Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
Paroxysmal Nocturnal Hemoglobinuria, PNH, Ravulizumab, Ultomiris, Eculizumab, Soliris
Brief summary
The primary purpose of this study is to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ravulizumab in participants who are prescribed and are receiving a higher than approved dose of eculizumab to treat paroxysmal nocturnal hemoglobinuria (PNH).
Interventions
BIOLOGICALEculizumab
Participants must have been prescribed and be receiving a stable dose of eculizumab 1200 milligrams (mg) every 2 weeks (q2w) for at least 3 months prior to the Screening Period. During the Screening Period, participants will continue to receive eculizumab 1200 mg q2w.
BIOLOGICALRavulizumab
During the Treatment Period, participants will receive a loading dose of ravulizumab on Day 1, followed by maintenance doses on Day 15 and every 8 weeks, administered by intravenous infusion. Ravulizumab loading and maintenance doses will be based on participants' body weight per approved dose regimen.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Documented diagnosis of PNH, confirmed by high-sensitivity flow cytometry evaluation of red blood cells and white blood cells, with granulocyte or monocyte clone size of ≥ 5%. 2. Received 1200 mg eculizumab every 12 to 16 days (every 2 weeks) for at least 3 months prior to Screening. 3. LDH ≤ 2 x upper limit of normal (ULN) according to central laboratory, at Screening. 4. To reduce the risk of meningococcal infection (Neisseria meningitidis), all participants must be vaccinated against meningococcal infections within 3 years prior to initiating study drug. 5. Body weight ≥ 40 kilograms. Key
Exclusion criteria
1. History of major adverse vascular events within 6 months of Day 1. 2. History of bone marrow transplantation. 3. Lymphoma, leukemia, myelodysplastic syndrome, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. 4. Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 2 weeks prior to Day 1. 5. Concomitant use of any of the following medications and not on a stable regimen (as judged by the Investigator) for the time period indicated prior to Screening: * Erythropoietin or immunosuppressants for at least 8 weeks * Systemic corticosteroids for at least 4 weeks * Vitamin K antagonists (for example, warfarin) with a stable international normalized ratio level for at least 4 weeks * Iron supplements or folic acid for 4 weeks 6. Live vaccine(s) within 1 month prior to Screening or plans to receive such vaccines during the study. 7. More than 1 LDH value \> 2 × ULN within the 6 months prior to Day 1. 8. Platelet count \< 30,000/cubic millimeter (30 × 10\^9/Liter \[L\]) at Screening. 9. Absolute neutrophil count \< 500/microliter (0.5 × 10\^9/L) at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Free C5-associated BTH | Baseline through Day 351 | Free C5-associated BTH was defined as BTH concurrent with free C5 concentrations ≥0.5 micrograms (μg)/milliliter (mL). 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 \[hemoglobin \<10 grams {g}/deciliter {dL}\], major adverse vascular event \[MAVE\], including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) ≥2 \* upper limit of normal (ULN). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced BTH | Baseline through Day 351 | 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 \[hemoglobin \<10 g/dL\], MAVE, including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 \* ULN. |
| Percent Change From Baseline in LDH at Day 351 | Baseline, Day 351 | — |
| Percentage of Participants Who Received a Red Blood Cell (RBC) Transfusion | Baseline through Day 351 | — |
| Percentage of Participants With Stabilized Hemoglobin | Baseline through Day 351 | Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion from Baseline to Day 351. |
Countries
United Kingdom
Participant flow
Pre-assignment details
The study consisted of a Screening Period of approximately 3 months and a Treatment Period of 351 days. Eligible participants were administered eculizumab 1200 milligrams (mg) every 2 weeks (q2w) optionally at home at the discretion of the Investigator, and preference of the participant during the Screening Period.
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab Participants received a loading dose of ravulizumab on Day 1 and maintenance treatment with ravulizumab on Day 15 and q8w thereafter until Day 351. Ravulizumab loading and maintenance doses were based on the participant's body weight measured at the prior visit, per approved dosing regimen. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Ravulizumab |
|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 11.34 |
| Age, Customized 85 years and over | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants |
| Age, Customized Adults (18-64 years) | 15 Participants |
| Age, Customized Children (2-11 years) | 0 Participants |
| Age, Customized From 65-84 years | 3 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants |
| Age, Customized In utero | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 1 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 15 / 18 |
| serious Total, serious adverse events | 3 / 18 |
Outcome results
Primary
Percentage of Participants Who Experienced Free C5-associated BTH
Free C5-associated BTH was defined as BTH concurrent with free C5 concentrations ≥0.5 micrograms (μg)/milliliter (mL). 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 \[hemoglobin \<10 grams {g}/deciliter {dL}\], major adverse vascular event \[MAVE\], including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) ≥2 \* upper limit of normal (ULN).
Time frame: Baseline through Day 351
Population: The FAS included all participants who received at least 1 dose of ravulizumab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Ravulizumab | Percentage of Participants Who Experienced Free C5-associated BTH | 0 percentage of participants | 95% Confidence Interval 0 |
Secondary
Percentage of Participants Who Experienced 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 \[hemoglobin \<10 g/dL\], MAVE, including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 \* ULN.
Time frame: Baseline through Day 351
Population: The FAS included all participants who received at least 1 dose of ravulizumab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Ravulizumab | Percentage of Participants Who Experienced BTH | 5.6 percentage of participants | 95% Confidence Interval 0.1 |
Secondary
Percentage of Participants Who Received a Red Blood Cell (RBC) Transfusion
Time frame: Baseline through Day 351
Population: The FAS included all participants who received at least 1 dose of ravulizumab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Ravulizumab | Percentage of Participants Who Received a Red Blood Cell (RBC) Transfusion | 33.3 percentage of participants | 95% Confidence Interval 13.3 |
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 from Baseline to Day 351.
Time frame: Baseline through Day 351
Population: The FAS included all participants who received at least 1 dose of ravulizumab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Ravulizumab | Percentage of Participants With Stabilized Hemoglobin | 61.1 percentage of participants | 95% Confidence Interval 35.7 |
Secondary
Percent Change From Baseline in LDH at Day 351
Time frame: Baseline, Day 351
Population: The FAS included all participants who received at least 1 dose of ravulizumab. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Percent Change From Baseline in LDH at Day 351 | -0.81 percent change | Standard Error 6.132 |