Non-Transfusion-dependent Alpha-Thalassemia, Non-Transfusion-dependent Beta-Thalassemia
Conditions
Brief summary
The primary purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).
Detailed description
The mitapivat group included 130 participants whereas the placebo group had 64 participants.
Interventions
Tablets
DRUGMitapivat
Tablets
Sponsors
Agios Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H \[HbH\] disease) based on Hb electrophoresis, Hb high-performance liquid chromatography (HPLC)), and/or deoxyribonucleic acid (DNA) analysis; * Hb concentration ≤10.0 grams per deciliter (g/dL) (100.0 grams per liter \[g/L\]), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period; * Non-transfusion-dependent, defined as ≤5 red blood cell (RBC) units during the 24-week period before randomization; and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period; * If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization; * Women of child-bearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method; * Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.
Exclusion criteria
* Pregnant, breastfeeding, or parturient * Documented history of homozygous or heterozygous sickle hemoglobin (HbS) or hemoglobin C (HbC); * Prior exposure to gene therapy or prior bone marrow or stem cell transplantation; * Currently receiving treatment with luspatercept; the last dose must have been administered ≥18 weeks before randomization; * Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization; * History of malignancy, (active or treated) ≤5 years before providing informed consent; * History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ; * Hepatobiliary disorders; * Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 m\^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation; * Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]); * Active infection requiring systemic antimicrobial therapy at the time of providing informed consent; * Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg); * Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab; * History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or a major surgical procedure planned during the study; * Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device; * Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization; * Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥10 weeks before randomization; * Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD\&C Blue #2\]); * Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data Also excluded are: * Participants who are institutionalized by regulatory or court order * Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline | Double-Blind Period: Baseline up to Week 12 through Week 24 | Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Period: Change From Baseline in Erythropoietin at Week 24 | Double-Blind Period: Baseline, Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24 | Double-Blind Period: Baseline, Week 12 through Week 24 | The FACIT-Fatigue subscale includes a 13-item self-reported fatigue subscale, which assesses the severity and impact of fatigue (including the impact on daily activities and functioning).The FACIT-Fatigue subscale is scored on a 5-point Likert scale: 0 (not at all) to 4 (very much). The total FACIT-Fatigue subscale score ranges from 0 to 52, with a higher score indicating better health-related quality of life (HRQOL). Baseline is defined as the last assessment before randomization for subjects randomized and not dosed or the last assessment before start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24 | Double-Blind Period: Baseline, Week 12 through Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline | Double-Blind Period: Baseline up to Week 12 through Week 24 | Hb 1.5+ response is defined as a ≥1.5 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb 1.5+ response will be summarized using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24 | Double-Blind Period: Baseline, Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Double-Blind Period: Baseline, Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Change From Baseline in Haptoglobin at Week 24 | Double-Blind Period: Baseline, Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | Double-Blind Period: At Weeks 12, 16, 20, and 24 | PGIS-Fatigue measured participants' perception of their fatigue severity (7-day recall) on a 4-point scale ranging from '1=none' to '4=severe'. A participant was considered to have achieved the PGIS-Fatigue response at Weeks 12, 16, 20, or 24, if their baseline to postbaseline score met one of the following conditions: 'none' at baseline to 'none' postbaseline; 'mild' to 'mild' or 'none'; 'moderate' to 'mild' or 'none'; or 'severe' to 'moderate', 'mild', or 'none'. |
| Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | Double-Blind Period: At Weeks 12, 16, 20, and 24 | The PGIC-Fatigue assesses change over time compared with baseline on a 5-point scale ranging from 0 to 4 where 0 indicates Much better and 4 as Much worse. A participant was considered to have achieved the PGIC-Fatigue response at Weeks 12, 16, 20, or 24 if their baseline PGIS and corresponding PGIC met one of the following conditions: if the PGIS at baseline was 'none' or 'mild' and PGIC at the visit was 'no change', 'a little better', or 'much better'; or if the PGIS at baseline was 'moderate' or 'severe' and PGIC at the visit was 'a little better' or 'much better'. |
| Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 | Double-Blind Period: Baseline, Week 24 | The 6MWT is a well-established performance outcome (PerfO) measure that is widely used to evaluate physical activity in terms of distance walked in patients with a variety of conditions. The test measures the distance an individual can walk on a hard, flat surface in 6 minutes. |
| Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24 | Double-Blind Period: Baseline, Week 24 | Iron metabolism was assessed based on serum ferritin levels. |
| Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24 | Double-Blind Period: Baseline, Week 24 | Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity. |
| Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Double-Blind Period: From the time of signing informed consent to Week 24 | AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
| Double-Blind Period: Plasma Concentration of Mitapivat | Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat | Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule. |
| Double-Blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat | Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat | Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20 | — |
| Double-Blind Period: Change From Baseline in Reticulocytes at Week 24 | Double-Blind Period: Baseline, Week 24 | Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed. |
| Open-Label Extension Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to Grade 3 | Open-Label Extension Period: From week 24 up to end of study (approximately 5 years) | AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
Countries
Brazil, Bulgaria, Canada, Denmark, France, Greece, Italy, Lebanon, Malaysia, Netherlands, Saudi Arabia, Spain, Taiwan, Thailand, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Contacts
STUDY_CHAIRMedical Affairs
Agios Pharmaceuticals, Inc.
Participant flow
Recruitment details
Participants took part in study at study sites in the United States of America, Brazil, Bulgaria, Canada, Denmark, France, Greece, Italy, Lebanon, Malaysia, Netherlands, Saudi Arabia, Spain, Taiwan, Thailand, Turkey, United Arab Emirates and the United Kingdom. Results are reported for 24-week DB period until primary completion date. Analysis of data for OLE period is still ongoing with anticipated completion in December 2028. Results for OLE period will be reported by December 2029.
Pre-assignment details
A total of 235 participants with a diagnosis of Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT) were screened. Of which, 194 were enrolled and 192 were treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| Mitapivat Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period. | 130 |
| Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period. | 64 |
| Total | 194 |
Baseline characteristics
| Characteristic | Total | Placebo | Mitapivat |
|---|---|---|---|
| Age, Continuous | 41.2 years STANDARD_DEVIATION 13.09 | 38.9 years STANDARD_DEVIATION 12.99 | 42.4 years STANDARD_DEVIATION 13.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 176 Participants | 58 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 76 Participants | 24 Participants | 52 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiracial | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 109 Participants | 36 Participants | 73 Participants |
| Sex: Female, Male Female | 123 Participants | 39 Participants | 84 Participants |
| Sex: Female, Male Male | 71 Participants | 25 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 130 | 0 / 64 |
| other Total, other adverse events | 80 / 129 | 33 / 63 |
| serious Total, serious adverse events | 8 / 129 | 0 / 63 |
Outcome results
Primary
Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline
Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline up to Week 12 through Week 24
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline | 42.3 Percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline | 1.6 Percentage of participants |
Comparison: The estimated adjusted difference in response rate, 95% CI, and p-value are based on Mantel-Haenszel stratum weighted method adjusting for the randomization stratification factors.p-value: <0.000195% CI: [32, 49.8]Cochran-Mantel-Haenszel
Secondary
Double-Blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat
Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat | 4262.57 Hours*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 31.4 |
Secondary
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)
Time frame: Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacodynamic (PD) Analysis Set is a subset of the safety analysis set including all participants with at least 1 blood 2,3-DPG or ATP concentration measurement ≥LLQ. Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Day 1 | 526.40 mcg/mL | Standard Deviation 125.196 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 12 | 434.90 mcg/mL | Standard Deviation 97.901 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 20 | 426.30 mcg/mL | Standard Deviation 107.173 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 30 Minutes Post-dose at Week 20 | 417.87 mcg/mL | Standard Deviation 102.853 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 1 Hour Post-dose at Week 20 | 417.83 mcg/mL | Standard Deviation 105.752 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 3 Hour Post-dose at Week 20 | 409.73 mcg/mL | Standard Deviation 96.379 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 5 Hour Post-dose at Week 20 | 412.72 mcg/mL | Standard Deviation 94.15 |
| Mitapivat | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 7 Hour Post-dose at Week 20 | 404.43 mcg/mL | Standard Deviation 97.586 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 7 Hour Post-dose at Week 20 | 471.10 mcg/mL | Standard Deviation 113.165 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Day 1 | 506.14 mcg/mL | Standard Deviation 108.033 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 1 Hour Post-dose at Week 20 | 457.71 mcg/mL | Standard Deviation 104.431 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 12 | 497.68 mcg/mL | Standard Deviation 112.055 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 5 Hour Post-dose at Week 20 | 464.24 mcg/mL | Standard Deviation 97.007 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 20 | 468.22 mcg/mL | Standard Deviation 99.783 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 3 Hour Post-dose at Week 20 | 454.39 mcg/mL | Standard Deviation 107.966 |
| Placebo | Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 30 Minutes Post-dose at Week 20 | 457.78 mcg/mL | Standard Deviation 89.932 |
Secondary
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP)
Time frame: Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacodynamic (PD) Analysis Set is a subset of the safety analysis set including all participants with at least 1 blood 2,3-DPG or ATP concentration measurement ≥ LLQ. Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | At Pre-dose at Day 1 | 180.87 microgram/milliliter (mcg/mL) | Standard Deviation 29.577 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 20 | 235.79 microgram/milliliter (mcg/mL) | Standard Deviation 46.099 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 3 Hour Post-dose at Week 20 | 409.73 microgram/milliliter (mcg/mL) | Standard Deviation 96.379 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 12 | 242.07 microgram/milliliter (mcg/mL) | Standard Deviation 45.782 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 5 Hour Post-dose at Week 20 | 412.72 microgram/milliliter (mcg/mL) | Standard Deviation 94.15 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 30 Minutes Post-dose at Week 20 | 417.87 microgram/milliliter (mcg/mL) | Standard Deviation 102.853 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 7 Hour Post-dose at Week 20 | 404.43 microgram/milliliter (mcg/mL) | Standard Deviation 97.586 |
| Mitapivat | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 1 Hour Post-dose at Week 20 | 417.83 microgram/milliliter (mcg/mL) | Standard Deviation 105.752 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 7 Hour Post-dose at Week 20 | 471.10 microgram/milliliter (mcg/mL) | Standard Deviation 113.165 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | At Pre-dose at Day 1 | 184.91 microgram/milliliter (mcg/mL) | Standard Deviation 31.299 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 12 | 176.81 microgram/milliliter (mcg/mL) | Standard Deviation 33.657 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 20 | 168.10 microgram/milliliter (mcg/mL) | Standard Deviation 29.962 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 30 Minutes Post-dose at Week 20 | 457.78 microgram/milliliter (mcg/mL) | Standard Deviation 89.932 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 1 Hour Post-dose at Week 20 | 457.71 microgram/milliliter (mcg/mL) | Standard Deviation 104.431 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 3 Hour Post-dose at Week 20 | 454.39 microgram/milliliter (mcg/mL) | Standard Deviation 107.966 |
| Placebo | Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 5 Hour Post-dose at Week 20 | 464.24 microgram/milliliter (mcg/mL) | Standard Deviation 97.007 |
Secondary
Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24
The FACIT-Fatigue subscale includes a 13-item self-reported fatigue subscale, which assesses the severity and impact of fatigue (including the impact on daily activities and functioning).The FACIT-Fatigue subscale is scored on a 5-point Likert scale: 0 (not at all) to 4 (very much). The total FACIT-Fatigue subscale score ranges from 0 to 52, with a higher score indicating better health-related quality of life (HRQOL). Baseline is defined as the last assessment before randomization for subjects randomized and not dosed or the last assessment before start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 12 through Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24 | 4.85 score on a scale | Standard Error 0.732 |
| Placebo | Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24 | 1.46 score on a scale | Standard Error 0.955 |
Comparison: The estimates, 95% CIs, and 2-sided p-value are based on an analysis of covariance (ANCOVA) model which includes average change from baseline in FACIT-Fatigue subscale score from Week 12 through Week 24 as the dependent variable, treatment group as the independent variable, and baseline and the randomization stratification factors as covariates.p-value: 0.002695% CI: [1.21, 5.59]ANCOVA
Secondary
Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 12 through Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24 | 8.57 Gram per Liter (g/L) | Standard Error 0.666 |
| Placebo | Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24 | -1.06 Gram per Liter (g/L) | Standard Error 0.867 |
Comparison: The estimates, 95% CIs, and 2-sided p-value are based on an ANCOVA model which includes average change from baseline in Hb concentrations from Week 12 through Week 24 as the dependent variable, treatment group as the independent variable, and baseline Hb concentration and the randomization stratification factors as covariates.p-value: <0.000195% CI: [7.8, 11.46]ANCOVA
Secondary
Double-Blind Period: Change From Baseline in Erythropoietin at Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Erythropoietin at Week 24 | 19.21 International units per Liter (IU/L) | Standard Error 37.773 |
| Placebo | Double-Blind Period: Change From Baseline in Erythropoietin at Week 24 | 115.71 International units per Liter (IU/L) | Standard Error 49.413 |
Secondary
Double-Blind Period: Change From Baseline in Haptoglobin at Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Haptoglobin at Week 24 | -0.002 Gram per Liter (g/L) | Standard Error 0.0145 |
| Placebo | Double-Blind Period: Change From Baseline in Haptoglobin at Week 24 | 0.017 Gram per Liter (g/L) | Standard Error 0.0199 |
Secondary
Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24 | -10.65 Micromole per Liter (umol/L) | Standard Error 1.047 |
| Placebo | Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24 | -0.03 Micromole per Liter (umol/L) | Standard Error 1.403 |
Secondary
Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | -30.07 Units per Liter (U/L) | Standard Error 7.131 |
| Placebo | Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | -5.79 Units per Liter (U/L) | Standard Error 9.44 |
Secondary
Double-Blind Period: Change From Baseline in Reticulocytes at Week 24
Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Reticulocytes at Week 24 | -32.11 10^9 cells per liter (10^9 cells/L) | Standard Error 10.6 |
| Placebo | Double-Blind Period: Change From Baseline in Reticulocytes at Week 24 | -14.74 10^9 cells per liter (10^9 cells/L) | Standard Error 14.932 |
Secondary
Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24
Iron metabolism was assessed based on serum ferritin levels.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24 | -34.75 Microgram/Liter (mcg/L) | Standard Error 32.71 |
| Placebo | Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24 | -32.48 Microgram/Liter (mcg/L) | Standard Error 43.09 |
Secondary
Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24
The 6MWT is a well-established performance outcome (PerfO) measure that is widely used to evaluate physical activity in terms of distance walked in patients with a variety of conditions. The test measures the distance an individual can walk on a hard, flat surface in 6 minutes.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 | 30.48 Meters | Standard Error 5.651 |
| Placebo | Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 | 7.11 Meters | Standard Error 7.346 |
Secondary
Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24
Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity.
Time frame: Double-Blind Period: Baseline, Week 24
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24 | -0.029 Ratio | Standard Error 0.0212 |
| Placebo | Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24 | -0.047 Ratio | Standard Error 0.0262 |
Secondary
Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat | 166.93 ng/mL | Geometric Coefficient of Variation 80.1 |
Secondary
Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | 1565.69 ng/mL | Geometric Coefficient of Variation 42.4 |
Secondary
Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
Time frame: Double-Blind Period: From the time of signing informed consent to Week 24
Population: Safety Analysis Set (SAS) includes all participants who had received at least 1 dose of study treatment. Participants were classified according to the treatment received. If a participant was randomized to placebo and received at least 1 dose of mitapivat in the Double-blind Period, then the participant was classified to the mitapivat arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 107 Participants |
| Mitapivat | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with Serious TEAEs | 8 Participants |
| Mitapivat | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 56 Participants |
| Mitapivat | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 18 Participants |
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 2 Participants |
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 50 Participants |
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 13 Participants |
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with Serious TEAEs | 0 Participants |
Secondary
Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline
Hb 1.5+ response is defined as a ≥1.5 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb 1.5+ response will be summarized using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Time frame: Double-Blind Period: Baseline up to Week 12 through Week 24
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline | 24.6 Percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline | 0 Percentage of participants |
Secondary
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24
PGIS-Fatigue measured participants' perception of their fatigue severity (7-day recall) on a 4-point scale ranging from '1=none' to '4=severe'. A participant was considered to have achieved the PGIS-Fatigue response at Weeks 12, 16, 20, or 24, if their baseline to postbaseline score met one of the following conditions: 'none' at baseline to 'none' postbaseline; 'mild' to 'mild' or 'none'; 'moderate' to 'mild' or 'none'; or 'severe' to 'moderate', 'mild', or 'none'.
Time frame: Double-Blind Period: At Weeks 12, 16, 20, and 24
Population: FAS included all participants who were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 12 | 65.4 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 16 | 63.1 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 20 | 61.5 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 24 | 62.3 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 24 | 46.9 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 12 | 46.9 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 20 | 48.4 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 16 | 42.2 percentage of participants |
Secondary
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24
The PGIC-Fatigue assesses change over time compared with baseline on a 5-point scale ranging from 0 to 4 where 0 indicates Much better and 4 as Much worse. A participant was considered to have achieved the PGIC-Fatigue response at Weeks 12, 16, 20, or 24 if their baseline PGIS and corresponding PGIC met one of the following conditions: if the PGIS at baseline was 'none' or 'mild' and PGIC at the visit was 'no change', 'a little better', or 'much better'; or if the PGIS at baseline was 'moderate' or 'severe' and PGIC at the visit was 'a little better' or 'much better'.
Time frame: Double-Blind Period: At Weeks 12, 16, 20, and 24
Population: FAS included all participants who were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 20 | 66.2 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 12 | 71.5 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 24 | 66.2 percentage of participants |
| Mitapivat | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 16 | 71.5 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 24 | 53.1 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 12 | 53.1 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 20 | 56.3 percentage of participants |
| Placebo | Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 | At Week 16 | 50.0 percentage of participants |
Secondary
Double-Blind Period: Plasma Concentration of Mitapivat
Time frame: Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ (lower limit of quantification). Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | Pre-dose at Week 12 | 59.23 nanograms per milliliter (ng/mL) | Standard Deviation 51.081 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | Pre-dose at Week 20 | 84.70 nanograms per milliliter (ng/mL) | Standard Deviation 138.852 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | 30 Minutes Post-dose at Week 20 | 1209.00 nanograms per milliliter (ng/mL) | Standard Deviation 931.211 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | 1 Hour Post-dose at Week 20 | 1386.35 nanograms per milliliter (ng/mL) | Standard Deviation 712.996 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | 3 Hour Post-dose at Week 20 | 740.26 nanograms per milliliter (ng/mL) | Standard Deviation 357.66 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | 5 Hour Post-dose at Week 20 | 359.42 nanograms per milliliter (ng/mL) | Standard Deviation 269.758 |
| Mitapivat | Double-Blind Period: Plasma Concentration of Mitapivat | 7 Hour Post-dose at Week 20 | 206.82 nanograms per milliliter (ng/mL) | Standard Deviation 185.657 |
Secondary
Double-Blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitapivat | Double-Blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | 6.825 hours |
Secondary
Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitapivat | Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat | 1.000 Hours |
Secondary
Open-Label Extension Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to Grade 3
AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
Time frame: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)