A study to determine if ravulizumab can help preserve kidney function in adults with immunoglobulin A nephropathy (IgAN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

23 Sep 2024 → ongoing

Decision date (initial)

2024-07-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-507851-31-00

ClinicalTrials.gov

NCT06291376

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Interim Analysis-To evaluate the efficacy of ravulizumab compared with placebo to reduce proteinuria in adult participants with IgAN
Final Analysis-To evaluate the efficacy of ravulizumab compared with placebo on change in eGFR in adult participants with IgAN

Secondary objectives 5

1. To evaluate the efficacy of ravulizumab compared with placebo on measures of kidney function in adult participants with IgAN
2. To assess quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo
3. To characterize the safety and tolerability of ravulizumab in adult participants with IgAN
4. To assess immunogenicity to ravulizumab in adult participants with IgAN
5. To characterize the PK/PD of ravulizumab in adult participants with IgAN

Conditions and MedDRA coding

Immunoglobulin A Nephropathy (IgAN)

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Participant must be ≥ 18 years of age at the time of signing the informed consent
2. 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
3. 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
4. Controlled blood pressure of < 140/90 mmHg at Screening
5. 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
6. 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.
7. 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
8. 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.
9. Body weight ≥ 30 kg at Screening
10. Male or female
11. Agree to follow protocol-specified contraception guidance
12. 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 27

1. Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss ≥ 50% over a period of 3 months prior to Screening
2. History of Neisseria meningitidis infection
3. 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.
4. 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)
5. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.
6. Drug or alcohol abuse or dependence within 1 year prior to Screening that interferes with ability to participate in the clinical study.
7. 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.
8. Hypersensitivity to any ingredient contained in the study intervention, including to murine proteins.
9. Systemic corticosteroid therapy or any other systemic immunosuppression within 3 months of Screening (except short course steroids [approximately 14 days] for non-IgAN treatment)
10. Ongoing budesonide therapy or budesonide therapy within 6 months prior to Screening
11. Biologic(s) for the treatment of IgAN ≤ 6 months prior to Screening
12. Secondary IgAN (eg, due to SLE, cirrhosis, or celiac disease; IgAV-N may be eligible, see Exclusion Criterion 5).
13. 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
14. Currently receiving or previously received a complement inhibitor within 30 days or 5 half-lives, whichever is longer, prior to Screening
15. 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.
16. Pregnant, breastfeeding, or intending to conceive during the study.
17. Inability to travel to the clinic for specified visits during the study or fulfill the logistical requirements of study intervention administration
18. Participant is imprisoned or lawfully retained at an institution via administrative or judicial order.
19. Participant is an employee or directly related to an employee of Alexion, AstraZeneca, or the institution/investigational site.
20. Concomitant clinically significant renal disease other than IgAN.
21. Uncontrolled diabetes mellitus with glycosylated hemoglobin (HbA1c) > 8.5%
22. Henoch-Schonlein purpura (IgAV) requiring systemic immunosuppressive therapy within 12 months of Screening
23. 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
24. 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.
25. Body mass index ≥ 38 kg/m2.
26. Splenectomy or functional asplenia
27. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 15

1. 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
2. Interim Analysis: Change from Baseline in eGFR at Week 34 Final Analysis: Change from Baseline in eGFR at Weeks 34 and 50
3. 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
4. Interim Analysis: Partial remission over time final analysis: Partial remission over time
5. Interim Analysis: Change from Baseline in albuminuria over time final analysis: Change from Baseline in albuminuria over time
6. Interim Analysis: Annualized eGFR slope over 50 weeks Final analysis: Time to sustained ≥ 30% eGFR decline up to Week 106
7. Final analysis: Time to individual components of composite kidney event endpoint up to Week 106
8. 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
9. interim and final analysis: Incidence of TEAEs, TESAEs, and AESI over time
10. interim and final analysis: ADA incidence, response categories, and titers; as well as NAb incidence for the duration for the study
11. interim and final analysis: • Serum ravulizumab concentrations over time • Serum total C5 and free C5 concentrations over time
12. 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
13. Final analysis: Time to sustained eGFR declinea ≥ 40% up to Week 106
14. Final Analysis: Time to individual components of composite kidney event endpoint up to Week 106
15. Final analysis: Use of alternative IgAN therapy over time

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Locations

12 EU/EEA countries · 89 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 281 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications