Patiromer Trial in CKD Stage IIIB to V

This phase III, prospective, randomized, double-blind, placebo-controlled trial will primarily aim to compare the effects of patiromer and placebo on the rate of withdrawal or down-titration of RAAS inhibition therapy because of refractory hyperkalemia (serum K+ levels ≥ 5.5 mEq/L at two consecutive visits, one-week apart) in non-dialysis patients with CKD stage IIIB to V receiving best available conservative therapy, including RAAS inhibition with ACE inhibitors and/or ARBs and/or aldosterone antagonists. Patients are expected to be included during an 18-month recruitment period. All randomized patients will be maintained on active follow-up for 12 months. At 12 months, a final visit will be performed for all patients who complete the follow-up period. During this final visit, all the parameters evaluated at baseline will be reassessed and the study treatment will be discontinued. Whenever feasible, a final visit will be planned within one month also for those patients who prematurely discontinue the treatment period for any intercurrent reason (adverse event, consent withdrawal and other). After the final visit the patient will be discharged from the study and will be referred to his nephrologist with the suggestion to check serum potassium levels within three days.

Refractory hyperkalemia is among the leading causes of initiation or chronic renal replacement therapy (RRT) by extracorporeal or peritoneal dialysis in patients with chronic kidney disease (CKD). Dialysis therapy is lifesaving but has a major impact on patients' quality of life and is terribly expensive. Thus, deferring dialysis initiation by preventing hyperkalemia would have major implications for patients and health care providers.

Among patients with CKD, glomerular filtration rate (GFR) \<45 ml/min/1.73 m2, older age, coexistence of diabetes or heart failure, and inhibition of the renin angiotensin aldosterone system (RAAS) by angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or aldosterone antagonists are the major risk factors for hyperkalemia. On the other hand, RAAS inhibitors - based on randomized trial results showing the superior effect of these medications compared to other antihypertensive drug classes in slowing the progression of chronic nephropathies to end-stage renal disease (ESRD) - are first-line therapy for patients with CKD, in particular for those with proteinuric nephropathies.

However, the risk of hyperkalemia is a major impediment to adequate RAAS blockade in CKD, especially when RAAS inhibitors are used in maximal doses or are combined.

Dietary counseling, correction of metabolic acidosis and treatment with loop diuretics are key components of potassium-lowering therapy in patients with CKD. Combined therapy with potassium binders, however, is often needed to prevent or treat hyperkalemia, particularly in patients with GFR \<45 ml/min/1.73 m2, concomitant diabetes and/or RAAS inhibitor therapy.

A newer potassium binder, patiromer, has been approved by FDA and EMA for the treatment of hyperkalemia. Patiromer is an organic, non-absorbed, sodium-free, potassium-binding polymer that exchanges potassium for calcium in the gastrointestinal tract. Because of the remarkably good risk/benefit profile, it is conceivable that patiromer may safely improve hyperkalemia control and reduce the need of RAAS inhibition interruption or down-titration (not only of ACE inhibitors and ARBs but also of potassium sparing diuretics such as spironolactone, eplerenone and finerenone) in patients with severe CKD. In turn, this could translate into improved nephroprotection and deferred initiation of dialysis, particularly in non-dialysis patients with CKD stage IV to V. This hypothesis, however, must be tested in prospective randomized controlled trials.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of informed consent prior to any study-specific procedures.
2. Age \>18 years.
3. GFR \<45 ml/min/1.73m2 as per CKD-EPI equation.
4. Serum potassium ≥5.0 mEq/L (in at least two consecutive evaluations, one week apart) despite dietary counseling, optimized metabolic acidosis control, diuretic therapy as needed for blood pressure control and fluid balance, and effective blood glucose control in diabetics.
5. Concomitant therapy with RAAS inhibitors (ACE inhibitors, ARBs and aldosterone antagonists, such as spironolactone and finerenone).

Exclusion Criteria:

1. Ongoing treatment with SPS before randomization (Patient eligibility could be reassessed during the screening period after at least one week from SPS therapy withdrawal)
2. Rapidly progressive kidney disease (eGFR reduction ≥ 30% over the last three months as per CKD-Epi equation) and expected risk of progression to ESKD and need of renal replacement therapy by dialysis or transplantation within six months.
3. Active systemic autoimmune diseases.
4. Concomitant treatment with steroids or any other immunosuppressive agent.
5. Hypersensitivity to the active ingredient or any of the excipients. Patients with Hereditary Fructose Intolerance.
6. Patients with or at risk of hypercalcaemia and/or hypomagnesaemia.
7. Severe/unstable heart failure with or without decreased systolic function requiring hospitalization or changes in pharmacological therapy over the last three months.
8. Refractory severe hypertension (BP \>180/100 mmHg despite optimized pharmacological treatment with at least three blood pressure-lowering medications and a diuretic).
9. Positive hepatitis C antibodies, hepatitis B virus surface antigens at screening.
10. Known to have tested positive for human immunodeficiency virus.
11. Drug or alcohol abuse.
12. Female subjects who are pregnant, lactating or who intend to become pregnant before or during the study period, or within 90 days of the last dose of study treatment. Female subjects who intend to donate ova over the same time period.
13. Male subjects who intend to donate sperm during the study period or for the 90 days following the last dose of study treatment.
14. Male and female subjects in childbearing age not using a highly effective contraception method according to the 2020 CTFG Recommendations related to contraception and pregnancy testing in clinical trials (9)
15. Inability to fully understand the potential risks and benefits related to study participation.
16. Involvement in the study planning and/or conduct.
17. Participation in another clinical study with an investigational product during the last month.