SZC for Hyperkalemia

(PEDZ-K Trial)

Recruiting at 44 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Lactulose, Rifaximin, CPS, others

Disqualifiers: HIV, Cardiac arrhythmias, Haemodialysis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

140 Participants Needed

Trial Summary

What is the purpose of this trial?

Sodium zirconium cyclosilicate has been shown to be effective and safe in adults for the treatment of hyperkalaemia, and therefore it is expected to be beneficial in children. This study will evaluate the efficacy, safety and tolerability of sodium zirconium cyclosilicate for the treatment of hyperkalaemia in children \<18 years of age. Approximately 140 participants will enter CP at approximately 46 sites in locations including but not limited to Europe and North America for this study. Treatment will include 3 phases: the CP, MP, and LTMP. Enrolment will start in 2 cohorts, ages 6 to \< 12 years and 12 to \< 18 years. After review of accumulated data, the independent Data Monitoring Committee (iDMC) will recommend whether to open enrolment in the ages 2 to \< 6 years cohort and later in the ages 0 to \< 2 years cohort. All eligible participants with hyperkalaemia will enter an open-label Correction Phase (CP) receiving a fixed dose of SZC three times daily (TID) for up to 3 days until normokalaemia is achieved. Within each age cohorts 2 to \< 18 years, initial participants will be allocated to the dose level (DL) based on body weight equivalent to an adult 5 g TID. After recommendation of higher DLs by the iDMC, subsequent participants may be allocated in the CP to on body weight equivalent to an adult 10 g TID and then potentially on body weight equivalent to an adult 15 g TID. All participants in the ages 0 to \< 2 years cohort will be assigned to the same DL which will be decided based on data from older age cohorts. Participants who successfully achieve normokalaemia in the CP will enter a 28-day open-label Maintenance Phase (MP), which will be initiated with once daily administration of the dose received TID in the CP. During MP, the Investigator is able to titrate the dose up or down in the range 2.5 g to 15 g body weight equivalent to maintain normokalaemia. For participants who, at the end of MP, are normokalaemic or hyperkalaemic without being on maximum dose, the MP is followed by the option to continue the study in a long term maintenance phase (LTMP) where the same titration regimen is used as in MP

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications like lactulose, rifaximin, sodium polystyrene sulfonate, or patiromer before starting the study treatment. If you are on these medications, you will need to stop them for a specified period before joining the trial.

What data supports the effectiveness of the drug Sodium Zirconium Cyclosilicate (SZC) for treating hyperkalemia?

Sodium Zirconium Cyclosilicate (SZC) is a new drug used to treat hyperkalemia (high potassium levels in the blood) and is noted for having fewer side effects compared to older treatments. It is specifically designed to bind potassium, helping to lower its levels in the body. ^{1 2 3 4 5}

Is Sodium Zirconium Cyclosilicate (SZC) safe for humans?

Sodium Zirconium Cyclosilicate (SZC) is generally considered safe for treating high potassium levels, with fewer side effects compared to older treatments. However, it can appear on imaging tests like CT scans and DXA, which might affect the results of these tests. ^{1 2 3 4 6}

What makes the drug Sodium Zirconium Cyclosilicate (SZC) unique for treating hyperkalemia?

Sodium Zirconium Cyclosilicate (SZC) is a novel drug for treating hyperkalemia (high potassium levels) that works by specifically binding to potassium in the gut, which helps to remove excess potassium from the body. It is known for having fewer side effects compared to older treatments and is also radiopaque, meaning it can appear on imaging tests like CT scans. ^{1 2 3 4 6}

Eligibility Criteria

This trial is for children under 18 with high blood potassium (hyperkalemia) who need long-term treatment. They must be able to have regular blood tests, not have severe gut issues or major surgeries, and can't be on certain medications or dialysis. Girls who can have babies must use two birth control methods.

Inclusion Criteria

I am under 18 years old.

My potassium levels are normal or high but I'm not on the highest dose of medication for it.

My heart's electrical activity, measured by an ECG, is within the normal range.

Exclusion Criteria

I might have a condition that reduces blood flow to my intestines.

You have false high levels of potassium in your blood due to certain health conditions.

My family has a history of long QT syndrome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Correction Phase (CP)

Participants receive a fixed dose of SZC three times daily for up to 3 days until normokalaemia is achieved

Up to 3 days

Maintenance Phase (MP)

Participants who achieve normokalaemia in the CP enter a 28-day open-label Maintenance Phase with dose titration to maintain normokalaemia

28 days

Long-term Maintenance Phase (LTMP)

Participants may continue in a long-term maintenance phase with the same titration regimen as in MP

Up to 22 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Sodium Zirconium Cyclosilicate (SZC)

Trial Overview The study tests different doses of Sodium Zirconium Cyclosilicate (SZC) in kids with hyperkalemia. It has three phases: correction, maintenance, and long-term maintenance where the dose may change to keep potassium levels normal.

Participant Groups

Group I: Active Arm ( Sodium Zirconium Cyclosilicate SZC) Experimental Treatment 5 Interventions

Dosage formulation: 5 g sachets 2.5 g sachets 0.25 g sprinkle capsules 0.125 g sprinkle capsules (can be manufactured to support participants \<2 years of age) Route of administration: Oral Dosing instructions: SZC is provided as a powder. At the time of dosing SZC is mixed with a quantity of water or sprinkled onto semi-solid food (eg, milk, baby food, yogurt, or ice cream) within an hour of drug administration. Packaging and labelling: Study treatment will be provided in sachets packed in cartons or sprinkle capsules in high density polyethylene bottles, as appropriate for the dose. Each carton of sachets, individual sachets, and bottle of capsules will be labelled in accordance with Good Manufacturing Practice Annex 13 and per country regulatory requirement. Participant-specific dosing cards (diary) will be provided.

Sodium Zirconium Cyclosilicate (SZC) is already approved in European Union, United States for the following indications:

Approved in European Union as Lokelma for:

• Hyperkalemia

Approved in United States as Lokelma for:

• Hyperkalemia

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a study of 24 patients with heart failure and hyperkalemia, sodium zirconium cyclosilicate (SZC) was safely administered for 3 months without causing adverse effects, including hypokalemia.

SZC therapy led to decreased serum potassium levels and allowed for increased doses of renin-angiotensin-aldosterone system inhibitors, which improved heart function as indicated by enhanced left ventricular ejection fraction and reduced plasma B-type natriuretic peptide levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Implications of Sodium Zirconium Cyclosilicate Therapy in Patients with Systolic Heart Failure and Hyperkalemia. Imamura, T., Oshima, A., Narang, N., et al.[2021]

Sodium zirconium cyclosilicate (Lokelma®) is effective in treating non-life-threatening hyperkalemia and has fewer side effects compared to older treatments.

The study suggests that Lokelma can appear radiopaque on CT imaging, which could help in differentiating it from other potential sources of radiopacity, thus providing a new perspective on imaging techniques in patients treated with this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiopacity of sodium zirconium cyclosilicate on CT imaging. Kolesnik, M., Berezovsky, D., Sayegh, M., et al.[2022]

The article reviews the use of Sodium Zirconium Cyclosilicate as a treatment for hyperkalaemia, a condition characterized by elevated potassium levels in the blood.

Sodium Zirconium Cyclosilicate is effective in lowering potassium levels, providing a safe and efficient option for managing hyperkalaemia in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction to: Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia. Hoy, SM.[2019]

Sodium zirconium cyclosilicate (SZC) significantly alters dual-energy X-ray absorptiometry (DXA) results, increasing bone mineral density (BMD) measurements by 18% to 110% in spine phantoms, indicating it may confound results in actual patients.

The study demonstrated a dose-dependent effect of SZC on body composition, with higher doses leading to significant increases in lean mass and decreases in fat mass, suggesting that DXA technologists should be cautious when interpreting results in patients taking SZC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Newly Recognized DXA Confounder: The Potassium-Binding Medication Sodium Zirconium Cyclosilicate. McCarney, B., Binkley, N., Krueger, D.[2021]

Adding zirconium dioxide (ZrO2) to tricalcium silicate (TCS) cements does not affect their mechanical strength, maintaining similar fracture toughness to Biodentine, a control cement.

The modified TCS cements showed improved calcium release over time and reduced cytotoxicity, particularly the TCS 50 formulation, indicating it could be a safer and more effective option for dental applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified tricalcium silicate cement formulations with added zirconium oxide. Li, X., Yoshihara, K., De Munck, J., et al.[2018]

The study tested a new dental material made of calcium silicate-based cement with zirconium oxide and found it to have low cytotoxicity, making it a promising option for root-end filling in dental procedures.

At a concentration of 10 mg/mL, both the white Portland cement and the zirconium oxide variant increased the viability of fibroblasts compared to the control group, suggesting potential benefits in dental applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental Calcium Silicate-Based Cement with and without Zirconium Oxide Modulates Fibroblasts Viability. Slompo, C., Peres-Buzalaf, C., Gasque, KC., et al.[2017]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Implications of Sodium Zirconium Cyclosilicate Therapy in Patients with Systolic Heart Failure and Hyperkalemia. [2021]

2. Japan pubmed.ncbi.nlm.nih.gov

Radiopacity of sodium zirconium cyclosilicate on CT imaging. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Correction to: Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

A Newly Recognized DXA Confounder: The Potassium-Binding Medication Sodium Zirconium Cyclosilicate. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Modified tricalcium silicate cement formulations with added zirconium oxide. [2018]

6. Brazil pubmed.ncbi.nlm.nih.gov

Experimental Calcium Silicate-Based Cement with and without Zirconium Oxide Modulates Fibroblasts Viability. [2017]