| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 |
28-day maintenance phase (MP) primary objective: To compare the effect of SZC vs placebo on maintaining normokalaemia during the MP
Correction phase (CP) primary objective: To evaluate SZC efficacy of
different dose levels (DLs) on achieving normokalaemia during the CP |
|
| E.2.2 | Secondary objectives of the trial |
CP secondary objectives evaluate SZC DLs on the following
achieving normokalaemia within the first 72 hrs
time to achieving normokalaemia during the CP
the reduction of S-K+ levels during the CP
time to reduction of S-K+ levels during the CP
MP secondary objectives evaluate SZC vs placebo on the following:
time from randomisation to relapse of hyperkalaemia;
the proportion of participants with normokalaemia per visit over the MP
the change in S-K+ levels over the MP
time to increase in S-K+ during the MP
proportion of days of normokalaemia during the MP;
mean S-K+ during the MP
proportion of participants experiencing hypo- or hyperkalaemia during the MP
serum aldosterone (S-Aldo) at the end of the MP plasma electrolytes(including bicarbonate)and spot urinary pH and electrolytes
Long term maintenance phase(LTMP)objectives: To evaluate long term maintenance of normokalaemia during treatment with SZC
Acceptability and palatability of SZC is evaluated in all study phases |
|
| 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 peritoneal dialysis) requiring long term treatment of hyperkalaemia (chronic hyperkalaemia) in the age cohort ≥2 years, and participants requiring either short- or longterm treatment for hyperkalaemia (acute and chronic hyperkalaemia) in the age cohort <2 years..
4. Participants must meet 1 of the following criteria for hyperkalaemia:
(a)For participants ≥2 years of age, mean i STAT K+ level >5.0 mmol/L
at Screening. Two consecutive i STAT K+ values, measured 60 (±15)
minutes apart, both >5.0 mmol/L and measured within 1 day before the first dose of SZC on CP Study Day 1.
(b)For participants <2 years of age, i STAT K+ level >6.0 mmol/L at
Screening, measured within 1 day before the first dose of SZC on CP
Study Day 1.
Note that if Day 1 is the same as the Screening day, the 60 (±15) minute K+ value is the same as the Day 1 time 0 K+ value. However, if Day 1 is not the same day as Screening, then the participant will actually have 3 i STAT-K+ values measured before starting treatment in the CP and the third value which is taken on Day 1 time 0 must also be hyperkalaemic.
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 ≥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 catheterization.
7. Females of childbearing potential must have a negative pregnancy test within 1 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 1 being a barrier method |
|
| 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 ischemia (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, betaadrenergic antagonists) and that would be more appropriately treated with other interventions (eg, fluid resuscitation, dose adjustments of medications)
6. Participants treated with lactulose, rifaximin (XIFAXAN™), or other
nonabsorbed antibiotics for hyperammonaemia within the last 7 days.
7. Participants treated with CPS, sodium polystyrene sulfonate (eg,
KAYEXALATE™), or patiromer within the last 4 days.
8. Participants with a life expectancy of less than 3 months.
9. Participants who are known to have tested Human Immunodeficiency Virus (HIV) positive.
10. 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.
11. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
12. Participants with cardiac arrhythmias that require immediate treatment.
13. Participants with a family history of long QT syndrome.
14. Participants on haemodialysis.
15. Participants with a history of bowel obstruction.
16. Participants with severe gastrointestinal disorder or major
gastrointestinal surgery (eg, large bowel resection).
17. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
18. Previous treatment with SZC.
19. Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry.
20. Previous enrolment in the present study.
21. Females who are pregnant, breastfeeding, or planning to become pregnant.
22. Judgment 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.
23. For the LTMP only: participants who are normokalaemic at Visit 8b and are receiving placebo at Visit 8a of the MP unless they received rescue treatment.
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
28-day MP primary endpoint (primary analysis endpoint):
The proportion of participants in whom normokalaemia can be
maintained throughout the MP
Correction phase primary endpoint:
The proportion of participants in whom serum K+ (S-K+) decreases by ≥0.5 mmol/L and who achieve normokalaemia at (by or before) 24, 48 and 72 hours during CP. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Correction Phase 24, 48 and 72 hours
Maintenance Phase 28 days |
|
| E.5.2 | Secondary end point(s) |
CP secondary endpoints:
- The proportion of participants in whom S-K+ decreases by ≥0.5
mmol/L and who achieve normokalaemia during the first 72 hours
- Time to first day achievement of normokalaemia
- Absolute and percent change from baseline in S-K+ levels at all
intervals of follow-up after dosing has been initiated
- Time to decrease of ≥ 0.5 mmol/L in S-K+ level
- Proportion of participants per response category in Study Medication Palatability Assessment questionnaires (self reported or observer assessment)
MP secondary endpoints:
- Time from randomisation to relapse of hyperkalaemia in each treatment group
- Proportion of participants within each treatment group who maintain normokalaemia per visit over the MP
- Both absolute and percent change from baseline in S- K+ levels post dose during the MP and at any time point thereafter in each treatment group
- Time to an increase in S-K+ concentration of ≥0.5 mmol/L in each
treatment group
- Number and percentage of days of normokalaemia
- The difference in mean of all S-K+ values obtained during the MP in
participants receiving either SZC or placebo
- The number and percentage of participants with hypo- or
hyperkalaemia in participants receiving either SZC or placebo
- Change from baseline in S-Aldo to end of the MP
- Change from baseline in plasma electrolytes (including bicarbonate) and spot urinary pH and electrolytes to end of the MP
- Proportion of participants per response category in Study Medication Palatability Assessment questionnaires (self reported or observer assessment)
LTMP secondary endpoints:
- Proportion of participants in whom normokalaemia can be maintained over the LTMP
- Proportion of participants who needed dose escalation/de escalation to higher DLs during the LTMP
- Proportion of participants who needed dose de-escalation to lower DLs during the LTMP
- The number and percentage of participants with hypo- or
hyperkalaemia during the LTMP
- Proportion of participants per response category in Study Medication Palatability Assessment questionnaires (self-reported or observer assessment) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CP secondary endpoints:
- 0, 24, 48, 72 hours
- 0, 24, 48, 72 hours
- 0, 24, 48, 72 hours
- 0, 24, 48, 72 hours
- Day 1 and 3
MP secondary endpoints:
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1, 7, 14, 21, 28
- Days 1 & 21
- Days 1 & 21
- Days 7 & 28
LTMP secondary endpoints:
- Days 28, 57, 85, 113, 141, 183
- Days 28, 57, 85, 113, 141, 183
- Days 28, 57, 85, 113, 141, 183
- Days 28, 57, 85, 113, 141, 183
- Day 28 & 183 |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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