Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
Paroxysmal Nocturnal Hemoglobinuria (PNH), Extravascular Hemolysis (EVH), Factor D inhibitor, Complement, Danicopan, C5 inhibitor
Brief summary
The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (eculizumab or ravulizumab) in participants with PNH who have clinically evident EVH.
Detailed description
This is a multiple-region, randomized, double-blind, placebo controlled, multiple-dose, study in participants with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or ravulizumab). Participants will be randomized to receive danicopan or placebo, in a 2:1 ratio for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor (eculizumab or ravulizumab) therapy. At Week 12, participants randomized to receive placebo will be switched to danicopan in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy. At the end of the 2 treatment periods (Week 24), participants may enter a Long-Term Extension (LTE) Period and continue to receive danicopan in addition to their C5 inhibitor therapy. The Long-Term Extension period will consist of a first year of LTE(Year1) and a second year of optional LTE(Year2).All patients will complete 72 weeks of LTE(Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete participation in this study or continue to the optional second year (Year2) of LTE.
Interventions
DRUGDanicopan
Oral tablet
DRUGPlacebo
Oral tablet
DRUGC5 Inhibitor
Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PNH * Clinically Evident EVH defined by: * Anemia (Hgb ≤9.5 gram/deciliter) with absolute reticulocyte count ≥120 x 10\^9/liter * Receiving an approved C5 inhibitor for at least 6 months prior to Day 1 * Platelet count ≥30,000/microliters (µL) * Absolute neutrophil counts ≥500/μL * Documentation of/or willingness to receive vaccinations for N. meningiditis and prophylactic antibiotics as required
Exclusion criteria
* History of a major organ transplant or hematopoietic stem cell transplantation (HSCT) * Participants with known aplastic anemia or other bone marrow failure that requires HSCT or other therapies including anti-thymocyte globulin and/or immunosuppressants * Known or suspected complement deficiency * Laboratory abnormalities at screening, including: * Alanine aminotransferase \>2 x ULN (\>3 x ULN in case of patients with documented liver iron overload defined by serum ferratin values * 500 ng/ML) * Direct bilirubin \>2 x ULN (unless due to EVH or documented Gilbert's Syndrome) * Current evidence of biliary cholestasis * Estimated glomerular filtration rate of \<30 milliliters/minute/1.73 meter squared and/or are on dialysis * Evidence of human immunodeficiency virus, hepatitis B, or active hepatitis C infection at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hgb at Week 12 | Baseline, Week 12 | Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Transfusion Avoidance Through Week 12 | Week 12 | Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 12. Participants who discontinued study treatment early before Week 12 were considered as not achieving transfusion avoidance. |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 | Baseline, Week 12 | The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM. |
| Change From Baseline in Absolute Reticulocyte Count at Week 12 | Baseline, Week 12 | LS mean and SE were produced using MMRM. |
| Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment | 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment | — |
| Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment | 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment | — |
| Percentage of Participants With Transfusion Avoidance Through Week 24 | 24 weeks | Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 24. Participants who discontinued study treatment early before Week 24 were considered as not achieving transfusion avoidance. |
| Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | 12 weeks prior to initiation of treatment to 12 weeks post initiation of treatment | LS mean and SE were produced using analysis of covariance (ANCOVA). |
| Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | 12 weeks prior to initiation of treatment to post 12 weeks of treatment (24 weeks) | LS mean and SE were produced using ANCOVA. |
| Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 | Week 12 | The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 12 and remaining transfusion free during the 12-Week TP1. Participants who withdrew from the study early during the 12-Week TP1 or had missing Hgb value at Week 12 were considered as not achieving the criterion. |
| Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan | Week 12 to Week 24 | The criterion was defined as Hgb stabilization avoidance of a \>1 g/dL (\>10 g/L) decrease in Hgb level at Week 24 from Week 12. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb stabilization regardless of the actual value observed at Week 24. |
| Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24 | Week 24 | The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 24 and remaining transfusion free during the 12-Week TP2. Participants who withdrew from the study early during the 12-Week TP2 or had missing Hgb value at Week 24 were considered as not achieving the criterion. |
| Change From Baseline in Total and Direct Bilirubin at Week 12 | Baseline, Week 12 | Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM. |
| Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 | Baseline, Week 12 | The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM. |
| Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 | Baseline, Week 12 | Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM. |
| Change From Baseline in Lactate Dehydrogenase at Week 12 | Baseline, Week 12 | Baseline was defined as the average of all available assessments prior to the first dose of study intervention. LS mean and SE were produced using MMRM. |
| Percentage of Participants With Hgb Normalization at Week 12 | Week 12 | Hgb normalization was defined as Hgb value above lower limit of normal (LLN) reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 12 were considered as not meeting Hgb normalization regardless of actual value observed at Week 12. |
| Percentage of Participants With Hgb Normalization at Week 24 | Week 24 | Hgb normalization was defined as Hgb value above LLN reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb normalization regardless of actual value observed at Week 24. |
| Change From Baseline FACIT Fatigue Scores at Week 24 | Baseline, Week 24 | The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM. |
Countries
Brazil, Canada, Czechia, France, Germany, Greece, Israel, Italy, Japan, Malaysia, Netherlands, Poland, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States
Participant flow
Pre-assignment details
The study consists of 2 treatment periods and a long-term extension period.
Participants by arm
| Arm | Count |
|---|---|
| Danicopan-Danicopan Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the long-term extension (LTE) for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy. | 57 |
| Placebo-Danicopan Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy. | 29 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-Term Extension (LTE) | Adverse Event | 1 | 1 |
| Long-Term Extension (LTE) | Death | 0 | 1 |
| Long-Term Extension (LTE) | Noncompliance with study intervention | 1 | 0 |
| Long-Term Extension (LTE) | Physician Decision | 3 | 0 |
| Long-Term Extension (LTE) | Withdrawal by Subject | 3 | 0 |
| Treatment Period 1 (TP1) | Adverse Event | 2 | 1 |
| Treatment Period 1 (TP1) | Withdrawal by Subject | 0 | 1 |
| Treatment Period 2 (TP2) | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Danicopan-Danicopan | Placebo-Danicopan | Total |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 17 | 52.9 years STANDARD_DEVIATION 14.34 | 52.8 years STANDARD_DEVIATION 16.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 24 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 9 Participants |
| Hemoglobin (Hgb) | 76.7 g/L STANDARD_DEVIATION 9.47 | 78.9 g/L STANDARD_DEVIATION 10.11 | 77.5 g/L STANDARD_DEVIATION 9.69 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 10 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) White | 28 Participants | 14 Participants | 42 Participants |
| Sex: Female, Male Female | 34 Participants | 20 Participants | 54 Participants |
| Sex: Female, Male Male | 23 Participants | 9 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 29 | 0 / 55 | 0 / 27 | 0 / 54 | 1 / 26 |
| other Total, other adverse events | 43 / 57 | 18 / 29 | 40 / 55 | 18 / 27 | 48 / 54 | 24 / 26 |
| serious Total, serious adverse events | 3 / 57 | 2 / 29 | 3 / 55 | 6 / 27 | 7 / 54 | 6 / 26 |
Outcome results
Primary
Change From Baseline in Hgb at Week 12
Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Hgb at Week 12 | Interim Efficacy Analysis | 29.40 g/L | Standard Error 2.107 |
| Danicopan (TP1) | Change From Baseline in Hgb at Week 12 | Full Analysis | 28.08 g/L | Standard Error 1.957 |
| Placebo (TP1) | Change From Baseline in Hgb at Week 12 | Interim Efficacy Analysis | 4.96 g/L | Standard Error 3.128 |
| Placebo (TP1) | Change From Baseline in Hgb at Week 12 | Full Analysis | 4.62 g/L | Standard Error 3.018 |
Comparison: Interim Efficacy Analysisp-value: 0.0007Re-randomization Test
Comparison: Full Analysisp-value: 0.0007Re-randomization Test
Comparison: Interim Efficacy Analysisp-value: <0.000195% CI: [16.9, 31.99]Mixed Models Analysis
Comparison: Full Analysisp-value: <0.000195% CI: [16.31, 30.61]Mixed Models Analysis
Secondary
Change From Baseline FACIT Fatigue Scores at Week 24
The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 24
Population: Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Danicopan (TP1) | Change From Baseline FACIT Fatigue Scores at Week 24 | 6.21 units on a scale | Standard Error 1.046 |
| Placebo (TP1) | Change From Baseline FACIT Fatigue Scores at Week 24 | 5.64 units on a scale | Standard Error 1.921 |
Secondary
Change From Baseline in Absolute Reticulocyte Count at Week 12
LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' and 'Number Analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Absolute Reticulocyte Count at Week 12 | Interim Efficacy Analysis | -0.0838 10^12 cells/L | Standard Error 0.00893 |
| Danicopan (TP1) | Change From Baseline in Absolute Reticulocyte Count at Week 12 | Full Analysis | -0.0925 10^12 cells/L | Standard Error 0.00816 |
| Placebo (TP1) | Change From Baseline in Absolute Reticulocyte Count at Week 12 | Interim Efficacy Analysis | 0.0035 10^12 cells/L | Standard Error 0.01268 |
| Placebo (TP1) | Change From Baseline in Absolute Reticulocyte Count at Week 12 | Full Analysis | -0.0008 10^12 cells/L | Standard Error 0.01184 |
Secondary
Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12
Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' and 'Number Analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 | Interim Efficacy Analysis | -15.06 percentage of the total cell population | Standard Error 2.824 |
| Danicopan (TP1) | Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 | Full Analysis | -19.00 percentage of the total cell population | Standard Error 1.814 |
| Placebo (TP1) | Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 | Interim Efficacy Analysis | 0.89 percentage of the total cell population | Standard Error 4.394 |
| Placebo (TP1) | Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 | Full Analysis | 0.68 percentage of the total cell population | Standard Error 2.69 |
Secondary
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12
The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 | Interim Efficacy Analysis | 7.97 units on a scale | Standard Error 1.128 |
| Danicopan (TP1) | Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 | Full Analysis | 8.13 units on a scale | Standard Error 0.919 |
| Placebo (TP1) | Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 | Interim Efficacy Analysis | 1.85 units on a scale | Standard Error 1.581 |
| Placebo (TP1) | Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 | Full Analysis | 2.35 units on a scale | Standard Error 1.289 |
Secondary
Change From Baseline in Lactate Dehydrogenase at Week 12
Baseline was defined as the average of all available assessments prior to the first dose of study intervention. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' and 'Number Analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Lactate Dehydrogenase at Week 12 | Interim Efficacy Analysis | -23.49 units/L | Standard Error 8.287 |
| Danicopan (TP1) | Change From Baseline in Lactate Dehydrogenase at Week 12 | Full Analysis | -25.60 units/L | Standard Error 7.932 |
| Placebo (TP1) | Change From Baseline in Lactate Dehydrogenase at Week 12 | Interim Efficacy Analysis | -2.92 units/L | Standard Error 11.914 |
| Placebo (TP1) | Change From Baseline in Lactate Dehydrogenase at Week 12 | Full Analysis | -16.92 units/L | Standard Error 11.38 |
Secondary
Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12
The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group. Here, 'Overall number of participants analyzed' and 'Number Analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 | Interim Efficacy Analysis | 24.60 percentage of the total cell population | Standard Error 4.18 |
| Danicopan (TP1) | Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 | Full Analysis | 26.35 percentage of the total cell population | Standard Error 2.369 |
| Placebo (TP1) | Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 | Interim Efficacy Analysis | -3.04 percentage of the total cell population | Standard Error 5.864 |
| Placebo (TP1) | Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 | Full Analysis | -0.18 percentage of the total cell population | Standard Error 2.96 |
Secondary
Change From Baseline in Total and Direct Bilirubin at Week 12
Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
Time frame: Baseline, Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Total Bilirubin (Interim Efficacy Analysis) | -9.77 micromoles/L | Standard Error 1.692 |
| Danicopan (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Direct Bilirubin (Interim Efficacy Analysis) | -2.88 micromoles/L | Standard Error 0.357 |
| Danicopan (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Total Bilirubin (Full Analysis) | -11.55 micromoles/L | Standard Error 1.541 |
| Danicopan (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Direct Bilirubin (Full Analysis) | -2.85 micromoles/L | Standard Error 0.317 |
| Placebo (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Direct Bilirubin (Full Analysis) | 0.17 micromoles/L | Standard Error 0.447 |
| Placebo (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Total Bilirubin (Interim Efficacy Analysis) | -2.15 micromoles/L | Standard Error 2.377 |
| Placebo (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Total Bilirubin (Full Analysis) | -1.42 micromoles/L | Standard Error 2.172 |
| Placebo (TP1) | Change From Baseline in Total and Direct Bilirubin at Week 12 | Direct Bilirubin (Interim Efficacy Analysis) | 0.30 micromoles/L | Standard Error 0.503 |
Secondary
Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
LS mean and SE were produced using ANCOVA.
Time frame: 12 weeks prior to initiation of treatment to post 12 weeks of treatment (24 weeks)
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Interim Efficacy Analysis | -0.92 transfusion instances | Standard Error 0.174 |
| Danicopan (TP1) | Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Full Analysis | -0.91 transfusion instances | Standard Error 0.138 |
| Placebo (TP1) | Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Interim Efficacy Analysis | -0.21 transfusion instances | Standard Error 0.246 |
| Placebo (TP1) | Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Full Analysis | -0.11 transfusion instances | Standard Error 0.193 |
Secondary
Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment
Time frame: 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Danicopan (TP1) | Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment | -1.5 transfusion instances | Standard Deviation 2.41 |
Secondary
Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
LS mean and SE were produced using analysis of covariance (ANCOVA).
Time frame: 12 weeks prior to initiation of treatment to 12 weeks post initiation of treatment
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan (TP1) | Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Interim Efficacy Analysis | -1.48 RBC units | Standard Error 0.271 |
| Danicopan (TP1) | Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Full Analysis | -1.44 RBC units | Standard Error 0.212 |
| Placebo (TP1) | Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Interim Efficacy Analysis | -0.18 RBC units | Standard Error 0.383 |
| Placebo (TP1) | Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | Full Analysis | -0.14 RBC units | Standard Error 0.297 |
Secondary
Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment
Time frame: 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Danicopan (TP1) | Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment | -2.7 RBC units | Standard Deviation 4.86 |
Secondary
Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24
The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 24 and remaining transfusion free during the 12-Week TP2. Participants who withdrew from the study early during the 12-Week TP2 or had missing Hgb value at Week 24 were considered as not achieving the criterion.
Time frame: Week 24
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24 | 41.8 percentage of participants |
Secondary
Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12
The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 12 and remaining transfusion free during the 12-Week TP1. Participants who withdrew from the study early during the 12-Week TP1 or had missing Hgb value at Week 12 were considered as not achieving the criterion.
Time frame: Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 | Interim Efficacy Analysis | 59.5 percentage of participants |
| Danicopan (TP1) | Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 | Full Analysis | 54.4 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 | Interim Efficacy Analysis | 0 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 | Full Analysis | 0 percentage of participants |
Secondary
Percentage of Participants With Hgb Normalization at Week 12
Hgb normalization was defined as Hgb value above lower limit of normal (LLN) reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 12 were considered as not meeting Hgb normalization regardless of actual value observed at Week 12.
Time frame: Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Hgb Normalization at Week 12 | Interim Efficacy Analysis | 28.6 percentage of participants |
| Danicopan (TP1) | Percentage of Participants With Hgb Normalization at Week 12 | Full Analysis | 26.3 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Hgb Normalization at Week 12 | Interim Efficacy Analysis | 0 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Hgb Normalization at Week 12 | Full Analysis | 0 percentage of participants |
Secondary
Percentage of Participants With Hgb Normalization at Week 24
Hgb normalization was defined as Hgb value above LLN reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb normalization regardless of actual value observed at Week 24.
Time frame: Week 24
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Hgb Normalization at Week 24 | 20.0 percentage of participants |
Secondary
Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan
The criterion was defined as Hgb stabilization avoidance of a \>1 g/dL (\>10 g/L) decrease in Hgb level at Week 24 from Week 12. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb stabilization regardless of the actual value observed at Week 24.
Time frame: Week 12 to Week 24
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan | 58.2 percentage of participants |
Secondary
Percentage of Participants With Transfusion Avoidance Through Week 12
Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 12. Participants who discontinued study treatment early before Week 12 were considered as not achieving transfusion avoidance.
Time frame: Week 12
Population: Interim Efficacy Analysis Set: Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group. Full Analysis Set: All enrolled participants that were randomized to either the danicopan or placebo treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Transfusion Avoidance Through Week 12 | Interim Efficacy Analysis | 83.3 percentage of participants |
| Danicopan (TP1) | Percentage of Participants With Transfusion Avoidance Through Week 12 | Full Analysis | 78.9 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Transfusion Avoidance Through Week 12 | Interim Efficacy Analysis | 38.1 percentage of participants |
| Placebo (TP1) | Percentage of Participants With Transfusion Avoidance Through Week 12 | Full Analysis | 27.6 percentage of participants |
Secondary
Percentage of Participants With Transfusion Avoidance Through Week 24
Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 24. Participants who discontinued study treatment early before Week 24 were considered as not achieving transfusion avoidance.
Time frame: 24 weeks
Population: Full Analysis Set: All enrolled participants that were randomized to the danicopan treatment group. Here, 'Overall Number of Participants Analyzed' signifies those participants who received danicopan who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan (TP1) | Percentage of Participants With Transfusion Avoidance Through Week 24 | 69.1 percentage of participants |