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 had never been treated with a complement inhibitor (treatment-naïve).
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 26-week Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 5 years.
Interventions
BIOLOGICALEculizumab
All treatments were given as IV infusions. Participants were administered induction doses of 600 mg followed by maintenance doses of 900 mg.
BIOLOGICALRavulizumab
All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to \<60 kilogram (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.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Criteria For Patient Cohort Originally Enrolled in ALXN1210-PNH-301 Study: Inclusion Criteria: 1. Male or female ≥18 years of age. 2. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry. 3. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin \<10 gram/deciliter), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cells (pRBC) transfusion due to PNH. 4. Lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal at screening. 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. Treatment with a complement inhibitor at any time. 2. History of bone marrow transplantation. 3. Body weight \<40 kg. 4. Females who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1. 5. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater. 6. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation. 7. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH). Eligibility Criteria For Roll-over Cohort: 1. All participants regardless of age, who are currently receiving ALXN1210 IV in an ongoing ALXN1210 study in patients with PNH 2. Participants must be willing and able to give written informed consent and to comply with all Extension study visits and procedures, including the use of any data collection device(s) to directly record patient data 3. Females of childbearing potential and male patients with female partners of childbearing potential must use highly effective contraception continuing until at least 8 months after the last dose of ravulizumab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels | Day 29 through Day 183 | LDH is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L. |
| Percentage Of Participants Who Achieved Transfusion Avoidance (TA) | 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 through Day 183. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants With Breakthrough Hemolysis (BTH) | Baseline through Day 183 | Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \<10 gram/deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to \<1.5 × ULN on therapy. |
| Percent Change From Baseline In LDH Levels | Baseline, Day 183 | Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used. |
| Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue | Baseline, Day 183 | FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used. |
| Percentage Of Participants With Stabilized Hemoglobin Levels | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Estonia, France, Germany, Italy, Japan, Malaysia, Mexico, Poland, Russia, Serbia, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
24 adult and 2 pediatric participants rolled over from other Alexion ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab until end of study.
Pre-assignment details
Participants were stratified into 6 groups based on transfusion history and LDH screening levels. Stratified participants were then randomly assigned in a 1:1 ratio to receive either ravulizumab or eculizumab in the 26-week Primary Evaluation Period.
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab/Ravulizumab Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks. After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years. | 125 |
| Eculizumab/Ravulizumab Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks. After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years. | 121 |
| Roll-Over Cohort: Ravulizumab - Adults Participants in this group rolled over from other ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab for up to 5 years. | 24 |
| Roll-Over Cohort: Ravulizumab - Pediatrics Participants in this group rolled over from other ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab for up to 5 years. | 2 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extension Period | Adverse Event | 1 | 2 | 0 | 0 |
| Extension Period | Death | 4 | 4 | 0 | 0 |
| Extension Period | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Extension Period | Other than specified | 2 | 3 | 2 | 0 |
| Extension Period | Physician Decision | 1 | 4 | 0 | 0 |
| Extension Period | Pregnancy | 3 | 1 | 0 | 0 |
| Extension Period | Withdrawal by Subject | 4 | 3 | 0 | 0 |
| Primary Evaluation Period | Physician Decision | 0 | 1 | 0 | 0 |
| Primary Evaluation Period | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Ravulizumab/Ravulizumab | Eculizumab/Ravulizumab | Roll-Over Cohort: Ravulizumab - Adults | Roll-Over Cohort: Ravulizumab - Pediatrics | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical >=65 years | 14 Participants | 18 Participants | 2 Participants | 0 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 111 Participants | 103 Participants | 22 Participants | 0 Participants | 236 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 13 Participants | 6 Participants | 2 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants | 102 Participants | 0 Participants | 0 Participants | 218 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 18 Participants | 0 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 72 Participants | 57 Participants | 1 Participants | 0 Participants | 130 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 8 Participants | 12 Participants | 0 Participants | 27 Participants |
| Race (NIH/OMB) White | 43 Participants | 51 Participants | 11 Participants | 2 Participants | 107 Participants |
| Sex: Female, Male Female | 60 Participants | 52 Participants | 12 Participants | 1 Participants | 125 Participants |
| Sex: Female, Male Male | 65 Participants | 69 Participants | 12 Participants | 1 Participants | 147 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 / 125 | 0 / 121 | 4 / 124 | 4 / 119 | 0 / 24 | 0 / 2 |
| other Total, other adverse events | 87 / 125 | 86 / 121 | 102 / 124 | 100 / 119 | 13 / 24 | 0 / 2 |
| serious Total, serious adverse events | 11 / 125 | 9 / 121 | 52 / 124 | 43 / 119 | 2 / 24 | 0 / 2 |
Outcome results
Primary
Percentage Of Participants Who Achieved Transfusion Avoidance (TA)
Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.
Time frame: Baseline through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Percentage Of Participants Who Achieved Transfusion Avoidance (TA) | 73.6 percentage of participants |
| Eculizumab | Percentage Of Participants Who Achieved Transfusion Avoidance (TA) | 66.1 percentage of participants |
Comparison: A minimum of 193 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab. The difference of percentages were calculated using stratified Newcombe CI method. Stratification factors were: observed stratification groups of packed red blood cells (pRBC)/whole blood units transfused in the 1 year prior to first dose of study drug and screening LDH levels.95% CI: [-4.66, 18.14]
Primary
Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels
LDH is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L.
Time frame: Day 29 through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels | 0.536 proportion of participants |
| Eculizumab | Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels | 0.494 proportion of participants |
Comparison: A minimum of 142 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab.95% CI: [0.796, 1.769]
Secondary
Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue
FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.
Time frame: Baseline, Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ravulizumab | Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue | 7.07 units on a scale |
| Eculizumab | Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue | 6.40 units on a scale |
95% CI: [-1.21, 2.55]
Secondary
Percentage Of Participants With Breakthrough Hemolysis (BTH)
Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \<10 gram/deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to \<1.5 × ULN on therapy.
Time frame: Baseline through Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Percentage Of Participants With Breakthrough Hemolysis (BTH) | 4.0 percentage of participants |
| Eculizumab | Percentage Of Participants With Breakthrough Hemolysis (BTH) | 10.7 percentage of participants |
Comparison: The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.95% CI: [-14.21, 0.18]
Secondary
Percentage Of Participants With Stabilized Hemoglobin Levels
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 study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Percentage Of Participants With Stabilized Hemoglobin Levels | 68.0 percentage of participants |
| Eculizumab | Percentage Of Participants With Stabilized Hemoglobin Levels | 64.5 percentage of participants |
Comparison: The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.95% CI: [-8.8, 14.64]
Secondary
Percent Change From Baseline In LDH Levels
Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used.
Time frame: Baseline, Day 183
Population: Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ravulizumab | Percent Change From Baseline In LDH Levels | -76.84 percent change |
| Eculizumab | Percent Change From Baseline In LDH Levels | -76.02 percent change |
95% CI: [-5.21, 3.56]