Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Brief summary
The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who were clinically stable after having been treated with eculizumab for at least 6 months.
Detailed description
The study consisted of a 4-week Screening Period and a 26-week Randomized Treatment Period (Primary Evaluation Period). After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 4 years.
Interventions
BIOLOGICALRavulizumab
All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to \<60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to \<100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.
BIOLOGICALEculizumab
All treatments were given as IV infusions. Participants received 900 mg of eculizumab q2w.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥18 years of age. 2. Treated with eculizumab for PNH for at least 6 months prior to Day 1. 3. Lactate dehydrogenase level ≤1.5 times the upper limit of normal (ULN) at screening. 4. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry. 5. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment. 6. Female participants of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab. 7. Willing and able to give written informed consent and comply with study visit schedule.
Exclusion criteria
1. History of bone marrow transplantation. 2. Body weight \<40 kilograms at screening. 3. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation. 4. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, or coexisting chronic anemia unrelated to PNH). 5. Female participants who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1. 6. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study treatment on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183 | Baseline, Day 183 | Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores | Baseline, Day 183 | FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score. |
| Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183 | Baseline through Day 183 | Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through Day 183. |
| Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183 | Baseline through Day 183 | Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through Day 183. |
| Number Of Participants With Breakthrough Hemolysis Through Day 183 | Baseline through Day 183 | Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia \[hemoglobin \<10 grams (g)/deciliter (dL)\], major adverse vascular event \[including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the upper limit of normal (ULN). |
| Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study | Baseline, End of Study (up to 4 years) | FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score. |
| Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study | Baseline through end of study (up to 4 years) | Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through the end of study. |
| Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study | Baseline through end of study (up to 4 years) | Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through end of study. |
| Number Of Participants With Breakthrough Hemolysis Through End of Study | Baseline through end of study (up to 4 years) | BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia \[hemoglobin \<10 g/dL\], major adverse vascular event \[including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the ULN. |
Countries
Australia, Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were stratified into 1 of 2 groups based on their transfusion history. Stratified participants were randomly assigned in a 1:1 ratio to receive ravulizumab or eculizumab.
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab/Ravulizumab On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight- based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 4 years. | 97 |
| Eculizumab/Ravulizumab Participants received 900 mg of eculizumab q2w for 26 weeks. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 4 years. | 98 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Period | Death | 0 | 3 |
| Extension Period | Lost to Follow-up | 0 | 1 |
| Extension Period | Physician Decision | 3 | 3 |
| Extension Period | Withdrawal by Subject | 1 | 0 |
| Primary Evaluation Period | Lack of Efficacy | 0 | 1 |
| Primary Evaluation Period | Pregnancy | 0 | 1 |
| Primary Evaluation Period | Randomized, not treated | 1 | 1 |
| Primary Evaluation Period | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Ravulizumab/Ravulizumab | Eculizumab/Ravulizumab | Total |
|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 14.41 | 48.8 years STANDARD_DEVIATION 13.97 | 47.7 years STANDARD_DEVIATION 14.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants | 77 Participants | 153 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 17 Participants | 35 Participants |
| Race/Ethnicity, Customized Asian | 23 participants | 19 participants | 42 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 3 participants | 8 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Reported | 13 participants | 13 participants | 26 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Unknown | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized White | 50 participants | 61 participants | 111 participants |
| Sex: Female, Male Female | 47 Participants | 50 Participants | 97 Participants |
| Sex: Female, Male Male | 50 Participants | 48 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 97 | 0 / 98 | 0 / 96 | 3 / 95 |
| other Total, other adverse events | 72 / 97 | 85 / 98 | 83 / 96 | 85 / 95 |
| serious Total, serious adverse events | 4 / 97 | 8 / 98 | 26 / 96 | 33 / 95 |
Outcome results
Primary
Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183
Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).
Time frame: Baseline, Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ravulizumab/Ravulizumab | Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183 | -0.82 percent change |
| Eculizumab/Ravulizumab | Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183 | 8.39 percent change |
Comparison: Adjusting for a possible 10% dropout rate, a minimum of 192 participants were estimated to provide 90% power to demonstrate noninferiority of ravulizumab to eculizumab.95% CI: [-18.84, 0.42]
Secondary
Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores
FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
Time frame: Baseline, Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ravulizumab/Ravulizumab | Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores | 2.01 units on a scale |
| Eculizumab/Ravulizumab | Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores | 0.54 units on a scale |
95% CI: [-0.21, 3.15]
Secondary
Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study
FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
Time frame: Baseline, End of Study (up to 4 years)
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab). Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab/Ravulizumab | Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study | -1.43 units on a scale | Standard Deviation 5.694 |
| Eculizumab/Ravulizumab | Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study | 0.00 units on a scale | Standard Deviation 5.944 |
Secondary
Number Of Participants With Breakthrough Hemolysis Through Day 183
Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia \[hemoglobin \<10 grams (g)/deciliter (dL)\], major adverse vascular event \[including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the upper limit of normal (ULN).
Time frame: Baseline through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Number Of Participants With Breakthrough Hemolysis Through Day 183 | 0 number of participants |
| Eculizumab/Ravulizumab | Number Of Participants With Breakthrough Hemolysis Through Day 183 | 5 number of participants |
Comparison: A difference in the percentages of participants with BTH was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.95% CI: [-18.99, 8.89]
Secondary
Number Of Participants With Breakthrough Hemolysis Through End of Study
BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia \[hemoglobin \<10 g/dL\], major adverse vascular event \[including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the ULN.
Time frame: Baseline through end of study (up to 4 years)
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab). Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Number Of Participants With Breakthrough Hemolysis Through End of Study | 9 number of participants |
| Eculizumab/Ravulizumab | Number Of Participants With Breakthrough Hemolysis Through End of Study | 6 number of participants |
Secondary
Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183
Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through Day 183.
Time frame: Baseline through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183 | 87.6 percentage of participants |
| Eculizumab/Ravulizumab | Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183 | 82.7 percentage of participants |
Comparison: A difference in the percentages of participants achieving transfusion avoidance was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug95% CI: [-4.27, 15.68]
Secondary
Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study
Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through the end of study.
Time frame: Baseline through end of study (up to 4 years)
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab). Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study | 70.83 percentage of participants |
| Eculizumab/Ravulizumab | Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study | 70.53 percentage of participants |
Secondary
Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183
Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through Day 183.
Time frame: Baseline through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183 | 76.3 percentage of participants |
| Eculizumab/Ravulizumab | Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183 | 75.5 percentage of participants |
Comparison: A difference in the percentages of participants with stabilized hemoglobin was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.95% CI: [-10.41, 13.31]
Secondary
Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study
Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through end of study.
Time frame: Baseline through end of study (up to 4 years)
Population: Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab). Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab/Ravulizumab | Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study | 58.33 percentage of participants |
| Eculizumab/Ravulizumab | Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study | 67.37 percentage of participants |