Clinical trial • Phase III • Immunology|Rare Disease
RAVULIZUMAB for Immunoglobulin A nephropathy (IgAN)
Phase III trial of RAVULIZUMAB for Immunoglobulin A nephropathy (IgAN).
Overview
- Trial Therapeutic Area
- Immunology|Rare Disease
- Trial Disease
- Immunoglobulin A nephropathy (IgAN)
- Trial Stage
- Phase III
- Drug Modality
- Monoclonal antibody
Key dates
- Initial CTIS Submission Date
- 12-03-2024
- First CTIS Authorization Date
- 02-07-2024
Trial design
Randomised, open-label, placebo infusions matching ravulizumab schedule (placebo prepared by unblinded pharmacist); ravulizumab arm: weight-based iv infusion with a loading dose on day 1 and maintenance dosing initiated on day 15 and administered every 8 weeks (q8w).-controlled, adaptive Phase III trial in France, Hungary, Greece and others.
- Randomised
- Yes
- Open Label
- Yes
- Comparator
- Placebo infusions matching ravulizumab schedule (placebo prepared by unblinded pharmacist); Ravulizumab arm: weight-based IV infusion with a loading dose on Day 1 and maintenance dosing initiated on Day 15 and administered every 8 weeks (q8w).
- Adaptive
- Yes
- Target Sample Size
- 350
- Trial Duration For Participant
- 742
Eligibility
Recruits 350 No vulnerable population selected. Inclusion requires participants be ≥ 18 years and "Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol." Consent is obtained from adult participants; no assent or parental consent procedures for minors are described..
- Pregnancy Exclusion
- Pregnant, breastfeeding, or intending to conceive during the study.
- Vulnerable Population
- No vulnerable population selected. Inclusion requires participants be ≥ 18 years and "Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol." Consent is obtained from adult participants; no assent or parental consent procedures for minors are described.
Inclusion criteria
- {"criterion_text":"- Participant must be ≥ 18 years of age at the time of signing the informed consent\n- Adherence to and compliance with stable and maximum allowed or tolerated RASI (ACEI and/or ARB) dose for ≥ 3 months prior to Screening with no planned change during Screening through Week 106. Participants with intolerance to RASI medications may be included\n- Participants who are receiving SGLT2I, DEARA (eg, sparsentan), MRA, or ERA must be on a stable and maximum allowed or tolerated dose for ≥ 3 months prior to Screening with no planned change in dose through Week 106\n- Controlled blood pressure of < 140/90 mmHg at Screening\n- To reduce the risk of meningococcal infection (N meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, W, Y (and B where available) within 3 years prior to study intervention on Day 1. If vaccination occurs < 2 weeks from Day 1, the participant will receive prophylactic antibiotics for at least 2 weeks after initial meningococcal vaccination\n- Documentation of IgAN diagnosis established on kidney biopsy obtained any time prior to or during the Screening Period for participants with eGFR ≥ 30 mL/min/1.73 m2 a. For participants in the AdKD cohorts: eGFR 20 to 29 mL/min/1.73 m2, a kidney biopsy is required within 6 months prior to Screening or during the Screening Period. Kidney biopsy report must demonstrate < 75% each of interstitial fibrosis, tubular atrophy, and glomerular sclerosis.\n- UPCR ≥ 0.75 g/g or UP ≥1 g/day calculated from the mean of two 24-hour urine samples collected during the Screening Period\n- Estimated GFR ≥ 30 mL/min/1.73 m2 at Screening as calculated by the CKD-EPI formula (Section 8.2.3). a. Participants in the AdKD cohorts require eGFR 20 to 29 mL/min/1.73 m2 at Screening.\n- Body weight ≥ 30 kg at Screening\n- Male or female\n- Agree to follow protocol-specified contraception guidance\n- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol"}
Exclusion criteria
- {"criterion_text":"- Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss ≥ 50% over a period of 3 months prior to Screening\n- Currently receiving or previously received a complement inhibitor within 30 days or 5 half-lives, whichever is longer, prior to Screening\n- Biologic(s) for the treatment of IgAN ≤ 6 months prior to Screening\n- Secondary IgAN (eg, due to SLE, cirrhosis, or celiac disease; IgAV-N may be eligible, see Exclusion Criterion 5).\n- Traditional Chinese medicines and Chinese proprietary medicines with systemic immunosuppressive properties including but not limited to Tripterygium Wilfordii or Tripterygium Wilfordii-containing medicines for the treatment of IgAN within 6 months prior to Screening\n- Currently receiving or previously received a complement inhibitor within 30 days or 5 half-lives, whichever is longer, prior to Screening\n- Participation in another investigational drug or investigational device study within 30 days before Day 1 or within 5 half-lives of that investigational product, whichever is greater.\n- Pregnant, breastfeeding, or intending to conceive during the study.\n- Inability to travel to the clinic for specified visits during the study or fulfill the logistical requirements of study intervention administration\n- Participant is imprisoned or lawfully retained at an institution via administrative or judicial order.\n- Participant is an employee or directly related to an employee of Alexion, AstraZeneca, or the institution/investigational site.\n- History of Neisseria meningitidis infection\n- Concomitant clinically significant renal disease other than IgAN.\n- Uncontrolled diabetes mellitus with glycosylated hemoglobin (HbA1c) > 8.5%\n- Henoch-Schonlein purpura (IgAV) requiring systemic immunosuppressive therapy within 12 months of Screening\n- History of kidney transplant or planned kidney transplant during the Treatment Period. a. Participants listed for kidney transplant may be eligible for the AdKD cohorts\n- History of other solid organ (heart, lung, small bowel, pancreas, or liver) or bone marrow transplant; or planned transplant during the Treatment Period or open-label Exploratory Cohort, except for corneal transplant.\n- Body mass index ≥ 38 kg/m2.\n- Splenectomy or functional asplenia\n- Evidence of active hepatitis C infection −Positive HCV antibody: Participants with positive HCV antibody and negative HCV RNA test during the Screening Period (local or central laboratory) and absence of cirrhosis may be enrolled.\n- Known history of human immunodeficiency virus (HIV) infection as documented by HIV-1/HIV-2 testing or positive HIV-1/HIV-2 antibody titer at Screening.\n- Evidence of active hepatitis B infection −Positive HBsAg or −Positive core antibody (anti-HBc): participants with positive anti-HBc but negative HBsAg may be enrolled if the hepatitis B virus DNA test result is negative during the Screening Period (local or central lab)\n- Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.\n- Drug or alcohol abuse or dependence within 1 year prior to Screening that interferes with ability to participate in the clinical study.\n- History of malignancy within 5 years of Screening, except for nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence.\n- Hypersensitivity to any ingredient contained in the study intervention, including to murine proteins.\n- Systemic corticosteroid therapy or any other systemic immunosuppression within 3 months of Screening (except short course steroids [approximately 14 days] for non-IgAN treatment)"}
Endpoints
Primary endpoints
- {"endpoint_text":"- Interim Analysis: Change from baseline in proteinuria based on 24-hour UPCR at Week 34 Final Analysis: Change from Baseline in eGFR at Week 106","definition_or_measurement_approach":"Proteinuria measured by 24-hour urine protein-to-creatinine ratio (UPCR) for the interim analysis at Week 34; eGFR change (as calculated by CKD-EPI) at Week 106 for final analysis."}
Secondary endpoints
- {"endpoint_text":"- Interim Analysis: Change from Baseline in proteinuria based on 24-hour UPCR at Weeks 10 and 26 Final Analysis: Change from Baseline in proteinuria based on 24-hour UPCR at Week 10, 26, 34, 50 and 106","definition_or_measurement_approach":"Proteinuria assessed by 24-hour UPCR at specified weeks."}
- {"endpoint_text":"- Interim Analysis: Change from Baseline in eGFR at Week 34 Final Analysis: Change from Baseline in eGFR at Weeks 34 and 50","definition_or_measurement_approach":"Change in eGFR (CKD-EPI) from baseline at specified weeks."}
- {"endpoint_text":"- Interim Analysis: Reduction in 24-hour UPCR ≥ 50% from Baseline over time Final Analysis: Reduction in 24-hour UPCR ≥ 50% from Baseline at Week 34 and over time","definition_or_measurement_approach":"Proportion of participants achieving ≥50% reduction in 24-hour UPCR from baseline at Week 34 and longitudinally."}
- {"endpoint_text":"- Interim Analysis: Partial remission over time final analysis: Partial remission over time","definition_or_measurement_approach":"Partial remission defined per protocol criteria (as specified in protocol); measured longitudinally."}
- {"endpoint_text":"- Interim Analysis: Change from Baseline in albuminuria over time final analysis: Change from Baseline in albuminuria over time","definition_or_measurement_approach":"Change in albuminuria from baseline over time (assessed by urine albumin measures)."}
- {"endpoint_text":"- Interim Analysis: Annualized eGFR slope over 50 weeks Final analysis: Time to sustained ≥ 30% eGFR decline up to Week 106","definition_or_measurement_approach":"Annualized slope of eGFR over 50 weeks; time-to-event for sustained ≥30% decline in eGFR up to Week 106."}
- {"endpoint_text":"- Final analysis: Time to individual components of composite kidney event endpoint up to Week 106","definition_or_measurement_approach":"Time to each component of composite kidney endpoint (sustained ≥30% eGFR decline, sustained eGFR <15 mL/min/1.73 m2, maintenance dialysis, kidney transplant, death from kidney failure) up to Week 106."}
- {"endpoint_text":"- interim analysis: Change from Baseline in FACIT-Fatigue at Weeks 34, 50, and 106 final analysis: Change from Baseline in FACIT-Fatigue at Weeks 34, 50, and 106","definition_or_measurement_approach":"Change in participant-reported FACIT-Fatigue questionnaire scores from baseline at specified weeks."}
- {"endpoint_text":"- interim and final analysis: Incidence of TEAEs, TESAEs, and AESI over time","definition_or_measurement_approach":"Incidence and timing of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and adverse events of special interest (AESIs) over the study period."}
- {"endpoint_text":"- interim and final analysis: ADA incidence, response categories, and titers; as well as NAb incidence for the duration for the study","definition_or_measurement_approach":"Immunogenicity assessments: incidence and titers of anti-drug antibodies (ADA), response categories, and neutralizing antibody (NAb) incidence throughout study."}
- {"endpoint_text":"- interim and final analysis: • Serum ravulizumab concentrations over time • Serum total C5 and free C5 concentrations over time","definition_or_measurement_approach":"PK/PD measurements: serum ravulizumab concentrations and serum total and free C5 concentrations measured at scheduled timepoints."}
- {"endpoint_text":"- Final Analysis: Time to first occurrence of composite kidney event endpoint up to Week 106, defined as reaching at least 1 of the following: −Sustained ≥ 30% decline in eGFR relative to Baselinea, or −Sustained eGFR < 15 mL/min/1.73 m2, or −Maintenance dialysis, or −Receipt of kidney transplant, or −Death from kidney failure","definition_or_measurement_approach":"Time-to-first composite renal event (any of the listed kidney outcomes) up to Week 106."}
- {"endpoint_text":"- Final analysis: Time to sustained eGFR declinea ≥ 40% up to Week 106","definition_or_measurement_approach":"Time to sustained ≥40% decline in eGFR from baseline up to Week 106."}
- {"endpoint_text":"- Final Analysis: Time to individual components of composite kidney event endpoint up to Week 106","definition_or_measurement_approach":"Time to the individual components of the composite kidney endpoint (as above) up to Week 106."}
- {"endpoint_text":"- Final analysis: Use of alternative IgAN therapy over time","definition_or_measurement_approach":"Recording and analysis of use of alternative/ rescue therapies for IgAN over time."}
Recruitment
- Registry Or Advocacy Recruitment
- True, Patient Advocacy Groups (PAG) (referenced in recruitment materials: "PAG Study Intro Letter")
- Digital Remote Recruitment
- True, digital methods include social media posts, online newsletter postings and digital ads described in recruitment materials (country-specific social posts and digital recruitment collateral).
- Planned Sample Size
- 350
- Recruitment Window Months
- 57
- Consent Approach
- Written informed consent obtained from participants who must be ≥18 and "Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol." Consent materials (SIS/ICF and addenda for genetic research, pregnant partner, optional biopsy, care partner guides) are provided in multiple languages (examples in documentation: English, French, German, Spanish, Dutch, Italian, Greek, Hungarian, Polish, Slovak) and include optional addenda (genetics, biopsy, pregnant partner). No assent/parental consent for minors is described.
Methods
- Posters and recruitment posters at sites (K2_Recruitment material_Recruitment Poster) — site-based printed recruitment material.
- Social media posts (K2_Recruitment material_Social Posts) — digital outreach via social channels.
- Half-page advertisements (K2_Recruitment material_Half Page Ad) — print/digital advertising.
- Study intro letters and PAG Study Intro Letter — outreach to patient advocacy groups and patient registries / direct mail to potential participants.
- Newsletter postings and PAG communications (K2 recruitment materials: Newsletter posting Long/Short) — electronic or print newsletters targeted at patients/clinicians.
- Country-specific recruitment arrangements documents (K1_Recruitment arrangements) — outlines local recruitment procedures per member state.
Geography
- Total Number Of Participants
- 350
France
- Earliest CTIS Part Ii Submission Date
- 08-05-2024
- Latest Decision Or Authorization Date
- 18-02-2026
- Number Of Sites
- 15
- Number Of Participants
- 16
Sites
- Site Name
- CHU Gabriel-Montpied
- Department Name
- Nephrology
- Contact Person Name
- Cyril Garrouste
- Contact Person Email
- cgarrouste@chu-clermontferrand.fr
- Site Name
- Centre Hospitalier Universitaire De Nantes
- Department Name
- Nephrology and Clinical Immunology
- Contact Person Name
- Simon Ville
- Contact Person Email
- simon.ville@chu-nantes.fr
- Site Name
- Centre Hospitalier Regional Et Universitaire De Brest
- Department Name
- Nephrology, Renal Transplant and Hemodialysis
- Contact Person Name
- Emilie Corenec-Le Gall
- Contact Person Email
- emilie.cornec-legall@chu-brest.fr
- Site Name
- Centre Hospitalier Regional De Marseille
- Department Name
- Nephrology and renal transplant
- Contact Person Name
- Stephane Burtey
- Contact Person Email
- stephaneb@ap-hm.fr
- Site Name
- Centre Hospitalier Universitaire Amiens Picardie
- Department Name
- Nephrology Department
- Contact Person Name
- Gabriel Choukroun
- Contact Person Email
- choukroun.gabriel@chu-amiens.fr
- Site Name
- Centre Hospitalier Universitaire De Nice
- Department Name
- Nephrology
- Contact Person Name
- Vincent Esnault
- Contact Person Email
- esnault.v@chu-nice.fr
- Site Name
- Centre Hospitalier Metropole Savoie
- Department Name
- Department of Nephrology and Dialysis
- Contact Person Name
- Stéphane Bally
- Contact Person Email
- stephane.bally@ch-metropole-savoie.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Nephrology
- Contact Person Name
- Evangeline Pillebout
- Contact Person Email
- evangeline.pillebout@aphp.fr
- Site Name
- Centre Hospitalier Universitaire De Saint Etienne
- Department Name
- Nephrology, Dialysis and Renal Transplant
- Contact Person Name
- Nicolas Maillard
- Contact Person Email
- nicolas.maillard@chu-st-etienne.fr
- Site Name
- Assistance Publique Hopitaux De Paris (Le Kremlin-Bicetre)
- Department Name
- Nephrology, Dialysis and Renal Transplant
- Contact Person Name
- Renaud Snanoudj
- Contact Person Email
- renaud.snanoudj@aphp.fr
- Site Name
- Centre Hospitalier Universitaire De Toulouse
- Department Name
- Department of Nephrology and Organ transplant
- Contact Person Name
- Dominique Chauveau
- Contact Person Email
- chauveau.d@chu-toulouse.fr
- Site Name
- Les Hopitaux Universitaires De Strasbourg
- Department Name
- Nephrology, Dialysis and Transplantation
- Contact Person Name
- Anna Duval
- Contact Person Email
- anna.duval@chru-strasbourg.fr
- Site Name
- Centre Hospitalier De La Cote Basque
- Department Name
- Nephrology and Dialysis Department
- Contact Person Name
- Adeline Lacraz
- Contact Person Email
- alacraz@ch-cotebasque.fr
- Site Name
- Assistance Publique Hopitaux De Paris (Paris 15)
- Department Name
- Nephrology and Adult transplant
- Contact Person Name
- Aude Servais
- Contact Person Email
- aude.servais@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris (Paris 20)
- Department Name
- Nephrology Department
- Contact Person Name
- Khalil El Karoui
- Contact Person Email
- khalil.el-karoui@aphp.fr
Hungary
- Earliest CTIS Part Ii Submission Date
- 14-05-2024
- Latest Decision Or Authorization Date
- 25-09-2024
- Number Of Sites
- 2
- Number Of Participants
- 4
Greece
- Earliest CTIS Part Ii Submission Date
- 07-06-2024
- Latest Decision Or Authorization Date
- 23-09-2024
- Number Of Sites
- 6
- Number Of Participants
- 7
Germany
- Earliest CTIS Part Ii Submission Date
- 23-05-2024
- Latest Decision Or Authorization Date
- 23-02-2026
- Number Of Sites
- 11
- Number Of Participants
- 11
Sites
- Site Name
- Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Department Name
- I. Medizinische Klinik und Poliklinik
- Contact Person Name
- Julia Weinmann-Menke
- Contact Person Email
- Julia.weinmann-menke@unimedizin-mainz.de
- Site Name
- Muenchner Studienzentrum
- Department Name
- Abteilung Nephrologie
- Contact Person Name
- Lutz Renders
- Contact Person Email
- lutz.renders@tum.de
- Site Name
- Nephrologisches Zentrum Villingen Schwenningen
- Contact Person Name
- Bernd Hohenstein
- Contact Person Email
- hohenstein@nephrologie-vs.de
- Site Name
- Medizinische Hochschule Hannover
- Department Name
- Klinik für Nieren- und Hochdruckerkrankungen
- Contact Person Name
- Kai Schmidt-Ott
- Contact Person Email
- schmidt-ott.kai@mh-hannover.de
- Site Name
- Universitaetsklinikum Essen AöR
- Department Name
- Abteilung Nephrologie Medizinisches Forschungszentrum
- Contact Person Name
- Anja Gäckler
- Contact Person Email
- anja.gaeckler@uk-essen.de
- Site Name
- Klinikum der Universitaet Muenchen AöR
- Department Name
- Medizinische Klinik und Poliklinik IV Nephrologisches Zentrum
- Contact Person Name
- Michael Fischereder
- Contact Person Email
- Michael.Fischereder@med.uni-muenchen.de
- Site Name
- Universitaetsklinikum Aachen AöR
- Department Name
- Abteilung für Nephrologie und klinische Immunologie
- Contact Person Name
- Claudia Seikrit
- Contact Person Email
- cseikrit@ukaachen.de
- Site Name
- Universitaetsklinikum Erlangen AöR
- Department Name
- Abteilung für Nephrologie und Hypertonie
- Contact Person Name
- Michael Wiesener
- Contact Person Email
- Michael.Wiesener@uk-erlangen.de
- Site Name
- University Hospital Cologne AöR
- Department Name
- Innere Medizin II
- Contact Person Name
- Linus Völker
- Contact Person Email
- linus.voelker@uk-koeln.de
- Site Name
- Charite Universitaetsmedizin Berlin KöR
- Department Name
- Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin
- Contact Person Name
- Adrian Schreiber
- Contact Person Email
- adrian.schreiber@charite.de
- Site Name
- Universitaetsmedizin Greifswald KöR
- Department Name
- Klinik für Innere Medizin A
- Contact Person Name
- Tilman Schmidt
- Contact Person Email
- Tilman.Schmidt@med.uni-greifswald.de
Spain
- Earliest CTIS Part Ii Submission Date
- 27-03-2024
- Latest Decision Or Authorization Date
- 23-02-2026
- Number Of Participants
- 36
Belgium
- Earliest CTIS Part Ii Submission Date
- 07-06-2024
- Latest Decision Or Authorization Date
- 19-02-2026
- Number Of Sites
- 5
- Number Of Participants
- 6
Austria
- Earliest CTIS Part Ii Submission Date
- 17-06-2024
- Latest Decision Or Authorization Date
- 19-02-2026
- Number Of Sites
- 3
- Number Of Participants
- 4
Poland
- Earliest CTIS Part Ii Submission Date
- 27-05-2024
- Latest Decision Or Authorization Date
- 22-02-2026
- Number Of Participants
- 21
Netherlands
- Earliest CTIS Part Ii Submission Date
- 10-06-2024
- Latest Decision Or Authorization Date
- 18-02-2026
- Number Of Sites
- 4
- Number Of Participants
- 6
Italy
- Earliest CTIS Part Ii Submission Date
- 07-06-2024
- Latest Decision Or Authorization Date
- 20-02-2026
- Number Of Participants
- 27
Slovakia
- Earliest CTIS Part Ii Submission Date
- 23-05-2024
- Latest Decision Or Authorization Date
- 19-02-2026
- Number Of Sites
- 4
- Number Of Participants
- 5
Czechia
- Earliest CTIS Part Ii Submission Date
- 13-06-2024
- Latest Decision Or Authorization Date
- 18-02-2026
- Number Of Sites
- 3
- Number Of Participants
- 5
Sponsor
Primary sponsor
- Full Name
- Alexion Pharmaceuticals Inc.
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- United States
Investigational products
- Investigational Product Name
- Ultomiris 1,100 mg/11 mL concentrate for solution for infusion
- Active Substance
- RAVULIZUMAB
- Modality
- Monoclonal antibody
- Routes Of Administration
- IV infusion
- Route
- IV infusion
- Authorisation Status
- Authorized product used in new indication (marketing authorisation EU/1/19/1371/003)
- Starting Dose
- Weight-based IV loading dose on Day 1 (weight-based regimen); maintenance dosing initiated Day 15
- Frequency
- Loading dose on Day 1, maintenance every 8 weeks (q8w); maintenance initiated Day 15
- Maximum Dose
- 3600 mg (max daily dose amount recorded in product data)
- Investigational Product Name
- Anti C5 Complement mAb Placebo
- Modality
- Other
- Authorisation Status
- Placebo (not authorised product)
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