Clinical trial NCT04861259: A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Adult and Adolescent 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 Adult and Adolescent 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: 2021-04-27
Enrollment: 83
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
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 adult and adolescent participants with aHUS.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with Complete Thormbotic Microangiopathy Response (cTMAr)
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 from Baseline in Estimated Glomerular Filtration Rate (eGFR)
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
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Platelet Count
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Lactate Dehydrogenase (LDH)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Observed Value in Hemoglobin
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Platelet Count
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Lactate Dehydrogenase (LDH)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Change from Baseline in Hemoglobin
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Mean Change From Baseline in Fatigue (in Adult Participants only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Platelet Count >= Lower Limits of Normal (LLN) (Naive Cohort only)
timeFrame: Baseline up to Week 25 (after 24 weeks on treatment)
measure: Percentage of Participants with Normalization of LDH (i.e. =< Upper Limit of 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 cTMAr (Naive Cohort only)
timeFrame: Up to 8 years
measure: Duration of cTMAr (Naive Cohort only)
timeFrame: Up to 8 years
measure: Percentage of Participants with Ongoing cTMAr (Naive Cohort only)
timeFrame: At Week 25
measure: Percentage of Participants with Maintained Thrombotic Microangiopathy Control (mTMAc) (Switch Cohort only)
timeFrame: Baseline up to 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: Number of Participants with 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 Those Participants who Switched to Crovalimab Treatment From Eculizumab Treatment or Ravulizumab Treatment
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: Orange
country: United States
facility: University of California Irvine Chao Family Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: Univ of CA San Francisco
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: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: San Antonio
country: United States
facility: UT Health Science Center
state: Texas
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia
state: Minas Gerais
city: Botucatu
country: Brazil
facility: UPECLIN Hospital das Clinicas da Faculdade de Medicina de Botucatu
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP
state: São Paulo
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Beijing City
country: China
facility: Beijing Children's Hospital, Capital Medical University
city: Beijing
country: China
facility: Peking University First Hospital
city: Montpellier
country: France
facility: Hopital Lapeyronie
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: Paris
country: France
facility: Hopital Tenon
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Essen
country: Germany
facility: Klinik für Nephrologie des Universitätsklinikum Essen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Köln
country: Germany
facility: Klinik II für Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin
city: Budapest
country: Hungary
facility: Del- Pesti Centrumkorhaz- Szent Laszlo Korhaz Telephely
city: New Delhi
country: India
facility: All India Institute Of Medical Sciences (AIIMS)
state: Delhi
city: Gurgaon
country: India
facility: Medanta-The Medicity
state: Haryana
city: Jaipur
country: India
facility: Sawai Man Singh Hospital and Medical College
state: Rajasthan
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Ramat-Gan
country: Israel
facility: Sheba MC
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
state: Lazio
city: Genova
country: Italy
facility: A.O. Universitaria S. Martino Di Genova
state: Liguria
city: Aichi
country: Japan
facility: Nagoya University Hospital
city: Mie
country: Japan
facility: Mie University Hospital
city: Saitama
country: Japan
facility: Saitama Medical University Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Ciudad de México
country: Mexico
facility: Instituto Nacional de Ciencias
state: Mexico CITY (federal District)
city: Distrito Federal
country: Mexico
facility: Hospital General de México
state: Mexico CITY (federal District)
city: Monterrey
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
state: Nuevo LEON
city: Zapopan
country: Mexico
facility: Hospital de Especialidades Puerta de Hierro S.A de C.V.
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Bellavista
country: Peru
facility: Hospital IV Alberto Sabogal Sologuren
city: Lima
country: Peru
facility: Hospital Nacional Dos de Mayo
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lodz
country: Poland
facility: Instytut ?Centrum Zdrowia Matki Polki
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: La Coruna
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: Kocaeli
country: Turkey
facility: Kocaeli University Medical Faculty
city: Konya
country: Turkey
facility: Necmettin Erbakan University Meram Medical Faculty
city: Malatya
country: Turkey
facility: Malatya Park Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: