Primary immunoglobulin A nephropathy

The aim of this trial was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of ravulizumab in pediatric subjects (aged 2 to <18 years) with immunoglobulin A nephropathy (IgAN) (Group 1) or immunoglobulin A vasculitis with nephritis (IgAVN) (Group 2) at risk of progressing to end-stage renal disease (ESKD), and to assess safety and efficacy. Furthermore, the trial aimed to help extrapolate PK/PD, safety, and efficacy from data in the adult population, based on the similar pathophysiology and overall clinical characteristics of adult and pediatric IgAN patients.

Ravulizumab

Ravulizumab

Intravenous infusion

1100 MG/11 ML

The change in proteinuria since baseline at week 34 was measured by the urinary total protein to creatinine ratio (UPCR).

Common Inclusion Criteria for Both Groups

Age
1. Subjects must be ≥ 2 to < 18 years old at the time of signing informed consent or consent form.

Subject Type and Disease Characteristics

2. UPCR ≥ 1 g/g, measured as the average of three first morning urine (FMV) samples collected within one week during the screening period (should be collected at home).

3. eGFR ≥ 30 mL/min/1.73 m2 during the screening period, calculated using the formula for children with chronic kidney disease (CKiD) under 25 years of age (U25) (cystatin C).

Previous/Concomitant Therapies

4. Prior to screening, adherence to and maintenance of stable (as determined by the trial principal investigator [PI] after weight adjustment) and maximum permissible or tolerated doses for ≥ 3 months with no planned dose changes between screening and week 106 (as determined by the PI after weight adjustment). Subjects who cannot tolerate RASI drugs may be included.

5. Subjects receiving sodium-glucose cotransporter-2 inhibitors (SGLT2i), dual endothelin-angiotensin receptor antagonists (DEARA) (e.g., sparsentan), aldosterone receptor antagonists (MRA), endothelin receptor antagonists (ERA), or glucagon-like peptide-1 receptor (GLP-1) agonists must maintain stable and tolerated doses for ≥ 3 months prior to screening and not plan to change the dose before week 34.

Weight
6. Weight at screening ≥ 10 kg.

Sex and Contraception/Barrier Method Requirements

7. Male or female as specified at birth (based on the reproductive organs and functions specified by their chromosome set), regardless of sex identity.

8. Based on the child subject's age and sexual history, and/or as required by local regulations, use appropriate contraception and barrier methods and undergo pregnancy testing as described in the trial protocol.

Vaccination and Antibiotics

9. To reduce the risk of meningococcal infection, all participants must be vaccinated against meningococcal serogroups A, C, W135, and Y (and serogroup B, if applicable, e.g., in the US, Europe, etc.) within 3 years to at least 2 weeks prior to the first dose of trial treatment. If this vaccination is less than 2 weeks after the first dose of trial treatment, the participant will receive prophylactic antibiotics for at least 2 weeks following the first dose. Vaccination must follow national/local guidelines.

10. Vaccination against Haemophilus influenzae type b and Streptococcus pneumoniae must have been received, unless previously administered according to current national and local vaccination guidelines.

Informed Consent and Agreement

11. Before any trial-specific activity, the trial principal investigator or their designated representative will obtain written informed consent and the participant's consent (if applicable) from each participant's legal guardian. All legal guardians and participants should receive adequate information about the trial, and the terminology used must be within their comprehension.

12. The legal guardian or primary caregiver must be able to properly maintain records of the child's return home, including overall health items.

Specific Inclusion Criteria for the IgAN Group

13. Diagnosis of primary immunoglobulin A nephropathy (IgAN) based on kidney tissue sections obtained within the 3 years prior to screening or during the screening period, showing interstitial fibrosis and tubular atrophy ≤ 50%, and glomerular sclerosis ≤ 50%.

Specific Inclusion Criteria for the IgAVN Group

14. Diagnosis of immunoglobulin A vasculitis with nephritis (IgAVN) based on kidney tissue sections obtained within the 3 years prior to screening or during the screening period, showing interstitial fibrosis and tubular atrophy ≤ 50%, and glomerular sclerosis ≤ 50%.

15. If you are currently receiving immunosuppressive drugs (e.g., corticosteroids, cyclophosphamide, calcineurin inhibitors [CNI], mizoribine, or mycophenolate mofetil [MMF]) to treat renal manifestations of IgAVN, the drug must have been stable for ≥ 1 month prior to screening.

Medical Conditions

1. A ≥50% decrease in eGFR within the 3 months prior to screening and/or the presence of >50% crescents in the kidney biopsy prior to screening, indicating a rapid worsening of glomerulonephritis.

2. Secondary IgAN that is not primary IgAN or IgAV (e.g., caused by systemic lupus erythematosus, cirrhosis, or celiac disease).

3. Concomitant clinically significant kidney disease other than IgAN or IgAVN.

4. Clinical remission of IgAN/IgAVN or significant improvement in proteinuria within the past 6 months.

5. Poorly controlled diabetes mellitus with HbA1c >8.5%.

6. A history of kidney transplantation or a planned kidney transplant during the primary evaluation period.

7. History of other solid organ (heart, lung, small intestine, pancreas, or liver) or bone marrow transplantation; or planned transplantation during the primary or extended evaluation period, except for corneal transplantation.

8. Splenectomy or functional asplenia.

9. Subjects receiving albumin infusions for nephrotic syndrome within 6 months prior to screening, or subjects requiring dialysis due to acute kidney injury.

10. Systemic blood pressure (BP) criteria.

 If age < 13 years: Systemic BP ≥ 95th percentile + 12 mmHg or ≥ 140/90 mmHg, whichever is lower, based on sex and height.

 If age ≥ 13 years: Systemic BP ≥ 140/90 mmHg.

11. Diagnosis of hemolytic uremic syndrome at any time prior to screening.

12. Scheduled urological surgery within the trial timeframe that is expected to affect kidney function.

13. Congenital immunodeficiency.

14. History of unexplained recurrent infections.

15. Known medical or psychological conditions (including substance abuse) or risk factors deemed by the trial administrator to potentially interfere with the participant's full participation in the trial, pose any additional risk to the participant, or confound the participant's assessment or trial results.

16. Previous or unresolved meningococcal infection.

17. Known history of human immunodeficiency virus (HIV), active hepatitis B infection, or active hepatitis C infection.

18. Active systemic bacterial, viral, or fungal infection within 14 days prior to enrollment.

19. Drug or alcohol abuse or dependence within 1 year prior to screening that would interfere with participation in the clinical trial.

20. History of malignant tumors within 5 years prior to screening, excluding non-melanoma skin cancer or cervical carcinoma in situ that has been treated and has no evidence of recurrence. 21. Hypersensitivity to any component of the investigational treatment, including hypersensitivity to rodent proteins.

Previous/Concurrent Therapies

22. Received a biologic for the treatment of IgAN or IgAVN within 6 months prior to screening.

23. Received traditional Chinese medicine or proprietary Chinese medicine with systemic immunosuppressive properties for the treatment of IgAN or IgAVN within 6 months prior to screening, including but not limited to Tripterygium wilfordii or drugs containing Tripterygium wilfordii.

24. Received a complement inhibitor, with the time elapsed since screening being ≤ 30 days or 5 half-lives, whichever is longer.

Previous/Concurrent Clinical Trial Experience

25. Currently enrolled or previously involved in any other clinical trial, and the administration of the relevant investigational treatment (e.g., drugs, vaccines, invasive devices) within 5 half-lives of the consent form signed for this clinical trial (if known).

Other Exclusion Criteria

26. Pregnancy, breastfeeding, or intention to conceive during the trial and within 8 months after the last dose of trial treatment.

27. Inability to attend designated follow-up appointments during the trial or failure to meet trial treatment dosing requirements.

28. The subject, their parent, or legal guardian will be involved in the planning and/or execution of the trial (applicable to trial commissioners and/or trial center personnel).

Specific Exclusion Criteria for the IgAN Group

29. Received systemic immunosuppression (e.g., corticosteroids, cyclophosphamide, CNI, mizoribine, or MMF) for the treatment of IgAN within 3 months prior to screening, or received budesonide treatment for IgAN within 6 months prior to screening.

Specific Exclusion Criteria for the IgAVN Group

30. Received systemic immunosuppression for extrarenal manifestations of IgAV within 3 months prior to screening.

31. History of severe IgAV symptoms (e.g., including but not limited to orchitis, cerebral vasculitis, pulmonary hemorrhage, gastrointestinal bleeding) within 1 year prior to screening.