BACKGROUND
In Canada, severe CKD prevalence is 14.9 per 1000 persons. The mortality risk is greatest for pre-dialysis patients with stage 4 or 5 CKD (182 deaths per 1000). The annual cost of medical services for Canadians with CKD is $32 billion, with an annual cost per patient of $20 124 and $23 303 at stages 4 and 5, respectively. Persons with stage 4 or 5 CKD also report a lower quality of life and experience the greatest decrement in quality-adjusted life years projected over time.
Kidney transplantation is recognized as the gold standard for RRT due to its benefit for improving clinical outcomes and quality of life. However, the median wait time in Canada for kidney transplantation is 4 years. Approximately 80% of patients with severe CKD are suitable to receive dialysis. Most CKD patients (76%) receive in-center hemodialysis (ICHD), while only 17% receive home hemodialysis (HHD) and 2.5% receive home peritoneal dialysis (HPD). When considering the systemic and patient burden of CKD, it is important to note that ICHD does not offer added survival benefits, and patients who receive home dialysis report greater quality of life. There is also a lower cost for providing HHD and HPD versus ICHD.
Task force statements and reviews advocate for informed patient choice about HHD and HPD, and patients who receive RRT education are more likely to select home dialysis. However, 38% of CKD patients on dialysis report that they were not informed or involved in the decision to select their dialysis modality, and 64% report that education on managing CKD was inadequate or not provided. During the SARS-CoV-2 pandemic, in-hospital dialysis was associated with a 3- to 4-fold increased risk of virus infection and a high mortality rate of 21-34%, which further supports HHD and HPD.
Task force committees concede that patients with severe CKD require specialized nephrology services that include (i) education to promote informed decision-making about RRT and (ii) counselling to improve quality of life and CKD self-care (i.e., attending medical appointments and adhering to medications, dialysis, fluid and dietary guidelines, monitoring symptoms, engaging in an active lifestyle, and refraining from smoking). A Cochrane review of 40 longitudinal cohort studies (pooled N = 63 887) reported that early access to specialized services predicted shorter hospitalization for initial admission \[-9.1 days; 95% confidence interval (CI): -11 to -7\], and reduced mortality at 12 months (RR =0.65; 95% CI: 0.62 to 0.69) and 5 years (RR = 0.66; 95% CI: 0.60 to 0.71). Corroborating findings from a meta-analysis (pooled N = 648) and a recent randomized trial (N = 130) show that CKD self-care education with telehealth services is associated with reduced hospital admissions and emergency department visits. A further meta-analysis (pooled N = 1647) reported improved quality of life with CKD self-care education or counselling. It is, therefore, vital to commence a CKD self-care and RRT initiative that is evidence-based, scalable, and patient-centred.
RATIONALE
Trials of CKD self-care education have achieved therapeutic benefits with moderate to high patient-provider contact. Direct contact time with individual patients has been estimated in a systematic review of behavioural counselling to range up to 6 hours, which limits the scalability of conventional programs. Moreover, current CKD patient education programs are infrequent and not standardized. CKD patients have reported in several studies that they are not adequately informed or involved in decision-making about their care. In addition, patient barriers that influence informed decision-making about home-based RRT are not adequately addressed. Importantly, patients with severe CKD express marked interest in counselling that extends beyond information about procedures or medical outcomes. Patient interests include ways to improve quality of life and psychosocial well-being, control of care, safety, ability to maintain daily activities, and communication with health care providers. There is high potential for a trial of digital counselling for CKD self-care and RRT education to enhance patient health and quality of life. The risk for mortality decreases in a stepwise manner with incremental adherence to self-care\[PR1\] . A digital strategy is feasible to promote CKD self-care since 90% of Canadians report internet access, which includes 81 to 93% of persons in the 2 lowest income quartiles, 87% of individuals aged 50 to 64 years, and 66% of those equal to or greater than 65 years.
HYPOTHESES
The primary hypothesis is that ODYSSEE-KH versus UC will significantly increase the incidence of home RRT, measured by a composite index27 of HHD, HPD, and preemptive kidney transplant at trial completion (median = 19 months; range: 12 to 27 months).
The secondary hypothesis is that ODYSSEE-KH versus UC will significantly improve the following:
1. Home RRT (composite index of HHD, HPD, and preemptive kidney transplant at trial completion)27
2. RRT preparation \[incidence of arteriovenous fistula (AVF) or arteriovenous graft (AVG), or PD catheter\] at trial completion (median = 19 months; range: 12 to 27 months)
3. Annual hospitalization rate, calculated as a rate per patient per year, at trial completion (median = 19 months; range: 12 to 27 months)
4. Engagement with CKD self-care resources at months 6 and 12 and trial completion (median = 19 months; range: 12 to 27 months), defined by the sum of logon minutes, the sum of logons, and the number of logon days prior to a lapse of equal to or greater than 2 months (taken from CHF-CePPORT49-52 and the former pilot study).
5. The following patient-reported outcome measures of HRQL at baseline, months 6 and 12, and trial completion (median = 19 months; range: 12 to 27 months):
* HRQL (KDQOL-SF and SF-36)
* Engagement in activities for living well (EUROIA)
* Depression (PHQ-9)
* Anxiety (GAD-7)
* Mattering in life domains (MIDLS)
* Social support (ESSI)
* Psychological well-being (PWB)
* Psychological needs (BMPN)
* Extrinsic and intrinsic aspirations (AI)
* Self-efficacy in managing a chronic disease (SEMCD-6)
POTENTIAL RISKS
There is a potential risk that patients in the intervention arm will feel uncomfortable while using ODYSSEE-KH because they are not familiar with the software. Participants may also feel uncomfortable answering certain questions posed in the questionnaire packages, such as those pertaining to mental health, social support, loneliness, and disease burden.
SAFETY PARAMETERS
This is a non-invasive, digital (behavioural) counselling trial. It is complementary in nature and patients will be aware that they can withdraw at any time based on the informed consent procedure. Therefore, there are no significant safety issues associated with this trial.
Personal accounts on the ODYSSEE program will be password-protected. The website itself is hosted on the secure UHN server.
Some of the items presented in the self-report measures of HRQL pertain to mental, physical, social, and occupational functioning. If participants have any concerns about answering one or more questions posed in the questionnaire package, they may contact our office by email or telephone so that their concerns may be addressed. A refusal to respond to any questionnaire item will be accommodated for.
STATISTICAL PLAN
A time-to-event analysis at trial completion (median = 19; range: 12 to 27 months) will be performed using a multivariable Cox Proportional Hazards (PH) model. It will evaluate if Digital Counselling versus UC significantly improves the likelihood for home-based RRT, based on a composite endpoint of first of HPD, HHD, or preemptive kidney transplant. Potential confounders (e.g., age, gender) will be selected using forward (p \< 0.05) and backward (p \< 0.10) stepwise selection.
A multivariable Cox PH model will assess if Digital Counselling versus UC significantly improves the likelihood for the composite endpoint of incidence of AVF, or AVG, or PD catheter at trial completion (median = 19; range: 12 to 27 months).
At trial completion (median = 19; range: 12 to 27 months), log-linear Poisson models will be conducted for hospitalization rate, per patient, per year. A multivariable Cox PH model will then evaluate if Digital Counselling versus UC significantly increases time to hospitalization.
Separate Generalized Linear Models (GLMs) will evaluate if Digital Counselling versus UC evokes greater CKD self-care program adherence at months 6 and 12- and trial completion (median = 19; range: 12 to 27 months). The dependent variable will be the sum of logon time and the predictors will include age, gender, and trial arm (Digital Counselling or UC), as well as potential baseline confounders (noted above). The GLM for the endpoints will be repeated using the sum of logons as the dependent variable. Finally, for these endpoints, a multivariable Poisson model will evaluate whether Digital Counselling versus UC is associated with greater duration of engagement (defined as the sum of logons, sum of logon hours, and number of logon days prior to a logon lapse of equal to or greater than 1 month), adjusting for sex, age, and potential confounding variables (noted above).
Separate GLMs will evaluate if Digital Counselling versus UC is independently associated with outcomes at months 6 and 12 and trial completion (median = 19; range: 12 to 27 months). Dependent variables include the KDQOL-SF, AI, EUROIA, ESSI, PHQ-9, GAD-7, BMPN, PWB, MIDLS and SF-36, as well as a modified SEMCD-6. Multivariable models will adjust for baseline assessments of each outcome and potential baseline covariates (noted above). In all GLMs, significant interactions will be followed by subgroup analyses with Bonferroni post-hoc tests.
After testing interactions between Digital Counselling versus UC and gender in the primary and secondary outcome analyses, separate exploratory analyses will be performed for gender categories sufficiently represented in the sample. Separate competing risk models will be employed to evaluate time to each of the following outcomes: HPD, HHD, and preemptive kidney transplant.
DEVIATIONS FROM STATISTICAL PLAN
A need to deviate from the original statistical plan is not anticipated because exploratory analyses are included. Nevertheless, the Statistical Analyses and Methodology Committee will be consulted regularly throughout the trial.
SAMPLE SIZE
The sample estimate for the ODYSSEE-KH trial, with monitoring over 19 months, is only 64 patients, type 1 error = 5% and power = 80%.The CKD pilot study achieved moderate program adherence, similar to the CHF-CEPPORT trial whereby the median proportion of sessions access was 61%. The sample estimate to detect this effect with a double-group design, type 1 error of 5%, and power of 80% is N = 114. In sum, the conservative sample estimate used for our primary outcome will ensure appropriate statistical power to evaluate our secondary outcomes of hospitalization and usability. The final sample estimate is N = 344, with a type 1 error of 5% and a power of 80%.
COMPLIANCE
Participation will be supported by senior clinical staff members to ensure that trial activities are presented as complementary to a patient's healthcare. The research team will promote adherence to online assessments via REDCap® with email, telephone, and in-person reminders.
WITHDRAWAL
This trial does not include invasive procedures or changes to medications that could trigger a significant clinical event. Therefore, the need to actively withdraw subjects from this complementary, behavioural (digital) counselling program is not anticipated.
CRITERIA FOR TRIAL TERMINATION
The ODYSSEE-KH trial would have been terminated prematurely in the event of a recurrent adverse event that was related to our trial procedures or content.
QUALITY CONTROL AND ASSURANCE
Daily management and monitoring of recruitment and assessment activities will be completed by the research coordinator.
Responsibility for quality control will remain with the full team. The multidisciplinary research team holds senior administrative, clinical, and research appointments at participating institutions
CONSENT
Initial contact with the patient will be made only by members of the circle of care, who will not attempt to obtain informed consent from the patients. Clinical staff in participating outpatient nephrology clinics will identify patients who meet trial criteria and will obtain verbal consent to be approached by the research team. Informed consent will be obtained either in person or virtually. Regardless of the method, A follow-up email will be sent to the participant by the research team containing the participant's onboarding information (i.e., hyperlink to ODYSSEE platform, username, and temporary password), as well instructions and tutorial videos on how to access the ODYSSEE platform.
In-person, a trained research team member will approach the potential participant during their clinic appointment and will provide them with a hard copy of the Informed Consent Form. The trained research team member will discuss the content of the Informed Consent Form with the patient and will address any questions and/or concerns relating to the trial that the patient may have. Patients will be informed that their participation is voluntary and that it will have no bearing on their healthcare. Moreover, this message is clearly conveyed in the Informed Consent Form. The trained research team member will provide the patient with as much time as they require to make an informed decision about participating in the trial.If the patient decides to consent to participate in the trial, informed consent will be obtained in person via double signatures on hard copies. One copy will be kept on file by the research team and the other copy will be retained by the participant.
Virtually, a trained research team member will contact the patient by telephone to confirm their interest in the trial. The trained research team member will email the patient a hyperlink to the Informed Consent Form, housed on the UHN REDCap server ®. The patient will be asked to refrain from signing the Informed Consent Form until they have had an opportunity to discuss the trial, as well as any questions and/or concerns they may have, with the research team. The trained research team member will discuss the content of the Informed Consent Form with the patient over the telephone and will address any questions and/or concerns relating to the trial that the patient may have. Patients will be informed that their participation is voluntary and that it will have no bearing on their healthcare. Moreover, this message is clearly conveyed in the Informed Consent Form. The trained research team member will provide the patient with as much time as they require to make an informed decision about participating in the trial. If the patient decides to consent to participate in the trial, informed consent will be obtained virtually via electronic signatures on PDF copies. A copy will be kept on file by the research team and the other copy will be sent to the participant by email.
DATA STORAGE
All data will be stored on secure servers within the UHN digital environment, ensuring that security measures are well-developed to protect the data from external intrusion. Data will be stored for 10 years as per UHN Research procedure.
The digital forms and materials will be retained on the secure UHN server for at least 10 years from the completion of the trial.
Data will be available from the corresponding author pending approval of research ethics boards of participating institutions and on a reasonable request received from qualified researchers trained in human subject confidentiality protocols.
PRIVACY AND CONFIDENTIALITY
Subjects are issued a tracking number when data involving identifying information is transmitted for analysis. Subject anonymity and confidentiality have been preserved. Only aggregate data will be published.
All research personnel have signed an employee confidentiality agreement ensuring that confidential information is not disclosed to any other person or entity. All source documents containing personal identifiers are stored in filing cabinets under lock and key. The database is stored electronically on the firewall-protected server, making it inaccessible externally. Access to the room containing the research file server is restricted to designated persons who are employed by the Behavioural Cardiology Research Unit at the UHN.
Discussion of the trial with persons outside the research team will never reveal the personal identifiers of participants. All-access to data is denied to persons outside the research team. Data transmission occurs via encrypted storage material over the Internet.
