Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Part A: Percentage of Participants With Response to Treatment |
A participant was considered a responder: if he or she did not receive blood transfusion from Week 5 through Week 26 (end of treatment) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, participant's hemoglobin (Hgb) level must have increased to >=1.5 grams per deciliter (g/dL) from baseline (defined as last Hgb value before administration of first dose of study drug) at treatment assessment timepoint (defined as average of values from the Week 23, 25, and 26 visits). Percentage of responders was calculated together with 95% exact Clopper-Pearson confidence interval (CI). |
From Week 5 through Week 26 |
|
| Primary |
Part B: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs) |
Adverse Event (AE): any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Treatment emergent serious adverse events (TESAEs) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. Treatment emergent adverse events (TEAEs): AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from first investigational medicinal product [IMP] administration in Part B to last IMP administration + 9 weeks follow-up period). |
Part B, 6.5 g cohort: From first dose (Week 26) up to 149 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 184); Part B, 7.5 g cohort: From first dose (Week 26) up to 137 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 172) |
|
| Secondary |
Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint |
Mean change from baseline (Week 0) in Hemoglobin (Hgb) at the treatment assessment timepoint is reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Least squares (LS) mean and 95 % confidence interval (CI) was assessed by Mixed Model for Repeated Measures (MMRM) approach using heterogeneous Toeplitz (TOEPH) covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. |
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26) |
|
| Secondary |
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint |
FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. Total score ranged from 0 to 52, with higher score indicating more fatigue. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95% CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline (Week 0) as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. |
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26) |
|
| Secondary |
Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint |
Mean change from baseline (Week 0) in total bilirubin at the treatment assessment timepoint is reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. |
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26) |
|
| Secondary |
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint |
Mean change from baseline (Week 0) in LDH at the treatment assessment timepoint is reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. |
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26) |
|
| Secondary |
Part A: Percentage of Participants With Solicited Symptomatic Anemia at Week 26 |
Symptomatic anemia was defined as having following symptoms: i. Fatigue; ii. Weakness; iii. Shortness of breath; iv. Palpitations, fast heartbeat; v. Light headedness and/or vi. Chest pain. Percentage of participants with solicited symptomatic anemia symptoms was reported in this outcome measure. |
Week 26 |
|
| Secondary |
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points |
Change from baseline (Week 0) in Hgb levels at each specified time points (i.e., Week 27, 29, 31, 33, 35, 37, 39, 41, 43,45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83,85,87, 89,91, 93, 95, 97, 99,101,103, 105, 107,109, 111,113,115,117,119, 121,123, 125, 127,129,131,133,135,137,139,141,143,145,147,149,151,153, 155,157,159,161,163,165,167,169,171,173,175 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. Early Termination (ET) visit/safety follow up (SFU) visit was 9 weeks after administration of last dose (i.e., up to Week 184). Here, "0" in the number analyzed field signifies that none of participants were available for assessment at the specified timepoints. |
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points |
Change from baseline (Week 0) in total bilirubin levels at each specified time points (i.e., Week 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65,67,69,71,73,75, 77, 79, 81,83, 85, 87, 89, 91, 93, 95, 97, 99,101,103, 105, 107,109, 111,113,115,117,119, 121, 123, 125, 127,129,131,133,135,137,139,141,143, 145,147,149,151,153,155,157,159, 161,163,165,167,169,171,173,175 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Here, "0" in the number analyzed field signifies that none of participants were available for assessment at the specified timepoints. |
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points |
FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. The Total score ranged from 0 to 52, with higher score indicating more fatigue. Baseline (Week 0) was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points |
SF-12: 12 item-questionnaire assessed health-related quality of life (HRQOL), contained 12 items, categorized into 8 domains (subscales) of functioning and well-being: physical functioning, role-physical, role emotional, mental health, bodily pain, general health, vitality and social functioning, with each domain score ranged from 0 (poor health) to 100 (better health). Higher scores = good health condition. These 8 domains were further summarized into 2 summary scores, PCS and MCS that ranged from 0 (poor health) to 100 (better health). Higher scores = better HRQOL. Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184) |
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| Secondary |
Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points |
EQ-5D-5L included 2 components: health state utility index (descriptive system) and Visual Analog Scale (VAS). EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response option: no problem, slight problem, moderate problem, severe problem and extreme problems measured with Likert scale. EQ-5D-5L responses converted into single index utility score between 0 to 1. Higher score=better health. EQ-5D-5L VAS rated participant's current health state on scale from 0 (worst imaginable health) to 100 (best imaginable health). Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Number of Participants With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points |
The PGIS is a self-reported scale. The PGIS is a 1-item questionnaire designed to assess participant's impression of disease severity using a 5-point scale ranging from 1 to 5, where 1=none, 2=mild, 3=moderate, 4=severe, 5=very severe. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Number of Participants With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points |
PGIC is a self-administered questionnaire to evaluate the improvement or worsening compared to the start of the study. PGIC was assessed on a 7-point Likert scale ranged from 1 (greatly improved) to 7 (greatly worsened). Categories were defined based on the PGIC scores as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worsen. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184) |
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| Secondary |
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points |
Change from baseline (Week 0) in LDH levels at each specified time points (i.e., Week 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107,109, 111, 113, 115, 117, 119, 121,123, 125, 127,129,131,133,135,137,139,141,143,145,147, 149, 151,153,155,157,159,161,163,165,167,169, 171, 173, 175 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). |
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184) |
|
| Secondary |
Part B: Number of Blood Transfusions Per Participant |
A participant was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the participant had symptoms of anemia or Hgb was <7 g/dL and the participant was asymptomatic. |
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176) |
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| Secondary |
Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points |
Change from baseline (Week 0) in haptoglobin values at each specified time points (i.e., Week 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97,99,101,103, 105, 107,109, 111,113,115,117,119, 121,123, 125, 127, 129,131,133,135,137,139,141,143, 145,147,149,151,153,155,157,159, 161,163,165,167,169,171,173,175 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Haptoglobin values <0.2 were imputed as 0.2. |
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184) |
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| Secondary |
Part B: Number of Healthcare Visits by Type |
In this outcome measure, number of healthcare visits which included non-study healthcare resource utilization visit (consisted mainly of extra visits to the office of the study doctor, visit to a generalist doctor or visit to a specialist doctor), hospitalization visit and visit to hospital emergency is reported. |
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176) |
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