Clinical Trial Results:
An Open-Label Study to Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
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Summary
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EudraCT number |
2017-003803-22 |
Trial protocol |
NL DK GB IE IT ES CZ |
Global end of trial date |
12 Nov 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Nov 2021
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First version publication date |
29 Nov 2021
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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 |
AG348-C-007
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03559699 | ||
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 |
12 Nov 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 |
12 Nov 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 |
The primary objective of the study was to evaluate the efficacy of treatment with AG-348, as assessed by the reduction in transfusion burden.
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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 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Denmark: 6
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Ireland: 1
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
United States: 3
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
Thailand: 2
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Worldwide total number of subjects |
27
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EEA total number of subjects |
18
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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) |
26
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 27 subjects were enrolled and treated in the study which was conducted across multiple sites in 9 countries: United States, Canada, Denmark, France, Ireland, Italy, Netherlands, Thailand, and United Kingdom. The study was conducted from 26 June 2018 to 12 November 2020. | ||||||||||||
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Pre-assignment
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Screening details |
Screening was done for a period of 8 weeks after the subject provided the informed consent. Investigators determined if the subjects met all the inclusion criteria and none of the exclusion criteria to enroll in Part 1: Dose Optimisation Period to receive AG-348 to determine the optimised dose followed by Part 2: Fixed Dose Period. | ||||||||||||
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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AG-348 | ||||||||||||
Arm description |
Subjects received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimised dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
AG-348
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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 |
AG-348, 5 mg, 20 mg and 50 mg tablets to be administered orally BID in Part 1 and Part 2.
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Baseline characteristics reporting groups
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Reporting group title |
AG-348
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Reporting group description |
Subjects received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimised dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AG-348
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Reporting group description |
Subjects received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimised dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. | ||
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End point title |
Percentage of Subjects Achieving a Reduction in Transfusion Burden in Part 2 [1] | ||||||||
End point description |
Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardised to 24 weeks compared with the historical transfusion burden standardised to 24 weeks (Standardised Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardised to 24 weeks. Full analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
From Part 2, Day 1 to Part 2 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: Descriptive statistics only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised Number of RBC Units Transfused During the Study | ||||||||
End point description |
The annualised total number of RBC units transfused during the entire study (both Part 1 and Part 2) is reported. It was calculated as the total number of RBC units transfused up to the end of Fixed Dose Period divided by the total number of days from the first dose date until the end date of Fixed Dose Period × 52. Full analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Part 1 Day 1 to Part 2 Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Transfusion Episodes in Part 2 | ||||||||
End point description |
This is the number of transfusion episodes in Part 2. The number of transfusion episodes were standardised to 24 weeks. Transfusions received over up to 3 consecutive days were counted as 1 episode. Full analysis set incuded all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
From Part 2 Day 1 to Part 2 Week 24
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| Notes [2] - Number analysed is the number of subjects evaluated for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Transfusion-Free Participants in Part 2 | ||||||||
End point description |
Transfusion-free responders are the subjects who were transfusion-free in Part 2. Full analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
From Part 2 Day 1 to Part 2 Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Normal Haemoglobin (Hb) Concentrations in Part 2 | ||||||||
End point description |
This is the percentage of subjects who achieved haemoglobin (Hb) concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2. Full analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
From Part 2 Day 1 to Part 2 Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Adverse Events (AEs) | ||||||||
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 drug. An AE can, therefore, be any unfavourable 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 drug.
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End point type |
Secondary
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End point timeframe |
Through 4 weeks after last dose (approximately Part 2, Week 31)
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197)
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Adverse event reporting additional description |
Safety analysis set included all subjects who received at least 1 dose of the study drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
AG-348
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Reporting group description |
Subjects received AG-348 tablets, administered orally, at a starting dose of 5 mg, BID, followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimised dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Oct 2018 |
• Added markers of iron metabolism to the endpoint of indicators of iron overload
• Added an exploratory endpoint for markers of erythropoietic activity
• Added an exploratory endpoint for markers of haemolysis
• Added an exploratory endpoint for relationship of mitapivat pharmacokinetic and clinical activity
• Removed Patient Global Impression of Severity as an exploratory endpoint under health-related quality of life assessments
• Revised the dose-escalation restrictions during the Fixed-Dose Period
• Revised the instructions for dose optimisation during the Dose Optimisation Period
• Revise the language on haemoglobin (Hb) monitoring in relation to the subject’s transfusion trigger during the Fixed-Dose Period to make the collection of additional haematology assessments more flexible
• Amended the inclusion criterion for renal function
• Amended the inclusion criterion for platelet count
• Amended the inclusion criterion for contraception requirements and added pregnancy tests every 4-6 weeks
• Added an exception for subjects who have genetic findings 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 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 to align with preexisting guidance in the prohibited concomitant
medication section of the protocol
• Redefined Hb overshoot, and subsequent study treatment dose decrease, to higher than 2 g/dL below the upper limit of normal
• Added detailed guidance on re-introducing or escalating study treatment after resolution of a Grade 3 adverse event (AE) that caused study treatment to be stopped or the dose to be reduced
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15 Oct 2018 |
• 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 language to provide previously ineligible subjects the opportunity to rescreen for enrollment into the study should they become eligible based on an amended protocol
• Added new laboratory assessments for iron-related markers and markers of erythropoietic activity
• Added collection of historical data for iron chelation therapy, serum iron, serum ferritin, transferrin saturation, and liver iron concentration
• Added further details for assessments after a transaminase increase that meets the criteria for an AE of special interest
• Removed the use of an Independent Data Monitoring Committee |
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19 Mar 2019 |
• Increased the sample size from “approximately 15-20” to “a minimum of 20, with up to 40 adult subjects”.
• Revised the central laboratory requirements for additional blood sampling necessary for subjects whose individual transfusion trigger has not been reached.
• Increased the length of contraception period for males exposed to mitapivat to cover 1 complete spermatogenesis cycle.
• Clarified the central laboratory requirements for urine/serum pregnancy tests. |
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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 | |||
