Phase 3 Study of Anifrolumab in Adult Patients with Active Proliferative Lupus Nephritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

8 Apr 2022 → ongoing

Decision date (initial)

2024-05-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-506359-68-00

EudraCT number

2021-002862-42

ClinicalTrials.gov

NCT05138133

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy of anifrolumab compared with placebo as added to SOC in active proliferative LN (Lupus Nephritis) on the proportion of participants achieving CRR (Complete renal response).

Secondary objectives 6

1. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Sustained OCS reduction
2. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Onset of sustained CRR
3. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Proteinuria
4. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Early onset of CRR
5. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Onset of renal-related event or death through Week 52
6. To evaluate the effect of anifrolumab as compared with placebo as added to SOC on Onset of renal-related event or death through Week 76

Conditions and MedDRA coding

Active Proliferative Lupus Nephritis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age 18 through 70 years at the time of Screening.
2. Fulfills updated 2019 SLE criteria.
3. Positive ANA, anti-dsDNA, or anti-Sm test result in sample obtained during Screening or historical.
4. Urine protein to creatinine ratio > 1 mg/mg (113.17 mg/mmol) (mean of 2 spot UPCR [FMV] samples obtained during Screening).
5. Active proliferative LN Class III or IV either with or without the presence of Class V (excluding pure Class III[C], IV-S[C], or IV-G[C]) according to the 2003 ISN/RPS classification based on a renal biopsy obtained within 6 months prior to signing the ICF or during Screening Period, and in the opinion of the investigator, participant needs high dose corticosteroids and immunosuppressive therapy.
6. eGFR ≥ 35 mL/min/1.73 m2 (as calculated by the Chronic Kidney Disease Epidemiology Collaboration formula).
7. Adequate peripheral venous access.
8. Chest radiograph (obtained during Screening or within 12 weeks prior to signing of the informed consent) or a CT scan of the chest (within 12 weeks of signing the informed consent) that meets all of the following criteria: No evidence of current active infection (eg, pneumonia, TB) or previous TB; No evidence of malignancy; No evidence of pulmonary nodules suspicious for lung cancer that have not been appropriately followed-up prior to enrolment, No clinically significant abnormalities (unless due to SLE).
9. Meets all of the following TB criteria: No signs or symptoms of active TB prior to or during any Screening visit; No medical history or past physical examinations suggestive of active TB; A chest radiograph during the Screening Period or within 12 weeks prior to signing the ICF with no evidence of active or signs of prior TB infection; No recent contact with a person with active TB OR if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to Week 0 (Day 1) (documented comprehensively in source) and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of study intervention; No history of latent TB prior to signing the ICF, with the exception of latent TB with documented completion of appropriate treatment. The participant must undergo an IGRA (eg, QFT-G test) test for TB obtained from the study central laboratory at Screening with results in line with protocol specified rules.
10. Any negative PCR or antigen test result (central or local laboratory, as appropriate) as per local policies at Screening in addition to no known or suspected COVID 19 exposure within 2 weeks prior to Screening.
11. Body weight ≥ 40.0 kg.
12. Females who have been or are sexually-active with an intact cervix must have documentation of a cervical cancer screening (Pap smear or HPV tests as per local guidelines) with a normal test result within 2 years prior to randomization.
13. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (as described in protocol).

Exclusion criteria 26

1. A diagnosis of pure Class V LN based on renal biopsy obtained within 6 months prior to signing the ICF or during Screening
2. History of dialysis within 12 months prior to the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 6-month period
3. History of, or current renal diseases (other than LN) that could interfere with the LN assessment and confound the disease activity assessment (eg, diabetic nephropathy)
4. "History of recurrent infection requiring hospitalization and/or IV antibiotics (eg, 2 or more of the same type of infection over the previous 52 weeks)"
5. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection, or a positive result for HIV confirmed by the central lab at Screening
6. Confirmed positive test for hepatitis B serology (HBsAB or HBcAB+HBV DNA above the LLOQ) To remain eligible for the study, the participant’s HBV DNA levels must remain below the LLOQ as per the central lab
7. Active hepatitis C infection (defined as positive hepatitis C virus antibody and detectable HCV ribonucleotide (RNA) as confirmed by central lab
8. Any severe case of HZ infection at any time prior to Week 0 (Day 1)
9. Any clinical CMV or EBV infection that has not completely resolved within 12 weeks prior to the ICF
10. Opportunistic infection requiring hospitalization or IV antimicrobial treatment within 3 years prior to the ICF
11. Clinically significant chronic infection within 8 weeks prior to signing the ICF (chronic nail infections are allowed) or any infection requiring hospitalization or treatment with IV anti-infectives not completed at least 4 weeks prior to the ICF
12. Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Week 0 (Day 1)
13. History of cancer, apart from: Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥3 months prior to Week 0 (Day 1); Cervical cancer in situ treated with apparent success with curative therapy ≥1 year prior to Week 0 (Day 1)
14. Any history of severe COVID-19 infection or any prior COVID-19 infection with documented long COVID and/or clinically significant unresolved sequelae. Any mild/asymptomatic COVID-19 infection within the last 6 weeks prior to first dosing
15. Failure to comply with all required Screening procedures due to circumstances related to pandemic or public health emergency
16. Prior receipt of anifrolumab
17. Previous receipt of >2 investigational treatments for LN since time of diagnosis of LN and through signing the ICF
18. Known intolerance to ≤1.0 g/day of MMF
19. Receipt of any commercially available biologic agent within 5 half-lives prior to signing of the ICF
20. Receipt of any of the following prior to signing the ICF: Receipt of B cell-depleting therapy ≤26 weeks prior to signing the ICF or if therapy was administered >26 weeks ago, if absolute B cell count is <50 cells/microliter
21. A known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy, human proteins, or monoclonal antibodies
22. "Receipt of any of the following: -Any live or attenuated vaccine within 8 weeks prior to signing the ICF (killed vaccines are acceptable) -Any prohibited medication listed in Appendix O not discontinued according to the prescribed timeframe prior to signing of ICF -Blood transfusion or receipt of blood products, except human albumin, within 4 weeks prior to signing the ICF -Any of the following for current LN flare (ie, since the qualifying renal biopsy): IV cyclophosphamide >2 pulses of high-dose (≥0.5 g/m2) or >4 doses of low dose (500 mg every 2 weeks) or Average MMF >2.5 g/day (or >1800 mg/day of enteric coated mycophenolate sodium) for > 8 weeks or Tacrolimus >4 mg/day for more than 8 weeks or 4 weeks prior to signing the ICF; Cyclosporine for more than 8 weeks or during last 8 weeks prior to signing the ICF; Voclosporin for more than 8 weeks or during last 8 weeks prior to signing the ICF; Belimumab for more than 12 weeks or during last 12 weeks prior to signing the ICF"
23. Receipt of any commercially available Janus kinase (JAK) inhibitor ≤12 weeks or Bruton’s tyrosine kinase (BTK) inhibitor ≤24 weeks prior to the ICF
24. Any new medicinal cannabinoid should not be started during the course of the study.
25. Participation in another clinical study with another intervention (besides anifrolumab) administered within 4 weeks prior to ICF signing or within 5 half-lives of the study intervention used in that study, whichever is longer
26. "Within 4 weeks of Week 0 (Day 1),any of the following: -AST >2.5 × ULN -ALT >2.5 × ULN -TBL >ULN (unless due to Gilbert’s syndrome) -Glycosylated hemoglobin > 8% (or >0.08) at Screening (diabetic participants only) -Neutrophil count <1 × 10^3/μL (or <1.0 × 109/L) -Platelet count <25 × 10^3/μL (or <25 × 109/L) -Hemoglobin <8 g/dL (or <80 g/L)"

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "CRR at Week 52, ie, meeting all of the following: - UPCR ≤ 0.5 mg/mg - eGFR ≥ 60 mL/min/1.73 m2 or no decrease from baseline of ≥ 20%"

Secondary endpoints 6

1. "Sustained OCS reduction, ie, meeting all of the following: - OCS dose of ≤ 7.5 mg/day prednisone or equivalent by Week 24 - Sustained OCS dose of ≤ 7.5 mg/day prednisone or equivalent from Week 24 through Week 52"
2. "Time to sustained CRR, ie, meeting all of the following: - UPCR ≤ 0.5 mg/mg - eGFR ≥ 60 mL/min/1.73 m2 or no decrease from baseline of ≥ 20% (ie, time from first study intervention dose to achieving CRR that is sustained from that time point through Week 52)"
3. Cumulative UPCR as determined by the standardized AUC from baseline up to and including Week 52.
4. CRR at Week 24 (see definition above)
5. Time to renal event as defined as any of the following: 1) ESKD, 2) doubling of serum creatinine, 3) renal worsening as evidenced by increased proteinuria and/or renal function impairment, or 4) renal disease treatment failure, or 5) death - through Week 52.
6. Time to renal-related event or death (see definition above) through Week 76

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

8 EU/EEA countries · 42 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 63 files

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

Application history

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