A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Pediatric Participants With Atypical Hemolytic Uremic Syndrome (aHUS)

Phase 3Active Not RecruitingNCT04958265

Hoffmann-La Roche41 enrolled

Overview

This study aims to evaluate the efficacy and safety of crovalimab in pediatric participants with aHUS.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Atypical Hemolytic Uremic Syndrome

Interventions

CrovalimabDRUG

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.

Eligibility

Sex: ALLMin age: 28 DaysMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (20)

Children's Hospital Colorado

Aurora, Colorado, United States

University of Nebraska

Omaha, Nebraska, United States

Outcomes

Primary Outcomes

Naïve Cohort: Percentage of Participants With Complete Thrombotic Microangiopathy Response (cTMAr) Anytime From Baseline 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. 95% confidence interval (CI) was calculated using Wilson's score method. Percentage has been rounded off.

Time frame: From baseline up to Week 25

Secondary Outcomes

Naïve and Switch Cohorts: Percentage of Participants Requiring Dialysis at Baseline or Week 25 and Who Completed 24 Weeks of 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.

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Percentage of Participants With Change From Baseline to Week 25 (After 24 Weeks on Treatment) on Dialysis Status (Yes/No)

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.

Time frame: From baseline up to Week 25

Naïve and Switch Cohorts: Observed Value of Estimated Glomerular Filtration Rate (eGFR), as Calculated From Central Serum Creatinine

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.

Data from ClinicalTrials.gov

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Hackensack University Medical Center

Hackensack, New Jersey, United States

UZ Gent

Ghent, Belgium

UZ Leuven Gasthuisberg

Leuven, Belgium

Inst. Da Criança- Faculdade de Medicina Usp

São Paulo, São Paulo, Brazil

CHU Sainte-Justine

Montreal, Quebec, Canada

Peking University First Hospital

Beijing, China

Beijing Children's Hospital, Capital Medical University

Beijing, China

The children's hospital , Zhejiang university school of medicine

Hangzhou, China

...and 10 more locations

Time frame: Baseline, Weeks 2, 3, 4, 5, 7, 9, 11, 13, 17, 21, and 25

Naïve and Switch Cohorts: Change From Baseline to Week 25 in eGFR, as Calculated From Central Serum Creatinine

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.

Time frame: Baseline, Weeks 2, 3, 4, 5, 7, 9, 11, 13, 17, 21, and 25

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

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.

Time frame: From baseline up to Week 25

Naïve and Switch Cohorts: Observed Value of Platelet Count

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Observed Value of LDH

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Observed Value of Hemoglobin (Hb)

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in Platelet Count

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in LDH

Time frame: Baseline and Week 25

Naïve and Switch Cohorts: Change From Baseline to Week 25 (After 24 Weeks on Treatment) in Hb

Time frame: 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)

This event was confirmed at two separate assessments obtained at least 4 weeks (a minimum of 26 days) apart and any measurement in between.

Time frame: From baseline up to Week 25

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)

Percentage has been rounded off.

Time frame: From baseline up to Week 25

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)

Percentage has been rounded off.

Time frame: From baseline up to Week 25

Naïve Cohort: Time to cTMAr

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.

Time frame: From baseline up to Week 25

Naïve Cohort: Duration of cTMAr, Among Participants Who Achieved cTMAr

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.

Time frame: From baseline up to primary CCOD (up to 190 weeks)

Naïve Cohort: Percentage of Participants With cTMAr Ongoing 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.

Time frame: At Week 25

Switch Cohort: Percentage of Participants With Maintained Thrombotic Microangiopathy Response Control (mTMAc) 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.

Time frame: From baseline up to Week 25

All Cohorts: Number of Participants With Adverse Events (AEs)

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.