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An Open-label Study to Assess Safety and Efficacy of SZC in Paediatric Patients With Hyperkalaemia (PEDZ-K)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03813407
Recruitment Status : Recruiting
First Posted : January 23, 2019
Last Update Posted : June 30, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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 be enrolled 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 determine 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) 5 g TID. After approval of higher DLs by the iDMC, subsequent participants may be allocated in the CP to 10 g TID and then potentially 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 an open-label long term maintenance phase (LTMP) where the same titration regimen is used as in MP.

Condition or disease Intervention/treatment Phase
Hyperkalaemia Drug: Sodium Zirconium Cyclosilicate (SZC) Reduced Dose Level Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 1 (DL1) Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 2 (DL2) Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 3 (DL3) Drug: Sodium Zirconium Cyclosilicate (SZC) Dose During 28 Day Maintenance Phase Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Treatment includes 3 phases:CP,MP,LTMP.Eligible participants with hyperkalaemia will enter CP receiving fixed dose of SZC three times daily (TID) for up to 3 days until normokalaemia.Within each cohort 2 to <18 years, initial participants will be allocated to dose level (DL) 5g TID. After higher DLs approval by iDMC,subsequent participants may be allocated in the CP to 10g TID and potentially 15g TID.Participants in 0 to <2 years cohort will be assigned to the same DL decided based on data from older cohorts.Those who achieve normokalaemia in the CP will enter a 28-day MP,which starts 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 2.5g to 15g body weight equivalent to maintain normokalaemia.For participants who, at the end of MP,are normokalaemic/hyperkalaemic without being on maximum dose,the MP is followed by option to continue in an LTMP where the same titration regimen is used as in MP
Masking: None (Open Label)
Masking Description: All phases in the study are open-label
Primary Purpose: Treatment
Official Title: An Open-label Study to Assess Safety and Efficacy of SZC in Paediatric Patients With Hyperkalaemia
Actual Study Start Date : April 2, 2019
Estimated Primary Completion Date : December 29, 2023
Estimated Study Completion Date : December 29, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Active Arm ( Sodium Zirconium Cyclosilicate SZC)
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.
Drug: Sodium Zirconium Cyclosilicate (SZC) Reduced Dose Level
Sodium Zirconium Cyclosilicate (SZC) Dose: Paediatric dose based on body weight equivalent to an adult 2.5 g

Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 1 (DL1)
Sodium Zirconium Cyclosilicate (SZC)Paediatric dose based on body weight equivalent to an adult 5 g

Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 2 (DL2)
Sodium Zirconium Cyclosilicate (SZC) Paediatric dose based on body weight equivalent to an adult 10 g

Drug: Sodium Zirconium Cyclosilicate (SZC) Dose Level 3 (DL3)
Sodium Zirconium Cyclosilicate (SZC) Paediatric dose based on body weight equivalent to an adult 15 g

Drug: Sodium Zirconium Cyclosilicate (SZC) Dose During 28 Day Maintenance Phase
A 28-day period during which SZC is administered orally once daily (QD) to maintain normokalaemia. A dose titration regimen starting with QD administration of the dose of SZC the participants received TID in the CP will be studied in the MP and continued in the LTMP. The maximum dose that can be used is the calculated body weight equivalent to the 15 g adult dose




Primary Outcome Measures :
  1. Correction phase (CP) primary objective: To evaluate the ability to achieve normokalaemia during the CP when initiating treatment with SZC of different dose levels in children with hyperkalaemia [ Time Frame: 3 days ]
    Normokalaemia achieved in the CP within 3 days (yes/no)

  2. 28-day Maintenance Phase (MP) primary objective: To evaluate the ability to maintain normokalaemia during the MP when continuing SZC treatment in children achieving normokalaemia [ Time Frame: last two scheduled visits in the MP ]
    28-day MP primary endpoint: Serum potassium (S-K+) value within normokalaemia range (yes/no) at each of the last two scheduled visits in the MP


Secondary Outcome Measures :
  1. All phases secondary objective: To evaluate the change in S-K+ in children treated with SZC [ Time Frame: at each scheduled visit ]
    All phases secondary endpoint: S-K+ level at each scheduled visit

  2. MP secondary objectives: To evaluate change in serum aldosterone levels in children treated with SZC during the MP [ Time Frame: from baseline to Week 3 of the IMP ]
    MP secondary endpoints: Change in serum aldosterone levels from baseline to Week 3 of the MP

  3. MP Secondary objective: To evaluate change in serum electrolytes (including bicarbonate), spot urinary pH and urinary electrolytes levels in children treated with SZC during the MP [ Time Frame: from baseline to week 3 of the MP ]
    Change in serum electrolytes (including bicarbonate), and spot urinary pH and urinary electrolytes from baseline to week 3 of the MP

  4. Long-term MP (LTMP) secondary objectives: To evaluate the ability of maintaining normokalaemia in children treated with SZC during the LTMP [ Time Frame: at each scheduled visit ]
    LTMP secondary endpoints: S-K+ value within normokalaemia range (yes/no) at each scheduled visit in the LTMP


Other Outcome Measures:
  1. Safety objective: To evaluate the safety and tolerability of SZC in the 3 phases (CP, MP and LTMP) [ Time Frame: Throughout the study, 27 weeks ]
    Adverse events/serious adverse events, Vital signs, Electrocardiogram, Clinical laboratory variables

  2. Tertiary/Exploratory objective: To evaluate the acceptability and palatability of SZC through the study [ Time Frame: At certain timepoints throughout the study ]
    Response categories in Study Medication Palatability Assessment questionnaires



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of written informed consent of the participant or legal representative, and informed assent from the participant (as appropriate)
  2. Female or male from birth to < 18 years of age.
  3. Participants (including those receiving a stable peritoneal dialysis regimen) requiring long-term treatment of hyperkalaemia (chronic hyperkalaemia) in the age cohort ≥ 2 years, and participants requiring either short- or long-term treatment for hyperkalaemia (acute and chronic hyperkalaemia) in the age cohort < 2 years.
  4. Participants must meet the following criteria for hyperkalaemia: For participants aged ≥ 2 years, Local Laboratory S-K+ level > 5.0 mmol/L and for participants aged 0 to < 2 years, Local Laboratory S-K+ level >6.0 mmol/L at Screening, measured 3 to 14 days prior to first dose of SZC on CP Study Day 1. This should also be confirmed prior to dosing on Day 1.
  5. Using digital ECG, QT interval corrected by Bazett's method (QTcB) must meet the age-appropriate parameters at Screening: a. For participants aged 0 to ≤ 3 days after birth: < 450 ms b. For participants aged >3 days to < 12 years: < 440 ms c. For participants aged ≥ 12 to < 18 years: < 450 ms (male), < 460 ms (female) All QTcB values outside the reference values specified in the protocol should be manually re-measured and re-calculated, and if there is a difference in measurement between the automatic and manual ECG, the manual measurement should always be considered correct.
  6. Ability to have repeated blood draws or effective venous catheterisation.
  7. Females of childbearing potential must have a negative pregnancy test within one day prior to the first dose of SZC on CP Study Day 1 and sexually active females of childbearing potential must be using 2 forms of medically acceptable contraception with at least one being a barrier method
  8. Optional open-label, LTMP only:

    1. Provision of written informed consent of the participant or legal representative, and informed assent from the participant (as appropriate) to take part in the LTMP.
    2. Participants who are normokalaemic at the end of MP or hyperkalaemic and not on maximum dose.
    3. Participants who would benefit from long-term treatment for their hyperkalaemia, as judged by the Investigator.

Exclusion Criteria:

  1. Neonates with a gestational age < 37 weeks at birth or a birth weight < 2500 g.
  2. Term and preterm neonates with suspected conditions predisposing them to intestinal ischaemia (eg, perinatal hypoxia or sepsis).
  3. Participants with pseudohyperkalaemia caused by excessive fist clenching to enable venepuncture, by haemolysed blood specimens, or by severe leukocytosis or thrombocytosis.
  4. Participants with hyperkalaemia due to soft-tissue damage from crush injury or burns. 5. Participants with hyperkalaemia due to a secondary cause, such as dehydration, excessive use of K+ supplements, or drug use (eg, beta-adrenergic antagonists) and that would be more appropriately treated with other interventions (eg, fluid resuscitation, dose adjustments of medications).

6. Participants with transient iatrogenic hyperkalaemia (eg, due to treatment with tacrolimus or cyclosporine).

7. Participants treated with lactulose, rifaximin (XIFAXAN™), or other nonabsorbed antibiotics for hyperammonaemia within the last 7 days.

8. Participants treated with CPS, sodium polystyrene sulfonate (eg, KAYEXALATE™), or patiromer within the last 4 days prior to first dose of study treatment.

9. Participants with a life expectancy of less than 3 months. 10. Participants who are known to have tested Human Immunodeficiency Virus (HIV) positive.

11. Presence of any condition which, in the opinion of the Investigator, places the participant at undue risk or potentially jeopardises the quality of the data to be generated. 12. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.

13. Participants with cardiac arrhythmias that require immediate treatment. 14. Participants with a family history of long QT syndrome. 15. Participants on haemodialysis. 16. Participants with a history of bowel obstruction. 17. Participants with severe gastrointestinal disorder or major gastrointestinal surgery (eg, large bowel resection).

18. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

19. Previous treatment with SZC. 20. Treatment with a drug or device within the last 30 days prior to first dose of study treatment that has not received regulatory approval at the time of study entry.

21. Previous enrolment in the present study. 22. Females who are pregnant, breastfeeding, or planning to become pregnant. 23. Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 24. If the participant has evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks prior to enrolment (a positive COVID-19 test or suspicion of COVID-19 infection) the participant cannot be enrolled in the study.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03813407


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03813407    
Other Study ID Numbers: D9481C00001
First Posted: January 23, 2019    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame:

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
sodium zirconium cyclosilicate
Hyperkalaemia in children
Additional relevant MeSH terms:
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Hyperkalemia
Water-Electrolyte Imbalance
Metabolic Diseases