Clinical Trial Results:
SOAR, Interventional phase II single-arm study to assess efficacy and safety of eltrombopag combined with cyclosporine as first-line therapy in adult patients with severe acquired aplastic anemia
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Summary
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EudraCT number |
2016-002814-29 |
Trial protocol |
ES NL HU IT |
Global end of trial date |
30 May 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Mar 2023
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First version publication date |
12 Mar 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CETB115E2403
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02998645 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
Novartis Campus, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 May 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 May 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of eltrombopag + cyclosporine as first-line therapy on overall hematologic response (partial response (PR) and complete response (CR)) by 6 months
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 May 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Brazil: 6
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Country: Number of subjects enrolled |
Hong Kong: 4
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Country: Number of subjects enrolled |
India: 4
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
Korea, Republic of: 6
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Country: Number of subjects enrolled |
Mexico: 9
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
Thailand: 8
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Country: Number of subjects enrolled |
Turkey: 5
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Worldwide total number of subjects |
54
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EEA total number of subjects |
12
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
37
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From 65 to 84 years |
17
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted across 20 centers in 9 countries. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
Participants received a combination of eltrombopag and cyclosporine for 6 months (Treatment period 1). Participants who were responders at 6 months were followed-up for cyclosporine tapering until relapse or Month 24 whichever was earlier (Treatment period 2) | ||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period 1
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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Eltrombopag + cyclosporine | ||||||||||||||||||||
Arm description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Cyclosporine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
The starting dose was based on body weight at 10.0 mg/kg/day (acceptable rounding range was from 9.5 to 10.5 mg/kg/day) in divided doses every 12 hours. After Day 1, dosing was titrated individually according to therapeutic trough level between 200 and 400 μg/L for 6 months. After 6 months (for responders), tapering of cyclosporine was done as follows:
- 6 to 9 months: at the 6 months visit, the dose was reduced by 25% for 3 months
- 9 to 12 months: at the 9 months visit, the dose was further reduced by 25% for another 3 months
- 12 to2 4 months: dose was maintained
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Investigational medicinal product name |
Eltrombopag
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Investigational medicinal product code |
ETB115
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily for up to 6 months. East and Southeast Asian participants were treated with 100 mg once daily, to adjust for the lower apparent clearance of eltrombopag. All other participants were treated with 150 mg once daily.
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Period 2
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Period 2 title |
Treatment period 2
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Is this the baseline period? |
No | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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Eltrombopag + cyclosporine | ||||||||||||||||||||
Arm description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Cyclosporine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
The starting dose was based on body weight at 10.0 mg/kg/day (acceptable rounding range was from 9.5 to 10.5 mg/kg/day) in divided doses every 12 hours. After Day 1, dosing was titrated individually according to therapeutic trough level between 200 and 400 μg/L for 6 months. After 6 months (for responders), tapering of cyclosporine was done as follows:
- 6 to 9 months: at the 6 months visit, the dose was reduced by 25% for 3 months
- 9 to 12 months: at the 9 months visit, the dose was further reduced by 25% for another 3 months
- 12 to2 4 months: dose was maintained
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only participants who were responders at Month 6 entered the treatment period 2 |
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Baseline characteristics reporting groups
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Reporting group title |
Eltrombopag + cyclosporine
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Reporting group description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Eltrombopag + cyclosporine
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Reporting group description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24. | ||
Reporting group title |
Eltrombopag + cyclosporine
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Reporting group description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24. | ||
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End point title |
Overall hematologic response rate by 6 months [1] | ||||||||
End point description |
Overall hematologic response rate by 6 months was defined as the percentage of participants with complete response (CR) or partial response (PR) any time on or before 6 months.
PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement:
● Absolute neutrophil count (ANC) >500/μL
● Platelet count >20 000/μL
● Reticulocyte count >60 000/μL
CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements:
● ANC > 1 000/μL
● Platelet count >100 000/μL
● Hemoglobin >10 g/L
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End point type |
Primary
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End point timeframe |
Up to 6 months
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were planned for the primary endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall hematologic response rate at 12 and 24 months | ||||||||||||
End point description |
Overall hematologic response rate at 12 and 24 months was defined as the percentage of participants with CR or PR at 12 and 24 months respectively.
PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement:
● ANC>500/μL
● Platelet count >20 000/μL
● Reticulocyte count >60 000/μL
CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements:
● ANC > 1 000/μL
● Platelet count >100 000/μL
● Hemoglobin >10 g/L
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End point type |
Secondary
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End point timeframe |
12 and 24 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall hematologic response rate by 3 months | ||||||||
End point description |
Overall hematologic response rate by 3 months was defined as the percentage of participants with CR or PR any time on or before 3 months.
PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement:
● ANC >500/μL
● Platelet count >20 000/μL
● Reticulocyte count >60 000/μL
CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements:
● ANC > 1 000/μL
● Platelet count >100 000/μL
● Hemoglobin >10 g/L
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End point type |
Secondary
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End point timeframe |
Up to 3 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of first hematologic response | ||||||||
End point description |
Duration of first hematologic response is the time from the date of the start of first response to the date of first relapse. Relapse is defined as no longer meeting definition of PR or CR. Kaplan-Meier method was used for the analysis. If no relapse occurred, the participant was censored at the date of last contact. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR was defined as any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement:
●ANC >500/μL
●Platelet count >20 000/μL
●Reticulocyte count >60 000/μL.
CR was defined as all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements:
●ANC >1 000/μL
●Platelet count >100 000/μL
●Hemoglobin >10 g/L
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of participants with evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH) and leukemia | ||||||
End point description |
The percentage of participants with evolution to myelodysplasia, PNH and acute leukemia occurring at any time during the study. Clonal evolution to myelodysplasia was defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Clonal evolution to leukemia was defined as greater than 20% peripheral blood and/or marrow blasts. Clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH) was defined as a clone at baseline < 10% that rose to greater than 50% on study.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||
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End point title |
Relapse rate by 6 and 24 months | ||||||||||||
End point description |
Relapse was defined as no longer meeting the definition of PR (and not CR). Relapse rate by 6 months and 24 was defined as the percentage of responders by 6 months who relapsed prior to 6 months or prior to 24 months respectively. Responders by 6 months were participants who achieved CR or PR any time on or before 6 months. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
PR: any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement:
●ANC>500/μL
●Platelet count>20 000/μL
●Reticulocyte count>60 000/μL.
CR: all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements:
●ANC>1 000/μL
●Platelet count>100 000/μL
●Hemoglobin>10 g/L
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of participants who were red blood cells (RBC) transfusion independent | ||||||||||||
End point description |
Percentage of participants who were RBC transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no RBC transfusion for at least 56 days.
Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of participants who were platelet transfusion independent | ||||||||||||
End point description |
Percentage of participants who were platelet transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no platelet transfusion for at least 28 days.
Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Longest duration of transfusion independence (platelet or RBC) | ||||||||||||||
End point description |
Longest duration of transfusion independence (platelet or RBC) by 6 months and by 24 months (responders only). Transfusion independence was defined as no transfusions required in at least a 28-day period for platelet transfusion and at least 56-day period for RBC transfusion. The duration of the longest interval with transfusion independence was summarized using Kaplan-Meier analysis.
Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
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End point type |
Secondary
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End point timeframe |
Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change from baseline in scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The FACT-G consists of 27-items divided into 4 domains (physical well-being, social well-being, emotional and functional well-being). All items of the FACT-G use a 5 point scale ranging from 0 to 4 with a 0 rating being “not at all” and a 4 rating being “very much”. Total FACT-G score is the sum of physical well-being score, social well-being score, emotional well-being score and functional well-being score. Score ranges from 0 to 108, with higher scores indicating better quality of life (QoL). A positive change from baseline indicates improvement in the QoL.
Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
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End point type |
Secondary
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End point timeframe |
Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change from baseline in scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire. FACT-G consists of 27-items divided into 4 domains (physical, social, emotional and functional well-being). FACT-TH18 has 18 additional items which asks the patient to rate degree of thrombocytopenia. All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4, with 0 = “not at all” and 4 = “very much”. Total FACT-TH18 score is the sum of physical, social, emotional and functional well-being scores, and thrombocytopenia subscale. Score ranges from 0 to 180, with higher scores indicating better QoL. A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
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End point type |
Secondary
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End point timeframe |
Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change from baseline in scores of Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The FACIT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACIT-Fatigue use a 5-point scale ranging from 0 to 4 with a 0 rating being “not at all” and a 4 rating being “very much”. Total score ranges from 0 to 52. Negatively worded items were reverse scored before summing so that higher total scores indicate less fatigue. A positive change from baseline indicates improvement.
Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders.
Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
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End point type |
Secondary
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End point timeframe |
Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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End point title |
Pharmacokinetic parameter- Cmax of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
Cmax is the observed maximum plasma concentration following administration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 microgram/milliliter (ug/mL). Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
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End point timeframe |
Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose.
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Pharmacokinetic parameter-AUClast of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
AUClast is the area under the curve calculated to the last quantifiable concentration point (Tlast). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
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End point timeframe |
Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Pharmacokinetic parameter- AUCtau of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
AUCtau is the area under the curve calculated to the end of the dosing interval (tau). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
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End point timeframe |
Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
|
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|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Pharmacokinetic parameter- Ctrough of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
Ctrough is the pre-dose plasma concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 2 at pre-dose
|
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|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Pharmacokinetic parameter- Tmax of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
Tmax is the time to reach peak or maximum concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Pharmacokinetic parameter- CLss/F of eltrombopag when combined with cyclosporine | ||||||||||||
End point description |
CLss/F is the apparent systemic (or total body) clearance at steady state from plasma. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
|
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End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
|
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From day of first dose of study medication to 30 days after last dose of study medication, assessed up to 25 months
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Adverse event reporting additional description |
Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Eltrombopag + cyclosporine
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Reporting group description |
Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, 6-month responders were treated with cyclosporine for up to Month 24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
17 May 2017 |
The scope of this amendment was to lower the upper limit of exclusion criterion 6 (renal function) and to further clarify wording and improve consistency in the document. |
||||||
26 Feb 2019 |
Rationale for this amendment was based on findings in the study that identified the need to clarify patient selection and dose management.
The occurrence of 6 fatal cases (four on treatment, one post treatment and one additional death in screening) warranted a thorough assessment by Novartis.
In order to accurately investigate these findings, assess their causalities, identify and implement any necessary corrective actions, Novartis voluntarily put the study on a partial/temporary
clinical hold (hold of recruitment of new patients), effective 05-Oct-2018. Health Authorities were notified in all participating countries.
In summary, none of these fatal cases were suspected to be related to study treatment (eltrombopag and cyclosporine) by the Investigators. Novartis and the Steering Committee
determined that the six fatal cases reported in this study were due to known complications of the underlying SAA, compounded by high-risk baseline demographics (notably age, frailty and
comorbidities), low adherence to study treatment and worse severity of disease. Likewise all six deaths were considered by the Investigators to be due to the underlying disease.
Novartis therefore considered the events that led to the fatal outcomes did not alter the established safety profile of eltrombopag and that the benefit-risk profile for eltrombopag remained positive. Based on the findings identified, changes were implemented in this protocol amendment to some inclusion, exclusion criteria and dose management sections.
The enrollment was re-started after approval of this amendment by the local HA/ECs.
Of note, in this amendment, the study duration was shortened from 60 months to 24 months. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/ for complete trial results | |||||||
