A Study Evaluating the Efficacy and Safety of Crovalimab in Pediatric Patients with Atypical Hemolytic Uremic Syndrome (aHUS)

• Register: EUCTR
• Last refreshed on: 8 October 2021
• Main ID: EUCTR2020-002437-15-ES
• Date of registration: 23/07/2021
• Prospective Registration: Yes
• Primary sponsor: Roche Farma S. A. que realiza el ensayo en España y que actúa como representante F. Hoffmann-La Roche Ltd
• Public title: A Study Evaluating the Efficacy and Safety of Crovalimab in Pediatric Patients with Atypical Hemolytic Uremic Syndrome (aHUS)
• Scientific title: A PHASE III, OPEN-LABEL, MULTICENTER, SINGLE-ARM STUDY EVALUATING THE EFFICACY AND SAFETY OF CROVALIMAB IN ADOLESCENT AND PEDIATRIC PATIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS)
• Date of first enrolment: 23/09/2021
• Target sample size: 35
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-002437-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Brazil, Canada, China, France, Hungary, Israel, Italy, Japan, Poland, South Africa, Spain, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
In addition to Naive and Switch patients (described above), Pretreated patients (patients who previously received treatment and then discontinued either eculizumab or ravulizumab and/or with a known C5 single nucleotide polymorphism [SNP]) will be enrolled as a separate third Cohort.
For ALL (Naive, Switch, and Pretreated) Cohorts:
• Age >=28 days and <18 years (at the time of signing the Informed Consent Form or Assent Form)
• Body weight >=5 kg at screening
• Vaccination against Neisseria meningitidis < 3 years prior to initiation of study treatment, in accordance with current local guidelines or standard-of-care, as applicable in 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 a known history of complement-mediated aHUS prior to the kidney transplant
For Naive Cohort ONLY:
• Onset of thrombotic microangiopathy (TMA) <=28 days prior to first crovalimab administration
For Switch Cohort ONLY:
• Documented treatment with either eculizumab or ravulizumab, according to the local product label for aHUS. Patients switching from IV eculizumab must have received treatment 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 Pretreated Cohort only:
• If TMA is present at time of screening: First crovalimab administration <=28 days from onset of TMA recurrence
• Received and subsequently discontinued treatment with either eculizumab or ravulizumab, for a minimum of 5.5 drug half-lives
• For C5 SNP patients: Known C5 polymorphism AND documented treatment with either eculizumab or ravulizumab for aHUS, with poorly controlled TMA
Are the trial subjects under 18? yes
Number of subjects for this age range: 40
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
For ALL (Naive, Switch, and Pretreated) Cohorts:
• At TMA onset, diagnosis of thrombotic thrombocytopenic purpura (TTP), diagnosis of Shiga toxin–producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), clinical suspicion of pneumococcal HUS, TMA secondary to cobalamin C defect or TMA related to diacylglycerol kinase-E (DGKE) nephropathy
• TMA associated with non-aHUS related renal disease
• Positive direct Coombs test
• Identified drug exposure-related TMA
• History of organ transplant, other than kidney transplant
• Chronic dialysis, and/or end stage renal disease (ESRD)
• History of a kidney disease other than aHUS, affecting renal function
• History of Neisseria meningitidis infection within 6 months prior to screening and up to the first drug administration
• 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 (scleroderma), systemic lupus erythematosus (SLE), or anti-phospholipid antibody positivity or syndrome
• Patients receiving chronic intravenous immunoglobulin (IVIg) within 8 weeks prior to start of screening, unless for unrelated medical condition
• Female patients who are pregnant, breastfeeding, or have the intention of becoming pregnant during the study or within 6 months 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:
• Current or previous treatment with a complement inhibitor
For Switch Cohort ONLY:
• Positive for hepatitis B surface antigen (HBsAg) at screening
• Positive for hepatitis C virus (HCV) antibody at screening
• History of or ongoing cryoglobulinemia at screening


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Atypical Hemolytic Uremic Syndrome (aHUS)
MedDRA version: 20.1 Level: LLT Classification code 10079841 Term: Atypical hemolytic uremic syndrome System Organ Class: 100000004851

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Crovalimab
Product Code: RO7112689/F03-10
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: CROVALIMAB
Current Sponsor code: RO7112689
Other descriptive name: C5 inh MAb, SKY59, RO/CH7092230
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 170-

Product Name: Crovalimab
Product Code: RO7112689/F03-01
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: CROVALIMAB
Current Sponsor code: RO7112689
Other descriptive name: C5 inh MAb, SKY59, RO/CH7092230
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 170-

Primary Outcome(s)

Primary end point(s): 1. Proportion of patients with cTMAr

Main Objective: • To evaluate the effect of crovalimab in complement inhibitor treatment-naive (Naive) patients

Timepoint(s) of evaluation of this end point: 1. Baseline to Week 25

Secondary Objective: • To evaluate the effect of crovalimab in Naive and Switch (switching from either eculizumab or ravulizumab treatment to crovalimab) patients
• To evaluate the overall safety and tolerability of crovalimab
• To evaluate the pharmacokinetics of crovalimab as well as confirm the dosing strategy for patients weighing < 40 kilograms (kg)
• To evaluate the immune response to crovalimab

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Baseline to Week 25
2-9. Up to 8 years
10. At baseline (prevalence) and up to 8 years (incidence)
11-15. Up to 8 years
16-18. At Week 25
19-20. Up to 8 years
21-23. At Week 25
24. From baseline to Week 13
25. Day 1
26-27. At Week 17

Secondary end point(s): For Naive and Switch Cohorts:
1. Change from baseline to Week 25 in dialysis requirement status
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 (CKD) stage classified as improved, stable (no change), or worsened based on the National Kidney Foundation Chronic Kidney Disease Stage
4. Observed value and change from baseline in hematologic parameters
5. Incidence and severity of adverse events
6. Change in targeted vital signs and clinical laboratory test results
7. Incidence and severity of injection site reactions, infusion related reactions, hypersensitivity, malignant hypertension, and infections
8. Incidence of adverse events leading to study drug discontinuation
9. Serum concentration of crovalimab
10. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab
11. Change in serum creatinine from baseline
12. Change from baseline in fatigue as measured by the Pediatric Quality of Life Inventory (PedsQLTM) Multidimensional Fatigue Scale (MFS) and physical functioning as measured by the PedsQL Core in pediatric patients aged 2 to < 18 years old
13. Change from baseline in physical functioning and physical symptoms as measured by the PedsQL Infant Scale in pediatric patients under 2 years old
14. Change from baseline in the number of missed days of daycare or school
15. For patients who discontinue crovalimab, describe the clinical course of patients who discontinue crovalimab after achieving cTMAr
For Naive and Pretreated Cohorts:
16. Proportion of patients with platelet count >= LLN
17. Proportion of patients with normalization of LDH
18. Proportion of patients with >=25% decrease in serum creatinine from baseline
19. Time to complete TMA response (cTMAr)
20. Duration of cTMAr, among patients who achieved cTMAr
21. Proportion of patients with cTMAr
22. Proportion of patients with increase in hemoglobin >=20 g/L, in the absence of a transfusion
For Switch Cohort ONLY:
23. Proportion of patients with maintained TMA control (mTMAc) from baseline through Week 25
24. Incidence and severity of clinical manifestations of drug-target-drug complexes (DTDCs) in patients who switched to crovalimab treatment from either eculizumab or ravulizumab treatment
25. Serum concentration of eculizumab or ravulizumab
26. In adolescents (12 - 17 years), proportion of patients with preference for crovalimab, after switching from eculizumab or ravulizumab, as assessed by a Patient Preference Questionnaire (PPQ) developed by the Sponsor
27. In children younger than 12 years old, proportion of caregivers with preference for crovalimab, after switching from eculizumab or ravulizumab, as assessed by the caregiver-reported version of the PPQ developed by the Sponsor

Secondary ID(s)

BO42354

Source(s) of Monetary Support

F. Hoffman-La Roche Ltd.

Ethics review

Status: Approved
Approval date: 21/09/2021
Contact: