Clinical trial NCT04958265: A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Pediatric Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
Official title: A Phase III, Multicenter, Single-Arm Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Pediatric Patients With Atypical Hemolytic Uremic Syndrome (aHUS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Atypical Hemolytic Uremic Syndrome
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Chugai Pharmaceutical
First posted: 2021-07-12
Enrollment: 41
Sex: ALL
Minimum age (years): 28
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with complete TMA response (cTMAr) (Naive Cohort only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
Secondary outcomes:
measure: Change from Baseline in Dialysis Status
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change in Estimated Glomerular Filtration Rate (eGFR) (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Change from Baseline in Chronic Kidney Disease (CKD) stage (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Platelet Count (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Lactate Dehydrogenase (LDH) (mg/dL) (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Hemoglobin (mg/dL) (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Platelet Count (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Lactate Dehydrogenase (LDH) (mg/dL) (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Hemoglobin (mg/dL) (Naive and Switch Cohorts)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Platelet Count >= LLN (Naive Cohort only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Normalisation of LDH (i.e., =< Upper Limit Normal (ULN)) (Naive Cohort only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with >=25% decrease in Serum Creatinine (Naive Cohort only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Time to complete TMA response (cTMAr) (Naive Cohort only)
timeFrame: Up to 8 years
measure: Duration of complete TMA response (cTMAr) (Naive Cohort only)
timeFrame: Up to 8 years
measure: Percentage of Participants with ongoing complete TMA response (cTMAr) (Naive Cohort only)
timeFrame: At Week 25
measure: Percentage of Participants with maintained TMA control (mTMAc) (Switch Cohort only)
timeFrame: Baseline through Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Up to 8 years
measure: Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity, Malignant Hypertension (including malignant renal hypertension) and Infections (including meningococcal meningitis)
timeFrame: Up to 8 years
measure: Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation
timeFrame: Up to 8 years
measure: 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)
timeFrame: Up to Week 25
measure: Serum Concentrations of Crovalimab over time
timeFrame: Up to 8 years
measure: Prevalence of Anti-Crovalimab Antibodies at Baseline
timeFrame: Baseline
measure: Percentage of Participants with Anti-Crovalimab Antibodies
timeFrame: Up to 8 years
measure: Observed value of Pharmacodynamic Markers (CH50, Free/Total C5)
timeFrame: Up to 8 years
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Hollywood
country: United States
facility: Memorial Healthcare Systems
state: Florida
city: Atlanta
country: United States
facility: Emory Children's Center
state: Georgia
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: San Antonio
country: United States
facility: UT Health Science Center
state: Texas
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liege
country: Belgium
facility: CHC MontLégia
city: Sao Paulo
country: Brazil
facility: Inst. Da Criança- Faculdade de Medicina Usp
state: São Paulo
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Beijing City
country: China
facility: Peking University First Hospital
city: Beijing City
country: China
facility: Beijing Children's Hospital, Capital Medical University
city: Hangzhou City
country: China
facility: The children's hospital , Zhejiang university school of medicine
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve
city: Paris
country: France
facility: Hôpital Robert Debré
city: Paris
country: France
facility: Gh Necker Enfants Malades
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital des Enfants
city: New Delhi
country: India
facility: All India Institute Of Medical Sciences (AIIMS)
state: Delhi
city: Ahmadabad CITY
country: India
facility: Institute of Kidney Diseases and Research Centre
state: Gujarat
city: Gurgaon
country: India
facility: Medanta-The Medicity
state: Haryana
city: Aichi
country: Japan
facility: Aichi Children?s Health and Medical Center
city: Chibashi, Chibaken
country: Japan
facility: Chiba Children's Hospital
city: Kanagawa
country: Japan
facility: Yokohama City University Medical Center
city: Zapopan
country: Mexico
facility: Hospital de Especialidades Puerta de Hierro S.A de C.V.
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lodz
country: Poland
facility: Instytut ?Centrum Zdrowia Matki Polki
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: