Atypical Hemolytic Uremic Syndrome
Conditions
Brief summary
This study aims to evaluate the efficacy and safety of crovalimab in adult and adolescent participants with aHUS.
Interventions
DRUGCrovalimab
Crovalimab will be administered at a dose of 1000 milligrams (mg) intravenous (IV) (for participants with body weight at least 40 (\>=) and up to 100 kilograms (kg) or 1500 mg IV (for participants with body weight \>=100kg) on Week 1 Day 1. On Week 1 Day 2 and on Weeks 2, 3 and 4, it will be administered at a dose of 340 mg subcutaneously (SC). On Week 5 and every 4 weeks (Q4W) thereafter, it will be administered at a dose of 680 mg SC (for participants with body weight \>= 40kg to \<100kg) or 1020 mg SC (for participants with body weight \>=100kg).
Sponsors
Hoffmann-La Roche
Chugai Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight \>= 40 kg at screening. * Vaccination against Neisseria meningitidis serotypes A, C, W, and Y; vaccination against serotypes B, according to national vaccination recommendations. * Vaccination against Haemophilus influenzae type B and Streptococcus pneumoniae, according to national vaccination recommendations. * For participants 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. * Female participants of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of crovalimab. * 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). * Known C5 polymorphism (for C5 SNP Cohort only). * Poorly controlled TMA following treatment with another C5 inhibitor (for C5 SNP 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 Human Immunodeficiency Virus (HIV) test. * Active systemic bacterial, viral, or fungal infection within 14 days before first crovalimab administration * Presence of fever (\>= 38°C) * 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 Chorot only). * Receiving PE/PI within 8 weeks of the first crovalimab administration (Switch Cohort only). * Positive for active Hepatitis B and C infection (HBV/HCV) (for Switch Cohort and C5 SNP 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 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 and TMA related to a known DGKE nephropathy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Naive Cohort: Percentage of Participants With Complete Thrombotic Microangiopathy Response (cTMAr) Anytime From Baseline to Week 25 | Baseline up to Week 25 (after 24 weeks on treatment) | 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. Percentage has been rounded off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Naive and Switch Cohorts: Percentage of Participants Requiring Dialysis at Baseline and at Week 25 Who Completed 24 Weeks of Treatment | Baseline up to Week 25 (after 24 weeks on treatment) | 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. Participants who were on dialysis at any time point from baseline to Week 25 were classified as "Initiated dialysis at any time point ". Participants who remained dialysis-free throughout the primary treatment period were classified as "Remained dialysis free throughout". Participants who were on dialysis at Week 25 were classified as "Remained on dialysis". Participants who discontinued dialysis at Week 25 were classified as "Discontinued dialysis. Percentages have been rounded off. |
| Naive and Switch Cohorts: Observed Values of Estimated Glomerular Filtration Rate (eGFR), as Calculated From Central Serum Creatinine | Baseline, Weeks 2, 3, 4, 5, 7, 9, 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 for adolescents and 2009 CKD-Epidemiology Collaboration (EPI) creatinine equation for adults. Formula for creatinine-based bedside Schwartz equation was 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, and formula for 2009 CKD-EPI creatinine equation was eGFR (mL/min/1.73 m\^2)= 141\*min(sCr /κ,1)\^α\*max(sCr/κ,1)\^ -1.209\*0.993\^AGE\[\*1.018 if female\]\[\*1.159 if black\], κ was 0.7 for females and 0.9 for males, α was -0.329 for females and -0.411 for males, min indicated the minimum of sCr/κ or 1, and max indicated the maximum of sCr/κ or 1. |
| Naive and Switch Cohorts: Change From Baseline up to Week 25 in eGFR, as Calculated From Central Serum Creatinine | Baseline, Weeks 2, 3, 4, 5, 7, 9, 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 for adolescents and 2009 CKD- EPI creatinine equation for adults. Formula for creatinine-based bedside Schwartz equation was 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, and formula for 2009 CKD-EPI creatinine equation was eGFR (mL/min/1.73 m\^2)= 141\*min(sCr /κ,1)\^α\*max(sCr/κ,1)\^ -1.209\*0.993\^AGE\[\*1.018 if female\]\[\*1.159 if black\], κ was 0.7 for females and 0.9 for males, α was -0.329 for females and -0.411 for males, min indicated the minimum of sCr/κ or 1, and max indicated the maximum of sCr/κ or 1. |
| Naive and Switch Cohorts: Percentage of Participants With Change in Chronic Kidney Disease (CKD) Stage From Baseline to Week 25, as Assessed Based on eGFR Calculated From Central Serum Creatinine | Baseline up to Week 25 (after 24 weeks on treatment) | CKD stage assessed using eGFR, classified per National Kidney Foundation CKD staging criteria: grade 1 (≥90 mL/min/1.73 m²; normal or high), grade 2 (60-89 mL/min/1.73 m²; mildly decreased), grade 3a (45-59 mL/min/1.73 m²; mildly to moderately decreased), grade 3b (30-44 mL/min/1.73 m²; moderately to severely decreased), grade 4 (15-29 mL/min/1.73 m²; severely decreased), grade 5 (\<15 mL/min/1.73 m²; kidney failure). Change in CKD stage from baseline to Week 25, categorized as improved (participants who improved in CKD stage from baseline to Week 25 were based on number of participants who completed 24 weeks \& were not stage 1 at baseline), stable (no change), or worsened (CKD stage 1-4 at baseline) among participants who completed 24 weeks of treatment. Percentages rounded off. |
| Naive and Switch Cohorts: Observed Value of Platelet Count | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Observed Value of Lactate Dehydrogenase (LDH) | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Observed Value of Hemoglobin | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Change From Baseline in Platelet Count at Week 25 | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Change From Baseline in LDH at Week 25 | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Change From Baseline in Hemoglobin at Week 25 | Baseline and Week 25 | — |
| Naive and Switch Cohorts: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 25 | Baseline, Weeks 1 (Day 1), 2, 5, 9, 17, and 25 | Fatigue was measured by the FACIT-Fatigue questionnaire in adult participants only (≥18 years at baseline). It consists of 13 items that assess fatigue using a 7-day recall period. Items are scored on a 0= 'Not at all' to 4= 'Very much so' response scale. Relevant items are reverse scored, and all items are summed to create total score where higher scores are indicative of better functioning (i.e., less fatigue). The FACIT-Fatigue total score ranges from 0 to 52, with higher scores representing less fatigue; therefore, an increase in score represents an improvement in fatigue. Only categories with non-zero values were reported. |
| Naive 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) | Baseline up to Week 25 (after 24 weeks on treatment) | This event was confirmed at two separate assessments obtained at least 4 weeks (a minimum of 26 days) apart and any measurement in between. Percentages are rounded off. |
| Naive Cohort: Percentage of Participants With LDH ≤ Upper Limit of Normal (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 through Week 25 (after 24 weeks on treatment) | Percentages are rounded off. |
| Naive Cohort: Percentage of Participants With ≥25% Decrease in Serum Creatinine From Baseline at Two Separate Assessments, Obtained at Least 4 Weeks Apart (Minimum of 26 Days), by Week 25 (After 24 Weeks on Treatment) | Baseline up to Week 25 (after 24 weeks on treatment) | Percentages are rounded off. |
| Naive Cohort: Time to Complete Thrombotic Microangiopathy Response (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 and \> ULN. Kaplan-Meier (K-M) method was used to estimate median time to cTMAr. Data for participants who did not reach cTMAr during the primary treatment period 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 primary treatment period 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. |
| Naive Cohort: Duration of cTMAr | From baseline up to primary CCOD (up to 207 weeks) | cTMAr was defined by 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 \& \> ULN. Duration of cTMAr was calculated as time from start of cTMAr to end of cTMAr. End of cTMAr was when all above-mentioned criteria were met during same visit \& confirmed at an assessment that took place at least 4 weeks (minimum of 26 days) later. K-M method was used to estimate median duration of cTMAr. Data for participants with no observed end of cTMAr at clinical cutoff date (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 a prohibited therapy prior to the CCOD were censored at date of the first received prohibited therapy or prior to the treatment discontinuation, whichever was earlier. |
| Naive 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 and \> ULN. Percentage has been rounded off. |
| Switch Cohort: Percentage of Participants With Maintained Thrombotic Microangiopathy Control (mTMAc) From Baseline Through Week 25 (After 24 Weeks on Treatment) | From baseline through Week 25 (After 24 weeks on treatment) | 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 and \> ULN. |
| All Cohorts: Number of Participants With 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 and Infections | 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. Infusion-related and injection-site reactions were adverse events that occured during or within 24 hours after crovalimab administration and were judged to be related to study drug infusion or injection. |
| All Cohorts: Number of Participants With AE 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 | In this study, the risk of DTDC is relevant only to participants who might switch to crovalimab from eculizumab or ravulizumab treatment at study enrollment, and to participants who discontinued crovalimab and switch to eculizumab or ravulizumab. Type III hypersensitivity may occur due to the transient formation of DTDCs made of eculizumab or ravulizumab, crovalimab, and C5 in participants switching from eculizumab or ravulizumab to crovalimab. |
| All Cohorts: Crovalimab Serum Concentration | Up to approximately 8 years | — |
| All Cohorts: Percentage 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 study 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 Complement Activity (CH50) Over Time, 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 in Crovalimab-treated Participants | Up to approximately 8 years | — |
Countries
Belgium, Brazil, Canada, China, France, Germany, Hungary, India, Israel, Italy, Japan, Mexico, Poland, Spain, Turkey (Türkiye), United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 83 participants were enrolled at 42 investigative sites across 16 countries. Participants were planned to be enrolled in 3 parallel cohorts, based on their previous exposure & response to complement inhibitor therapy: Naïve, Switch, & component 5 (C5) single nucleotide polymorphism (SNP) (documented C5 polymorphism) cohorts.
Pre-assignment details
Participants were enrolled to receive crovalimab according to body weight during a 24-week primary treatment period (PTP). Participants who derived clinical benefit during the PTP could continue treatment during 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 | 36.9 years STANDARD_DEVIATION 15.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 1 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 | 0 Participants |
| Race (NIH/OMB) White | 58 Participants |
| Sex: Female, Male Female | 51 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 41 | 0 / 41 | 0 / 1 |
| other Total, other adverse events | 33 / 41 | 39 / 41 | 1 / 1 |
| serious Total, serious adverse events | 14 / 41 | 10 / 41 | 1 / 1 |
Outcome results
None listed