgroups are based on the baseline data:

1) Age (years): < 65, ≥ 65.

2) Sex: Male, Female.

3) Diabetes: Yes, No.

4) Use of automated PD: Yes, No.

5) Daily urine volume (mL): < 1,000, ≥ 1,000.

6) Use of diuretics: Yes, No.

7) PET category: High, High average, Low average, Low.

8) BNP (pg/mL): < 100, ≥ 100.

9) LVEF (%): < 40, ≥ 40.

Interim analysis

No interium analysis is planned.

Missing data

Imputation will not be performed for missing values in this study. The handling of missing, rejected, and abnormal data will be determined through discussion in a review meeting in which research personnel participate.

Confidentiality

All data collected in this study will be carefully kept at each site in a locked cabinet accessible only to the study investigators/administrators and stored for five years from the date of study completion, after which it will be disposed of as unrecoverable. Publications will contain only aggregated data; no identifying information will be included to ensure individual participant anonymization of all data and results made public.

This study examines the efficacy and safety of dapagliflozin compared with the standard treatment in patients with CHF on PD. Dapagliflozin may improve fluid overload in patients on PD, particularly those who still have substantial residual kidney function, by increasing urine volume due to the enhancement of urinary sodium and glucose excretion and by increasing ultrafiltration via the suppression of glucose absorption from the peritoneum. In the long-term, dapagliflozin is expected to protect the kidneys and mitigate the risk of cardiovascular mortality, as observed in the DAPA-CKD study[17], as well as preventing metabolic disorders by increasing urinary glucose excretion. In addition, the inhibition of glucose absorption from the peritoneum may reduce the frequency of high-concentration glucose dialysate use and may be beneficial in the prevention of peritoneal damage.

The risks of administering SGLT2 inhibitors to patients with CHF on PD include a rapid decline in residual kidney function due to an initial dip in GFR, hypoglycemia, urogenital infection, and ketoacidosis. However, the risk in patients on PD is not considered high because a recent emulated target study demonstrated that SGLT2 inhibitor use was associated with a lower risk for dialysis in patients with type 2 diabetes and stage 5 CKD[23]. The risk of hypoglycemia is also considered low because hypoglycemia is safe in nondiabetic patients and because of intraperitoneal glucose dialysis fluid retention. No signals of increased risk for urogenital tract infection or ketoacidosis have also been identified in cases of kidney function decline in the DAPA-CKD study[17]. The risk of known adverse events was not so high based on a review of risk extracted from previously reported studies.

Recently, a review article suggested that the multifaceted pharmacological effects of SGLT2 inhibitors are likely to be beneficial in patients on PD and that clinical trials on this subject are warranted[24]. However, to the best of our knowledge, no randomized controlled trials of dapagliflozin in patients on PD have been identified on PubMed, ClinicalTrials.gov, or jRCT. This study may provide new evidence of the efficacy and safety of dapagliflozin in patients on PD based on a randomized controlled trial.

The small number of participants/facilities and open-label study design are major limitations to this study. Furthermore, we do not have pharmacokinetics/pharmacodynamics data of dapagliflozin in patients on PD, although 10 mg of dapagliflozin administered orally once daily in this study population is acceptable based on a recent pharmacokinetics study in patients with kidney failure[25]. Furthermore, patients without CHF will not be investigated. In this proof-of-concept study, we will determine the feasibility, viability, and tolerability of dapagliflozin therapy for patients on PD and determine whether it shows promise for further development.

Strengths and limitations of this study

1) This study will provide a proof-of-concept for dapagliflozin therapy for the treatment of body fluid management in patients with chronic heart failure on peritoneal dialysis (PD).

2) This study will examine the multidimensional effects of dapagliflozin on morbidity and mortality, cardio/renal protection, and peritoneal functions in patients on PD.

3) The limitations of this study are the small number of participants/facilities involved, lack of pharmacokinetics/pharmacodynamics data, and limited generalizability to a wide range of patients on PD.

The present study will provide evidence of dapagliflozin therapy in patients on PD with CHF that is expected not only to improve fluid overload but also to preserve their residual kidney function (which is the key factor in patients on PD) and reduce the risk of cardiovascular mortality and peritoneal disorders.

Trial status

This manuscript is based on the protocol (version 1.1, last updated on May 10, 2024). The first participant was recruited on May 17, 2024. Recruitment is expected to be completed by June 30, 2025.

BNP Brain natriuretic peptide

CHF Chronic heart failure

CKD Chronic kidney disease

ESKD End-stage kidney disease

FAS Full analysis set

LAD Left atrial diameter

LVD Left ventricular end-systolic diameter

LVEF Left ventricular ejection fraction

LVMI Left ventricular mass index

MMRM Mixed-effects models for repeated measures

PPS Per protocol set

Ethics approval and consent to participate
This study will be conducted in compliance with the latest Declaration of Helsinki, the Clinical Trials Act, and the Act on the Protection of Personal Information in Japan. This study protocol was approved by the Niigata University Central Review Board of Clinical Research and was registered at the Japan Registry of Clinical Trials (jRCT) on February 5, 2024 (jRCT1031230624). Written informed consent to participate will be obtained from all participants.

Consent for publication
Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authorship contributions

MT: conceptualization, methodology, and draft writing, MI: project administration, RT: statistical analysis; AH: draft writing; TT and HM: methodology; YT and IN: supervision; KW, HY, AO, and NI: implementation; SY: principal investigator, conceptualization, and implementation. All authors have read and approved the final manuscript.

Dissemination policy

The results of this study will be published in a peer-reviewed journal and presented at national and international medical congresses.

Funding

This study is funded by the Niigata University Medical and Dental Hospital Clinical Research Support Package Contest Fiscal Year 2022.

Acknowledgements

Not applicable.

Availability of data and materials

The corresponding authors will have access to the final trial dataset. There are no contractual agreements that limit such access for investigators, and the dataset will be available on request.

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Table 1 is available in the Supplementary Files section.

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You are reading this latest preprint version

Dapagliflozin for peritoneal dialysis patients with chronic heart failure in Japan: study protocol for a multicenter, open-label randomized controlled trial (the jDAPA-PD study)

Status:

Version 1

Abstract

Background

Methods/design

Discussion

Trial registration

Figures

Background and rationale

Methods

Study design and setting

Study population

Recruitment and consent

Intervention

Relevant concomitant care prohibited or restricted during the study

Withdrawal of participants

Endpoint

Efficacy primary endpoint

Safety endpoint

Adverse event reporting

Sample size calculation

Data management and monitoring

Statistical analysis

General principles

Analysis sets

Statistical methods for efficacy primary endpoint

Statistical methods for efficacy secondary endpoints

Statistical methods for safety endpoints

Methods for subgroup analysis

Interim analysis

Missing data

Confidentiality

Discussion

Conclusions

Trial status

Abbreviations

Declarations

Consent for publication Not applicable.

Competing interests

Authorship contributions

Dissemination policy

Funding

Acknowledgements

Availability of data and materials

References

Tables

Supplementary Files

Status:

Version 1

Consent for publication
Not applicable.