Atypical Hemolytic Uremic Syndrome
Conditions
Brief summary
This study aims to evaluate the efficacy and safety of crovalimab in pediatric participants with aHUS.
Interventions
DRUGCrovalimab
Crovalimab will be administered at a dose of 1000 mg intravenously (IV) (for participants weighing =\> 40 to \<100 kg) or 1500 mg IV (for participants weighing \>=100 kg) on Week 1 Day 1. On Week 1 Day 2 and on Weeks 2, 3 and 4, crovalimab will be administered at a dose of 340 mg subcutaneously (SC). On Week 5 and Q4W thereafter, it will be administered at a dose of 680 mg SC (for participants weighing =\> 40 to \<100 kg) or 1020 mg SC (for participants weighing \>=100 kg). Enrollment of participants weighing \<40 kg will be staggered using two weight-based dose confirmation groups (Group 1 participants weighing \>=20 kg to \<40 kg, followed by Group 2 participants weighing \>=5 kg to \<20 kg). All participants will receive an initial IV loading dose, which will be followed by SC dosing at either Q2W or Q4W intervals (depending on body weight), until study completion.
Sponsors
Hoffmann-La Roche
Chugai Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
* Body weight \>= 5 kg at screening. * Vaccination against Neisseria meningitis serotypes A, C, W, and Y; vaccination against serotype B, according to national vaccination recommendations. * Vaccination against Haemophilus influenzae type B and Streptococcus pneumoniae, according to national vaccination recommendations. * For patients continuing to receive other therapies concomitantly with crovalimab (e.g., immunosuppressants, corticosteroids, mammalian target of rapamycin inhibitor (mTORi), or calcineurin inhibitors): stable dose for \>=28 days prior to screening and up to the first crovalimab administration. * For female participants of childbearing potential: an agreement to remain abstinent or use contraception. * Participants with a prior kidney transplant are eligible if they have a known history of complement-mediated aHUS prior to the kidney transplant. * Onset of initial TMA presentation within 28 days prior to the first dose of crovalimab (for Naive Cohort only). * Documented treatment with either eculizumab or ravulizumab (for Switch Cohort only). * Clinical evidence of response to a C5 inhibitor (for Switch Cohort only). * Poorly controlled TMA following treatment with another C5 inhibitor (for C5 SNP participants in the Pretreated Cohort only). * Known C5 polymorphism (for C5 SNP participants in the Pretreated Cohort only).
Exclusion criteria
* TMA associated with non-aHUS related renal disease. * Positive direct Coombs test. * Chronic dialysis within 90 days prior to first crovalimab administration , and /or end stage renal disease * Identified drug exposure-related TMA. * Presence or history of a condition that could trigger TMA, such as malignancy, bone marrow or organ transplant (other than kidney transplant) or autoimmune disease. * History of a kidney disease, other than aHUS. * History of Neisseria meningitidis infection within 6 months of study enrollment. * Known or suspected immune deficiency (e.g., history of frequent recurrent infections). * Positive HIV test. * Active systemic bacterial, viral, or fungal infection within 14 days before first crovalimab administration. * Presence of fever (\>= 38°C) before the first crovalimab administration (If fevers are solely due to the underlying aHUS pathology, and there is no evidence or suspicion of a systemic infection, participants may enroll). * Multi-system organ dysfunction or failure. * Recent intravenous immunoglobulin (IVIg) treatment. * Pregnant or breastfeeding or intending to become pregnant. * Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within 28 days of screening or within five half lives of that investigational product, whichever is greater. * Recent use of tranexamic acid. * Current or previous treatment with a complement inhibitor (for Naive Cohort only). * First initiation of plasma exchange/plasma infusions (PE/PI) should not be more than 28 days prior to first crovalimab administration (for Naive Cohort only). * Last PE/PI completed less than 2 hours prior to first crovalimab administration (for Naive Cohort only). * Receiving PE/PI within 8 weeks of the first crovalimab administration (Switch Cohort only). * Normalization of serum creatinine values at baseline (\<97.5th percentile for age), (for Naive Cohort only). * Positive for active Hepatitis B and/or C infections (HBV/HCV) (for Switch Cohort and switching C5 SNP Pretreated Cohort participants who recently received C5 inhibitor treatment). * Cryoglobulinemia at screening (for Switch Cohort and C5 SNP Cohort participants who recently received C5 inhibitor treatment). * Diagnosis of a condition leading to non-aHUS TMA: Thrombotic Thrombocytopenic Purpura (TTP), Shiga Toxin producing Escherichia Coli (STEC)-TMA, Pneumococcal HUS, TMA secondary to cobalamin C defect (as demonstrated by either increased total blood homocysteine levels or MMACHC gene mutation) and TMA related to Diacylglycerol kinase ε (DGKE) nephropathy.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants with complete TMA response (cTMAr) (Naive Cohort only) | Baseline up to Week 25 (after 24 weeks on treatment) |
Secondary
| Measure | Time frame |
|---|---|
| Change from Baseline in Dialysis Status | Baseline up to Week 25 (after 24 weeks on treatment) |
| Change in Estimated Glomerular Filtration Rate (eGFR) (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Percentage of Participants with Change from Baseline in Chronic Kidney Disease (CKD) stage (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Observed Value in Platelet Count (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Observed Value in Lactate Dehydrogenase (LDH) (mg/dL) (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Observed Value in Hemoglobin (mg/dL) (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Change from Baseline in Platelet Count (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Change from Baseline in Lactate Dehydrogenase (LDH) (mg/dL) (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Change from Baseline in Hemoglobin (mg/dL) (Naive and Switch Cohorts) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Percentage of Participants with Platelet Count >= LLN (Naive Cohort only) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Percentage of Participants with Normalisation of LDH (i.e., =< Upper Limit Normal (ULN)) (Naive Cohort only) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Percentage of Participants with >=25% decrease in Serum Creatinine (Naive Cohort only) | Baseline up to Week 25 (after 24 weeks on treatment) |
| Time to complete TMA response (cTMAr) (Naive Cohort only) | Up to 8 years |
| Duration of complete TMA response (cTMAr) (Naive Cohort only) | Up to 8 years |
| Percentage of Participants with ongoing complete TMA response (cTMAr) (Naive Cohort only) | At Week 25 |
| Percentage of Participants with maintained TMA control (mTMAc) (Switch Cohort only) | Baseline through Week 25 (after 24 weeks on treatment) |
| Percentage of Participants with Adverse Events (AEs) | Up to 8 years |
| Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity, Malignant Hypertension (including malignant renal hypertension) and Infections (including meningococcal meningitis) | Up to 8 years |
| Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation | Up to 8 years |
| Percentage of Participants with Clinical Manifestations of Drug-Target-Drug Complex (DTDC) formation amongst participants who switched to crovalimab treatment from eculizumab/ravulizumab treatment (Switch Cohort and switching Pretreated participants) | Up to Week 25 |
| Serum Concentrations of Crovalimab over time | Up to 8 years |
| Prevalence of Anti-Crovalimab Antibodies at Baseline | Baseline |
| Percentage of Participants with Anti-Crovalimab Antibodies | Up to 8 years |
| Observed value of Pharmacodynamic Markers (CH50, Free/Total C5) | Up to 8 years |
Countries
Belgium, Brazil, Canada, China, France, India, Japan, Mexico, Poland, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed