Clinical Trial Results:
A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency
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Summary
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EudraCT number |
2015-000484-13 |
Trial protocol |
GB FR NL IT |
Global end of trial date |
02 Apr 2025
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Apr 2026
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First version publication date |
08 Apr 2026
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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 |
AG-348-C-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02476916 | ||
WHO universal trial number (UTN) |
- | ||
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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 |
02 Apr 2025
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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 |
02 Apr 2025
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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 |
Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 (mitapivat) in subjects with PK deficiency.
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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 |
26 Jun 2015
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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: 4
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
France: 12
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Country: Number of subjects enrolled |
Italy: 5
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Country: Number of subjects enrolled |
United States: 21
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Country: Number of subjects enrolled |
Canada: 2
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Worldwide total number of subjects |
52
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EEA total number of subjects |
21
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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) |
52
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects took part in the study across multiple study sites in 6 countries from 26 June 2015 to 02 April 2025. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 52 subjects were enrolled in the Core Period of the study. Subjects were randomized 1:1 to receive AG-348 50 mg or AG-348 300 mg. Subjects who completed the 24-week Core Period, had clinical activity, and tolerated the AG-348 dose entered the Extension Period for up to 102 months. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Core Period
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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AG-348 50 mg BID | |||||||||||||||||||||||||||||||||
Arm description |
Subjects with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | |||||||||||||||||||||||||||||||||
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 milligrams (mg), twice daily (BID), administered orally for 24 weeks (Core Period).
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Arm title
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AG-348 300 mg BID | |||||||||||||||||||||||||||||||||
Arm description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | |||||||||||||||||||||||||||||||||
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, 300 mg, as initial dose, BID, administered orally for 24 weeks (Core Period).
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Period 2
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Period 2 title |
Extension Period
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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AG-348 50 mg BID | |||||||||||||||||||||||||||||||||
Arm description |
Subjects with Pyruvate Kinase (PK) deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months. | |||||||||||||||||||||||||||||||||
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, BID, administered orally up to 102 months.
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Arm title
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AG-348 300 mg BID | |||||||||||||||||||||||||||||||||
Arm description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months. | |||||||||||||||||||||||||||||||||
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-348 300 mg, BID, administered orally, up to 102 months.
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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: Out of 43, 36 participants entered Extension Period. |
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Baseline characteristics reporting groups
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Reporting group title |
AG-348 50 mg BID
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Reporting group description |
Subjects with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348 300 mg BID
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Reporting group description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AG-348 50 mg BID
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Reporting group description |
Subjects with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | ||
Reporting group title |
AG-348 300 mg BID
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Reporting group description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If subjects chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | ||
Reporting group title |
AG-348 50 mg BID
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Reporting group description |
Subjects with Pyruvate Kinase (PK) deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months. | ||
Reporting group title |
AG-348 300 mg BID
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Reporting group description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months. | ||
Subject analysis set title |
AG-348 50 mg BID (Core Period+ Extension Period)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects with PK deficiency received AG-348, 50 mg, as initial dose, BID, for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 50 mg, BID, up to 102 months.
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Subject analysis set title |
AG-348 300 mg BID (Core Period + Extension Period)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID, for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months.
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End point title |
Percentage of Subjects Experiencing at Least One Adverse Event (AEs) in the Core Period [1] | ||||||||||||
End point description |
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related. The Safety Analysis Set included all subjects who had received at least one dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to Week 24
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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 formal statistical hypotheses were tested for the primary end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects Experiencing at Least One AE up to Month 102 [2] | ||||||||||||
End point description |
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related. Safety data for cumulative period (Core period and Extension period) has been reported in this outcome measure. The Safety Analysis Set included all participants who had received at least one dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to Month 102
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| Notes [2] - 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 formal statistical hypotheses were tested for the primary end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Hemoglobin (Hb) Value at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline Hb Value up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Hematocrit at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Hematocrit up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Reticulocyte Count at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Reticulocyte Count up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure.. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Haptoglobin at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Haptoglobin up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point. '9999' signifies that standard deviation was not estimable for a single subject.
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End point type |
Secondary
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End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Carboxyhemoglobin (COHb) at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased COHb values indicate improvement. The Full Analysis Set included all subjects. Number of subjects analysed is the number of subjects with evaluable data. 'n' indicates number of subjects with evaluable data at the given time-point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in COHb up to Month 30 | ||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased COHb values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 18, 24, and 30
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in LDH up to Month 30 | ||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 18, 24, and 30
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Total Bilirubin at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Change From Baseline in Total Bilirubin up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Indirect Bilirubin at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Change From Baseline in Indirect Bilirubin up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Erythropoietin (EPO) at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in EPO up to Month 30 | ||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 18, 24, and 30
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Hepcidin at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Hepcidin up to Month 30 | ||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point. '9999' signifies that standard deviation was not estimable for a single subject.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 18, 24, and 30
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Ferritin at Week 24 | ||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Change From Baseline in Ferritin up to Month 102 | |||||||||||||||||||||||||||
End point description |
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Transferrin Saturation at Week 24 | ||||||||||||||||||
End point description |
Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement. The Full Analysis Set included all randomised subjects. 'n' indicates number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Change From Baseline in Transferrin Saturation up to Month 102 | |||||||||||||||||||||||||||
End point description |
Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement. The Full Analysis Set included all randomised subjects. Number of subjects analysed is the number of subjects with evaluable data for this outcome measure. 'n' indicates number of subjects with evaluable data at the given time-point.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Months 12, 36, 60, 84, and 102
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | ||||||||||||||||||||||||
End point description |
Subjects with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. The Pharmacokinetic Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number of subjects analysed is the number of subjects with evaluable data. 'n' indicates the number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | ||||||||||||||||||||||||
End point description |
Subjects with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. The Pharmacokinetic Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number of subjects analysed is the number of subjects with evaluable data. 'n' indicates the number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | ||||||||||||||||||||||||
End point description |
Subjects with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. The Pharmacokinetic Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number of subjects analysed is the number of subjects with evaluable data. 'n' indicates the number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | ||||||||||||||||||
End point description |
Subjects with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. The Pharmacokinetic Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number of subjects analysed is the number of subjects with evaluable data. 'n' indicates the number of subjects with evaluable data at the given time-point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | ||||||||||||
End point description |
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. The Pharmacodynamic (PD) Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number of subjects analysed is the number of subjects with evaluable data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Maximum Change From Baseline Response Value Over 8 Hours Post-dose at Steady State (BRmax ss) for ATP | ||||||||||||
End point description |
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. The PD Analysis Set included all subjects from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number of subjects analysed is the number of subjects with evaluable data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
BRmax for 2,3 - Diphosphoglycerate (2,3-DPG) | ||||||||||||
End point description |
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. The PD Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number of subjects analysed is the number of subjects with evaluable data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
BRmax ss for 2,3-DPG | ||||||||||||
End point description |
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. The PD Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number of subjects analysed is the number of subjects with evaluable data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to Month 102
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Safety Analysis Set included all subjects who had received at least one dose of study drug. As pre-specified in Protocol, cumulative Safety data for Core period and Extension period was reported.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
27.1
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Reporting groups
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Reporting group title |
AG-348 50 mg BID (Core Period+ Extension Period)
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Reporting group description |
Subjects with PK deficiency received AG-348, 50 mg, as initial dose, BID, for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 50 mg, BID, up to 102 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AG-348 300 mg BID (Core Period + Extension Period)
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Reporting group description |
Subjects with PK deficiency received AG-348, 300 mg, as initial dose, BID, for 24 weeks (Core Period). Subjects were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period subjects who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were rolled over to the Extension Period. During the extension period, subjects continued to receive AG-348 300 mg, BID, up to 102 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
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02 Feb 2015 |
• Corrected errors in the summary of clinical data, safety section. • Added new safety assessment of dual-energy x-ray absorptiometry (DXA) scans (hip and spine) to monitor bone measure density. |
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05 Aug 2015 |
• Added new dosage form of 5 mg capsules.
• Updated Inclusion Criteria #13 and #16 to include a revised
definition of abstinence.
• Updated Exclusion Criterion #11 to clarify rules surrounding
glucocorticoids.
• Updated clinical data from studies of AG-348 in healthy
volunteers.
• Added text to explain what Agios will do in case of new,
unexpected pre-clinical toxicology findings.
• Clarified dose modifications for safety.
• Added justification for duration of treatment.
• Added clarifications for Day 8 and Day 22 assessments, if being
performed by the patient’s primary care physician.
• Added an additional time point to the complete blood count
assessments and removed a PK/PD sampling timepoint.
• Updated drug-drug interaction recommendations and prohibited
concomitant medications.
• Added new safety assessments of 25-hydroxy vitamin D2 and D3
to provide additional context for interpreting any observed changes
in DXA scan results and markers of bone turnover, menstrual
cycle diary to monitor hormonal changes, and serum
osteocalcin-N-mid (removed serum N-terminal telopeptide)
because of greater clinical experience with the former than the
latter. Added neurological assessment to physical examination. |
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10 Nov 2015 |
• Clearly delineated the first 24 weeks of the study (Core Period)
from the safety extension portion of the study (Extension Period).
• Added details regarding the Extension Period of the study
including objectives, inclusion/exclusion criteria, assessments,
duration, and statistical analyses.
• Inclusion Criteria #5 and #9 was clarified for the Core Period. |
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30 Mar 2016 |
• Dose modification language was adjusted to account for increases
in hemoglobin concentrations.
• New assessments of clinical activity of end tidal carbon monoxide
(at select sites during the Core Period) and hepcidin were added.
• Screening Period was extended to 42 days to better accommodate
the turnaround time required for certain specialty laboratory
examinations; clarifications were made surrounding recording of
concomitant medications during this time period.
• Inclusion/exclusion criteria were modified to allow for local
laboratory evaluation of pyruvate kinase enzyme activity and
G6PD; PKR genotyping from another laboratory will be allowed
for enrollment, but genotype must be confirmed by the central
laboratory; additional changes were made to other criteria for
clarity.
• Option for intra-patient dose escalation was added.
• Unblinded hormone data from Study AG348-C-002 was added.
• Corticosteroids were eliminated from the list of prohibited
medications because the likelihood of clinically significant pharmacokinetic interaction between corticosteroids and AG-348
is considered low. |
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30 Jun 2017 |
• Implement within the Extension Period of the study a gradual
dose-taper regimen used to identify the optimal maintenance dose
for each subject, with corresponding new secondary study
objective, rationale, schedule of assessments, and analysis
methodology.
• Updated information regarding identified and potential risks
associated with AG-348, as presented in Version 4.0 of the
Investigator’s Brochure (22 May 2017).
• Incorporated updated toxicology data from nonclinical studies of
AG-348 and updated safety and efficacy data from the current
study.
• Identified a new adverse event of special interest, transaminase
increase, and added both a corresponding safety measure/endpoint
and corresponding new reporting guidance.
• Updated AG-348 dose discontinuation and modification directives.
• Added guidance for 2 new concomitant therapy categories:
sensitive CYP2B6 substrates and proton-pump
inhibitors/H2-receptor antagonists. |
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14 Dec 2017 |
• Added 2 years to the Extension Period (total of up to 4 years).
• Introduced a tablet formulation of AG-348.
• Removed pharmacokinetic assessments from the Extension Period.
• Reduced the number of pharmacodynamic assessments during the
Extension Period.
• Added a criterion for withdrawal from the Extension Period for
subjects who have not had a robust and sustained increase in
hemoglobin.
• Removed withdrawal criterion for pregnancy to allow pregnant
subjects to remain on study, but off treatment.
• Added a dose-taper regimen to support discontinuation of AG-348. |
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04 Sep 2019 |
• Simplified the recommended dose taper for discontinuation of
study drug.
• Extended the duration of the study from 4 years to 8 years
following completion of the Core Period.
• Removed strict avoidance of concomitant transfusions.
• Added further details for assessments following a transaminase
increase that meet the criteria for an AESI.
• Increased the length of the contraception period for males exposed
to study treatment and the pregnancy reporting follow-up in female
partners of male subjects.
• Reduced the number of DRT reviews during the Extension Period. |
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27 Aug 2020 |
• The Data Review Team (DRT) is no longer required to meet at
least annually if there are no subjects still being treated in the Core
Period, and the only subjects on treatment are those in the
Extension Period.
• Telemedicine visits and direct-to-subject shipment of study drug
were implemented in the Extension Period (every other visit
starting Month 75) to alleviate the burden on subjects associated
with on-site study visits.
• Photosensitivity was removed from the list of potential risks
associated with AG-348 based on the results of a neutral red
uptake phototoxicity assay in BALB/c 3T3 mouse fibroblasts.
• Guidance on allowed modifications to study conduct during
declared public health emergencies and natural disasters was
added for situations during which adherence to protocol-specified
procedures is impeded, such as the COVID-19 pandemic.
• Management of concomitant therapy was updated per the AG-348
Investigator’s Brochure. |
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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 | |||
