Paroxysmal Nocturnal Hemoglobinuria
Conditions
Brief summary
A study designed to evaluate the non-inferiority of crovalimab compared with eculizumab in participants with PNH who have not been previously treated with complement inhibitor therapy.
Interventions
DRUGCrovalimab
Dosing depends on body weight. Participants will be dosed as follows: * 5 kg to \< 12 kg: 100 mg IV on Week 1 Day 1 (W1D1); 85 mg SC on Week 1 Day 2 (W1D2) and Q2W from Week 3 until end of study * 12 kg to \< 20 kg: 200 mg IV on W1D1; 85 mg SC on W1D2, Weeks 2, 3 and 4; 170 mg SC, Q2W from Week 5 until end of study * 20 kg to \< 30 kg: 300 mg IV on W1D1; 85 mg SC on W1D2, Weeks 2, 3 and 4; 340 mg SC, Q4W from Week 5 until end of study * 30 kg to \< 40 kg: 400 mg IV on W1D1; 170 mg SC on W1D2, Weeks 2, 3 and 4; 510 mg SC, Q4W from Week 5 until end of study * 40 kg to \< 100 kg: 1000 mg IV on W1D1; 340 mg SC W1D2, Weeks 2, 3 and 4; 680 mg SC, Q4W from Week 5 until end of study * 100 kg: 1500 mg IV on W1D1; 340 mg SC W1D2, Weeks 2, 3 and 4; 1020 mg SC, Q4W from Week 5 until end of study.
DRUGEculizumab
Eculizumab will be administered as specified in the respective arm.
Sponsors
Hoffmann-La Roche
Chugai Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight ≥ 40 kg at screening (pediatric participants with body weight \< 40 kg) * Willingness and ability to comply with all study visits and procedures * Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry * LDH level ≥ 2x ULN at screening (as per local assessment) * Vaccination against Neisseria meningitidis serotypes A, C, W, and Y\< 3 years prior to initiation of study treatment; or, if not previously done, vaccination administered no later than one week after the first drug administration * Women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for 10.5 months after the final dose of crovalimab or for 3 months after the final dose of eculizumab (or longer if required by the local product label)
Exclusion criteria
* Current or previous treatment with a complement inhibitor * History of allogeneic bone marrow transplantation * History of Neisseria meningitidis infection within 6 months prior to screening and up to first study drug administration * History of myelodysplastic syndrome with Revised International Prognostic Scoring System (IPSS-R) prognostic risk categories of intermediate, high and very high * Pregnant or breastfeeding, or intending to become pregnant during the study, within 10.5 months after the final dose of crovalimab, or 3 months after the final dose of eculizumab (or longer if required by the local product label) * Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within 28 days of screening or within 5 half-lives of that investigational product, whichever is greater * Concurrent disease, treatment, procedure or surgery, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose any additional risk for the participant, or would, in the opinion of the Investigator, preclude the participant's safe participation in and completion of the study * Splenectomy \< 6 months before screening * Positive for Active Hepatitis B and C infection (HBV/HCV) * History of or ongoing cryoglobulinemia at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hemolysis Control Measured by LDH | Week 5 to Week 25 | A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by LDH ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. Percentages are rounded off to the nearest single decimal. |
| Percentage of Participants With Transfusion Avoidance (TA) | Baseline to Week 25 | TA is defined as participants who are packed red blood cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines. 95% Confidence Interval (CI) for percentage of participants with TA was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have had a transfusion. Percentages are rounded off to the nearest single decimal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Absolute Reticulocyte Count | Baseline, Day 1 Week 1, Week 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25 | — |
| Percentage of Participants With Breakthrough Hemolysis (BTH) | Baseline to Week 25 | BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \< 10 grams per deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. 95% CI for percentage of participants with BTH was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have experienced a BTH event. Percentages are rounded off to the nearest single decimal. |
| Percentage of Participants With Stabilization of Hemoglobin | Baseline to Week 25 | Stabilized hemoglobin is defined as avoidance of a \>= 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. 95% CI for percentage of participants with stabilized hemoglobin was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to not have had hemoglobin stabilization. Percentages are rounded off to the nearest single decimal. |
| Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | Baseline to Week 25 | Fatigue was assessed using FACIT-F scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 ("not at all") to 4 ("very much so"). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only. |
| Percentage of Participants With Adverse Events (AEs) | Up to 6 years | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. |
| Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (Including Meningococcal Meningitis) | Up to 6 years | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Injection-site reactions or infusion-related reaction are AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection. |
| Percentage of Participants With AEs Leading to Study Drug Discontinuation | Up to 6 years | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. |
| Percentage of Participants With Clinical Manifestations of Drug-Target-Drug Complex (DTDC) Formation Amongst Participants Who Switched to Crovalimab Treatment From Eculizumab Treatment | Up to 6 years | — |
| Serum Concentrations of Crovalimab And Eculizumab Over Time | Up to 6 years | — |
| Percentage of Participants With Anti-Crovalimab Antibodies | Up to 6 years | — |
| Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time | Up to 6 years | — |
| Change Over Time in Free C5 Concentration in Crovalimab-Treated Participants | Up to 6 years | — |
| Change From Baseline in Free Hemoglobin | Baseline, Week 2, 3, 4, 5, 9, 13, 17, 21, and 25 | — |
| Observed Value in Reticulocyte Count (Count/Milliliters [mL]) | Up to 6 years | — |
| Change From Baseline in Haptoglobin | Baseline, Week 2, 3, 4, 5, 9, 13, 15, 17, 21, and 25 | — |
| Observed Value in Haptoglobin (Milligrams Per Deciliter [mg/dL]) | Up to 6 years | — |
Countries
Argentina, Brazil, China, France, Germany, Greece, Japan, Lithuania, Malaysia, Mexico, Netherlands, Philippines, Poland, Portugal, Romania, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Participants were enrolled at centres in Argentina, Brazil, China, France, Greece, Germany, Hong Kong, Japan, Lithuania, Malaysia, Mexico, Netherlands, Philippines, Poland, Portugal, Romania Republic of Korea, Singapore, Spain, Sweden, Thailand, Türkiye, Taiwan, Ukraine, and United Kingdom from 08 Oct 2020 to 16 Nov 2022. The study is ongoing.
Pre-assignment details
A total of 204 participants who were diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) and who had not been previously treated with a complement-inhibitor therapy were randomized in a ratio of 2:1, 135 to crovalimab (Arm A) and 69 to eculizumab (Arm B). 6 paediatric participants were enrolled into non-randomized crovalimab (Arm C).
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Crovalimab Crovalimab was administered at an initial loading dose of 1000 milligram (mg) (for participants with body weight between 40 and 100 kilogram (kg)) or 1500 mg (for participants with body weight \>=100kg), as intravenous (IV) injection on Day 1 of Week 1 followed by four weekly subcutaneous (SC) injections of 340 mg starting on Day 2 of Week 1 and then once weekly (QW) at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight \>=100kg) once every 4 weeks (Q4W) from Week 5 until 24 weeks in primary treatment period. After Week 24, participants continued to receive maintenance dose of crovalimab up to a maximum of 5 years in the extension treatment period. | 135 |
| Arm B: Eculizumab Participants received loading doses of eculizumab 600 mg IV on Days 1, 8, 15, and 22, followed by maintenance doses of 900 mg IV on Day 29 and every 2 weeks (Q2W) thereafter up to Week 24 in the primary treatment period. Participants who switched to crovalimab received crovalimab as an IV loading dose of 1000 mg (if body weight was between 40 kg to \<100 kg) or 1500 mg (if body weight was \>=100kg) on Week 25 Day 1, 340 mg SC on Week 25 Day 2, then 340 mg SC QW on Weeks 26, 27, 28, followed by crovalimab maintenance dose of 680 mg SC (if body weight was between 40 kg to \<100 kg) or 1020 mg SC (if body weight was \>=100kg) on Week 29 and Q4W thereafter up to a maximum of 5 years in the extension treatment period. | 69 |
| Arm C: Crovalimab Pediatric participants received initial loading dose of 1000 mg (for participants with body weight between 40 and 100 kg) or 1500 mg (for participants with body weight \>=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight \>=100kg) Q4W from Week 5 until 24 weeks in primary treatment period. After Week 24, participants continued to receive maintenance dose of crovalimab up to a maximum of 5 years in the extension treatment period. | 6 |
| Total | 210 |
Baseline characteristics
| Characteristic | Arm A: Crovalimab | Arm B: Eculizumab | Arm C: Crovalimab | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 2 Participants | 6 Participants | 8 Participants |
| Age, Categorical >=65 years | 13 Participants | 9 Participants | 0 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 58 Participants | 0 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 6 Participants | 1 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 114 Participants | 61 Participants | 5 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 86 Participants | 51 Participants | 5 Participants | 142 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 45 Participants | 16 Participants | 0 Participants | 61 Participants |
| Sex: Female, Male Female | 58 Participants | 34 Participants | 2 Participants | 94 Participants |
| Sex: Female, Male Male | 77 Participants | 35 Participants | 4 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 135 | 1 / 69 | 0 / 6 |
| other Total, other adverse events | 102 / 135 | 55 / 69 | 5 / 6 |
| serious Total, serious adverse events | 22 / 135 | 14 / 69 | 0 / 6 |
Outcome results
Primary
Percentage of Participants With Hemolysis Control Measured by LDH
A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by LDH ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. Percentages are rounded off to the nearest single decimal.
Time frame: Week 5 to Week 25
Population: PAP included all randomized participants in Arms A and B who received at least one dose of the originally assigned treatment and having at least one valid LDH level assessment by the central laboratory after the first IV infusion by planned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Crovalimab | Percentage of Participants With Hemolysis Control Measured by LDH | 79.3 percentage of participants |
| Arm B: Eculizumab | Percentage of Participants With Hemolysis Control Measured by LDH | 79.0 percentage of participants |
95% CI: [0.57, 1.82]
Primary
Percentage of Participants With Transfusion Avoidance (TA)
TA is defined as participants who are packed red blood cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines. 95% Confidence Interval (CI) for percentage of participants with TA was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have had a transfusion. Percentages are rounded off to the nearest single decimal.
Time frame: Baseline to Week 25
Population: Primary Analysis Population (PAP) included all randomized participants in Arms A and B who received at least one dose of the originally assigned treatment and having at least one valid lactate dehydrogenase (LDH) level assessment by the central laboratory after the first IV infusion by planned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Crovalimab | Percentage of Participants With Transfusion Avoidance (TA) | 65.7 percentage of participants |
| Arm B: Eculizumab | Percentage of Participants With Transfusion Avoidance (TA) | 68.1 percentage of participants |
95% CI: [-15.67, 11.14]
Secondary
Change From Baseline in Absolute Reticulocyte Count
Time frame: Baseline, Day 1 Week 1, Week 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25
Population: Randomized Safety Population includes all randomized participants who have received at least one dose of study treatment. Includes only participants from Arms A and B. Overall number of participants analyzed is the number of participants ≥18 years with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 13 | 24.47 10^9 cells/liter (L) | Standard Deviation 48.92 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 1 Day 1 | -58.50 10^9 cells/liter (L) | — |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 15 | -838.52 10^9 cells/liter (L) | Standard Deviation 6735.13 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 5 | -1126.63 10^9 cells/liter (L) | Standard Deviation 9074.19 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 17 | 1929.82 10^9 cells/liter (L) | Standard Deviation 15576.37 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 3 | -71.08 10^9 cells/liter (L) | Standard Deviation 533.01 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 19 | 62.91 10^9 cells/liter (L) | Standard Deviation 390.39 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 7 | -3517.66 10^9 cells/liter (L) | Standard Deviation 26606.21 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 21 | 633.95 10^9 cells/liter (L) | Standard Deviation 4919.97 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 9 | 12.60 10^9 cells/liter (L) | Standard Deviation 62.05 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 23 | 698.79 10^9 cells/liter (L) | Standard Deviation 5409.05 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 2 | 542.90 10^9 cells/liter (L) | Standard Deviation 4314.07 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 25 | 1396.46 10^9 cells/liter (L) | Standard Deviation 11622.57 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 11 | 425.66 10^9 cells/liter (L) | Standard Deviation 3343.99 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Baseline | 2865.56 10^9 cells/liter (L) | Standard Deviation 22637.24 |
| Arm A: Crovalimab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 4 | 8.52 10^9 cells/liter (L) | Standard Deviation 58.01 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 7 | 7020.33 10^9 cells/liter (L) | Standard Deviation 38344.72 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Baseline | 164.26 10^9 cells/liter (L) | Standard Deviation 114.27 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 2 | 105.88 10^9 cells/liter (L) | Standard Deviation 601.77 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 3 | -15.62 10^9 cells/liter (L) | Standard Deviation 53.79 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 4 | -10.56 10^9 cells/liter (L) | Standard Deviation 51.36 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 5 | 4.85 10^9 cells/liter (L) | Standard Deviation 49.43 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 9 | 20.65 10^9 cells/liter (L) | Standard Deviation 60.04 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 11 | 26.12 10^9 cells/liter (L) | Standard Deviation 81.8 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 13 | 28.61 10^9 cells/liter (L) | Standard Deviation 78.48 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 15 | 37.20 10^9 cells/liter (L) | Standard Deviation 77.52 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 17 | 33.22 10^9 cells/liter (L) | Standard Deviation 73.34 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 19 | 22.16 10^9 cells/liter (L) | Standard Deviation 70.68 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 21 | 15.90 10^9 cells/liter (L) | Standard Deviation 72.72 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 23 | 27.51 10^9 cells/liter (L) | Standard Deviation 85.87 |
| Arm B: Eculizumab | Change From Baseline in Absolute Reticulocyte Count | Change at Week 25 | 32.31 10^9 cells/liter (L) | Standard Deviation 97.79 |
Secondary
Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale
Fatigue was assessed using FACIT-F scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 (not at all) to 4 (very much so). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only.
Time frame: Baseline to Week 25
Population: PAP included all randomized participants in Arms A and B who received at least one dose of the originally assigned treatment and having at least one valid LDH level assessment by the central laboratory after the first IV infusion by planned treatment. Overall number of participants analyzed is the number of participants ≥18 years with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Crovalimab | Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | Baseline | 36.02 score on scale | Standard Error 0.877 |
| Arm A: Crovalimab | Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | Change at Week 25 | 7.79 score on scale | Standard Error 0.661 |
| Arm B: Eculizumab | Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | Baseline | 35.09 score on scale | Standard Error 1.408 |
| Arm B: Eculizumab | Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | Change at Week 25 | 5.15 score on scale | Standard Error 0.88 |
95% CI: [0.68, 4.6]
Secondary
Change From Baseline in Free Hemoglobin
Time frame: Baseline, Week 2, 3, 4, 5, 9, 13, 17, 21, and 25
Population: Randomized Safety Population includes all randomized participants who have received at least one dose of study treatment. Includes only participants from Arms A and B. Overall number of participants analyzed is the number of participants ≥18 years with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 4 | -413.16 milligram per litre (mg)/L | Standard Deviation 281.4 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 13 | -409.94 milligram per litre (mg)/L | Standard Deviation 298.14 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 3 | -409.10 milligram per litre (mg)/L | Standard Deviation 286.35 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 17 | -408.15 milligram per litre (mg)/L | Standard Deviation 285.24 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 5 | -386.62 milligram per litre (mg)/L | Standard Deviation 424.67 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 21 | -367.86 milligram per litre (mg)/L | Standard Deviation 341.53 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 2 | -406.39 milligram per litre (mg)/L | Standard Deviation 273.33 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 25 | -431.50 milligram per litre (mg)/L | Standard Deviation 277.83 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Change at Week 9 | -404.29 milligram per litre (mg)/L | Standard Deviation 298.64 |
| Arm A: Crovalimab | Change From Baseline in Free Hemoglobin | Baseline | 474.88 milligram per litre (mg)/L | Standard Deviation 276.49 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 2 | -407.10 milligram per litre (mg)/L | Standard Deviation 339.84 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Baseline | 495.69 milligram per litre (mg)/L | Standard Deviation 393.56 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 3 | -393.20 milligram per litre (mg)/L | Standard Deviation 352.22 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 4 | -418.00 milligram per litre (mg)/L | Standard Deviation 441.01 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 5 | -421.14 milligram per litre (mg)/L | Standard Deviation 402.64 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 9 | -405.89 milligram per litre (mg)/L | Standard Deviation 425.73 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 13 | -328.56 milligram per litre (mg)/L | Standard Deviation 586.25 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 17 | -340.00 milligram per litre (mg)/L | Standard Deviation 503.24 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 21 | -387.63 milligram per litre (mg)/L | Standard Deviation 462.1 |
| Arm B: Eculizumab | Change From Baseline in Free Hemoglobin | Change at Week 25 | -334.96 milligram per litre (mg)/L | Standard Deviation 516.4 |
Secondary
Change From Baseline in Haptoglobin
Time frame: Baseline, Week 2, 3, 4, 5, 9, 13, 15, 17, 21, and 25
Population: Randomized Safety Population includes all randomized participants who have received at least one dose of study treatment. Includes only participants from Arms A and B. Overall number of participants analyzed is the number of participants ≥18 years with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Baseline | 0.05 gram (g)/L | Standard Deviation 0 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 2 | 0.05 gram (g)/L | Standard Deviation 0.14 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 3 | 0.05 gram (g)/L | Standard Deviation 0.16 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 4 | 0.08 gram (g)/L | Standard Deviation 0.21 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 5 | 0.06 gram (g)/L | Standard Deviation 0.16 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 9 | 0.05 gram (g)/L | Standard Deviation 0.17 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 13 | 0.04 gram (g)/L | Standard Deviation 0.17 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 17 | 0.05 gram (g)/L | Standard Deviation 0.16 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 21 | 0.06 gram (g)/L | Standard Deviation 0.18 |
| Arm A: Crovalimab | Change From Baseline in Haptoglobin | Change at Week 25 | 0.06 gram (g)/L | Standard Deviation 0.17 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 17 | 0.05 gram (g)/L | Standard Deviation 0.14 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Baseline | 0.05 gram (g)/L | Standard Deviation 0 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 9 | 0.07 gram (g)/L | Standard Deviation 0.23 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 2 | 0.08 gram (g)/L | Standard Deviation 0.19 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 25 | 0.05 gram (g)/L | Standard Deviation 0.21 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 3 | 0.11 gram (g)/L | Standard Deviation 0.28 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 13 | 0.06 gram (g)/L | Standard Deviation 0.21 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 4 | 0.12 gram (g)/L | Standard Deviation 0.28 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 21 | 0.06 gram (g)/L | Standard Deviation 0.22 |
| Arm B: Eculizumab | Change From Baseline in Haptoglobin | Change at Week 5 | 0.09 gram (g)/L | Standard Deviation 0.23 |
Secondary
Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time
Time frame: Up to 6 years
Secondary
Change Over Time in Free C5 Concentration in Crovalimab-Treated Participants
Time frame: Up to 6 years
Secondary
Observed Value in Haptoglobin (Milligrams Per Deciliter [mg/dL])
Time frame: Up to 6 years
Secondary
Observed Value in Reticulocyte Count (Count/Milliliters [mL])
Time frame: Up to 6 years
Secondary
Percentage of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
Time frame: Up to 6 years
Secondary
Percentage of Participants With AEs Leading to Study Drug Discontinuation
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
Time frame: Up to 6 years
Secondary
Percentage of Participants With Anti-Crovalimab Antibodies
Time frame: Up to 6 years
Secondary
Percentage of Participants With Breakthrough Hemolysis (BTH)
BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \< 10 grams per deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. 95% CI for percentage of participants with BTH was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have experienced a BTH event. Percentages are rounded off to the nearest single decimal.
Time frame: Baseline to Week 25
Population: PAP included all randomized participants in Arms A and B who received at least one dose of the originally assigned treatment and having at least one valid LDH level assessment by the central laboratory after the first IV infusion by planned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Crovalimab | Percentage of Participants With Breakthrough Hemolysis (BTH) | 10.4 percentage of participants |
| Arm B: Eculizumab | Percentage of Participants With Breakthrough Hemolysis (BTH) | 14.5 percentage of participants |
95% CI: [-14.82, 5.26]
Secondary
Percentage of Participants With Clinical Manifestations of Drug-Target-Drug Complex (DTDC) Formation Amongst Participants Who Switched to Crovalimab Treatment From Eculizumab Treatment
Time frame: Up to 6 years
Secondary
Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (Including Meningococcal Meningitis)
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Injection-site reactions or infusion-related reaction are AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection.
Time frame: Up to 6 years
Secondary
Percentage of Participants With Stabilization of Hemoglobin
Stabilized hemoglobin is defined as avoidance of a \>= 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. 95% CI for percentage of participants with stabilized hemoglobin was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to not have had hemoglobin stabilization. Percentages are rounded off to the nearest single decimal.
Time frame: Baseline to Week 25
Population: PAP included all randomized participants in Arms A and B who received at least one dose of the originally assigned treatment and having at least one valid LDH level assessment by the central laboratory after the first IV infusion by planned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Crovalimab | Percentage of Participants With Stabilization of Hemoglobin | 63.4 percentage of participants |
| Arm B: Eculizumab | Percentage of Participants With Stabilization of Hemoglobin | 60.9 percentage of participants |
95% CI: [-11.37, 16.31]
Secondary
Serum Concentrations of Crovalimab And Eculizumab Over Time
Time frame: Up to 6 years