Paroxysmal Nocturnal Hemoglobinuria, PNH
Conditions
Keywords
complement inhibitor
Brief summary
The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of multiple intravenous (IV) doses of ravulizumab administered to complement inhibitor treatment-naïve participants with PNH.
Detailed description
The study consisted of a screening period of up to 30 days and a Treatment Period of up to 253 days for Cohorts 1-3 and 281 days for Cohort 4. After completion of the Treatment Period, all participants had the opportunity to enter the Extension Period, wherein participants continue to receive ravulizumab for up to 5 years. The first dose in the Extension Period occurred on Day 253 for Cohorts 1-3 and on Day 281 for Cohort 4. The data presented includes the Primary Completion date of the study for the Treatment Period. The results for the Extension Period will be reported after study completion.
Interventions
BIOLOGICALRavulizumab
All treatments were given as IV infusions.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥18 years of age 2. PNH diagnosis confirmed by documented high-sensitivity flow cytometry 3. Documented meningococcal vaccination not more than 3 years prior to dosing 4. Female participants of childbearing potential were to use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab. 5. Willing and able to give written informed consent and comply with the study visit schedule
Exclusion criteria
1. Treatment with a complement inhibitor at any time 2. Female participants who are planning to become pregnant, or are pregnant, breastfeeding or who had a positive pregnancy test at screening or Day 1 3. Participation in an interventional clinical study within 30 days before initiation of dosing on Day 1, or use of any experimental therapy within 30 days prior to dosing on Day 1, or within 5 half-lives of the investigational product, whichever was greater 4. History of allergy to any drug, allergen, excipients of ravulizumab or known allergy to Chinese hamster ovary cell proteins 5. Inability to comply with study requirements 6. History of any clinically significant cardiac, hepatic, immunologic, pulmonary, or rheumatoid disease that, in the Investigator's judgment, would preclude participation 7. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the participant unsuitable for enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4) | The percent change in LDH levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4) | The percent change in haptoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. |
| Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4) | The percent change in reticulocyte/erythrocyte count levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. |
| Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4) | The percent change in free hemoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. |
| Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Baseline to Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4) | The percent change in D-dimer levels were assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. |
| Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Baseline, Day 253 (Cohorts 1 to 3) and Day 281 (Cohort 4) | Clinical manifestations were assessed from Baseline to Day 253 for Cohorts 1 to 3 and from Baseline to Day 281 for Cohort 4 only. Clinical manifestations were defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (male participants only). Improvement was defined as present at Baseline and absent at Day endpoint. Worsening was defined as absent at Baseline and present at Day endpoint. No Change was defined as no change from Baseline and time point of endpoint. |
| Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253 | Baseline, Day 253 (Cohorts 1 to 4) | The percent change in paroxysmal nocturnal hemoglobinuria (PNH) red blood cell (RBC), summed types II and III, clone size levels were assessed from Baseline to Day 253 for Cohorts 1 to 4. |
Countries
Canada, France, Germany, South Korea, Spain, Taiwan, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 During the Treatment Period, participants were administered ravulizumab 1400 mg on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. | 6 |
| Cohort 2 During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. | 6 |
| Cohort 3 During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. | 7 |
| Cohort 4 During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses. During the Extension Period, participants were administered ravulizumab 5400 mg every 12 weeks for up to 5 years. | 7 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extension Period | Participant underwent bone marrow transplantation due to chronic myelomonocytic leukemia | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.1 years STANDARD_DEVIATION 14.57 | 48.6 years STANDARD_DEVIATION 23.48 | 37.3 years STANDARD_DEVIATION 14.03 | 48.5 years STANDARD_DEVIATION 13.43 | 44.3 years STANDARD_DEVIATION 16.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 7 Participants | 7 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Lactate Dehydrogenase (LDH) Levels | 1026.88 units/liter (U/L) STANDARD_DEVIATION 547.843 | 1223.55 units/liter (U/L) STANDARD_DEVIATION 149.693 | 2127.57 units/liter (U/L) STANDARD_DEVIATION 815.875 | 2142.24 units/liter (U/L) STANDARD_DEVIATION 366.511 | 1668.90 units/liter (U/L) STANDARD_DEVIATION 724.341 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 4 Participants | 3 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 6 Participants | 5 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 7 / 7 | 7 / 7 |
| serious Total, serious adverse events | 3 / 6 | 3 / 6 | 4 / 7 | 1 / 7 |
Outcome results
Primary
Percent Change In LDH Levels From Baseline To Day 253 And Day 281
The percent change in LDH levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
Time frame: Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. Last observation carried forward (LOCF) was used for participants with a missing Day 253 or Day 281 assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Day 253 | -72.85 Percent Change | Standard Deviation 12.082 |
| Cohort 2 | Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Day 253 | -78.12 Percent Change | Standard Deviation 6.635 |
| Cohort 3 | Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Day 253 | -84.96 Percent Change | Standard Deviation 4.423 |
| Cohort 4 | Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Day 253 | -87.63 Percent Change | Standard Deviation 6.923 |
| Cohort 4 | Percent Change In LDH Levels From Baseline To Day 253 And Day 281 | Day 281 | -89.89 Percent Change | Standard Deviation 2.885 |
Comparison: Statistical Analysis presented is of Cohorts 1 to 4 combined at Day 253. A sample size of 20 participants from the combined cohorts was required to provide approximately 95% power to detect a mean paired difference in LDH from Baseline of -40% at Day 253 for Cohorts 1 to 4, with an estimated standard deviation (SD) of 45%. This was based on a 2-sided paired t-test, with 5% type I error rate. To account for a possible 15% dropout rate, up to 26 participants were enrolled.p-value: <0.0001Mixed Model for Repeated Measures (MMRM)
Comparison: Statistical Analysis presented is of Cohort 4 at Day 281. A sample size of 20 participants from the combined cohorts was required to provide approximately 95% power to detect a mean paired difference in LDH from Baseline of -40% at Day 281 for Cohort 4 only, with an estimated SD of 45%. This was based on a 2-sided paired t-test, with 5% type I error rate. To account for a possible 15% dropout rate, up to 26 participants were enrolled.p-value: <0.0001MMRM
Secondary
Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281
Clinical manifestations were assessed from Baseline to Day 253 for Cohorts 1 to 3 and from Baseline to Day 281 for Cohort 4 only. Clinical manifestations were defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (male participants only). Improvement was defined as present at Baseline and absent at Day endpoint. Worsening was defined as absent at Baseline and present at Day endpoint. No Change was defined as no change from Baseline and time point of endpoint.
Time frame: Baseline, Day 253 (Cohorts 1 to 3) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF is used for participants with a missing Day 253 or Day 281 assessment. Erectile dysfunction affects only male participants.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Not Applicable | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Not Applicable | 2 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | No Change | 2 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | No Change | 2 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | No Change | 5 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Not Applicable | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | No Change | 6 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Improved from Baseline | 2 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Improved from Baseline | 4 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | No Change | 5 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Not Applicable | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | No Change | 5 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Improved from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 1 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | No Change | 5 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | No Change | 5 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Not Applicable | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Not Applicable | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Improved from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Not Applicable | 1 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | No Change | 6 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Improved from Baseline | 2 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Improved from Baseline | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Not Applicable | 0 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | No Change | 5 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | No Change | 4 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | No Change | 5 Participants |
| Cohort 2 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Improved from Baseline | 3 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | No Change | 4 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Not Applicable | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | No Change | 6 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | No Change | 3 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | No Change | 6 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Not Applicable | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Improved from Baseline | 2 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Improved from Baseline | 4 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Not Applicable | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | No Change | 5 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | No Change | 5 Participants |
| Cohort 3 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Not Applicable | 1 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 281 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 281 | No Change | 5 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 281 | No Change | 4 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Improved from Baseline | 2 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 281 | Improved from Baseline | 2 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | No Change | 4 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | No Change | 5 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 281 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dyspnea at Day 253 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 281 | No Change | 7 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 281 | Improved from Baseline | 1 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 281 | No Change | 6 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 281 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 281 | Improved from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | No Change | 7 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Improved from Baseline | 3 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Improved from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 281 | Not Applicable | 2 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 281 | Improved from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 281 | No Change | 7 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 281 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 281 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 281 | No Change | 3 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Improved from Baseline | 1 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 281 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 281 | Improved from Baseline | 4 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | Not Applicable | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | No Change | 7 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Chest Pain at Day 253 | Improved from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Fatigue at Day 253 | No Change | 4 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 253 | Not Applicable | 2 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Erectile Dysfunction at Day 281 | Improved from Baseline | 1 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | No Change | 6 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Abdominal Pain at Day 253 | Worsened from Baseline | 0 Participants |
| Cohort 4 | Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281 | Dysphagia at Day 253 | Improved from Baseline | 1 Participants |
Secondary
Percent Change In D-dimer From Baseline To Day 253 And Day 281
The percent change in D-dimer levels were assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
Time frame: Baseline to Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF is used for participants with a missing Day 253 or Day 281 assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Day 253 | -24.80 Percent Change | Standard Deviation 32.436 |
| Cohort 2 | Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Day 253 | -29.47 Percent Change | Standard Deviation 26.547 |
| Cohort 3 | Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Day 253 | -10.90 Percent Change | Standard Deviation 41.032 |
| Cohort 4 | Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Day 253 | -16.08 Percent Change | Standard Deviation 34.783 |
| Cohort 4 | Percent Change In D-dimer From Baseline To Day 253 And Day 281 | Day 281 | -27.05 Percent Change | Standard Deviation 27.663 |
Comparison: Statistical Analysis presented is of Cohorts 1 to 4 combined at Day 253.p-value: 0.0029MMRM
Comparison: Statistical Analysis presented is of Cohort 4 at Day 281.p-value: 0.125MMRM
Secondary
Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281
The percent change in free hemoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
Time frame: Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF was used for participants with a missing Day 253 or Day 281 assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | 14.07 Percent Change | Standard Deviation 124.755 |
| Cohort 2 | Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | -12.32 Percent Change | Standard Deviation 57.213 |
| Cohort 3 | Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | -22.14 Percent Change | Standard Deviation 94.388 |
| Cohort 4 | Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | -40.80 Percent Change | Standard Deviation 27.474 |
| Cohort 4 | Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281 | Day 281 | -45.64 Percent Change | Standard Deviation 28.938 |
Comparison: Statistical Analysis presented is of Cohorts 1 to 4 combined at Day 253.p-value: 0.0214MMRM
Comparison: Statistical Analysis presented is of Cohort 4 at Day 281.p-value: 0.0313MMRM
Secondary
Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281
The percent change in haptoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
Time frame: Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF was used for participants with a missing Day 253 or Day 281 assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | 21.67 Percent Change | Standard Deviation 53.072 |
| Cohort 2 | Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | 81.67 Percent Change | Standard Deviation 200.042 |
| Cohort 3 | Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | 4.29 Percent Change | Standard Deviation 11.339 |
| Cohort 4 | Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Day 253 | 34.29 Percent Change | Standard Deviation 74.578 |
| Cohort 4 | Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281 | Day 281 | 27.14 Percent Change | Standard Deviation 56.188 |
Comparison: tatistical Analysis presented is of Cohorts 1 to 4 combined at Day 253.p-value: 0.0625MMRM
Comparison: Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from 0 for the combined cohorts.p-value: 0.5MMRM
Secondary
Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253
The percent change in paroxysmal nocturnal hemoglobinuria (PNH) red blood cell (RBC), summed types II and III, clone size levels were assessed from Baseline to Day 253 for Cohorts 1 to 4.
Time frame: Baseline, Day 253 (Cohorts 1 to 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF was used for participants with a missing Day 253 assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253 | 6.65 Percent Change | Standard Deviation 24.101 |
| Cohort 2 | Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253 | 5.47 Percent Change | Standard Deviation 21.94 |
| Cohort 3 | Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253 | 54.14 Percent Change | Standard Deviation 98.713 |
| Cohort 4 | Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253 | 88.21 Percent Change | Standard Deviation 138.29 |
Comparison: Statistical Analysis presented is of Cohorts 1 to 4 combined at Day 253.p-value: 0.0023MMRM
Secondary
Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281
The percent change in reticulocyte/erythrocyte count levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
Time frame: Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Population: Full Analysis Set: Participants in the safety set with a Baseline and at least 1 LDH measurement after first dose of ravulizumab. Data summarized only for participants with data at Baseline and the specified time point. LOCF was used for participants with a missing Day 253 or Day 281 assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Day 253 | -1.27 Percent Change | Standard Deviation 43.019 |
| Cohort 2 | Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Day 253 | -5.05 Percent Change | Standard Deviation 35.691 |
| Cohort 3 | Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Day 253 | 10.46 Percent Change | Standard Deviation 59.51 |
| Cohort 4 | Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Day 281 | -4.66 Percent Change | Standard Deviation 68.502 |
| Cohort 4 | Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281 | Day 253 | 14.66 Percent Change | Standard Deviation 81.39 |
Comparison: Statistical Analysis presented is of Cohorts 1 to 4 combined at Day 253.p-value: 0.4871MMRM
Comparison: Statistical Analysis presented is of Cohort 4 at Day 281.p-value: 0.4688MMRM