| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hyperkalemia |
| hiperkaliemija |
|
| E.1.1.1 | Medical condition in easily understood language |
Elevated potassium levels in the blood
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| povišana koncentracija kalija v krvi |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020647 |
| E.1.2 | Term | Hyperkalemia |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A:
To evaluate the efficacy and safety of patiromer for the treatment of hyperkalemia.
Part B:
To evaluate the effect of withdrawing patiromer on serum potassium control;
To assess whether chronic treatment with patiromer prevents the recurrence of hyperkalemia
To provide placebo-controlled safety data.
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Del A:
• Preizkusiti učinkovitost in varnost zdravljenja hiperkaliemije s patiromerom.
Del B:
• Preizkusiti učinek prekinitve zdravljenja s patiromerom na serumsko koncentracijo kalija;
• Oceniti ali kronično zdravljenje hiperkaliemije s patiromerom zavira ponoven pojav hiperkaliemije. Zagotoviti s placebom primerjane podatke o varnosti zdravila.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All subjects must have CKD and be on any dose of at least one RAAS inhibitor medication at Screening. Subjects must also have pre-existing hyperkalemia.
Part A - Inclusion Criteria:
Subjects in Part A must meet ALL the following criteria:
1.Age 18 – 80 years old at screening.
2.Chronic kidney disease: eGFR 15 to < 60 mL/min/1.73m2 at screening (calculated using the CKD-EPI formula or the MDRD formula): the local lab serum creatinine value will be used to assess this entry criterion.
3.Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before patiromer administration. Female subjects must agree to continue using contraception throughout the study and for one month after study completion.
4.Provide written informed consent prior to participation in the study.
5.Serum Potassium: the local laboratory serum K+ value of 5.1 to < 6.5 mEq/L at screening.
6.On any stable dose of at least one RAAS inhibitor medication (an ACEI, ARB, or AA) for at least 28 days prior to screening.
7.If on anti-hypertensive medications, have a stable dose for 28 days prior to screening.
Part B - Inclusion Criteria
To be eligible for Part B, subjects must meet ALL of the following:
1.Completed Part A, the Patiromer Treatment Phase AND
2.Have a Part A baseline central laboratory serum K+ ≥ 5.5 mEq/L
3.Have a locally measured serum K+ value at the Part A Week 4 Visit (AW4) in the target range of 3.8 to < 5.1 mEq/L AND
4.Be on 8.4 to 50.4 g/d patiromer AND
5.Still receiving treatment with a RAAS inhibitor medication at the Part A Week 4 Visit (AW4).
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Pacienti v delu A morajo ustrezati vsem naslednjim kriterijem:
1. Starost 30-80 let na presejanju
2. Kronična ledvična bolezen (KLB): eGFR 15 do < 60 mL/min/1.73m2 na presejanju (z uporabo CKB-EPI ali MDRD enačbe): uporabljene bodo vrednosti kreatinina v serumu, ki jih bodo določili v lokalnem laboratoriju
3. Ženske, ki so sposobne zanositi, ne smejo dojiti, na presejalnem pregledu morajo imeti negativen serumski test nosečnosti in morajo uporabljati visoko učinkovito kontracepcijsko zaščito vsaj 3 mesece pred začetkom uporabe patiromera, med študijo in 1 mesec po koncu študije.
4. Bolniki morajo podpisati Obrazec privolitve v sodelovanje po poučitvi pred začetkom sodelovanja v študiji.
5. Serumska koncentracija K + na presejalnem pregledu - izmerjena v lokalnem laboratoriju - med 5,1 do < 6,5 mEq/l.
6. V primeru uporabe antihipertenzivov mora biti odmerjanje stabilno vsaj zadnji 28 dni pred presejalnim pregledom.
Del B – Vklučitveni kriteriji
Ustrezni pacienti za del B morajo izpolnjevati VSE naslednje zahteve:
zaključen del A študije – zdravljenje s patiromerom IN
serumska koncentracija K+ na izhodiščnem pregledu za del A ≥ 5,5 mEq/l - določena v centralnem laboratoriju IN
serumska koncentracija K+ na pregledu del A 4. teden (AW4) v ciljnem razponu 3,8 do < 5,1 mEq/l - določena v lokalnem laboratoriju IN
jemljejo 8,4 do 50,4 g/d patiromera IN
še vedno jemljejo RAAS inhibitor na pregledu del A 4. teden (AW4).
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| E.4 | Principal exclusion criteria |
Part A - Exclusion Criteria
Subjects in Part A must NOT meet ANY of the following exclusion criteria:
1.Subjects with any level of hyperkalemia at screening that, in the opinion of the investigator, requires emergency intervention.
2.Any subject with potassium-related ECG changes at Screening.
3.Subjects with auto-immune related chronic kidney disease such as lupus nephritis, renal scleroderma/scleroderma renal crisis, or mixed connective tissue disease with renal involvement.
4.Type 1 diabetes or a hemoglobin A1c (HbA1c) measurement of > 10.0% within the previous 6 months in subjects with type 2 diabetes (T2DM).
5.Hospitalization (either in-patient or emergency room treatment) for hyper- or hypoglycemia in subjects with T2DM or for acute exacerbations of heart failure (HF) within the last 3 months.
6.A history of, or currently diagnosed diabetic gastroparesis or history of bariatric surgery
7.A confirmed SBP ≥ 180 mm Hg or < 110 mm Hg OR DBP ≥ 110 mm Hg or < 60 mm Hg at screening, based on the mean of the triplicate measurements.
8.Subjects with symptoms associated with postural hypotension.
9.Anuria or history of acute renal insufficiency in the past 3 months.
10.Confirmed diagnosis or history of renal artery stenosis (unilateral or bilateral).
11.NYHA Class IV HF.
12.Uncorrected hemodynamically significant primary valvular disease, known obstructive or restrictive cardiomyopathy, or uncontrolled or hemodynamically unstable arrhythmia.
13.Coronary artery bypass graft, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic), or major surgery including thoracic and cardiac, within 3 months prior to baseline or anticipated need during study participation.
14.Heart or kidney transplant recipient, or anticipated need for transplant during study participation.
15.Any of the following cardio-or cerebrovascular events having occurred within 2 months prior to screening:
a.Any unresolved acute coronary syndrome (ST elevation myocardial infarction, non-ST elevation myocardial infarction, or unstable angina);
b.Cardiac arrest;
c.Clinically significant ventricular arrhythmias;
d.Transient ischemic attack or stroke;
e.Use of any intravenous cardiac medication.
16.Body mass index (BMI) ≥ 40 kg/m2.
17.Serum magnesium < 1.4 mg/dL (< 0.58 mmol/L) at screening based on the local lab results.
18.Liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] > 3 times upper limit of normal at screening, based on the local lab ALT and AST results.
19.Active cancer, currently on cancer treatment or history of cancer in the past two years except for non-melanocytic skin cancer that is considered cured.
20.History of alcoholism or drug/chemical abuse within 1 year of screening.
21.Use of potassium supplements, bicarbonate or baking soda in the last 7 days prior to screening.
22.Any of the potassium-altering chronic medications that are stated in the protocol if doses have not been stable for at least 28 days prior to screening or if doses are anticipated to change during study participation
23.Use of the drugs stated in the protocol.
24.Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior to screening.
25.Prior participation (excluding screen or enrollment failures) in any study assessing the efficacy and safety of patiromer.
26.Inability to consume the investigational product or, in the opinion of the Investigator, inability to comply with the protocol.
27.History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., large bowel resection).
28.In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, or serious intercurrent illness that would significantly decrease study compliance or jeopardize the safety of the subject or affect the validity of the trial results.
Part B - Exclusion Criteria
Subjects who meet ANY of the criteria below at the end of Part A are not eligible for Part B:
1.Did not complete Part A, the Patiromer Treatment Period; OR
2.Have a Part A baseline central laboratory serum K+ < 5.5 mEq/L; OR
3.Have a locally measured serum K+ value at the Part A Week 4 Visit (AW4) outside of the target range, either < 3.8 or ≥ 5.1 mEq/L; OR
4.On 0 g/d patiromer at the Part A Week 4 Visit (AW4); OR
5.Not receiving treatment with a RAAS inhibitor medication at the Part A Week 4 Visit (AW4).
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Del A – Izključitveni kriteriji
1. Pacienti s kakršnokoli vrednostjo hiperkaliemije na presejalnem pregledu, ki po oceni zdravnika potrebuje urgentno obravnavo.
2. Pacienti s spremembami v EKG-ju na presejalnem pregledu zaradi K+.
3. Pacienti s KLB povezano z avtoimunimi reakcijami kot npr. ledvični lupus, renalna sklerodermija / renalna kriza povezana s sklerodermijo ali kombinirana obolenja vezivnega tkiva in ledvic.
4. Diabetes mellitus tipa I ali hemoglobin A1c (HbA1c) v vrednosti
> 10% izmerjen v zadnjih 6 mesecih pri pacientih z diabetesom tipa II (T2DM).
5. Hospitalizacija (ali tudi samo urgentna obravnava) bodisi zaradi hiper ali hipo glikemije pri pacientih s T2DM bodisi zaradi akutnih poslabšanj srčnega popuščanja v zadnjih 3 mesecih.
6. Diabetična gastropareza ali bariatrični kirurški poseg v zgodovini.
7. Potrjen SKT ≥ 180 mmHg ali ≤ 110 mmHg ALI DKT ≥ 110 mmHg ali ≤ 60 mmHg na presejalnem pregledu (izračunano kot povprečje treh zaporednih meritev).
8. Pacienti s simptomi povezanimi s posturalno hipotenzijo.
9. Anurija ali zgodovina akutne ledvične insuficience v zadnjih 3 mesecih.
10. Potrjena diagnoza ali zgodovina stenoze renalnih arterij (unilateralno in bilateralno).
11. Diagnoza srčnega popuščanja po NYHA Class IV.
12. Nekorigirana hemodinamsko signifikantna primarna bolezen zaklopk, poznana obstruktivna ali restriktivna kardiomiopatija, nekontrolirane ali hemodinamsko nestabilne aritmije
13. Koronarni bypass vsadek, perkutane intervencije (npr. srčne, cerebrovaskularne, aortne) ali velike operacije na prsnem košu in srcu, v zadnjih 3 mesecih pred izhodiščnim pregledom ali planirana potreba po zgoraj opisanem med trajanjem študije.
14. Transplantirana ledvica ali srce ali načrtovana transplantacija med trajanjem študije.
15. Katerikoli od naslednjih kardio- ali cerebrovaskularnih dogodkov, ki so se zgodili znotraj 2 mesecev pred presejalnim pregledom:
a. kakršenkoli nerešen akutni koronarni sindrom (miokardni infarkt z ali brez elevacije veznice ST – STEMI, NSTEMI ali nestabilna angina pektoris)
b. zastoj srca
c. klinično signifikantne ventrikularne aritmije
d. prehodni ishemični napad ali insult
e. uporaba IV kardioloških zdravil
16. Indeks telesne teže (BMI) ≥ 40 kg/m2.
17. Serumska koncentracija magnezija določena v lokalnem laboratoriju, ki je
< 1.4 mg/dl (< 0.58 mmol/l) na presejalnem pregledu.
18. Vrednosti jetrnih encimov [alanin aminotransferaza (ALT), aspartat aminotransferaza (AST)] > 3 x presežena zgornja meja normalnega razpona na presejalnem pregledu, ki jih izmeri lokalni laboratorij.
19. Aktivna rakava bolezen zaradi katere poteka zdravljenje ali zgodovina rakave bolezni v zadnjih dveh letih, z izjemo ozdravljen nemelanocitni kožni rak.
20. Zgodovina alkoholizma ali odvisnosti od drog / kemikalij v zadnjem letu pred presejalnim pregledom.
21. Uporaba sredstev za nadomeščanje kalija, sode bikarbone ali pecilnega praška zadnjih 7 dni pred presejalnim pregledom.
22. Katerokoli od naslednjih zdravil, ki vplivajo na kalij in se uporabljajo kronično, če njihovi odmerki niso bili stabilni zadnjih 28 dni pred presejalnim pregledom, ali če se bodo odmerki spremenili v času sodelovanja v študiji:
a. tiazidni diuretiki in diuretiki Henlejeve pentlje
b. neselektivni inhibitorji beta adrenergičnih receptorjev
c. amilorid
d. triamteren
e. drospirenon
f. nesteroidne protivnetne učinkovine
g. COX-2 inhibitorji
h. digoksin
i. bronhodilatatorji
j. teofilin
k. heparin
l. sintetični hormoni ščitnice
23. Uporaba naslednjih zdravil:
a. kalcijev acetat ali kalcijev karbonat
b. lantanov karbonat
c. sevelamer
d. natrijev polistiren sulfonat ali kalcijev polistiren sulfonat
e. holesevelam
f. holestipol
g. holestiramin
h. drospirenon
i. nadomestki za kalij
j. pripravki z litijem
k. soda bikarbona ali pecilni prašek
l. trimetoprim
m. takrolimus
n. ciklosporin
26. Nezmožnost uporabe zdravila v preskušanju po presoji raziskovalca ali nezmožnost izpolnjevanja zahtev protokola
27. Zgodovina črevesne obstrukcije, težave s požiranjem, resne gastrointestinalne bolezni ali veliki gastrointestinalni operativni posegi (npr., resekcija debelega črevesa)
28. Kakršnokoli zdravstvano stanje, nekontrolirana sistemska bolezen ali resna ponavljajoča se bolezen, ki bi po presoji raziskovalca lahko signifikantno zmanjšala doslednost študije ali bi pomenila nevarnost za pacienta ali bi vplivala na verodostojnost rezultatov študije
Del B – Izključitveni kriteriji
niso zaključili dela A študije – zdravljenje s patiromerom, ALI
serumska koncentracija K+ na izhodiščnem pregledu za del A < 5,5 mEq/l - določena v centralnem laboratoriju, ALI
imajo serumsko koncentracijo K+ na pregledu del A 4. teden (AW4) zunaj ciljnega razpona 3,8 do < 5,1 mEq/l, ALI
so na odmerku 0 g/d patiromera na pregledu del A 4. teden (AW4), ALI
ne jemljejo več RAAS inhibitorja na pregledu del A 4. teden (AW4)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: Change in serum potassium
Part B: Change in serum potassium |
Del A: sprememba serumske koncentracije K+
Del B: sprememba serumske koncentracije K+ |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Part A baseline to Part A Week 4
Part B: Part B Week 4, without any modification to either renin angiotensin aldosterone system (RAAS) inhibition therapy or investigational drug (patiromer); or
At an earlier time point when either the RAAS inhibition therapy or the dose of investigational drug (patiromer) needs to be adjusted to manage a serum potassium (K+) < 3.8 mEq/L or ≥ 5.5 mEq/L.
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Del A:
Sprememba serumske koncentracije kalija od izhodiščne vrednosti dela A do 4. tedna dela A.
Del B:
Sprememba v serumski koncentraciji kalija od izhodiščne vrednosti dela B do:
4. tedna dela B, brez spremembe zdravljenja z inhibitorji sistema renin angiotenzin aldosteron (RAAS) ali z zdravilom v preskušanju (patiromer); ali
dne, ko je bilo potrebno spremeniti odmerek zdravljenja z inhibitorji sistema renin angiotenzin aldosteron (RAAS) ali zdravila v preskušanju (patiromer) z namenom uravnavanja serumske koncentracije kalija kadar vrednosti dosežejo < 3,8 mEq/l ali ≥ 5,5 mEq/l.
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| E.5.2 | Secondary end point(s) |
Part A:
• Having serum K+ level in the target range of 3.8 to < 5.1 mEq/L at Week 4.
Part B:
• Having K+ ≥ 5.1 mEq/L at any time through Week 8
• Having K+ ≥ 5.5 mEq/L at any time through Week 8 |
Del A:
Serumska koncentracija K+ v ciljnem razponu med 3,8 in < 5,1 mEq/L v
4. tednu zdravljenja.
Del B:
Serumska koncentracija K+ ≥ 5,1 mEq/L v kateremkoli času do 8. tedna.
Serumska koncentracija K+ ≥ 5,5 mEq/L v kateremkoli času do 8. tedna
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: Week 4
Part B: at any time through Week 8
at any time through Week 8
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Del A: 4. teden
Del B: kadarkoli v 8 tednih
kadarkoli v 8 tednih
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Croatia |
| Czech Republic |
| Denmark |
| Georgia |
| Hungary |
| Russian Federation |
| Serbia |
| Slovenia |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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