Condition médicale (spécialité visée)
Choix aire thérapeutique
Néphrologie
Stades de cancer
Non applicable
Biomarqueur
Autre
Complément3, Complément4, Bb, sC5b-9, NGAL, IL-18, cystatine C
Profil des participants
Sexe(s) des participants
TOUS
Aptitude des participants
Majeurs aptes
Mineurs
Critères de sélection
Critères d'inclusion
Critères d'inclusion :
* Patients masculins et féminins y compris les adultes (âgés d'au moins 18 ans à ≤ 60 ans) et les adolescents (12 -17 ans dans les pays non-UE lors du dépistage et 16-17 ans dans les pays de l'UE lors du dépistage).
* Diagnostic de IC-MPGN idiopathique confirmé par biopsie rénale dans les 12 mois précédant le dépistage chez les adultes et dans les 3 ans précédant le dépistage chez les adolescents (un rapport de biopsie, examen et confirmation par l'investigateur sont requis). Si une telle biopsie n'est pas disponible chez un participant adulte, elle doit être obtenue lors du dépistage (réalisée et évaluée localement pour les adultes seulement).
* Avant la randomisation, tous les participants doivent avoir été sous une dose maximale recommandée ou tolérée d'inhibiteurs du système rénine-angiotensine (RASi), par exemple un ACEi ou un ARB pendant au moins 90 jours (ou selon les directives locales). Les doses d'autres médicaments administrés pour réduire la protéinurie et contrôler la maladie incluant les acides mycophénoliques (MPAs - mycophénolate mofetil ou mycophénolate de sodium), les corticostéroïdes, les inhibiteurs de SGLT2 et les antagonistes des récepteurs minéralocorticoïdes doivent être stables pendant au moins 90 jours avant la randomisation
* UPCR ≥ 1.0 g/g (≥ 113 mg/mmol) prélevé à partir de l'échantillon d'urine de la première miction matinale au jour -75 et au jour -15
* Estimation du DFG (utilisant la formule CKD-EPI pour les participants adultes et la formule de Schwartz modifiée pour les adolescents âgés de 12 à 17 ans) ou DFG mesuré ≥ 30 ml/min/1.73m2 lors du dépistage et au jour -15.
* Vaccination obligatoire contre l'infection à Neisseria meningitidis et Streptococcus pneumoniae avant le début du traitement de l'étude. Si le participant n'a pas été précédemment vacciné, ou si un rappel est nécessaire, le vaccin doit être administré selon la réglementation locale au moins 2 semaines avant la première administration du traitement de l'étude. Si le traitement de l'étude doit commencer plus tôt que 2 semaines après la vaccination, un traitement antibiotique prophylactique doit être initié conformément aux normes de soins locales.
* Si non précédemment vacciné, ou si un rappel est nécessaire, la vaccination contre les infections à Haemophilus influenzae doit être administrée, si disponible et selon la réglementation locale, au moins 2 semaines avant la première administration du traitement de l'étude.
Critères d'exclusion :
* Participants ayant subi une transplantation de cellules ou d'organes solides, y compris une transplantation rénale.
* Participants diagnostiqués avec une IC-MPGN secondaire incluant mais non limité à l'une des conditions suivantes :
* Dépôt de complexes immuns antigène-anticorps résultant de toute infection chronique, y compris
* Virus de l'hépatite C (VHC) incluant la cryoglobulinémie mixte associée au VHC, virus de l'hépatite B (VHB);
* Endocardite bactérienne, shunt ventriculo-atrial infecté, abcès viscéraux, lèpre, méningite à méningocoques; infections bactériennes chroniques
* Protozoaires/autres infections- paludisme, schistosomiase, mycoplasme, leishmaniose, filariose, histoplasmose
Dépôt rénal de complexes immuns résultant d'une maladie auto-immune systémique :
* Lupus érythémateux systémique (LES)
* Syndrome de Sjögren
* Polyarthrite rhumatoïde
* Maladie mixte du tissu conjonctif Dépôt d'immunoglobulines monoclonales en raison d'une gammapathie monoclonale due à des troubles des cellules plasmiques ou des cellules B. Gammapathie monoclonale de signification indéterminée (MGUS) confirmée par la mesure des chaînes légères libres sériques ou autre enquête selon les normes de soins locales.
Glomérulonéphrite fibrillaire
* Glomérulonéphrite rapidement progressive à croissants définie comme un déclin de 50% du DFG en 3 mois avec des résultats de biopsie rénale montrant la formation de croissants glomérulaires observés dans au moins 50% des glomérules sur la biopsie la plus récente.
* Biopsie rénale montrant une fibrose interstitielle/tubulaire atrophie (IF/TA) de plus de 50%.
* Participants avec une infection bactérienne, virale ou fongique systémique active dans les 14 jours précédant l'administration du traitement de l'étude ou la présence de fièvre ≥ 38°C (100.4°F) dans les 7 jours précédant l'administration du traitement de l'étude.
* Antécédents d'infections invasives récurrentes causées par des organismes encapsulés, par exemple, Neisseria meningitidis et Streptococcus pneumoniae.
* L'utilisation d'inhibiteurs des facteurs du complément (par exemple, Facteur B, Facteur D, inhibiteurs du complément 3 (C3), anticorps anti-Complément 5 (C5), antagonistes du récepteur C5a) dans les 3 mois ou 5 demi-vies avant la visite de dépistage.
* L'utilisation d'immunosuppresseurs (sauf MPAs), cyclophosphamide ou corticostéroïdes systémiques à une dose > 7,5 mg/jour (ou équivalent pour un médicament corticostéroïde similaire) dans les 90 jours de l'administration du médicament de l'étude.
* L'utilisation de MPAs n'est pas autorisée dans les 90 jours précédant la randomisation en Inde, selon l'exigence de l'autorité sanitaire locale.
* Glomérulonéphrite post-infectieuse aiguë lors du dépistage, selon l'avis de l'investigateur.
* Indice de masse corporelle (IMC) >38 kg/m2 lors du dépistage et de la randomisation. Poids corporel <35 kg lors du dépistage et de la randomisation
Inclusion Criteria:
* Male and female patients including adults (aged at least 18 years to ≤ 60 years) and adolescents (12 -17 years in non-EU countries at screening and 16-17 years in EU countries at screening).
* Diagnosis of idiopathic IC-MPGN as confirmed by kidney biopsy within 12 months prior to screening in adults and within 3 years of screening in adolescents (a biopsy report, review and confirmation by the Investigator is required). If such a biopsy is not available in an adult participant, this must be obtained at screening (performed and assessed locally for adults only).
* Prior to randomization, all participants must have been on a maximally recommended or tolerated dose of renin angiotensin system inhibitors (RASi), e.g an ACEi or ARB for at least 90 days (or as according to local guidelines). The doses of other drugs administered to reduce proteinuria and control the disease including mycophenolic acids (MPAs - mycophenolate mofetil or mycophenolate sodium), corticosteroids, SGLT2 inhibitors and mineralocorticoid receptor antagonists should be stable for at least 90 days prior to randomization
* UPCR ≥ 1.0 g/g (≥ 113 mg/mmol) sampled from the first morning void urine sample at Day -75 and Day -15
* Estimated GFR (using the chronic kidney disease \[CKD\]-EPI formula for adult participants and modified Schwartz formula for adolescents aged 12 to 17 years) or measured GFR ≥ 30 ml/min/1.73m2 at screening and Day -15.
* Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection prior to the start of study treatment. If the participant has not been previously vaccinated, or if a booster is required, the vaccine should be given according to local regulations at least 2 weeks prior to the first administration of study treatment. If the study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated in accordance with local standard of care.
* If not previously vaccinated, or if a booster is required, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to the first study treatment administration.
Exclusion Criteria:
* Participants who have undergone cell or solid organ transplantation, including kidney transplantation.
* Participants diagnosed with secondary IC-MPGN including but not limited to any of the following conditions:
* Deposition of antigen-antibody immune complexes as a result of any chronic infections, including
* Hepatitis C virus (HCV) including HCV-associated mixed cryoglobulinemia, hepatitis B virus (HBV);
* Bacterial-endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis; chronic bacterial infections
* Protozoa/other infections- malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histroplasmosis
Renal deposition of immune complexes as a result of a systemic autoimmune disease:
* Systemic lupus erythematosus (SLE)
* Sjögren syndrome
* Rheumatoid arthritis
* Mixed connective tissue disease Deposition of monoclonal immunoglobulins because of a monoclonal gammopathy due to plasma cell or B cell disorders. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care.
Fibrillary glomerulonephritis
* Rapidly progressive crescentic glomerulonephritis defined as a 50% decline in the eGFR within 3 months with kidney biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli on the most recent biopsy.
* Kidney biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than 50%.
* Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration or the presence of fever ≥ 38°C (100.4°F) within 7 days prior to study treatment administration.
* A history of recurrent invasive infections caused by encapsulated organisms, e.g., Neisseria meningitidis and Streptococcus pneumoniae.
* The use of inhibitors of complement factors (e.g., Factor B, Factor D, complement 3 (C3) inhibitors, anti-Complement 5 (C5) antibodies, C5a receptor antagonists) within 3 months or 5 half-lives prior to the Screening visit.
* The use of immunosuppressants (except MPAs), cyclophosphamide or systemic corticosteroids at a dose \>7.5 mg/day (or equivalent for a similar corticosteroid medication) within 90 days of study drug administration.
* The use of MPAs is not permitted within 90 days prior to randomization in India, as per the local health authority requirement.
* Acute post-infectious glomerulonephritis at screening, based upon the opinion of the investigator.
* Body mass index (BMI) \>38 kg/m2 at screening and randomization. Body weight \<35 kg at screening and randomization
Critères d'exclusion
1. Participants who have received any cell or organ transplantation, including kidney transplantation.
2. Patients diagnosed with secondary IC-MPGN including but not limited to any of the following conditions:
• Deposition of antigen-antibody immune complexes as a result of any infection,
including
o Viral- hepatitis C including HCV-associated mixed cryoglobulinemia, hepatitis B;
o Bacterial-endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis; chronic bacterial infections
o Protozoa/other infections- malaria, schistosomiasis, mycoplasma, leishmaniasis,
filariasis, histroplasmosis)
• Deposition of immune complexes as a result of an autoimmune disease:
o SLE
o Sjögren’s syndrome
o Rheumatoid arthritis
o Mixed connective tissue disease, etc
• Disposition of monoclonal Ig because of a monoclonal gammopathy due to plasma cell or B cell disorders. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care.
• Fibrillary glomerulonephritis
3. Rapidly progressive crescentic glomerulonephritis (defined as a 50% decline in the eGFR within 3 months) with renal biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli.
4. Participants with acute post-infectious glomerulonephritis.
5. Renal biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than 50%.
6. Adult participants (≥ 18 and ≤ 60 years) with systolic blood pressure (SBP) < 80 mmHg or > 160 mmHg, or diastolic blood pressure (DBP) < 50 mmHg or > 100 mmHg, or pulse rate < 45 bpm or > 100 bpm.
7. Adolescent participants (ages 12-17 years) with systolic blood pressure (SBP) < 80 mmHg or > 150 mmHg, or diastolic blood pressure (DBP) < 50 mmHg or > 95 mmHg, or pulse rate < 50 bpm or > 110 bpm.
8. Body mass index (BMI) >38 kg/m2 at screening and randomization. Body weight <35 kg at screening and randomization.
9. Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration.
10. The presence of fever ≥ 38°C (100.4°F) within 7 days prior to study treatment
administration.
11. A history of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae.
12. Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV antibody at screening).
13. Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection defined as hepatitis B virus surface antigen (HBsAg) positive or hepatitis C virus ribonucleic acid (HCV RNA) positive, or liver injury as indicated by abnormal liver function tests at screening as defined below:
• Any single parameter of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) or alkaline phosphatase must not exceed 3 x upper limit of normal (ULN)
• Serum bilirubin must not exceed 2 x upper limit of normal (ULN) (with the exception of those participants with a known confirmed diagnosis of Gilbert syndrome).
14. Evidence of urinary obstruction or difficulty in voiding at screening and randomization.
15. Severe concurrent comorbidities including but not limited to advanced cardiac disease (e.g., New York Heart Association [NYHA] class IV), severe pulmonary disease (e.g., severe pulmonary hypertension (World Health Organization [WHO] class IV)) or any other condition that in the opinion of the investigator precludes the participant's involvement in the study.
16. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia and clinically significant second or third degree atrioventricular block (AV block) without a pacemaker.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
18. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes or history of medium to high severity allergies, as per Investigator's judgement.
19. History of drug or alcohol abuse within the 12 months prior to study treatment
administration.
20. Any medical condition deemed likely to interfere with the patient's participation in the study.
21. The use of inhibitors of complement factors (e.g., Factor B, Factor D, C3 inhibitors, anti C5 antibodies, C5a receptor antagonists) within 3 months or 5 half-lives after stopping this medication whichever is longerprior to the Screening visit.
22. The use of immunosuppressants (except mycophenolic acids), cyclophosphamide or systemic prednisone at a dose >7.5 mg/day (or equivalent for a similar corticosteroid medication) within 90 days of study drug administration. The use of mycophenolic acids (MMF or mycophenolate sodium) is not permitted within 90 days prior to randomization in India and is an exclusion criterion for India.
23. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days,
whichever is longer; or longer if required by local regulations.
24. Female participants who are pregnant or breastfeeding or intending to conceive during the course of the study.
25. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of investigational drug and for 1 week after stopping of investigational drug.
Effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- Surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks before taking study treatment).
• Male sterilization (at least 6 months prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant.
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal
suppository.
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).