Paroxysmal Nocturnal Hemoglobinuria
Conditions
Brief summary
This study will enroll participants aged 12 years or older with a body weight ≥ 40 kilograms (kg) diagnosed with PNH who have not been previously treated with complement inhibitor therapy. Approximately 50 participants will be treated with Crovalimab for at least 24 weeks.
Interventions
DRUGCrovalimab
Crovalimab will be administered at a dose of 1000 milligrams (mg) IV (for participants with body weight between 40 and 100 kg) or 1500 mg IV (for participants with body weight ≥ 100 kg) on Week 1 Day 1. On Week 1 Day 2 and on Weeks 2, 3 and 4, it will be administered at a dose of 340 mg SC. For Week 5 and Q4W thereafter, it will be administered at a dose of 680 mg SC (for participants with body weight between 40 and 100 kg) or 1020 mg SC (for participants with body weight ≥ 100 kg). Dosing schedule will be as described above.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight ≥ 40 kg at screening * Willingness and ability to comply with all study visits and procedures * Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry * LDH Levels ≥ 2x the ULN at screening * Participants who have at least four transfusions during 12 months prior to screening (documented in the medical record) * Presence of one or more of the PNH-related signs or symptoms within 3 months of screening * Vaccination against Neisseria meningitidis serotypes A, C, W, and Y \< 3 years prior to initiation of study treatment (Day 1) * Vaccination against Haemophilius influenzae type B and Streptococcus pneumonia according to national vaccination recommendations * For participants receiving other therapies (e.g., immunosuppressants, corticosteroids): stable dose for ≥ 28 days prior to screening and up to the first drug administration * Adequate hepatic and renal function * Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 46 weeks (approximately 10.5 months) after the final dose of crovalimab * Platelet count ≥30,000 per cubic millimeter (mm\^3) at screening * ANC \> 500/microlitres (μl) at screening
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 drug administration * Known or suspected immune or hereditary complement deficiency * Known HIV infection with cluster of differentiation 4 (CD4) count \< 200 cells/µl within 24 weeks prior to screening * Infection requiring hospitalization or treatment with IV antibiotics within 28 days prior to screening and up to the first drug administration, or oral antibiotics within 14 days prior to screening and up to the first drug administration * Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration * Presence of fever (≥ 38˚C) within 7 days before the first drug administration * Splenectomy \< 6 months before screening * History of malignancy within 5 years prior to screening and up to the first drug administration * Pregnant or intending to become pregnant during the study or within 46 weeks (10.5 months) after the final dose of study treatment * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage of Participants With Hemolysis Control | From Week 5 up to Week 25 | A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by lactate dehydrogenase (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. The dependent variable was the binary indicator for hemolysis control. Independent variables are categorical effects of visits, continuous baseline LDH. |
| Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening | 24 Weeks Prior to Screening, Baseline to Week 25 | TA was defined as participants who were packed red blood cell (pRBC) transfusion-free and did not require transfusion per protocol-specified guidelines. TA within 24 weeks prior to screening was based on the pRBC transfusion history in the medical records. Reported in this outcome measure is the difference in the percentage of participants between "baseline through Week 25" and "within 24 weeks prior to screening". 95% Confidence Interval (CI) for the difference between the percentage of participants with transfusion avoidance between Pre-screening and Post-baseline is calculated using the Newcombe method. Screening= Day -28 to Day -1 and Baseline= Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Breakthrough Hemolysis (BTH) | Baseline, 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. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to have experienced a BTH event. Percentages have been rounded off to the first decimal point. |
| Percentage of Participants With Stabilized Hemoglobin | Baseline, Week 25 | Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to not have hemoglobin stabilization. |
| Change From Baseline in Fatigue in Adults Aged >=18 Years | Baseline, Week 2, Week 5, Week 9, Week 17, Week 25 | Fatigue was assessed using functional assessment of chronic illness therapy-fatigue (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. FACIT-F assessment was unintentionally missed in the Schedule of Activities (SoA) table, which site used to guide the assessments at each timepoint. Therefore, data were not collected at Week 25. |
| Percentage of Participants With Adverse Events (AEs) | Up to 7 years | — |
| Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity, and Infections (Including Meningococcal Meningitis) | Up to 7 years | — |
| Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation | Up to 7 years | — |
| Trough Serum Concentration of Crovalimab Over Time | Up to 7 years | — |
| Serum Concentrations of Crovalimab | Up to 7 years | — |
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab | Up to 7 years | — |
| Terminal Complement Activity as Measured by Liposome Immunoassay (LIA) | Up to 7 years | — |
| Change Over Time in Total and Free C5 Concentration | Up to 7 years | — |
| Observed Value in Absolute Reticulocyte Count | Up to 7 years | — |
| Observed Value in Free Hemoglobin | Up to 7 years | — |
| Observed Value in Haptoglobin | Up to 7 years | — |
| Percent Change From Baseline in Absolute Reticulocyte Count | Baseline, Week 25 | — |
| Percent Change From Baseline in Free Hemoglobin | Baseline, Week 25 | — |
| Percent Change From Baseline in Haptoglobin | Baseline, Week 25 | — |
Countries
China
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in China.
Pre-assignment details
A total of 51 participants with a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) were enrolled in the study and received at least 1 dose of crovalimab.
Participants by arm
| Arm | Count |
|---|---|
| Crovalimab Crovalimab was administered at an 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 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab. | 51 |
| Total | 51 |
Baseline characteristics
| Characteristic | Crovalimab |
|---|---|
| Age, Continuous | 33.0 Years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 51 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 51 |
| other Total, other adverse events | 46 / 51 |
| serious Total, serious adverse events | 4 / 51 |
Outcome results
Primary
Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening
TA was defined as participants who were packed red blood cell (pRBC) transfusion-free and did not require transfusion per protocol-specified guidelines. TA within 24 weeks prior to screening was based on the pRBC transfusion history in the medical records. Reported in this outcome measure is the difference in the percentage of participants between baseline through Week 25 and within 24 weeks prior to screening. 95% Confidence Interval (CI) for the difference between the percentage of participants with transfusion avoidance between Pre-screening and Post-baseline is calculated using the Newcombe method. Screening= Day -28 to Day -1 and Baseline= Day 1.
Time frame: 24 Weeks Prior to Screening, Baseline to Week 25
Population: PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crovalimab | Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening | 50.98 percentage of participants |
Comparison: Percentage of participants who achieved TA from baseline through Week 25 were compared with the percentage of participants who reported TA within 24 weeks prior to screening.p-value: <0.0001Paired McNemar
Primary
Mean Percentage of Participants With Hemolysis Control
A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by lactate dehydrogenase (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. The dependent variable was the binary indicator for hemolysis control. Independent variables are categorical effects of visits, continuous baseline LDH.
Time frame: From Week 5 up to Week 25
Population: Primary Analysis Population (PAP) included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Crovalimab | Mean Percentage of Participants With Hemolysis Control | 78.66 mean percentage of participants |
Secondary
Change From Baseline in Fatigue in Adults Aged >=18 Years
Fatigue was assessed using functional assessment of chronic illness therapy-fatigue (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. FACIT-F assessment was unintentionally missed in the Schedule of Activities (SoA) table, which site used to guide the assessments at each timepoint. Therefore, data were not collected at Week 25.
Time frame: Baseline, Week 2, Week 5, Week 9, Week 17, Week 25
Population: PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion. Overall number analyzed is the number of participants ≥18 years with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crovalimab | Change From Baseline in Fatigue in Adults Aged >=18 Years | Baseline | 31.77 score on a scale | Standard Deviation 8.53 |
| Crovalimab | Change From Baseline in Fatigue in Adults Aged >=18 Years | Change from Baseline at Week 2 | 6.67 score on a scale | Standard Deviation 8.02 |
| Crovalimab | Change From Baseline in Fatigue in Adults Aged >=18 Years | Change from Baseline at Week 5 | 8.08 score on a scale | Standard Deviation 9.28 |
| Crovalimab | Change From Baseline in Fatigue in Adults Aged >=18 Years | Change from Baseline at Week 9 | 8.15 score on a scale | Standard Deviation 10.61 |
| Crovalimab | Change From Baseline in Fatigue in Adults Aged >=18 Years | Change from Baseline at Week 17 | 8.77 score on a scale | Standard Deviation 9.63 |
Secondary
Change Over Time in Total and Free C5 Concentration
Time frame: Up to 7 years
Secondary
Observed Value in Absolute Reticulocyte Count
Time frame: Up to 7 years
Secondary
Observed Value in Free Hemoglobin
Time frame: Up to 7 years
Secondary
Observed Value in Haptoglobin
Time frame: Up to 7 years
Secondary
Percentage of Participants With Adverse Events (AEs)
Time frame: Up to 7 years
Secondary
Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
Time frame: Up to 7 years
Secondary
Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab
Time frame: Up to 7 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. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to have experienced a BTH event. Percentages have been rounded off to the first decimal point.
Time frame: Baseline, Week 25
Population: PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crovalimab | Percentage of Participants With Breakthrough Hemolysis (BTH) | 3.9 percentage of participants |
Secondary
Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity, and Infections (Including Meningococcal Meningitis)
Time frame: Up to 7 years
Secondary
Percentage of Participants With Stabilized Hemoglobin
Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to not have hemoglobin stabilization.
Time frame: Baseline, Week 25
Population: PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crovalimab | Percentage of Participants With Stabilized Hemoglobin | 51.0 percentage of participants |
Secondary
Percent Change From Baseline in Absolute Reticulocyte Count
Time frame: Baseline, Week 25
Population: Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crovalimab | Percent Change From Baseline in Absolute Reticulocyte Count | 40.9411 percent change | Standard Deviation 66.0292 |
Secondary
Percent Change From Baseline in Free Hemoglobin
Time frame: Baseline, Week 25
Population: Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crovalimab | Percent Change From Baseline in Free Hemoglobin | -45.6180 percent change | Standard Deviation 51.8421 |
Secondary
Percent Change From Baseline in Haptoglobin
Time frame: Baseline, Week 25
Population: Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crovalimab | Percent Change From Baseline in Haptoglobin | 295.1351 percent change | Standard Deviation 1735.418 |
Secondary
Serum Concentrations of Crovalimab
Time frame: Up to 7 years
Secondary
Terminal Complement Activity as Measured by Liposome Immunoassay (LIA)
Time frame: Up to 7 years
Secondary
Trough Serum Concentration of Crovalimab Over Time
Time frame: Up to 7 years