PaRatHyroidectomy versus cInacalcet for the correctioN of secondary hyperparathyrOidism in end-stage renal disease patients (RHINO-trial), a pilot-study

Hyperparathyroidism (HPT) is one of the most common abnormalities of mineral
metabolism in patients with end stage renal disease (ESRD), with a prevalence
up to 25-30%.1 It is characterized by parathyroid gland hyperplasia and
increased plasma levels of parathyroid hormone (PTH). This condition results in
disturbances in vitamin D, phosphorus, calcium and PTH metabolism. In end stage
renal disease, HPT leads to severe bone disorders.2,3 HPT is associated with an
increased cardiovascular morbidity and mortality risk.1 Currently, for
treatment of patients with HPT the (KDIGO) guidelines advise to perform
parathyroidectomy (PTx) only after initiation of pharmacological therapy such
as vitamin D analogues, phosphate binders or calcimimetics.4
The global prescription patterns have dramatically shifted from surgery to
predominantly medical treatment. However, calcimimetics have never been
directly compared with (sub-)total parathyroidectomy (PTx). Currently,
calcimimetics form the largest single drug cost for dialysis patients in the
USA and EU (>260 million dollars per year).5 The hypothesis is that
calcimimetics lower PTH levels in ESRD. However, the long-term benefits and
harms on patient-level are uncertain. Brunaud et al. showing no significant
difference in PTH levels after two years of follow-up in patients treated with
cinacalcet versus standard care.6 In addition, the EVOLVE trial clearly showed
cinacalcet not to significantly reduce the risk of death or major
cardiovascular events in patients with moderate-to-severe HPT who were
undergoing dialysis.7 More importantly, an impressive rate of cinacalcet
related adverse effects such as vomiting and nausea was reported (45,9% versus
18,9 in placebo group) compromising treatment compliance. A large multicenter
randomized control trial comparing PTx and cinacalcet with long term follow-up
would ultimately define the treatment of choice in patients with chronic renal
failure.

The aim of the RHINO trial is to compare the effect of parathyroidectomy and
cinacalcet treatment on quality of life in end-stage renal disease patients
with hyperparathyroidism and to evaluate cost-effectiveness.

The aim of this pilot study is to establish the rate of inclusion of ESRD
patients with sHPT in this trial, and to evaluate logistic challenges in
including and treating patients in this multidisciplinary and multicentre
trial.

Multicenter randomized controlled superiority trial.

(sub-)total parathyroidectomy versus cinacalcet

Interventions
Both treatments, PTX and cinacalcet are recognized medical treatments for the
indication sHPT.
Parathyroidectomy:
Overall, the strong association between high PTH levels and increased mortality
support (sub-)total PTx as valuable treatment option to acquire immediate and
durable adjustment of PTH levels. Multiple studies showed that PTx is very
effective in lowering PTH levels.1,2 Although PTx has improved in quality in
the last decades it remains an invasive procedure executed in a fragile
population with cause-specific morbidity (i.e. hypocalcaemia, emergency
admissions) and hospital readmissions (myocardial dysrhythmias, cerebrovascular
events). However, in our previous study, we showed that PTx is a very safe
procedure with low complication rates.3 Moreover, several studies conclude that
patients experience an improved quality of life after they underwent PTx.4-6

Cinacalcet:
Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of
calcium on tissues) by allosteric activation of the calcium-sensing receptor
that is expressed in various human organ tissues. It is sold by Amgen under the
trade name Sensipar in North America and Australia and as Mimpara in Europe.
Cinacalcet is used to treat secondary hyperparathyroidism as a consequence of
end-stage renal disease.16 Cinacalcet was FDA approved in March 2004 and was
the first allosteric G protein-coupled receptor modulator to enter the
pharmaceutical market.17 Since its introduction in 2004, the calcimimetic agent
cinacalcet has become a common first-line therapy for HPT patients
insufficiently responsive to vitamin D and phosphate binders. Since this policy
change several questions have been raised about the efficacy, side effect
profile and costs of cinacalcet.7,8 The EVOLVE trial reported an impressive
rate of cinacalcet related adverse events (AE) such as vomiting and nausa
(45.9% versus 18.9%).9 Moreover, studies evaluating the effect of cinacalcet on
lowering PTH levels show contradictory results 7,9,10 Consequently, cinacalcet
is no longer subsidized by the Australian Government.11

Overall, no extra hospital days / visits are required. Required biochemical
tests are part of routine follow-up, of which patients will not experience
additional burden. We do not expect additional physical and/or physiological
discomfort. No investigational treatment with possible risks is being used.
The additional burden consist of a quality of life questionnaire that needs to
be filled in. We expect patients to fill in these surveys in approximately 30
minutes.