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    Summary
    EudraCT Number:2020-002475-35
    Sponsor's Protocol Code Number:BO42353
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-04-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-002475-35
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Evaluating the Efficacy and Safety of Crovalimab in Adult and Adolescent Patients with Atypical Hemolytic Uremic Syndrome (aHUS)
    A.4.1Sponsor's protocol code numberBO42353
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/124/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namecrovalimab
    D.3.2Product code RO7112689/F03-10
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcrovalimab
    D.3.9.1CAS number 1917321-26-6
    D.3.9.2Current sponsor codeRO7112689
    D.3.9.3Other descriptive nameC5 inh MAb, SKY59, RO/CH7092230
    D.3.9.4EV Substance CodeSUB183839
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number170
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Atypical Hemolytic Uremic Syndrome (aHUS)
    E.1.1.1Medical condition in easily understood language
    aHUS is a rare disease, characterized by damage to the lining of small blood vessels, leading to red blood cell destruction, blood clots and kidney damage.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10079841
    E.1.2Term Atypical hemolytic uremic syndrome
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To evaluate the effect of crovalimab in complement inhibitor treatment-naive (Naive) patients
    E.2.2Secondary objectives of the trial
    •To evaluate the effect of crovalimab in patients in the Naïve and Switch (switching from an existing complement inhibitor treatment to crovalimab) patients
    •To evaluate the overall safety and tolerability of crovalimab
    •To evaluate the pharmacokinetics of crovalimab
    •To evaluate the immune response to crovalimab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For all Cohorts (all patients, in the Naïve, Switch and C5 SNP Cohorts, must meet the following criteria for study entry):
    • Age >= 12 years
    • Body weight >= 40 kg at screening
    • Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 3 years prior to initiation of crovalimab treatment. Vaccination against serotype B should be administered in accordance with current local guidelines or standard of care, as applicable for patients with complement deficiency
    • For female patients of childbearing potential, an agreement to remain abstinent or use contraception
    • Patients with a prior kidney transplant are eligible if they have known history of complement-mediated aHUS prior to the kidney transplant

    For Naive Cohort ONLY:
    • Onset of initial TMA presentation, as defined by a patient with all of the following laboratory findings, within 28 days prior to the first dose of crovalimab:
    – Platelet count < LLN, and
    – LDH >=1.5 x ULN, and
    – Hemoglobin <= LLN (adjusted for age and sex), and
    – Serum creatinine . ULN in adults, or >= 97.5th percentile for age in adolescents (12-18 years). Patients who require dialysis for acute kidney injury are also eligible.
    NOTE: If the patient has been receiving plasma exchange/plasma infusion (PE/PI), the patient's eligibility must be ascertained based on
    the above qualifying laboratory findings, obtained at onset of initial TMA presentation (prior to receiving any PE/PI) and must be within 28 days of the first crovalimab dose. The qualifying laboratory findings, even if obtained prior to screening, can be used as screening values to enroll the patient, but only if documented in the medical records.

    For Switch Cohort ONLY:
    • Documented treatment with eculizumab or ravulizumab according to the local product label for aHUS. Eculizumab treatment received for at least 90 days. Patients switching from IV ravulizumab must have received at least two maintenance doses
    • Clinical evidence of response to either eculizumab or ravulizumab

    For C5 SNP Cohort only:
    • Documented diagnosis of aHUS
    • Known C5 polymorphism (e.g., Arg885)
    • Documented treatment with eculizumab or ravulizumab for aHUS, with poorly controlled TMA, per investigator's assessment
    E.4Principal exclusion criteria
    For ALL Cohorts (all patients, in the Naïve, Switch and C5 SNP Cohorts, patients must meet the following criteria for study entry):
    • Diagnosis of TTP, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), clinical suspicion of Pneumococcal HUS,
    • TMA secondary to cobalamin C defect
    • TMA related to diacylglycerol kinase (DGKE) nephropathy
    • TMA associated with non-aHUS related renal disease
    • Positive direct Coombs test
    • Identified drug exposure-related TMA
    • History of bone marrow transplant or organ transplant, other than kidney transplant
    • Chronic dialysis, and/or end stage renal disease
    • History of a kidney disease, other than aHUS, affecting renal function
    • 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
    • Life expectancy of < 4 weeks
    • Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration
    • Presence of fever (>=38 Degrees Celsius) within 7 days before the first drug administration
    • Patient with active or evolving multisystem organ dysfunction or failure
    • Immunized with a live attenuated vaccine within 1 month before first drug administration
    • Known systemic sclerosis, systemic lupus erythematosus, or anti-phospholipid antibody positivity or syndrome
    • Patients receiving chronic IV immunoglobulin (IVIg) within 8 weeks prior to start of screening, unless for unrelated medical condition
    • Female patients who are pregnant, are breastfeeding, or have the intention of becoming pregnant during the study or within 46 weeks after the final dose of the study treatment
    • Splenectomy < 6 months prior to screening
    • Use of tranexamic acid within 7 days prior to screening
    • Concurrent disease, treatment, procedure or surgery, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose any additional risk for the patient, or would, in the opinion of the investigator, preclude the patient's safe participation in and completion of the study

    For Naive Cohort ONLY:
    • First initiation of PE/PI not more than 28 days prior to first crovalimab administration
    • PE/PI should not be administered within 6 hours of first crovalimab administration
    • Current or previous treatment with a complement inhibitor

    For Switch Cohort and C5 SNP Cohort ONLY (additional exclusion criteria for Switch patients and for patients with a C5 polymorphism):
    • Receiving PE/PI within 8 weeks of the first crovalimab administration (Switch Cohort only)
    • Positive for hepatitis B surface antigen (HBsAg) at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago)
    • Positive for hepatitis C virus (HCV) antibody at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago). Patients who are seropositive for HCV but without detectable HCV RNA are eligible
    • History of or ongoing cryoglobulinemia at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago)
    E.5 End points
    E.5.1Primary end point(s)
    1. Proportion of patients with complete TMA response (cTMAr)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From baseline to Week 25
    E.5.2Secondary end point(s)
    For ALL (Naive, Switch, and C5 SNP) Cohorts:
    1. Dialysis requirement status (yes/no) change
    2. Observed value and change from baseline in estimated glomerular filtration rate (eGFR)
    3. Proportion of patients with change from baseline in chronic kidney disease stage
    4. Observed value and change from baseline in hematologic parameters
    5. In adults (>= 18 years), change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire
    6. Incidence and severity of adverse events
    7. Change in targeted vital signs and clinical laboratory test results
    8. Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, malignant hypertension, and infections
    9. Incidence of adverse events leading to study drug discontinuation
    10. Serum concentrations of crovalimab
    11. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab

    For Naive Cohort ONLY:
    12. Proportion of patients with platelet count >= LLN
    13. Proportion of patients with normalization of LDH
    14. Proportion of patients with >= 25% decrease in serum creatinine from baseline
    15. Time to cTMAr
    16. Duration of cTMAr
    17. Proportion of patients with cTMAr

    For Switch Cohort ONLY:
    18. Proportion of patients with maintained TMA control (mTMAc)
    19. Incidence and severity of clinical manifestations of drug-target-drug complexes in patients who switched to crovalimab treatment from either eculizumab or ravulizumab treatment
    20. Serum concentration of eculizumab or ravulizumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. From baseline to Week 25
    2-10. Up to 8 years
    11. At baseline (prevalence) and up to 8 years (incidence)
    12-14. At Week 25
    15-16. Up to 8 years
    17. At Week 25
    18. Up to 8 years
    19. From baseline to Week 10
    20. Day 1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Canada
    China
    Israel
    Korea, Republic of
    Mexico
    Peru
    South Africa
    United States
    France
    Luxembourg
    Poland
    Spain
    Czechia
    Germany
    Italy
    Belgium
    Hungary
    Turkey
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 90
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor will offer post-trial access to the study drug (RO7112689) free of charge to eligible patients, i.e., patients who derive clinical benefit from RO7112689, in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. Please see section 4.3.4 of the protocol for further information.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-04-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-20
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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