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TerminatedNCT03225287Updated Sep 28, 2023Results posted

Extension Study of RA101495 for Patients With PNH Who Have Completed a Zilucoplan (RA101495) Clinical Study

A Phase 2 interventional study of Zilucoplan (RA101495) in Paroxysmal Nocturnal Hemoglobinuria (PNH), sponsored by Ra Pharmaceuticals, Inc.. Terminated at 12 sites in 8 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-09-28.

Sponsored by Ra Pharmaceuticals, Inc. · Phase 2, Interventional, and Treatment

Why this study was terminated
After careful consideration, UCB has decided to no longer pursue PNH as a potential indication for zilucoplan.
Phase
Phase 2
Study type
Interventional
Enrollment
19
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of this study is to enable continued access to zilucoplan (RA101495) for patients with paroxysmal nocturnal hemoglobinuria (PNH) after they complete a zilucoplan clinical study.

02

Conditions studied

  • Paroxysmal Nocturnal Hemoglobinuria (PNH)
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Completion of a qualifying Ra Pharmaceuticals sponsored zilucoplan (RA101495) PNH study
  • Evidence of ongoing clinical benefit in the opinion of the Investigator

Exclusion criteria

Exclusion criteria:

  • History of meningococcal disease
  • Current systemic infection or suspicion of active bacterial infection
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
19 participants (actual)

Study arms

  • Experimental
    Zilucoplan (RA101495)

    Subjects will continue to receive the final maintenance dose they were receiving in the qualifying study

    Drug: Zilucoplan (RA101495)

Interventions

  • DrugZilucoplan (RA101495)

    Subjects will continue to receive the final maintenance dose they were receiving in the qualifying study.

05

What researchers measure

Primary outcomes

  1. Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

    TEAEs were defined as an AE that occurs after a participant's initial treatment zilucoplan start for this study (RA101495-01.202) that was not present at the time of treatment start, or an AE that increases in severity after treatment start in this study, if the event was present at the time of treatment start.

    Time frame: From Day 1 until the Final Study Visit (up to Month 49)

  2. Percentage of Participants With Serious TEAEs

    Serious Adverse event (SAE) was defined as any untoward medical occurrence that:• results in death, • is life-threatening threatening (note that this refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe), • requires hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, and • results in a congenital anomaly/birth defect.

    Time frame: From Day 1 until the Final Study Visit (up to Month 49)

Secondary outcomes

  1. Number of Participants With Anti-drug Antibodies (ADA)

    Blood samples collection were planned to analyze for the presence/absence of ADAs to zilucoplan for immunogenicity assessments.

    Time frame: At Day 1, Month 1, 2, 3, 6, 9, and 12

  2. Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels at Each Time Point

    Serum LDH levels were measure of intravascular hemolysis. As high level of LDH in the blood was indicative of hemolysis in participants with PNH.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  3. Change From Baseline in Total Bilirubin Values at Each Time Point

    Total Bilirubin was monitored for signs and symptoms of hepatic or biliary dysfunction.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  4. Change From Baseline in Total Hemoglobin Values at Each Time Point

    Total Hemoglobin Values were analyzed for hematology assessments.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  5. Change From Baseline in Free Hemoglobin Values at Each Time Point

    Free Hemoglobin Values were analyzed for hematology assessments.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  6. Change From Baseline in Haptoglobin Values at Each Time Point

    Haptoglobin values were analyzed for hematology assessments.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  7. Change From Baseline in Reticulocytes at Each Time Point

    Reticulocytes values were analyzed for hematology assessments.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)

  8. Change From Baseline in Hemoglobinuria Values at Each Time Point

    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: Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and Final Study Visit (Month 49)

  9. Plasma Concentrations of RA101495 and Its Major Metabolite(s)

    Blood samples of RA101495 (zilucoplan) and its metabolites (RA102758 and RA103488) were collected for Plasma concentration analysis.

    Time frame: Predose: At Day 1 (Screening), Month 1, 2, 3, 6, 9, 12, and Final Study Visit (Month 49)

  10. Maximum Plasma Concentration (Cmax) of RA101495

    Cmax is the maximum plasma concentration.

    Time frame: At Day 1, Month 1, 2, 3, 6, 9, and 12

  11. Time Corresponding to Cmax (Tmax) of RA101495

    tmax is the time to corresponding Cmax.

    Time frame: At Day 1, Month 1, 2, 3, 6, 9, and 12

  12. Area Under the Drug Concentration-time Curve (AUC0-t) of RA101495

    AUC0-t is area under the drug concentration-time curves.

    Time frame: At Day 1, Month 1, 2, 3, 6, 9, and 12

  13. Total Complement (CH50) Levels

    Blood samples collection were planned to assess complement (CH50) levels. The planned analysis of CH50 was not performed because the CH50 assay was not able to be validated due to lack of reproducibility of the manufacturer's kits.

    Time frame: At Day 1, Month 1, 2, 3, 6, 9, and 12

  14. Change From Baseline in Sheep Red Blood Cell (sRBC) Values at Each Time Point

    Blood samples were collected for measurement of sRBC lysis for the Classical Complement Pathways.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)

  15. Change From Baseline in Wieslab Enzyme-linked Immunosorbent Assay (ELISA) Values for Alternative Complement Pathway at Each Time Point

    Blood samples were collected for measurement of membrane attack complex (MAC) by Wieslab ELISA for alternative complement pathway.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)

  16. Change From Baseline in Complement Component 5 (C5) Values at Each Time Point

    Blood samples were collected for measurement of Complement component 5 (C5) levels.

    Time frame: Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)

06

Results

Posted Oct 27, 2022

Participant flow

The study started to enroll participants in July 2017 and concluded in October 2021.

Participant flow — Overall Study
MilestoneZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Started1063
Completed000
Not completed1063
Withdrew: Adverse event001
Withdrew: Protocol non-compliance001
Withdrew: Subject withdraws consent300
Withdrew: Sponsor, regulatory, or ec/irb request731
Withdrew: Trial drug not effective010
Withdrew: Need of transfusions and signs of hemolysis010
Withdrew: Stem cell transplantation010

Outcome measures

PrimaryPercentage of Participants With Treatment Emergent Adverse Events (TEAEs)

TEAEs were defined as an AE that occurs after a participant's initial treatment zilucoplan start for this study (RA101495-01.202) that was not present at the time of treatment start, or an AE that increases in severity after treatment start in this study, if the event was present at the time of treatment start.

Time frame:
From Day 1 until the Final Study Visit (up to Month 49)
Reported as:
Number · percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
percentage of participantsZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)90.010066.7
PrimaryPercentage of Participants With Serious TEAEs

Serious Adverse event (SAE) was defined as any untoward medical occurrence that:• results in death, • is life-threatening threatening (note that this refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe), • requires hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, and • results in a congenital anomaly/birth defect.

Time frame:
From Day 1 until the Final Study Visit (up to Month 49)
Reported as:
Number · percentage of participants
Percentage of Participants With Serious TEAEs
percentage of participantsZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Percentage of Participants With Serious TEAEs10.050.066.7
SecondaryNumber of Participants With Anti-drug Antibodies (ADA)

Blood samples collection were planned to analyze for the presence/absence of ADAs to zilucoplan for immunogenicity assessments.

Time frame:
At Day 1, Month 1, 2, 3, 6, 9, and 12

No measurements were reported for this outcome.

SecondaryChange From Baseline in Serum Lactate Dehydrogenase (LDH) Levels at Each Time Point

Serum LDH levels were measure of intravascular hemolysis. As high level of LDH in the blood was indicative of hemolysis in participants with PNH.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · Units per litre (U/L)
Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels at Each Time Point
Units per litre (U/L)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 1-3.7 ± 71.510.0 ± 16.4336.7 ± 636.9
Month 250.3 ± 156.2-2.4 ± 22.2676.5 ± 970.9
Month 3-6.5 ± 58.2-1.6 ± 40.539.5 ± 40.3
Month 632.4 ± 142.5-28.4 ± 127.3-3.5 ± 12.0
Month 9-18.1 ± 59.722.7 ± 23.6-5.0 ± 35.4
Month 12-39.7 ± 54.98.7 ± 10.1456.0 ± 640.6
Month 15-24.5 ± 70.84.0 ± 30.4174.5 ± 215.7
Month 18-27.9 ± 54.85.7 ± 56.8-56.0 ± NA
Month 21-12.0 ± 93.9-7.3 ± 33.573.0 ± NA
Month 24-18.7 ± 53.9-27.0 ± 64.1-29.0 ± NA
Month 27-14.0 ± 99.358.0 ± 8.5—
Month 30-28.0 ± 36.159.0 ± 140.01817.0 ± NA
Month 33-39.0 ± 65.9-16.3 ± 66.7—
Month 36-61.6 ± 47.10.5 ± 4.9—
Month 39-78.4 ± 80.9-29.7 ± 83.5—
Month 42-42.3 ± 78.335.5 ± 75.7—
Month 4527.0 ± NA53.0 ± NA—
Final Study Visit (Month 49)41.6 ± 303.1-93.2 ± 139.8682.0 ± 548.7
SecondaryChange From Baseline in Total Bilirubin Values at Each Time Point

Total Bilirubin was monitored for signs and symptoms of hepatic or biliary dysfunction.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · micromole per litre (umol/L)
Change From Baseline in Total Bilirubin Values at Each Time Point
micromole per litre (umol/L)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 1-2.1 ± 7.71.7 ± 6.2-0.3 ± 4.5
Month 20.1 ± 10.72.0 ± 7.26.0 ± 2.8
Month 31.4 ± 13.78.2 ± 13.13.5 ± 2.1
Month 64.6 ± 14.83.2 ± 7.22.5 ± 0.7
Month 9-0.3 ± 7.46.0 ± 3.0-1.0 ± 1.4
Month 123.9 ± 8.43.0 ± 2.02.5 ± 3.5
Month 15-0.4 ± 6.46.0 ± 9.58.5 ± 9.2
Month 182.8 ± 9.52.0 ± 6.23.0 ± NA
Month 213.9 ± 8.32.0 ± 7.87.0 ± NA
Month 245.1 ± 16.0-1.3 ± 3.18.0 ± NA
Month 274.3 ± 12.2-2.0 ± 5.7—
Month 305.8 ± 14.63.0 ± 7.113.0 ± NA
Month 332.6 ± 5.73.0 ± 2.6—
Month 36-3.8 ± 6.83.0 ± 0.0—
Month 390.2 ± 3.10.7 ± 4.6—
Month 424.8 ± 15.54.0 ± 15.6—
Month 455.0 ± 17.0-2.0 ± NA—
Final Study Visit (Month 49)8.0 ± 17.30.4 ± 3.90.0 ± 9.9
SecondaryChange From Baseline in Total Hemoglobin Values at Each Time Point

Total Hemoglobin Values were analyzed for hematology assessments.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · grams per litre (g/L)
Change From Baseline in Total Hemoglobin Values at Each Time Point
grams per litre (g/L)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 10.0 ± 11.40.0 ± 8.2-5.7 ± 3.8
Month 21.1 ± 8.3-5.0 ± 9.9-2.0 ± 11.3
Month 36.4 ± 6.43.0 ± 9.1-3.5 ± 6.4
Month 61.1 ± 11.22.0 ± 17.9-5.0 ± 17.0
Month 92.9 ± 7.1-1.3 ± 4.0-9.0 ± 5.7
Month 122.9 ± 6.1-1.7 ± 6.8-5.0 ± 17.0
Month 153.9 ± 8.4-5.0 ± 5.3-9.0 ± 28.3
Month 185.0 ± 4.91.7 ± 9.5-2.0 ± NA
Month 216.4 ± 6.3-6.7 ± 7.6-1.0 ± NA
Month 247.9 ± 12.6-5.0 ± 2.6—
Month 277.0 ± 10.0-5.0 ± 11.3—
Month 3010.8 ± 7.0-4.5 ± 12.0-8.0 ± NA
Month 3310.0 ± 8.8-3.0 ± 4.4—
Month 368.4 ± 14.2-2.0 ± 4.2—
Month 397.6 ± 10.14.7 ± 2.9—
Month 425.2 ± 11.25.5 ± 0.7—
Month 45-1.3 ± 23.3-4.0 ± NA—
Final Study Visit (Month 49)1.8 ± 10.6-2.0 ± 4.1-7.0 ± NA
SecondaryChange From Baseline in Free Hemoglobin Values at Each Time Point

Free Hemoglobin Values were analyzed for hematology assessments.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · milligrams per decilitre (mg/dL)
Change From Baseline in Free Hemoglobin Values at Each Time Point
milligrams per decilitre (mg/dL)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 1-0.20 ± 2.782.86 ± 4.300.80 ± 4.38
Month 2-1.14 ± 3.040.48 ± 1.776.10 ± NA
Month 31.34 ± 0.48-0.02 ± 0.950.80 ± NA
Month 6-0.43 ± 1.240.55 ± 2.451.20 ± NA
Month 9-1.10 ± 2.11-1.50 ± 1.570.00 ± NA
Month 12-0.56 ± 2.800.80 ± 0.282.10 ± NA
Month 153.93 ± 11.61-1.35 ± 2.191.60 ± NA
Month 181.98 ± 3.050.77 ± 1.56—
Month 213.15 ± 5.84-1.30 ± 0.85—
Month 240.27 ± 0.35-0.50 ± 0.99—
Month 300.33 ± 2.37——
Month 330.17 ± 2.665.80 ± NA—
Month 39-0.60 ± NA-0.95 ± 0.64—
Month 421.30 ± NA0.50 ± 3.68—
Final Study Visit (Month 49)-2.70 ± NA-0.60 ± 1.13-3.10 ± NA
SecondaryChange From Baseline in Haptoglobin Values at Each Time Point

Haptoglobin values were analyzed for hematology assessments.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · g/L
Change From Baseline in Haptoglobin Values at Each Time Point
g/LZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 10.032 ± 0.0970.000 ± 0.0000.000 ± 0.000
Month 20.053 ± 0.1600.000 ± 0.0000.000 ± 0.000
Month 30.021 ± 0.0600.000 ± 0.0000.000 ± 0.000
Month 60.031 ± 0.0880.036 ± 0.0800.020 ± 0.028
Month 90.008 ± 0.0210.000 ± 0.0000.000 ± 0.000
Month 120.000 ± 0.0000.000 ± 0.0000.000 ± 0.000
Month 150.000 ± 0.0000.000 ± 0.0000.000 ± 0.000
Month 180.000 ± 0.0000.000 ± 0.0000.000 ± NA
Month 210.030 ± 0.0790.000 ± 0.0000.000 ± NA
Month 240.030 ± 0.0790.000 ± 0.0000.000 ± NA
Month 270.000 ± 0.0000.000 ± 0.000—
Month 300.004 ± 0.0090.000 ± 0.0000.000 ± NA
Month 330.002 ± 0.0040.000 ± 0.000—
Month 360.036 ± 0.0800.000 ± 0.000—
Month 390.020 ± 0.0450.000 ± 0.000—
Month 420.034 ± 0.0760.000 ± 0.000—
Month 450.080 ± 0.1130.000 ± NA—
Final Study Visit (Month 49)0.042 ± 0.1270.006 ± 0.0130.000 ± 0.000
SecondaryChange From Baseline in Reticulocytes at Each Time Point

Reticulocytes values were analyzed for hematology assessments.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and Final Study Visit (Month 49)
Reported as:
Mean · 10^12 reticulocytes (cells)/L
Change From Baseline in Reticulocytes at Each Time Point
10^12 reticulocytes (cells)/LZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 10.0104 ± 0.04840.0107 ± 0.0299-0.0457 ± 0.0505
Month 2-0.0046 ± 0.0354-0.0046 ± 0.01300.0115 ± 0.0049
Month 3-0.0249 ± 0.0310-0.0112 ± 0.02510.0170 ± 0.0113
Month 6-0.0006 ± 0.0452-0.0042 ± 0.03630.0200 ± 0.0382
Month 90.0063 ± 0.03340.0070 ± 0.01710.0640 ± 0.0297
Month 12-0.0041 ± 0.0427-0.0070 ± 0.03460.0240 ± 0.0113
Month 15-0.0264 ± 0.0601-0.0343 ± 0.01910.0285 ± 0.0290
Month 18-0.0040 ± 0.03820.0027 ± 0.03800.0460 ± NA
Month 21-0.0223 ± 0.0554-0.0087 ± 0.0380—
Month 24-0.0123 ± 0.0711-0.0093 ± 0.0186—
Month 27-0.0017 ± 0.05530.0150 ± 0.0127—
Month 300.0016 ± 0.05240.0060 ± 0.05940.0300 ± NA
Month 33-0.0302 ± 0.0446-0.0093 ± 0.0234—
Month 36-0.0630 ± 0.0621-0.0215 ± 0.0078—
Month 39-0.0340 ± 0.0860-0.0133 ± 0.0291—
Month 42-0.0270 ± 0.0721-0.0015 ± 0.0078—
Month 45-0.0423 ± 0.1189-0.0050 ± NA—
Final Study Visit (Month 49)-0.0433 ± 0.0480-0.0333 ± 0.01160.0100 ± NA
SecondaryChange From Baseline in Hemoglobinuria Values at Each Time Point

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:
Baseline, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and Final Study Visit (Month 49)
Reported as:
Mean · score on a scale
Change From Baseline in Hemoglobinuria Values at Each Time Point
score on a scaleZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 10.1 ± 1.00.2 ± 1.51.7 ± 1.5
Month 20.9 ± 1.40.8 ± 1.31.0 ± 1.4
Month 30.4 ± 1.20.8 ± 1.30.0 ± NA
Month 60.4 ± 0.90.8 ± 1.30.0 ± NA
Month 90.4 ± 0.91.5 ± 2.10.0 ± NA
Month 120.9 ± 1.41.0 ± 1.71.0 ± 1.4
Month 150.9 ± 1.11.0 ± 1.71.0 ± 1.4
Month 180.1 ± 0.90.3 ± 0.60.0 ± NA
Month 210.7 ± 1.61.0 ± 1.70.0 ± NA
Month 240.6 ± 1.60.3 ± 0.60.0 ± NA
Month 270.7 ± 1.51.5 ± 2.10.0 ± NA
Month 300.6 ± 1.31.5 ± 2.10.0 ± NA
Month 331.4 ± 0.91.0 ± 1.7—
Month 361.4 ± 1.91.5 ± 2.1—
Month 390.4 ± 1.71.0 ± 1.7—
Month 421.0 ± 1.21.5 ± 2.1—
Month 451.0 ± 1.0-1.0 ± NA—
Final Study Visit (Month 49)0.4 ± 1.10.6 ± 0.92.5 ± 3.5
SecondaryPlasma Concentrations of RA101495 and Its Major Metabolite(s)

Blood samples of RA101495 (zilucoplan) and its metabolites (RA102758 and RA103488) were collected for Plasma concentration analysis.

Time frame:
Predose: At Day 1 (Screening), Month 1, 2, 3, 6, 9, 12, and Final Study Visit (Month 49)
Reported as:
Mean · micrograms per litre (ug/L)
Plasma Concentrations of RA101495 and Its Major Metabolite(s)
micrograms per litre (ug/L)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
RA101495- Day 110999.99 ± 2698.2913616.08 ± 1490.816976.50 ± 5663.23
RA101495- Month 110879.13 ± 2405.1912645.38 ± 1620.317630.03 ± 7060.56
RA101495- Month 211276.17 ± 2896.9812220.10 ± 2188.786865.45 ± 8108.18
RA101495- Month 310806.17 ± 3418.9212315.28 ± 2515.8412430.00 ± 16.55
RA101495- Month 69393.42 ± 2224.5212218.72 ± 2166.0512254.00 ± NA
RA101495- Month 911848.67 ± 2685.9212282.83 ± 3064.4215193.35 ± 2756.66
RA101495- Month 1211495.99 ± 2885.8113279.97 ± 2148.6012038.65 ± 7934.94
RA101495- Final Study Visit (Month 49)——7174.20 ± NA
RA102758- Day 11883.49 ± 593.932443.62 ± 560.971280.07 ± 1109.03
RA102758- Month 11865.06 ± 594.312185.00 ± 631.37757.30 ± 997.44
RA102758- Month 21894.86 ± 608.462090.04 ± 831.80757.85 ± 1018.59
RA102758- Month 31758.55 ± 689.031990.54 ± 700.701954.05 ± 160.58
RA102758- Month 61467.85 ± 563.681819.20 ± 613.141725.50 ± NA
RA102758- Month 91686.80 ± 554.871881.73 ± 583.871238.55 ± 166.24
RA102758- Month 121646.99 ± 536.001954.23 ± 725.5410.00 ± NA
RA102758- Final Study Visit (Month 49)——1094.60 ± NA
RA103488- Day 13587.68 ± 1747.124887.98 ± 1969.222084.83 ± 1791.35
RA103488- Month 14344.99 ± 2319.104400.68 ± 1823.931703.73 ± 1605.96
RA103488- Month 24799.29 ± 3113.574365.84 ± 1537.671591.35 ± 1552.03
RA103488- Month 34191.36 ± 2347.654541.78 ± 1706.072715.60 ± 1345.48
RA103488- Month 64027.53 ± 2730.924436.46 ± 2341.161929.60 ± NA
RA103488- Month 93132.54 ± 1320.614217.97 ± 2015.362954.85 ± 1754.97
RA103488- Month 123903.41 ± 1960.304334.47 ± 1976.472319.20 ± 2534.84
RA103488- Final Study Visit (Month 49)——2210.00 ± NA
SecondaryMaximum Plasma Concentration (Cmax) of RA101495

Cmax is the maximum plasma concentration.

Time frame:
At Day 1, Month 1, 2, 3, 6, 9, and 12

No measurements were reported for this outcome.

SecondaryTime Corresponding to Cmax (Tmax) of RA101495

tmax is the time to corresponding Cmax.

Time frame:
At Day 1, Month 1, 2, 3, 6, 9, and 12

No measurements were reported for this outcome.

SecondaryArea Under the Drug Concentration-time Curve (AUC0-t) of RA101495

AUC0-t is area under the drug concentration-time curves.

Time frame:
At Day 1, Month 1, 2, 3, 6, 9, and 12

No measurements were reported for this outcome.

SecondaryTotal Complement (CH50) Levels

Blood samples collection were planned to assess complement (CH50) levels. The planned analysis of CH50 was not performed because the CH50 assay was not able to be validated due to lack of reproducibility of the manufacturer's kits.

Time frame:
At Day 1, Month 1, 2, 3, 6, 9, and 12

No measurements were reported for this outcome.

SecondaryChange From Baseline in Sheep Red Blood Cell (sRBC) Values at Each Time Point

Blood samples were collected for measurement of sRBC lysis for the Classical Complement Pathways.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)
Reported as:
Mean · percent lysis of sheep erythrocytes
Change From Baseline in Sheep Red Blood Cell (sRBC) Values at Each Time Point
percent lysis of sheep erythrocytesZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 11.378 ± 2.2770.523 ± 0.77293.870 ± NA
Month 21.248 ± 1.789-0.308 ± 0.45293.870 ± NA
Month 31.256 ± 1.7990.576 ± 0.972-2.620 ± NA
Month 61.493 ± 2.8380.458 ± 1.657-2.300 ± NA
Month 90.683 ± 1.0550.757 ± 0.673-1.410 ± NA
Month 120.759 ± 0.5570.773 ± 0.4158.390 ± NA
Final Study Visit (Month 49)—25.230 ± 35.200—
SecondaryChange From Baseline in Wieslab Enzyme-linked Immunosorbent Assay (ELISA) Values for Alternative Complement Pathway at Each Time Point

Blood samples were collected for measurement of membrane attack complex (MAC) by Wieslab ELISA for alternative complement pathway.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)
Reported as:
Mean · percentage of activity
Change From Baseline in Wieslab Enzyme-linked Immunosorbent Assay (ELISA) Values for Alternative Complement Pathway at Each Time Point
percentage of activityZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 11.7 ± 5.81.0 ± 1.748.0 ± 67.9
Month 20.1 ± 1.9-1.0 ± 1.051.5 ± 74.2
Month 30.1 ± 2.00.0 ± 0.72.0 ± 1.4
Month 61.0 ± 4.5-0.2 ± 1.95.0 ± NA
Month 9-0.9 ± 0.8-0.7 ± 0.6-2.0 ± NA
Month 12-1.4 ± 1.4-1.3 ± 0.64.5 ± 6.4
Final Study Visit (Month 49)—1.0 ± 2.8—
SecondaryChange From Baseline in Complement Component 5 (C5) Values at Each Time Point

Blood samples were collected for measurement of Complement component 5 (C5) levels.

Time frame:
Baseline, Month 1, 2, 3, 6, 9, 12 and Final Study Visit (Month 49)
Reported as:
Mean · ug/mL
Change From Baseline in Complement Component 5 (C5) Values at Each Time Point
ug/mLZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
Month 1-11.231 ± 24.96020.488 ± 31.024-27.505 ± 90.092
Month 2-15.914 ± 32.73717.716 ± 33.12516.310 ± 36.077
Month 3-24.404 ± 50.084-2.898 ± 49.74722.355 ± 19.764
Month 6-6.823 ± 44.7879.572 ± 24.92791.640 ± NA
Month 9-0.019 ± 53.4751.177 ± 27.65489.670 ± NA
Month 12-40.591 ± 34.977-23.487 ± 30.911-24.905 ± 17.685
Final Study Visit (Month 49)-28.663 ± 46.526-19.770 ± 74.604—

Adverse events

Collected over From Day 1 until the Final Study Visit (up to Month 49). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Zilucoplan-Cohort A (Eculizumab Naïve)0/10 (0%)1/10 (10%)9/10 (90%)
Zilucoplan-Cohort B (Eculizumab Switch)0/6 (0%)3/6 (50%)6/6 (100%)
Zilucoplan (Inadequate Responder to Eculizumab)0/3 (0%)2/3 (66.7%)2/3 (66.7%)
Most frequent serious events
Showing 10 of 11
Most frequent serious events
EventZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
AnaemiaBlood and lymphatic system disorders1/100/61/3
Pneumonia pneumococcalInfections and infestations0/100/61/3
EncephalopathyNervous system disorders0/100/61/3
Suicide attemptPsychiatric disorders0/100/61/3
Tongue haematomaGastrointestinal disorders0/101/60/3
Enterocolitis infectiousInfections and infestations0/101/60/3
Deep vein thrombosisVascular disorders0/101/60/3
NauseaGastrointestinal disorders1/100/60/3
OsteoarthritisMusculoskeletal and connective tissue disorders1/100/60/3
Rotator cuff syndromeMusculoskeletal and connective tissue disorders1/100/60/3
Most frequent other events
Showing 10 of 108
Most frequent other events
EventZilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)
DiarrhoeaGastrointestinal disorders5/101/60/3
NauseaGastrointestinal disorders4/100/60/3
FatigueGeneral disorders4/102/61/3
NasopharyngitisInfections and infestations4/101/60/3
Upper respiratory tract infectionInfections and infestations4/101/60/3
ConstipationGastrointestinal disorders1/100/61/3
VomitingGastrointestinal disorders0/100/61/3
Chest painGeneral disorders0/100/61/3
Influenza like illnessGeneral disorders0/100/61/3
SinusitisInfections and infestations1/100/61/3

Baseline characteristics

Baseline Characteristics refer to the Safety Population which consisted of all participants who received at least 1 injection of zilucoplan on or after Day 1 of the extension study.

Age, Categorical
Age, Categorical(Participants)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)Total
<=18 years0000
Between 18 and 65 years64313
>=65 years4206
Age, Continuous
Age, Continuous(years)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)Total
Mean59.6 ± 14.545.0 ± 23.035.3 ± 16.351.2 ± 19.4
Sex: Female, Male
Sex: Female, Male(Participants)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)Total
Female6118
Male45211
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)Total
Black or African American0011
White106117
Not Reported0011
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Zilucoplan-Cohort A (Eculizumab Naïve)Zilucoplan-Cohort B (Eculizumab Switch)Zilucoplan (Inadequate Responder to Eculizumab)Total
Not Hispanic or Latino105318
Not Reported0101
07

Study locations

12 sites
  • Investigative Site 4
    Los Angeles, California 90033, United States
  • Investigative Site 19
    Dallas, Texas 75390, United States
  • Investigative Site 3
    Gosford, Australia
  • Investigative Site 5
    Melbourne, Australia
  • Investigative Site 10
    Toronto, Canada
  • Investigative Site 14
    Helsinki, Finland
  • Investigative Site 9
    Ulm, Germany
  • Investigative Site 17
    Budapest, Hungary
  • Investigative Site 13
    Christchurch, New Zealand
  • Investigative Site 12
    Hamilton, New Zealand
  • Investigative Site 6
    Leeds, United Kingdom
  • Investigative Site 7
    London, United Kingdom
08

References and documents

Publications

  • Kulasekararaj AG, Lehtinen AE, Forsyth C, Gandhi S, Griffin M, Korper S, Mikala G, Muus P, Overgaard U, Patriquin CJ, Pullon H, Shen YM, Spearing R, Szer J, De la Borderie G, Duda PW, Farzaneh-Far R, Ragunathan S, Sayegh CE, Vadysirisack DD, Schrezenmeier H. Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria. Haematologica. 2024 Mar 1;109(3):929-935. doi: 10.3324/haematol.2022.281780. No abstract available. PubMed 37534517 ↗

Study documents

  • Study protocol · Oct 20, 2016
  • Statistical analysis plan · Oct 15, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.

Supporting information: Study protocol, Sap, Csr

09

Registry details

Key details

Study ID
NCT03225287
Lead sponsor
Ra Pharmaceuticals, Inc.
Responsible party
Sponsor
First posted
Jul 21, 2017
Start date
Jul 17, 2017
Primary completion
Sep 7, 2021
Completion
Oct 26, 2021
Results posted
Oct 27, 2022
Last update
Sep 28, 2023

Study contacts

Dr. Anita Hill
study chair · St James' Institute of Oncology

Oversight

FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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