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 | Description |
|---|---|---|
| Naïve Cohort: Percentage of Participants With Complete Thrombotic Microangiopathy Response (cTMAr) Anytime From Baseline to Week 25 (After 24 Weeks on Treatment) | From baseline up to Week 25 | cTMAr was defined by meeting all of the following criteria at two separate assessments, obtained at least 4 weeks (a minimum of 26 days) apart, and any measurement in between: Platelet count ≥ lower limit of normal (LLN); Lactate dehydrogenase (LDH) ≤ upper limit of normal (ULN); and ≥ 25% decrease in serum creatinine from baseline. Participants with normalized creatinine (i.e., LLN ≤ creatinine ≤ ULN) at baseline were excluded from analysis. 95% confidence interval (CI) was calculated using Wilson's score method. Percentage has been rounded off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Naïve and Switch Cohorts: Percentage of Participants Requiring Dialysis at Baseline or Week 25 and Who Completed 24 Weeks of Treatment | Baseline and Week 25 | Participants were considered to be on dialysis at baseline or at Week 25 if dialysis occurred within 5 days prior to the first crovalimab administration or prior to the end date of the primary treatment period, respectively. The percentage of participants who required dialysis at baseline and Week 25 has been reported here. Percentages have been rounded off. |
| Naïve and Switch Cohorts: Percentage of Participants With Change From Baseline to Week 25 (After 24 Weeks on Treatment) on Dialysis Status (Yes/No) | From baseline up to Week 25 | Participants were considered as being on dialysis at baseline or at Week 25 if dialysis occurred within 5 days prior to the first crovalimab administration or prior to the end date of the primary treatment period, respectively. Percentages have been rounded off. |
| Naïve and Switch Cohorts: Observed Value of Estimated Glomerular Filtration Rate (eGFR), as Calculated From Central Serum Creatinine | Baseline, Weeks 2, 3, 4, 5, 7, 9, 11, 13, 17, 21, and 25 | GFR is an index of kidney function that describes the flow rate of filtered fluid through the kidneys. It was categorized according to chronic kidney disease (CKD) staging criteria. eGFR was calculated using the creatinine-based bedside Schwartz equation. eGFR (milliliters per minute per 1.73 square meter \[mL/min/1.73 m\^2\])=0.413\*(height \[ht\]/serum creatinine \[sCr\]), if height is expressed in centimeters, or 41.3\*(ht/sCr), if height is expressed in meters. |
| Naïve and Switch Cohorts: Change From Baseline to Week 25 in eGFR, as Calculated From Central Serum Creatinine | Baseline, Weeks 2, 3, 4, 5, 7, 9, 11, 13, 17, 21, and 25 | GFR is an index of kidney function that describes the flow rate of filtered fluid through the kidneys. It was categorized according to CKD staging criteria. eGFR was calculated using the creatinine-based bedside Schwartz equation. eGFR (mL/min/1.73 m\^2\])=0.413\*(ht/sCr), if height is expressed in centimeters, or 41.3\*(ht/sCr), if height is expressed in meters. |
| Naïve and Switch Cohorts: Percentage of Participants With Change From Baseline to Week 25 (After 24 Weeks on Treatment) in CKD Stage, as Assessed Based on eGFR Calculated From Central Serum Creatinine | From baseline up to Week 25 | CKD stage was assessed using eGFR, calculated from central serum creatinine using Creatinine-based bedside Schwartz equation \& classified according to National Kidney Foundation CKD staging criteria as follows: G1 (≥90 mL/min/1.73 m²; normal or high kidney function), G2 (60-89 mL/min/1.73 m²; mildly decreased kidney function), G3a (45-59 mL/min/1.73 m²; mildly to moderately decreased kidney function), G3b (30-44 mL/min/1.73 m²; moderately to severely decreased kidney function), G4 (15-29 mL/min/1.73 m²; severely decreased kidney function), \& G5 (\<15 mL/min/1.73 m²; kidney failure). Change in CKD stage from baseline to Week 25 was categorized as improved (participants who improved in CKD stage from Baseline to Week 25 were based on the number of participants who completed 24 weeks and were not Stage 1 at baseline), stable (no change), or worsened (participants with CKD Stage 1 to 4 at baseline) among participants who completed 24 weeks of treatment. Percentages have been rounded off. |
| Naïve and Switch Cohorts: Observed Value of Platelet Count | Baseline and Week 25 | — |
| Naïve and Switch Cohorts: Observed Value of LDH | Baseline and Week 25 | — |
| Naïve and Switch Cohorts: Observed Value of Hemoglobin (Hb) | Baseline and Week 25 | — |
| Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in Platelet Count | Baseline and Week 25 | — |
| Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in LDH | Baseline and Week 25 | — |
| Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in Hb | Baseline and Week 25 | — |
| Naïve Cohort: Percentage of Participants With Platelet Count ≥ LLN at Two Separate Assessments, Obtained at Least 4 Weeks Apart (Minimum of 26 Days), by Week 25 (After 24 Weeks on Treatment) | From baseline up to Week 25 | This event was confirmed at two separate assessments obtained at least 4 weeks (a minimum of 26 days) apart and any measurement in between. |
| Naïve Cohort: Percentage of Participants With LDH Normalization (i.e., ≤ ULN) at Two Separate Assessments, Obtained at Least 4 Weeks Apart (Minimum of 26 Days), by Week 25 (After 24 Weeks on Treatment) | From baseline up to Week 25 | Percentage has been rounded off. |
| Naïve Cohort: Percentage of Participants With ≥ 25% Decrease in Serum Creatinine From Baseline, Confirmed at Two Separate Assessments, Obtained at Least 4 Weeks Apart (Minimum of 26 Days), by Week 25 (After 24 Weeks on Treatment) | From baseline up to Week 25 | Percentage has been rounded off. |
| Naïve Cohort: Time to cTMAr | From baseline up to Week 25 | cTMAr was defined by meeting all of the following criteria at two separate assessments, obtained at least 4 weeks (a minimum of 26 days) apart, and any measurement in between: Platelet count ≥ LLN; LDH ≤ ULN; and ≥ 25% decrease in serum creatinine from baseline. Kalpan-Meier (K-M) method was used to estimate median time to cTMAr. Data for participants who did not reach cTMAr during PTP were censored at the date of their last visit when cTMAr was assessed during the primary treatment period or prior to the treatment discontinuation, whichever was earlier. Data for participants who received a prohibited therapy during the PTP were censored at the date of the first received prohibited therapy during the primary treatment period or prior to the treatment discontinuation, whichever was earlier. |
| Naïve Cohort: Duration of cTMAr, Among Participants Who Achieved cTMAr | From baseline up to primary CCOD (up to 190 weeks) | cTMAr=meeting following criteria at 2 separate assessments, obtained at least 4 weeks (minimum of 26 days) apart \& any measurement in between: Platelet count ≥LLN; LDH ≤ULN; \& ≥25% decrease in serum creatinine from baseline. Duration of cTMAr was calculated as time from start of cTMAr to end of cTMAr. End of cTMAr=when all of following criteria were met during same visit \& confirmed at assessment that took place at least 4 weeks (minimum of 26 days) later: Platelet count \<LLN; LDH \>ULN; \& ≥25% increase in serum creatinine from baseline \& ULN. K-M method was used to estimate the median duration of cTMAr. Data for participants with no observed end of cTMAr at CCOD were censored at the date of their last visit when cTMAr was assessed before CCOD or before treatment discontinuation, whichever was earlier. Data for participants who received prohibited therapy before CCOD were censored at date of first receiving prohibited therapy or before treatment discontinuation, whichever was earlier. |
| Naïve Cohort: Percentage of Participants With cTMAr Ongoing at Week 25 | At Week 25 | cTMAr at Week 25 was defined by meeting all of the three cTMAr criteria at Week 25: Platelet count ≥ LLN; LDH ≤ ULN; and ≥ 25% decrease in serum creatinine from baseline. Percentage has been rounded off. |
| Switch Cohort: Percentage of Participants With Maintained Thrombotic Microangiopathy Response Control (mTMAc) From Baseline Through Week 25 (After 24 Weeks on Treatment) | From baseline up to Week 25 | mTMAc was considered not maintained if all of the following criteria were met during one of the visits between baseline and Week 25, and were confirmed at an assessment that took place at least 4 weeks (a minimum of 26 days) later: Platelet count \< LLN; LDH \> ULN; and 25% increase in serum creatinine from baseline. |
| All Cohorts: Number of Participants With Adverse Events (AEs) | Up to approximately 8 years | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| All Cohorts: Number of Participants With Injection-site Reactions, Infusion-related Reactions, Hypersensitivity, Malignant Hypertension (Including Malignant Renal Hypertension), and Infections (Including Meningococcal Meningitis) | Up to approximately 8 years | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| All Cohorts: Number of Participants With AEs Leading to Study Drug Discontinuation | Up to approximately 8 years | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Switch Cohort: Number of Participants With Clinical Manifestations of Drug-target-drug Complexes (DTDCs) | Up to approximately 8 years | Crovalimab and eculizumab bind distinct epitopes on complement component C5, and formation of DTDCs comprising crovalimab, eculizumab, and C5 are formed when participants switch treatment. DTDCs will be characterized using size exclusion chromatography (SEC) coupled with enzyme-linked immunosorbent assay (ELISA). |
| All Cohorts: Serum Concentrations of Crovalimab Over Time | Up to approximately 8 years | — |
| All Cohorts: Number of Participants With Anti-drug Antibodies (ADAs) to Crovalimab | Up to approximately 8 years | Participants will be considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following stuy drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater than the titer of the baseline sample (treatment-enhanced ADA response). |
| All Cohorts: Observed Value of Total Complement Activity 50 (CH50), as Measured by Liposome Immunoassay (LIA) | Up to approximately 8 years | — |
| All Cohorts: Change From Baseline in CH50 Over Time, as Measured by LIA | Up to approximately 8 years | — |
| All Cohorts: Observed Value of Free Complement Component 5 (C5) Concentrations in Crovalimab-treated Participants | Up to approximately 8 years | — |
| All Cohorts: Change From Baseline in Free C5 Concentrations Over Time in Crovalimab-treated Participants | Up to approximately 8 years | — |
| All Cohorts: Observed Value of Total C5 Concentrations in Crovalimab-treated Participants | Up to approximately 8 years | — |
| All Cohorts: Change From Baseline in Total C5 Concentrations Over Time in Crovalimab-treated Participants | Up to approximately 8 years | — |
Countries
Belgium, Brazil, Canada, China, France, India, Japan, Mexico, Poland, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 41 pediatric participants with hemolytic uremic syndrome (aHUS), took part in the study at 19 investigative sites across 10 countries. Participants were planned to be enrolled in 3 parallel cohorts, based on their previous exposure & response to complement inhibitor therapy: Naïve, Switch, & Pretreated cohorts. No participants were enrolled in the pre-treated cohort.
Pre-assignment details
Participants were enrolled to receive crovalimab according to a weight-based tiered dosing schedule during the primary treatment period (PTP). Participants demonstrating clinical benefit during the PTP were eligible to enter the crovalimab continuation period, & all participants who discontinued treatment should enter the safety follow-up (SFU) period. The study is still ongoing.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 6.8 years STANDARD_DEVIATION 3.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 20 |
| other Total, other adverse events | 15 / 21 | 19 / 20 |
| serious Total, serious adverse events | 8 / 21 | 4 / 20 |
Outcome results
None listed