Convince Study

An international, multi-centre, prospective, randomised, controlled study comparing high-dose

Haemodiafiltration (HDF) versus conventional high-flux Haemodialysis (HD).

End stage kidney disease

End stage kidney disease (ESKD) ranks among the most severe chronic non-communicable
diseases with an unmet medical need.

Haemodialysis (HD) treatment is the current standard of care for the vast majority of patients
with ESKD. HD is associated with high risks of fatal and non-fatal cardiovascular disease, for
infections, hospitalisation and low quality of life.

Improvement required

Improvement in the currently available standard is urgently needed. The CONVINCE study aims
to determine the best possible dialysis treatment by comparing high-dose HDF versus
conventional high-flux HD treatment by carrying out a prospective randomised controlled
clinical trial addressing clinical endpoints, quality of life and a cost-utility analysis.

Background
Information about end-stage kidney disease.

End-stage kidney disease

End stage kidney disease (ESKD) ranks among the most severe chronic, non-communicable
diseases.

Given the high annual mortality rate in Europe (between 10% and 20%) in ESKD patients
treated with dialysis, which has only marginally decreased over the last three decades despite
introduction of multiple pharmacological and non-pharmacological interventions, there is a clear
unmet need for assessing the benefits and harms of novel interventions.

At the end of 2013, there were around 3,2 million patients worldwide being treated for ESKD. In
recent years, this number has increased by approximately 6% each year, which is significantly
higher than the population growth rate. Out of those 3,2 million patients, around 2,25 million
were undergoing kidney replacement therapy in the form of dialysis treatment. At 31 December
2014 in Europe, 490.743 patients were on kidney replacement therapy based on collective
information of national registries representing 531.690.000 population.
Kidney replacement therapy

Kidney replacement therapy, including transplantation and dialysis, is necessary for ESKD
patients with kidney function below roughly 10% of the normal value. Kidney replacement
therapy can be done by transplantation or dialysis, including peritoneal dialysis, low-flux and
high-flux haemodialysis (HD) and haemodiafiltration (HDF).

Limited number of patients

Kidney transplantation is the best option but only available for a limited number of patients due
to various reasons. Presently, peritoneal dialysis is only utilised by a minority of patients. Major
drawbacks are the loss of efficacy and peritonitis. The vast majority of patients who cannot (yet)
have kidney transplantation, are on intermittent HD. Present standard treatment schedules
include three 4 hour sessions per week in a dialysis centre. During HD, excess waste products of
body metabolism and excess fluid are removed. Without treatment, patients will die.

Despite the HD treatment, ESKD is associated with high risks for fatal and non-fatal
cardiovascular disease and infections, as well as poor quality of life, with most patients feeling
fatigued post-dialysis. Because of the intensive impact of treatment, this is a great burden to the
patient and to society .

Dialysis
Over the past decade, an alternative to standard HD has become available ‒ HDF with on-line
production of substitution fluid. This treatment offers, within the same logistical and
organisational infrastructure, a more efficient removal of waste products, especially when it is
applied in “high dose”. While HD removes water soluble toxic compounds mainly by diffusion,
HDF is a more advanced technique that combines diffusion with convection, which as a
consequence removes waste products more efficiently and effectively. In addition, HDF is able
to provide better removal of larger compounds, a limitation of HD, and thereby resembles
normal kidney function to a greater extent.

A recent Cochrane review and meta-analysis examining any form of convective therapy vs.
standard HD found no convincing benefit for HDF , which confirms several, but not all, previous
meta-analyses. A specific feature of earlier meta-analyses is that any form of convective therapy
(i.e. HDF or HD) was included. In contrast, a more recent individual patient-level data meta-
analysis of the four recent European randomised controlled trials, which comprised 2753 patients
with a median follow up of 2,5 years, specifically focusing on dosage of HDF, clearly suggests
that when delivered in high dose, HDF is associated with beneficial effects on relevant clinical
outcome variables. The results of this the meta-analysis indicates the presence of a potential
considerable beneficial effect of HDF compared to HD in this particular patient group in terms of
a 22% reduction in all-cause mortality and 31% reduction in cardiovascular mortality.
However, definite proof of the superiority of HDF when delivered in high dose is still needed.
The main beneficial effect was demonstrated by an observed 30% reduction of cardiovascular
mortality and specifically cardiac mortality. Importantly, the pooled analysis also suggests a 30%
reduction in sudden death rate of borderline significance. A recent large observational study
supports the notion that increased clinical benefit is related with higher convective volumes.
Despite these recent findings, the scientific community remains critical, largely due to results
that the beneficial effects might be explained by patient selection (i.e. a healthier patient receives
more convection volume). Furthermore, the mechanism(s) of a possible beneficial effect is/are
unproven. This also reduces the acceptance of the idea of superiority of HDF.

The current uncertainty regarding the optimal dialysis strategy for patients with ESKD in Europe
results in a heterogeneous delivery of care, not driven by the best evidence base but by local
physician and/or centre preference. Convective modalities such as HDF are accepted by
regulatory authorities and can be performed in the same settings and logistical framework under
country specific rules. Costs differences between the two therapies may be absent or limited,
although differences do exist between HDF systems, as well as between countries and deals
between dialysis centres and suppliers of medical equipment.

Recent work by this consortium indicates that high dose HDF can be readily achieved in all
ESKD patients, although dialysis staff may need some initial training to become aware of the
specific requirements to achieve high dose HDF. Ultimately, the combination of clinical
uncertainty, heterogeneity in clinical practice between centres (physicians) and countries, the
sometimes slightly higher costs and the little extra attention needed of the staff has resulted in
HD still being the therapy of choice for the majority (approximately 80%) of patients in Europe.
Hence, final proof on superiority of HDF over HD would directly improve the outcomes of a
considerable proportion of up to 80% of ESKD patients currently receiving HD, which every
year represent over 260,000 patients in Europe alone. This great unmet need among ESKD
patients requires action and given the fact that clear protocol is available how to deliver high
dose, we have now a unique opportunity to obtain decisive proof of the superiority of high-dose
online HDF over high-flux HD (named HD from now on). Since delivery of high dose is
possible in the vast majority of cases, HDF has the potential to establish as the new therapy of
choice for improving quality of life and clinical prognosis of many ESKD patients in an
affordable and cost-effective way.

CONVINCE posits that HDF can replace HD as the primary therapy of choice for all ESKD
patients. To this end, the CONVINCE consortium will pursue to prove the superiority of high-
dose HDF as compared to high-flux HD (i.e. current standard of care) in terms of morbidity,
mortality and Health-related Quality of Life (HRQL), by conducting a large, international, multi-
centre, randomised controlled trial and use Patient Reported Outcome Measures (PROs) and
Patient Reported Experience Measures (PREs) to capture.
Results from the CONVINCE study will be used to:
1. Collect data to conduct a economic evaluation of high dose HDF compared to HD in
patients with ESKD, to support Health Technology Assessment considerations among
Member States and healthcare to facilitate patient acceptance and uptake of high-dose
HDF across Europe;
2. Develop best practises and new guidelines on the most effective and efficient dialysis
strategy;
3. Disseminate, promote and exploit results in close collaboration with all stakeholders and
end-users, and to establish a sound evidence and regulatory basis for the implementation
of high-dose HDF across Europe, when and where proven superior as compared to
conventional HD.
Study Inclusion Criteria
A subject must meet ALL of the following criteria in order to participate:

 Signed and dated written Informed Consent Form obtained from the subject or his/her
guardian or in accordance with local regulations.
 Male or female aged ≥ 18 years.
 Diagnosed with ESKD.
 Established on haemodialysis for 3 months or longer.
 Likely to achieve high-dose HDF (≥ 23 L in post-dilution mode), according to the
protocol (Appendix I).
 Willing to have a dialysis session with duration of ≥ 4 hours, three times a week.
 Understands study procedures and is able to comply.

Study Exclusion Criteria

A subject who meets any of the following criteria will be excluded from participation:

1. Severe subject non-compliance defined as severe non-adherence to the dialysis procedure

and accompanying prescriptions, especially frequency and duration of dialysis treatment.
2. Life expectancy < 3 months.
3. HDF treatment < 90 days before screening.
 4. Anticipated living donor kidney transplantation < 6 months after screening.
5. Evidence of any other diseases or medical conditions that may interfere with the planned
treatment, affect subject compliance or place the subject at high risk for treatment-related
complications.
6. Participation in any other study will be discussed with and decided by the Executive
Board depending on the extent of interference on this study. Registries are expected to be
approved.
7. Unavailable ≥ 3 months during the study conduct for study visits.

Primary Objective

The primary objective of the CONVINCE study is to compare high-dose haemodiafiltration with
high-flux haemodialysis treatment in terms of all-cause mortality.

Primary Endpoint

The primary endpoint is defined as difference in rate for all-cause mortality.

Secondary Objectives
1. Compare high-dose high-dose haemodiafiltration with high-flux haemodialysis treatment
in terms of cause specific morbidity and mortality.
2. Assess patient reported outcome measures and patient reported experience measures to
capture and patient perspectives and compare between high-dose haemodiafiltration with
high-flux haemodialysis treatment.

3. Assess cost effectiveness of high-dose haemodiafiltration compared to high-flux

haemodialysis.

Secondary Endpoints

The secondary endpoints are:

1. Cause specific mortality (at least cardiovascular and non-cardiovascular death; others
with high frequency may be added);
2. Non-fatal and fatal cardiovascular events;
3. Hospitalisation for infection-related conditions;
4. All cause hospitalisations;
5. PREMS and PROMS;
6. Cost effectiveness.