| Primary | Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) | Hemoglobin 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 participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. | Posted | | Number | | percentage of participants | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| | Group IDs | Group Description | Statistical Method | Statistical Comment | P-Value | P-Value Comment | Parameter Type | Parameter Value | Dispersion Type | Dispersion Value | Confidence Interval Sides | Confidence Interval % | CI Lower Limit | CI Upper Limit | CI Lower Limit Comment | CI Upper Limit Comment | Estimate Comment | Tested Non-Inferiority | Non-Inferiority Type | Non-Inferiority Comment | Other Analysis Description |
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| | Exact Cochran-Mantel-Haenszel | | <0.0001 | | | | | | | | | | | | | | Superiority | | |
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| Secondary | Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 | This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. 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 randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. | Posted | | Least Squares Mean | Standard Error | grams per liter (g/L) | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Maximum Change From Baseline in Hb Concentration | This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Mean | Standard Deviation | g/L | | Baseline, up to Week 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More | This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Mean | Standard Deviation | weeks | | Baseline, up to Week 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 | The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. 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 randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Least Squares Mean | Standard Error | micromoles per liter (μmol/L) | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 | The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. 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 randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Least Squares Mean | Standard Error | units per litre (U/L) | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 | The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. 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 randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. | Posted | | Least Squares Mean | Standard Error | g/L | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 | The change from baseline in reticulocyte percentage was summarized. 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 randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. | Posted | | Least Squares Mean | Standard Error | Reticulocyte percentages | | Baseline, Weeks 16, 20, 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 | The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants 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 outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Least Squares Mean | Standard Error | score on a scale | | Baseline, Week 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 | The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants 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 outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). | Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Least Squares Mean | Standard Error | score on a scale | | Baseline, Week 24 | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 | Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized 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 optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose. |
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| Secondary | Percentage of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant 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 participants who received at least 1 dose of study treatment. | Posted | | Number | | percentage of participants | | From signing of informed consent form to the end of study, including follow-up (up to Day 197) | | | | ID | Title | Description |
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| OG000 | Placebo Comparator: Placebo | Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed dose. | | OG001 | Experimental: AG-348 5 mg | Participants 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 optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose |
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| Secondary | Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 | | Pharmacokinetic analysis population consisted of all participants 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 participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | | | | ID | Title | Description |
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| OG000 | AG-348, 5mg | Participants received 5mg AG-348 tablets BID at Week 12. | | OG001 | AG-348, 20 mg | Participants received 20mg AG-348 tablets BID at Week 12. | | OG002 | AG-348, 50mg | Participants received 50mg AG-348 tablets BID at Week 12. |
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| Secondary | Maximum Plasma Concentration (Cmax) for AG-348 | | Pharmacokinetic analysis population consisted of all participants 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 participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Nanograms per milliliter (ng/mL) | | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | | | | ID | Title | Description |
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| OG000 | AG-348, 5mg | Participants received 5mg AG-348 tablets BID at Week 12. | | OG001 | AG-348, 20 mg | Participants received 20mg AG-348 tablets BID at Week 12. | | OG002 | AG-348, 50mg | Participants received 50mg AG-348 tablets BID at Week 12. |
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| Secondary | Time to Cmax (Tmax) for AG-348 | | Pharmacokinetic analysis population consisted of all participants 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 participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Median | Full Range | hours (h) | | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | | | | ID | Title | Description |
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| OG000 | AG-348, 5mg | Participants received 5mg AG-348 tablets BID at Week 12. | | OG001 | AG-348, 20mg | Participants received 20mg AG-348 tablets BID at Week 12. | | OG002 | AG-348, 50mg | Participants received 50mg AG-348 tablets BID at Week 12. |
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| Secondary | Time to Last Measurable Concentration (Tlast) for AG-348 | | Pharmacokinetic analysis population consisted of all participants 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 participants analyzed is the number of participants evaluated for the outcome measure. | Posted | | Geometric Mean | Geometric Coefficient of Variation | hours (h) | | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | | | | ID | Title | Description |
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| OG000 | AG-348, 5mg | Participants received 5mg AG-348 tablets BID at Week 12. | | OG001 | AG-348, 20mg | Participants received 20mg AG-348 tablets BID at Week 12. | | OG002 | AG-346, 50mg | Participants received 50mg AG-348 tablets BID at Week 12. |
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| Secondary | Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | 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: Participants who were administered the study drug. Participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 52 participants; study AG348-C-006 (NCT03548220): 40 participants; study AG348-C-007 (NCT03559699): 27 participants; and study AG348-C-011 (NCT03853798): 36 participants, were pooled for the analysis of this outcome measure. | Posted | | Mean | 95% Confidence Interval | Percent probability | | From first dose of mitapivat to the end of study, including follow-up (up to Day 197) | | | | ID | Title | Description |
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| OG000 | Experimental: AG-348 5 mg | Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, participants continued to receive the same dose as determined by the investigator based on safety and efficacy up to Week 12, followed by the same optimized dose of 5 mg BID, for a period of 12 weeks as a fixed-dose. | | OG001 | Experimental: AG-348 20 mg | Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 12 as an optimized dose as determined by the investigator based on safety and efficacy, followed by the same optimized dose of 20 mg BID further for a period of 12 weeks as a fixed-dose. |
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| Other Pre-specified | Percentage of Participants With Adverse Events of Special Interest (AESI) | An AE is any untoward medical occurrence in a participant 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. An AESI can be serious or non-serious. | | Not Posted | | | | | | Through 4 weeks after last dose (approximately Week 31) | | Participants | | | | |
| Other Pre-specified | Change From Baseline in Bone Mineral Density Z-Score at Week 24 | | | Not Posted | | | | | | Baseline, Week 24 | | Participants | | | | |
| Other Pre-specified | Change From Baseline in Bone Mineral Density T-Score at Week 24 | | | Not Posted | | | | | | Baseline, Week 24 | | Participants | | | | |
| Secondary | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | 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 participants. | Safety Set: Participants who were administered the study drug. Male participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 32 participants; study AG348-C-006 (NCT03548220):15 participants; study AG348-C-007 (NCT03559699): 7 participants; and study AG348-C-011 (NCT03853798): 14 participants were pooled for analysis of this outcome measure. | Posted | | Mean | 95% Confidence Interval | Percent change | | Baseline, Week 24 | | | | ID | Title | Description |
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| OG000 | Experimental: AG-348 5 mg | Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, participants continued to receive the same dose as determined by the investigator based on safety and efficacy up to Week 12, followed by the same optimized dose of 5 mg BID, for a period of 12 weeks as a fixed-dose. | | OG001 | Experimental: AG-348 20 mg | Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 12 as an optimized dose as determined by the investigator based on safety and efficacy, followed by the same optimized dose of 20 mg BID further for a period of 12 weeks as a fixed-dose. |
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