Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
Summary
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EudraCT number |
2017-003823-31 |
Trial protocol |
DE GB FR PT ES DK NL CZ IT |
Global end of trial date |
09 Oct 2020
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Results information
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Results version number |
v2(current) |
This version publication date |
14 Oct 2022
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First version publication date |
24 Oct 2021
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Other versions |
v1 |
Version creation reason |
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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 |
AG348-C-006
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03548220 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Agios Pharmaceuticals, Inc.
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Sponsor organisation address |
88 Sidney Street, Cambridge, , United States, MA 02139-4169,
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Public contact |
Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.com
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Scientific contact |
Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.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 |
09 Oct 2020
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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 |
09 Oct 2020
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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 treatment with AG-348 compared with placebo in increasing haemoglobin (Hb) concentrations.
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Protection of trial subjects |
All study subjects were required to read and sign an informed consent form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Aug 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Netherlands: 3
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Denmark: 7
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
Germany: 5
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Korea, Republic of: 2
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
Japan: 6
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Country: Number of subjects enrolled |
United States: 28
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
Brazil: 1
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Country: Number of subjects enrolled |
Turkey: 1
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Worldwide total number of subjects |
80
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EEA total number of subjects |
34
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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) |
76
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 80 subjects were randomised in the study which was conducted across multiple sites in 14 countries: Brazil, Canada, Denmark, France, Germany, Italy, Japan, Republic of Korea, Netherlands, Spain, Switzerland, Turkey, United Kingdom and United States. The study was conducted from 9 August 2018 to 9 October 2020. | |||||||||||||||||||||||||
Pre-assignment
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Screening details |
Screening was done for a period of 42 days after the subject provided the informed consent. Investigators determined if the subjects met all the inclusion criteria and none of the exclusion criteria to receive AG-348 or placebo to determine the optimised dose to be received for 12 weeks as fixed-dose. | |||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||
Arm description |
Subjects received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimised dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | |||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo matching AG-348 tablets, administered to maintain the blind.
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Arm title
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AG-348, 5 mg | |||||||||||||||||||||||||
Arm description |
Subjects received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 5 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
AG-348
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Investigational medicinal product code |
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Other name |
Mitapivat
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
AG-348 5 mg tablets BID administered orally.
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Arm title
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AG-348, 20 mg | |||||||||||||||||||||||||
Arm description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 20 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
AG-348
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Investigational medicinal product code |
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Other name |
Mitapivat
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
AG-348 20 mg tablets BID administered orally.
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Arm title
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AG-348, 50 mg | |||||||||||||||||||||||||
Arm description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 50 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
AG-348
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Investigational medicinal product code |
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Other name |
Mitapivat
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
AG-348 50 mg tablets BID administered orally.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimised dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 5 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 5 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 20 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 20 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 50 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 50 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimised dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | ||
Reporting group title |
AG-348, 5 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 5 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||
Reporting group title |
AG-348, 20 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 20 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||
Reporting group title |
AG-348, 50 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 50 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||
Subject analysis set title |
AG-348
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimised dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimised dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.
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Subject analysis set title |
AG-348 50 mg
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 50 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose.
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End point title |
Percentage of Subjects Achieving a Haemoglobin (Hb) Response (HR) [1] | ||||||||||||
End point description |
Haemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a subject during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised.
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End point type |
Primary
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End point timeframe |
Baseline, Weeks 16, 20, 24
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
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Statistical analysis title |
Hemoglobin response Response (HR) | ||||||||||||
Comparison groups |
Placebo v AG-348
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Exact Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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Notes [2] - 2-sided p-value |
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End point title |
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 [3] | ||||||||||||
End point description |
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to that of baseline. Data presented represents the value of change from baseline at Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 16, 20, 24
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Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
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Statistical analysis title |
Average Change in Hemoglobin Concentration | ||||||||||||
Comparison groups |
Placebo v AG-348
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
18.21
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
12.41 | ||||||||||||
upper limit |
24.01 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.913
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End point title |
Maximum Change From Baseline in Hb Concentration [4] | ||||||||||||
End point description |
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, up to Week 24
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Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
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No statistical analyses for this end point |
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End point title |
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More | ||||||||
End point description |
This is the time taken to first achieve an increase of haemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the end point.
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End point type |
Secondary
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End point timeframe |
Baseline, up to Week 24
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No statistical analyses for this end point |
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End point title |
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 [5] | ||||||||||||
End point description |
The change from baseline in indirect bilirubin levels was summarised. Indirect bilirubin is a marker for haemolysis. Data presented represents the average change from baseline at Week 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. As pre-specified in the protocol, the data for this outcome measure is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the end point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 16, 20, 24
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
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Statistical analysis title |
Average Change From Baseline in Bilirubin | ||||||||||||
Comparison groups |
Placebo v AG-348
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-26.26
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-37.82 | ||||||||||||
upper limit |
-14.7 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
5.788
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End point title |
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 [6] | ||||||||||||
End point description |
The change from baseline in LDH levels was summarised. LDH is a marker for haemolysis. Data presented represents the average change from baseline at Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the end point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 16, 20, 24
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
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Statistical analysis title |
Average Change From Baseline in Lactic Acid Dehydr | ||||||||||||
Comparison groups |
Placebo v AG-348
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Number of subjects included in analysis |
79
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0027 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-70.81
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-115.88 | ||||||||||||
upper limit |
-25.74 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
22.488
|
|
|||||||||||||
End point title |
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 [7] | ||||||||||||
End point description |
The change from baseline in haptoglobin levels were summarised. Haptoglobin levels are markers for haemolysis. Data presented represents the average change from baseline at Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Weeks 16, 20, 24
|
||||||||||||
Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Average Change From Baseline in Haptoglobin | ||||||||||||
Comparison groups |
Placebo v AG-348
|
||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0079 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.158
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.043 | ||||||||||||
upper limit |
0.273 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0578
|
|
|||||||||||||
End point title |
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 [8] | ||||||||||||
End point description |
The change from baseline in reticulocyte percentage was summarised. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before the start of study treatment for subjects randomised and dosed. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Weeks 16, 20, 24
|
||||||||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Change From Baseline in Reticulocyte Percentage | ||||||||||||
Comparison groups |
Placebo v AG-348
|
||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.1011
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.1391 | ||||||||||||
upper limit |
-0.0632 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.01904
|
|
|||||||||||||
End point title |
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 [9] | ||||||||||||
End point description |
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Subjects rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, to Week 24
|
||||||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Change From Baseline in PKDD Score | ||||||||||||
Comparison groups |
Placebo v AG-348
|
||||||||||||
Number of subjects included in analysis |
73
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0247 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.8 | ||||||||||||
upper limit |
-0.41 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.352
|
|
|||||||||||||
End point title |
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 [10] | ||||||||||||
End point description |
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Subjects rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this end point is summarised between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo). Full analysis set included all subjects who were randomised. Overall number of subjects analysed is the number of subjects evaluated for the end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As pre-specified in the protocol, AG-348 5 mg, 20 mg and 50 mg arms are analysed and reported together in comparison to Placebo for this end point. Hence, only data for AG 348 and Placebo arms have been reported. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Change From Baseline in PKDIA Score | ||||||||||||
Comparison groups |
Placebo v AG-348
|
||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0421 | ||||||||||||
Method |
Mixed-effect Model Repeated Measure | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.25
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-6.39 | ||||||||||||
upper limit |
-0.12 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.574
|
|
|||||||||||||||||||||
End point title |
Percentage of Subjects With Adverse Events | ||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Safety analysis set included all subjects who received at least 1 dose of study treatment.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
From signing of informed consent form to the end of study, including follow-up (up to Day 197)
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 [11] | ||||||||||||||||
End point description |
Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of subjects analysed is the number of subjects evaluated for the end point. 9999 indicates the standard deviation for AG-348 arm was not reported due to low number of subjects evaluated.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
|
||||||||||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG-348 20mg, and AG-348 50mg arms have been reported. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Maximum Plasma Concentration (Cmax) for AG-348 [12] | ||||||||||||||||
End point description |
Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of subjects analysed is the number of subjects evaluated for the end point. 9999 indicates the standard deviation for AG-348 arm was not reported due to low number of subjects evaluated.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
|
||||||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG 348 20mg and AG-348 50mg arms have been reported. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time to Cmax (Tmax) for AG-348 [13] | ||||||||||||||||
End point description |
Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of subjects analysed is the number of subjects evaluated for the end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
|
||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG-348 20mg, and AG-348 50mg arms have been reported. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time to Last Measurable Concentration (Tlast) for AG-348 [14] | ||||||||||||||||
End point description |
Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of subjects analysed is the number of subjects evaluated for the end point. 9999 indicates the standard deviation for AG-348 arm was not reported due to low number of subjects evaluated.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
|
||||||||||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG-348 20mg, and AG-348 50mg arms have been reported. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [15] | ||||||||||||
End point description |
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model. Safety set included subjects who were administered the study drug. Subjects who received mitapivat in studies: study AG348-C-003 (NCT02476916): 52 subjects; study AG348-C-006 (NCT03548220): 40 subjectts; study AG348-C-007 (NCT03559699): 27 subjects; and study AG348-C-011 (NCT03853798): 36 subjects, were pooled for the analysis of this end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
|
||||||||||||
Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG-348 20mg, and AG-348 50mg arms have been reported. |
|||||||||||||
|
|||||||||||||
Attachments |
AG348-C-006_ Subject Analysis Set |
||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [16] | ||||||||||||||||||||||||||||
End point description |
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male subjects. Safety set included subjects who were administered the study drug. Male subjects who received mitapivat in studies: study AG348-C-003 (NCT02476916): 32 subjects; study AG348-C-006 (NCT03548220):15 subjects; study AG348-C-007 (NCT03559699): 7 subjects; and study AG348-C-011 (NCT03853798): 14 subjects were pooled for analysis of this end point.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||||||||||||||||||
Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is for AG-348 only. Hence, only data for AG-348 5mg, AG-348 20mg, and AG-348 50mg arms have been reported. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From time of signing of informed consent form to end of study, including follow-up (up to Day 197)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The placebo arm includes AEs that occurred in subjects who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for subjects who received AG-348 treatment during the study are reported based on the fixed dose treatment received.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimised dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 5 mg
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 5 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 20 mg
|
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Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 20 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348, 50 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimised dose for each subject was determined as 50 mg BID at Week 12, and subjects then received that optimised dose for a period of 12 weeks as a fixed dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
26 Feb 2018 |
Removed dose escalation restrictions after the Week 8 Visit.
• Added detailed guidance on re-introducing or escalating study treatment after resolution of a Grade 3 AE that caused study treatment to be stopped or reduced.
• Removed the requirement that subjects must be receiving study treatment at Week 24 to be potentially eligible for an extension study.
• Added an exclusion criterion to exclude subjects who have not stopped using haematopoietic stimulating agents at least 28 days before the first dose of study treatment.
• Added clarity to the dose modification guidance for Grade 3 and Grade 4 AEs that are deemed by the Investigator to be related to study treatment.
• Added new laboratory assessments for biomarkers (iron-related markers, known markers of erythropoietic activity, circulating haeme, and to be identified markers of iron metabolism or erythropoiesis). |
||
15 Aug 2018 |
Consolidated iron-related secondary and exploratory endpoints into 1 exploratory endpoint for markers of iron metabolism.
• Revised the instructions for dose optimisation.
• Clarified that unblinding before database lock will occur only in the subjects who enter the planned mitapivat extension study and that subjects undergoing a dose taper should remain blinded through the taper.
• Amended the inclusion criterion for renal function.
• Amended the absolute neutrophil count (ANC) and platelet count inclusion criteria to be assessed via 2 measurements.
• Amended the inclusion criterion for contraception requirements and added monthly pregnancy tests for applicable subjects.
• Added an exception for subjects who have concurrent disorders that in isolation are predicted to be insufficient to explain the observed clinical phenotype to the exclusion criterion for congenital or genetic disorders.
• Corrected the exclusion criterion for splenectomy to require subjects to wait at least 12 months after splenectomy before starting screening.
• Added a subsection under Section 9.3, Blinding, to provide details on handling of restricted data and to add the role of an Independent Medical Monitor to handle restricted data.
• Amended the unblinding language such that the unblinding of a subject for a medical emergency or pregnancy does not require confirmation by the Sponsor’s Medical Monitor.
• Redefined the definition of Hb overshoot, and subsequent study treatment dose decrease, to higher than 20 g/L (2 g/dL) below the upper limit of normal
(ULN).
• Added historical data for iron chelation therapy, iron serum, transferrin saturation, and liver iron concentration (LIC) and removed some iron-related laboratory assessments.
• Added further details for assessments after a transaminase increase |
||
14 Aug 2019 |
Revised the dose optimisation language to allow dosing decisions to be based on results from local laboratories at the Week 4 and Week 8 Visit
• Revised the inclusion criterion for platelet count
• Increased the length of the contraception period for males exposed to study treatment to cover 1 complete spermatogenesis cycle
• Revised the handling of restricted data such that the subject’s dose levels were no longer maintained as part of the restricted data and hormone data were considered restricted data for Investigators
• Removed the option for a rapid dose taper and simplified the recommended gradual dose taper
• Added language to provide previously ineligible subjects the opportunity to rescreen for enrollment into the study should they
become eligible based on an amended protocol
• Revised the requirements for clinical laboratory results, allowing Investigators the flexibility to use local laboratory results when results from central laboratories are not available
• Added further details for assessments after a transaminase increase that meet the criteria for an AESI
• Added ability to extend the Screening Period duration beyond 42 days |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
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. | |||
None reported |