Rotation for Optimal Targeting of Albuminuria and Treatment Evaluation (ROTATE-1)

Current guidelines advise treatment with angiotensin receptor blockers (ARBs)
or angiotensin-converting enzyme inhibitors (ACEi) in patients with diabetes
and persistent albuminuria, as these drugs assert renoprotective effects.
Despite being standard of care, it is known that a large proportion of patients
treated with ARBs/ACE-i do not respond to the treatment. This means that a
large proportion of patients receives suboptimal treatment, which highlights
the necessity for a more personalized approach to albuminuria-lowering
treatment. Alternative treatment regimens may be more suited to lower
albuminuria and reduce the risk of renal failure in individual patients.

It is known that ARBs/ACE-I mainly assert their renoprotective effects in
patients with diabetes through their albuminuria-lowering effect. Albuminuria
is a strong risk marker for renal and cardiovascular disease in different
patient populations including patients with type 1 diabetes. Various drugs,
other than ARBs/ACE-I are available that also decrease albuminuria. Examples
include drugs such as atorvastatin, sulodexide, SGLT-2 inhibitors, and
endothelin antagonists. By analyzing multiple large clinical trials we have
shown that in diabetes (but also in non-diabetes) that the treatment group with
more effective reduction of albuminuria during the first weeks/months of
treatment invariably shows more renal/cardiovascular protection indicating that
the initial albuminuria lowering response is crucial for long-term
renal/cardiovascular protection.

Although these different drugs decrease albuminuria on a group level, a large
variability exist in the albuminuria lowering response between individuals.
Whether individual patients show different albuminuria responses to different
drug classes has not been prospectively investigated but could be expected
given the variable pathogenesis of diabetes.

A better understanding on the individual response to different albuminuria
lowering drugs and a better understanding why these drugs, of which some are
developed for another indication, may help to tailor optimal therapy. Therefore
in this study individual patients will be subjected to four different drug
classes that have all been shown to reduce albuminuria on a group level. The
drug that induces the strongest albuminuria-lowering response will be repeated
in a fifth treatment period to assess whether this particular drug again
produces the strongest albuminuria-lowering response. This design will allow us
to determine whether an individual patient truly responds more strongly to a
particular drug, or whether the albuminuria-lowering response is based on
chance.

The study is designed as a randomized multicenter crossover trial with a total
duration of 48 weeks and a total of 26 patients diagnosed with type 1 diabetes
and microalbuminuria. Eligible patients are not allowed to use drugs
intervening in the renin-angiotensin-system. Patients who are using such
medications will be subjected to a 4 week run-in period in which their
angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or direct
renin inhibtior will be discontinued. After the 4-week run-in period, patients
will be randomly assigned to a four way treatment schedule consisting of an
angiotensin receptor blocker (telmisartan 80 mg/day), SGLT-2 inhibitor
(empagliflozin 10 mg/day), a DPP-4 inhibitor (linagliptin 5 mg/day) or
sulodexide (200 mg/day) with each treatment period lasting four weeks. After
each four weeks treatment period a wash-out period of four weeks will follow.
For each patient, the drug that induced the strongest albuminuria-lowering
response will be repeated on completion of the rotation. If contraindicated by
an adverse event, the drug will be substituted by the next most effective drug.
This rotation schedule is repeated until each patient has received all
treatment periods.

Drugs (telmisartan, empagliflozin, linagliptin, sulodexide) are commercially
bought and prepared by the hospital pharmacy of the University Medical Center
Groningen. Patients will be randomized to a treatment schedule consisting of
each of the four drugs with washout periods in between based on the treatment
schedule set up by the pharmacy. Study medication is received at the study site
by a designated person, handled and stored safely and properly, and kept in a
secured location. The study medication is stored according to the instructions
specified on the drug labels. Storage conditions are adequately monitored.
Subjects are asked to return all unused study drug and packaging at the end of
the study or at the time of study drug discontinuation or in every visit to the
outpatient nephrology clinic. Appropriate documentation of the subject specific
dispensing process is maintained. Unused drugs are destroyed by the pharmacy
department at the end of the study.

Patients will visit the clinic 14 times during the study period of 48 weeks. At
every visit blood and urine samples will be taken. The risks for this study
include increased blood pressure due to stopping ACE inhibitors and AII
antagonists. Blood pressure will therefore be monitored and if needed (>180mmHg
systolic blood pressure) amlodipine will be started at an initial dose of 1 dd
5mg, which will be uptitrated to 1 dd 10mg if necessary. The medication used in
the study is deemed safe as it is registered for use in the European Union and
adverse events are generally mild in nature. No risks are associated with the
glycocalyx measurement as it is a non-invasive measurement with a camera. It is
placed under the tongue for several minutes, which does not infer a high burden
on the patient.