| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
Correction phase (CP) primary objective:
To evaluate the ability to achieve normokalaemia during the CP when initiating treatment with SZC of different dose levels (DLs) in children with hyperkalaemia
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 |
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| E.2.2 | Secondary objectives of the trial |
All phases secondary objective:
To evaluate the change in S-K+ in children treated with SZC
MP secondary objectives:
To evaluate change in serum aldosterone levels in children treated with SZC during the MP
To evaluate change in serum electrolytes (including bicarbonate), spot urinary pH and urinary electrolytes levels in children treated with SZC during the MP
Long-term MP (LTMP) secondary objectives:
To evaluate the ability of maintaining normokalaemia in children treated with SZC during the LTMP |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 for a minimum of 2 months) 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, for participants aged 1 month to < 2 years, Local Laboratory S-K+ level >6.0 mmol/L and for participants aged 0 to < 1 month, Local Laboratory S-K+ level > 6.5 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, LTMP only:
a. 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.
b. Participants who are normokalaemic at the end of MP or hyperkalaemic and not on maximum dose.
c. Participants who would benefit from long-term treatment for their hyperkalaemia, as judged by the Investigator. |
|
| E.4 | Principal 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).
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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
CP primary endpoint:
Normokalaemia achieved in the CP within 3 days (yes/no)
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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Correction Phase (CP) - each day during CP
Maintenance Phase - at each of the last two scheduled visits in the MP |
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| E.5.2 | Secondary end point(s) |
All phases secondary endpoint:
S-K+ level at each scheduled visit
MP secondary endpoints:
Change in serum aldosterone levels 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
LTMP secondary endpoints:
S-K+ value within normokalaemia range (yes/no) at each scheduled visit in the LTMP |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All phases secondary endopoint
- S-K+ level: at each scheduled visit
MP secondary endpoints:
- Change in serum aldosterone: at baseline and Week 3 of the MP
- Change in serum electrolytes (including bicarbonate), and spot urinary pH and urinary electrolytes: at baseline and Week 3 of the MP
LTMP secondary endpoints
- S-K+ value within normokalaemia range: at each scheduled visit in the LTMP |
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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 | No |
| E.6.3 | Therapy | No |
| 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 | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Canada |
| China |
| Japan |
| United States |
| Poland |
| Romania |
| Spain |
| Germany |
| Ukraine |
| United Kingdom |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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