| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal nocturnal hemoglobinuria (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Paroxysmal nocturnal hemoglobinuria is a rare, acquired, life-threatening disease of the blood that leads to the premature death and impaired production of red blood cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055629 |
| E.1.2 | Term | Paroxysmal nocturnal hemoglobinuria |
| E.1.2 | System Organ Class | 100000004857 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
•Evaluate the safety and tolerability of single doses of crovalimab in healthy volunteers (HVs) Part 2, 3 and 4
•Evaluate the safety and tolerability of crovalimab for a total duration of 5 months in treatment naïve patients with PNH and PNH patients
switching treatment to crovalimab
•Evaluate the pharmacodynamic (PD) effect of multiple doses of crovalimab on complement activity in patients with PNH Open Label Extension (OLE)
•Assess the long term safety of crovalimab |
|
| E.2.2 | Secondary objectives of the trial |
Part 1
•Characterize the PD effects of a single-dose of crovalimab on complement activity (CA) & other related biomarkers
•Describe the single-dose pharmacokinetic (PK) profile of crovalimab
•Assess the bioavailability of subcutaneous (SC) administration of crovalimab
Part 2, 3 and 4
•Describe the multiple-dose PK properties of crovalimab in treatment naïve patients (Pts) with PNH and PNH Pts switching treatment to crovalimab
•Characterize other PD effects of crovalimab
•Characterize the exposure-response relationship of crovalimab following different SC dosing regimens
•Assess the efficacy, Pt-related outcomes & treatment satisfaction of crovalimab in treatment naïve Pts with PNH, and/or PNH Pts switching treatment to crovalimab
Parts 1, 2 & 3
•Explore the PK/PD relationship of single-ascending & multiple doses of crovalimab on CA & other related biomarkers
•Evaluate the immunogenicity of crovalimab in HVs and in Pts with PNH OLE
•Assess the long term safety of crovalimab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1 (HVs only)
- Healthy male volunteers between the age of 21 and 55 years
- Neisseria meningitidis vaccination against serogroups B and A, C, W, and Y
- Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study
- Subjects who have been vaccinated against hepatitis B Parts 2, 3 and 4 (PNH patients only)
- Male or female patients between the age of 18 and 75 years
- Neisseria meningitidis vaccination in accordance with most current local guidelines or Standard of Care (SOC) for patients at increased risk
for meningococcal disease (Part 2 and Part 4 Arm A)
- Patient has been vaccinated with Neisseria meningitidis vaccine(s) in accordance with most current local guidelines or SOC for patients at
increased risk for meningococcal disease or is being revaccinated if applicable (Part 3 and Part 4 Arm B)
- Stable dose for >= 28 days prior to screening of other therapies (immunosuppressant therapy, corticosteroids, iron supplements)
- Negative pregnancy test for women of childbearing potential Part 2 and Part 4 Arm A only (currently untreated PNH patients who are
candidates for treatment with complement inhibitors only):
- Hepatitis B patients can be enrolled if their LFT values are less than 2 × ULN and there is no liver function impairment
- PNH patients who have not been treated with any complement inhibitor or if previously treated stopped treatment due to lack of efficacy based on a single missense C5 heterozygous mutation Part 3 and Part 4 Arm B only (PNH patients currently treated with eculizumab only):
- Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study.
o Subjects seropositive for HCV but adequately treated without detectable HCV RNA are eligible
o Subjects who have been vaccinated against hepatitis B are eligible
o Subjects seropositive for HBV but adequately treated without detectable HBV DNA are eligible
- Patients are adequately controlled based on investigator opinion
- Patients receive regular infusions of eculizumab OLE only - PNH patients:
- PNH patients who have completed Parts 2, 3 and 4 respectively
- PNH patients who derived, in the Investigator's opinion, benefit from treatment with crovalimab
- For women who are not post menopausal and have not undergone surgical sterilization agreement to remain abstinent or use a contraception method that results in a failure rate of <1% per year, during the treatment period and for 5 half-lives or at least 6 months after the last dose of crovalimab
|
|
| E.4 | Principal exclusion criteria |
Parts 1, 2, 3 and 4:
- Known or suspected hereditary complement deficiency
- History of meningococcal meningitis
- Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks prior to screening and up to first study drug administration
- History of or currently active primary or secondary immunodeficiency, including known history of HIV infection
- Evidence of malignant disease including myelodysplastic syndrome, or malignancies diagnosed within the previous 5 years
Part 1 (HVs only):
- Any clinically relevant history or the presence of moderate to severe respiratory, renal, hepatic, gastrointestinal, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, or connective tissue disease
- Any major illness within one month before the screening examination or any febrile illness within 2 weeks prior to screening and up to first study drug Administration
- Prior splenectomy
- History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
- Congenital or acquired complement deficiency
- Carriers of Neisseria meningitides based on cultures from naso-pharyngeal swabs
Parts 2, 3 and 4 (PNH patients only):
- Evidence of moderate to severe concurrent renal, liver, cardiac, pulmonary or gastrointestinal disease not related to PNH as determined by the Investigator
- History of bone marrow transplantation
- Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to first study drug Administration
- Splenectomy < 1 year before start of crovalimab.
Part 3 and 4 Arm B ( PNH patients only):
- Any evidence of sero-positive auto-immune connective tissue
diseases
- Any evidence of active inflammatory conditions |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety (Parts 1, 2, 3 and 4):
1. Incidence of dose-limiting events
2. Incidence and severity of adverse events (AEs), serious adverse events and AEs leading to withdrawal
PD (Parts 1, 2, 3 and 4):
3. Ex vivo liposome lysis in serum and ex-vivo lysis of antibody-coated erythrocytes
4. Total and target engaged C5 concentration
5. Serum LDH |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety and PD (Parts 1, 2, 3 and 4):
1-5. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3; up to a maximum of five years from entry into OLE |
|
| E.5.2 | Secondary end point(s) |
Efficacy (Parts 2, 3 and 4):
1. Change in LDH
2. Time to (1) first transfusion or (2) persistent elevation of LDH
3. Proportion of patients with LDH below ULN, proportion of patients with LDH <= 1.5 x ULN
4. Change in free-haemoglobin
5. Proportion of patients with stabilized haemoglobin levels
6. Change in fatigue as measured by the functional assessment of chronic illness therapy fatigue
7. Change in health-related quality of life as measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30
8. Comparison of patient treatment satisfaction between IV and SC modes of administration
9. Number of packed RBC (pRBC) units transfused per patient
10. Monthly rate of pRBC transfusions per patient
11. Proportion of transfusion-free patients
12. Annual rate of transfusion avoidance per patient
13. Annual rate of breakthrough hemolysis per patient PK (Parts 1, 2, 3 and 4):
14. Pharmacokinetic profile of crovalimab; Cmax, Tmax, AUC, T1/2, bioavailability following SC administration |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy and PK (Parts 1, 2, 3 and 4):
1-10. Approximately 6 months for Part 1; approximately 8 months for Parts 2, 3 and 4; up to a maximum of five years from entry into OLE |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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