Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Keywords
PNH
Brief summary
The purpose of the study is to evaluate the safety and efficacy of zilucoplan (RA101495) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). There will be two groups of patients in the study: the first group will include patients who have never received eculizumab for treatment of PNH. The second group will include patients who have received treatment with eculizumab for at least 6 months prior to the study. Patients will be treated with RA101495 for 12 weeks.
Interventions
0.3mg/kg subcutaneously (SC) at Day 1 (loading dose) followed by a starting maintenance dose of 0.1 mg/kg daily SC
Sponsors
Ra Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PNH by flow cytometry * For treatment naive patients: subjects must not have received treatment with eculizumab prior to or during the Screening Period and must have a lactate dehydrogenase (LDH) level ≥2 times the upper limit of normal (xULN) during Screening * For patients who previously received eculizumab: subjects must have received treatment with eculizumab for at least 6 months prior to Screening
Exclusion criteria
* History of meningococcal disease * Current systemic infection or suspicion of active bacterial infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change-from-baseline in Serum Lactate Dehydrogenase (LDH) Level. | Through Week 12 of the study | The primary efficacy endpoint is the change-from-baseline in serum LDH levels during this period, defined as the mean LDH values of Weeks 6, 8, 10, and 12 minus the baseline value of LDH. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Hemoglobin | Through Week 12 of the Study | Changes from baseline at each of the scheduled post-baseline time-points |
| Changes From Baseline in Free Hemoglobin Values | Through Week 12 of the study | Changes from baseline at each of the scheduled post-baseline time-points |
| Changes From Baseline in Bilirubin Values | Through Week 12 of the study | Changes from baseline at each of the scheduled post-baseline time-points |
| Reticulocyte Values | Through Week 12 of the Study | Changes from baseline at each of the scheduled post-baseline time-points |
| Hemoglobinuria Values | Through Week 12 of the Study | Changes from baseline at each of the scheduled post-baseline time-points; Hemoglobinuria was assessed using a urine colorimetric scoring system with a score of 1 through 10. Where 1 represents no hemoglobinuria and 10 represents maximum hemoglobinuria. |
| Haptoglobin Values | Through Week 12 of the Study | Changes from baseline at each of the scheduled post-baseline time-points |
Countries
Australia, Canada, Denmark, Finland, Germany, Hungary, New Zealand, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (Treatment Naive) 0.3mg/kg subcutaneously (SC) at Day 1 (loading dose) followed by a starting maintenance dose of 0.1 mg/kg daily SC | 10 |
| Cohort B (Previously on Eculizumab) 0.3mg/kg subcutaneously (SC) at Day 1 (loading dose) followed by a starting maintenance dose of 0.1 mg/kg daily SC | 16 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 8 |
Baseline characteristics
| Characteristic | Cohort A (Treatment Naive) | Cohort B (Previously on Eculizumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 11 Participants | 18 Participants |
| Age, Continuous | 59.4 years STANDARD_DEVIATION 14.5 | 49.6 years STANDARD_DEVIATION 18.5 | 53.4 years STANDARD_DEVIATION 17.4 |
| BMI | 27.30 kg/m2 STANDARD_DEVIATION 6.15 | 26.95 kg/m2 STANDARD_DEVIATION 4.14 | 27.08 kg/m2 STANDARD_DEVIATION 4.89 |
| Height | 168.25 cm STANDARD_DEVIATION 11.08 | 171.10 cm STANDARD_DEVIATION 8.69 | 170.00 cm STANDARD_DEVIATION 9.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 14 Participants | 24 Participants |
| Region of Enrollment Australia | 0 participants | 5 participants | 5 participants |
| Region of Enrollment Canada | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Denmark | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Finland | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Germany | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 2 participants |
| Region of Enrollment New Zealand | 4 participants | 0 participants | 4 participants |
| Region of Enrollment United Kingdom | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 13 Participants |
| Weight | 77.77 kg STANDARD_DEVIATION 20.64 | 79.16 kg STANDARD_DEVIATION 14.86 | 78.63 kg STANDARD_DEVIATION 16.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 16 |
| other Total, other adverse events | 10 / 10 | 15 / 16 |
| serious Total, serious adverse events | 2 / 10 | 1 / 16 |
Outcome results
Primary
Change-from-baseline in Serum Lactate Dehydrogenase (LDH) Level.
The primary efficacy endpoint is the change-from-baseline in serum LDH levels during this period, defined as the mean LDH values of Weeks 6, 8, 10, and 12 minus the baseline value of LDH.
Time frame: Through Week 12 of the study
Population: Efficacy Evaluable
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A (Treatment Naive) | Change-from-baseline in Serum Lactate Dehydrogenase (LDH) Level. | -695.2 U/L | Standard Deviation 589.2 |
| Cohort B (Previously on Eculizumab) | Change-from-baseline in Serum Lactate Dehydrogenase (LDH) Level. | 216.7 U/L | Standard Deviation 209.2 |
Secondary
Changes From Baseline in Bilirubin Values
Changes from baseline at each of the scheduled post-baseline time-points
Time frame: Through Week 12 of the study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 1 | 1.3 umol/L | Standard Deviation 7.2 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 2 | 3.1 umol/L | Standard Deviation 7.7 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 3 | 4.4 umol/L | Standard Deviation 9 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 4 | 4.0 umol/L | Standard Deviation 6.7 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 6 | 4.1 umol/L | Standard Deviation 7.4 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 8 | 4.0 umol/L | Standard Deviation 6.1 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 10 | 5.7 umol/L | Standard Deviation 10.9 |
| Cohort A (Treatment Naive) | Changes From Baseline in Bilirubin Values | Week 12 | 4.6 umol/L | Standard Deviation 11.8 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 12 | 0.9 umol/L | Standard Deviation 4.5 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 1 | 1.9 umol/L | Standard Deviation 4.5 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 6 | 3.8 umol/L | Standard Deviation 7.8 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 2 | 4.4 umol/L | Standard Deviation 6.5 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 10 | 1.5 umol/L | Standard Deviation 6.1 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 3 | 6.8 umol/L | Standard Deviation 7.5 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 8 | 4.4 umol/L | Standard Deviation 9.9 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Bilirubin Values | Week 4 | 4.3 umol/L | Standard Deviation 6.5 |
Secondary
Changes From Baseline in Free Hemoglobin Values
Changes from baseline at each of the scheduled post-baseline time-points
Time frame: Through Week 12 of the study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 1 | -7.84 mg/dL | Standard Deviation 8.37 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 2 | -8.31 mg/dL | Standard Deviation 9.07 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 3 | -5.65 mg/dL | Standard Deviation 10.25 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 4 | -7.57 mg/dL | Standard Deviation 8.12 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 6 | -8.24 mg/dL | Standard Deviation 9.19 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 8 | -7.62 mg/dL | Standard Deviation 9.07 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 10 | -7.60 mg/dL | Standard Deviation 9.03 |
| Cohort A (Treatment Naive) | Changes From Baseline in Free Hemoglobin Values | Week 12 | -7.39 mg/dL | Standard Deviation 10.1 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 12 | -2.23 mg/dL | Standard Deviation 11.32 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 1 | 3.55 mg/dL | Standard Deviation 18.51 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 6 | -3.53 mg/dL | Standard Deviation 10.66 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 2 | -1.00 mg/dL | Standard Deviation 11.66 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 10 | -2.02 mg/dL | Standard Deviation 10.06 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 3 | -0.21 mg/dL | Standard Deviation 3.87 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 8 | -2.39 mg/dL | Standard Deviation 9.25 |
| Cohort B (Previously on Eculizumab) | Changes From Baseline in Free Hemoglobin Values | Week 4 | 16.90 mg/dL | Standard Deviation 50.64 |
Secondary
Haptoglobin Values
Changes from baseline at each of the scheduled post-baseline time-points
Time frame: Through Week 12 of the Study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 1 | 0.090 g/L | Standard Deviation 0.285 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 2 | 0.080 g/L | Standard Deviation 0.253 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 3 | 0.006 g/L | Standard Deviation 0.019 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 4 | 0.012 g/L | Standard Deviation 0.038 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 6 | 0.000 g/L | Standard Deviation 0 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 8 | 0.004 g/L | Standard Deviation 0.013 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 10 | 0.000 g/L | Standard Deviation 0 |
| Cohort A (Treatment Naive) | Haptoglobin Values | Week 12 | 0.000 g/L | Standard Deviation 0 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 12 | -0.064 g/L | Standard Deviation 0.18 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 1 | 0.010 g/L | Standard Deviation 0.019 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 6 | -0.064 g/L | Standard Deviation 0.18 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 2 | -0.003 g/L | Standard Deviation 0.007 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 10 | -0.064 g/L | Standard Deviation 0.18 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 3 | -0.003 g/L | Standard Deviation 0.007 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 8 | -0.064 g/L | Standard Deviation 0.18 |
| Cohort B (Previously on Eculizumab) | Haptoglobin Values | Week 4 | -0.064 g/L | Standard Deviation 0.18 |
Secondary
Hemoglobinuria Values
Changes from baseline at each of the scheduled post-baseline time-points; Hemoglobinuria was assessed using a urine colorimetric scoring system with a score of 1 through 10. Where 1 represents no hemoglobinuria and 10 represents maximum hemoglobinuria.
Time frame: Through Week 12 of the Study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 1 | -0.2 score on a scale | Standard Deviation 2.3 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 2 | 0.4 score on a scale | Standard Deviation 2.2 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 3 | 0.3 score on a scale | Standard Deviation 2.7 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 4 | -0.2 score on a scale | Standard Deviation 2 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 6 | 0.3 score on a scale | Standard Deviation 2.5 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 8 | -0.2 score on a scale | Standard Deviation 2.3 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 10 | 0.3 score on a scale | Standard Deviation 2.9 |
| Cohort A (Treatment Naive) | Hemoglobinuria Values | Week 12 | -0.2 score on a scale | Standard Deviation 2.9 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 12 | 0.0 score on a scale | Standard Deviation 2.2 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 1 | 0.8 score on a scale | Standard Deviation 1.8 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 6 | 0.8 score on a scale | Standard Deviation 2.3 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 2 | 0.1 score on a scale | Standard Deviation 1.3 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 10 | 0.9 score on a scale | Standard Deviation 1.6 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 3 | 0.7 score on a scale | Standard Deviation 1.8 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 8 | 0.3 score on a scale | Standard Deviation 1.6 |
| Cohort B (Previously on Eculizumab) | Hemoglobinuria Values | Week 4 | 0.4 score on a scale | Standard Deviation 1.6 |
Secondary
Reticulocyte Values
Changes from baseline at each of the scheduled post-baseline time-points
Time frame: Through Week 12 of the Study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 12 | -0.0047 10^12 cells/L (SI Units) | Standard Deviation 0.057 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 2 | -0.0157 10^12 cells/L (SI Units) | Standard Deviation 0.0591 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 3 | -0.0099 10^12 cells/L (SI Units) | Standard Deviation 0.0584 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 4 | -0.0137 10^12 cells/L (SI Units) | Standard Deviation 0.0439 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 6 | 0.0000 10^12 cells/L (SI Units) | Standard Deviation 0.0538 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 8 | -0.0042 10^12 cells/L (SI Units) | Standard Deviation 0.0619 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 10 | -0.0060 10^12 cells/L (SI Units) | Standard Deviation 0.0608 |
| Cohort A (Treatment Naive) | Reticulocyte Values | Week 1 | -0.0113 10^12 cells/L (SI Units) | Standard Deviation 0.0494 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 12 | 0.0061 10^12 cells/L (SI Units) | Standard Deviation 0.0166 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 1 | -0.0147 10^12 cells/L (SI Units) | Standard Deviation 0.0326 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 6 | 0.0170 10^12 cells/L (SI Units) | Standard Deviation 0.0259 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 2 | 0.0022 10^12 cells/L (SI Units) | Standard Deviation 0.0279 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 10 | 0.0085 10^12 cells/L (SI Units) | Standard Deviation 0.0304 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 3 | 0.0063 10^12 cells/L (SI Units) | Standard Deviation 0.0197 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 8 | 0.0050 10^12 cells/L (SI Units) | Standard Deviation 0.0346 |
| Cohort B (Previously on Eculizumab) | Reticulocyte Values | Week 4 | 0.0004 10^12 cells/L (SI Units) | Standard Deviation 0.0289 |
Secondary
Total Hemoglobin
Changes from baseline at each of the scheduled post-baseline time-points
Time frame: Through Week 12 of the Study
Population: Efficacy Evaluable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 6 | 3.6 g/L | Standard Deviation 9.8 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 2 | 1.6 g/L | Standard Deviation 7.4 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 8 | 3.1 g/L | Standard Deviation 9.6 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 4 | 2.7 g/L | Standard Deviation 10.5 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 10 | 4.5 g/L | Standard Deviation 8.8 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 1 | -1.5 g/L | Standard Deviation 10.4 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 12 | 6.9 g/L | Standard Deviation 10.6 |
| Cohort A (Treatment Naive) | Total Hemoglobin | Week 3 | 4.3 g/L | Standard Deviation 9.5 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 12 | 0.5 g/L | Standard Deviation 7.2 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 2 | 0.9 g/L | Standard Deviation 5.4 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 3 | -1.1 g/L | Standard Deviation 9 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 4 | -0.9 g/L | Standard Deviation 5.1 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 6 | -1.4 g/L | Standard Deviation 5.3 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 8 | -1.0 g/L | Standard Deviation 7.6 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 10 | -1.3 g/L | Standard Deviation 8.7 |
| Cohort B (Previously on Eculizumab) | Total Hemoglobin | Week 1 | -0.7 g/L | Standard Deviation 7.1 |