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 |
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 dose levels on achieving normokalaemia during the CP |
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E.2.2 | Secondary objectives of the trial |
CP secondary objectives evaluate SZC dose levels on the following:
achieving normokalaemia within the first 72 hours
time to achieving normokalaemia during the CP
the reduction of serum K levels during the CP
time to reduction of serum K levels during the CP
MP secondary objectives evaluate SZC vs placebo on the following:
time from randomization to relapse of hyperkalaemia
the proportion of subjects with normokalaemia per visit over the MP
the change in serum K levels over the MP
time to increase in serum K during the MP
proportion of days of normokalaemia during the MP
mean serum K during the MP
proportion of subjects experiencing hypo- or hyperkalaemia during the MP
serum aldosterone at end of the MP
plasma electrolytes (including bicarbonate) and spot urinary pH and electrolytes
Long term maintenance phase(LTMP)objective:To evaluate long term maintenance of normokalemia during treatment with SZC
Acceptability and palatability of SZC is evaluated in all study phases |
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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 subject or legal representative, and informed assent from the subject (as appropriate)
2. Female or male from birth to <18 years of age.
3. Subjects requiring long term treatment of hyperkalaemia (chronic hyperkalaemia) in the age cohort ≥2 years, and subjects requiring either short- or long-term treatment for hyperkalaemia (acute and chronic hyperkalaemia) in the age cohort <2 years.
4. Subjects must meet 1 of the following criteria for hyperkalaemia:
(a) For subjects ≥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 subjects <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.
5. Using digital ECG, QT interval corrected by Bazett's method (QTcB) must meet the age-appropriate parameters at Screening:
(a) For subjects aged 0 to ≤3 days after birth: <450 ms
(b) For subjects aged >3 days to <12 years: <440 ms
(c) For subjects ≥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 |
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E.4 | Principal exclusion criteria |
1. Neonates with a gestational age <30 weeks or a birth weight <1500 g.
2. Subjects with pseudohyperkalaemia caused by excessive fist clenching to enable venepuncture, by haemolysed blood specimens, or by severe leukocytosis or thrombocytosis.
3. Subjects with hyperkalaemia due to soft-tissue damage from crush injury or burns.
4. Subjects treated with lactulose, rifaximin (XIFAXAN™), or other nonabsorbed antibiotics for hyperammonaemia within the last 7 days.
5. Subjects treated with calcium polystyrene sulfonate (CPS), sodium polystyrene sulfonate (e.g., KAYEXALATE™), or patiromer within the last 4 days.
6. Subjects with a life expectancy of less than 3 months.
7. Subjects who are known to have tested Human Immunodeficiency Virus (HIV) positive.
8. Presence of any condition which, in the opinion of the Investigator, places the subject at undue risk or potentially jeopardises the quality of the data to be generated.
9. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
10. Subjects with cardiac arrhythmias that require immediate treatment.
11. Subjects with a family history of long QT syndrome.
12. Subjects on dialysis to exclude subjects requiring acute or chronic renal replacement therapy.
13. Subjects with a history of bowel obstruction.
14. Subjects with severe gastrointestinal disorder or major gastrointestinal surgery (e.g., large bowel resection).
15. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
16. Previous treatment with SZC.
17. Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry.
18. Previous enrolment in the present study.
19. Females who are pregnant, breastfeeding, or planning to become pregnant.
20. Judgment by the Investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements. |
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E.5 End points |
E.5.1 | Primary end point(s) |
28-day maintenance phase (MP) primary endpoint (primary analysis endpoint):
The proportion of subjects in whom normokalaemia can be maintained throughout the MP
Correction phase (CP) primary endpoint:
The proportion of subjects in whom serum K decreases by ≥0.5 mmol/L and who achieve normokalaemia at (by or before) 24, 48 and 72 hours during CP. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Correction Phase 24, 48 and 72 hours
Maintenance Phase 28 days |
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E.5.2 | Secondary end point(s) |
CP secondary endpoints:
- The proportion of subjects in whom serum 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 serum K levels at all intervals of follow-up after dosing has been initiated
- Time to decrease of 0.5 mmol/L in serum K level
- Proportion of patients per response category in Study Medication Palatability Assessment questionnaires (self reported or observer assessment)
MP secondary endpoints:
- Time from randomization to relapse of hyperkalaemia (return to serum K level >5.0 mmol/L for subjects 2 to <18 years and >6.0 mmol/L for subjects <2 years) in each treatment group
- Proportion of subjects within each treatment group who maintain normal serum K levels (defined as serum K of ≥3.5 mmol/L and ≤5.0 mmol/L for subjects aged 2 to <18 years and serum K of ≥3.5 mmol/L and ≤6.0 mmol/L for subjects <2 years) per visit over the MP
- Both absolute and percent change from baseline in serum K levels post dose during the MP and at any time point thereafter in each treatment group
- Time to an increase in serum K concentration of 0.5 mmol/L in each treatment group
- Number and percentage of days of normokalaemia
- The difference in mean of all serum K values obtained during the MP in subjects receiving either SZC or placebo
- The number and percentage of subjects with hypo- (<3.0 mmol/L) or hyperkalaemia (>6.0 mmol/L) in subjects receiving either SZC or placebo
- Change from baseline in serum aldosterone (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 patients per response category in Study Medication Palatability Assessment questionnaires (self reported or observer assessment)
LTMP secondary endpoints:
- Proportion of subjects in whom normokalaemia can be maintained over the LTMP
- Proportion of subjects who needed dose escalation to higher dose levels during the LTMP
- Proportion of subjects who needed dose de-escalation to lower dose levels during the LTMP
- The number and percentage of subjects with hypo- (<3.0 mmol/L) or hyperkalaemia (>6.0 mmol/L) during the LTMP
- Proportion of patients per response category in Study Medication Palatability Assessment questionnaires (self reported or observer assessment) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
CP secondary endpoints:
- 24, 48, 72 hours
- 24, 48, 72 hours
- 24, 48, 72 hours
- 24, 48, 72 hours
- Day 1 and 3
MP secondary endpoints:
- MP Endpoints 1-7 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 |
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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 | 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 |
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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 | 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 |
Germany |
Italy |
Poland |
Romania |
Russian Federation |
South Africa |
Ukraine |
United Kingdom |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |