| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Proliferative Lupus Nephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lupus Nephritis, an autoimmune disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025140 |
| E.1.2 | Term | Lupus nephritis |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of anifrolumab as compared with placebo as added to SOC on:
-sustained OCS reduction
-onset of sustained CRR (Complete renal response)
-proteinuria
-onset of renal-related event or death through Week 52
-onset of renal-related event or death through Week 104
-aCRR (Alternative complete renal response)
-CRR with sustained OCS reduction
-early onset of CRR
-onset of sustained CRR through Week 104
-onset of proteinuria reduction
-proteinuria at Week 52
-PRR
-improvement in extra-renal SLE disease activity from baseline
To evaluate patient-reported HRQOL and health status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
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.
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 CS 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. Negative SARS-Cov-2 RT-PCR test result at Screening and no known or suspected COVID-19 infection or exposure between signing the ICF and Week 0 (Day 1). There must be a minimum of 2 weeks between the 2 tests at Screening and Week 0 (Day 1).
11. Body weight ≥ 40.0 kg.
12. Females with an intact cervix must have documentation of a Pap smear with no documented malignancy (eg, CIN III, carcinoma in situ, or adenocarcinoma in situ) within 2 years prior to Week 0 (Day 1)
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). |
|
| E.4 | Principal exclusion criteria |
1. A diagnosis of pure Class V LN based on the 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 after enrollment.
3. History of, or current renal diseases (other than LN) that, in the opinion of the Investigator, 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 - an HIV test must be performed during Screening, and the result should be available prior to Week 0 (Day 1).
6. At Screening, confirmed positive test for hepatitis B serology, as confirmed by central lab, for: HBsAg or HBcAb and HBV DNA detected above the LLOQ by reflex testing by the central lab at Screening. Participants who are HBcAb positive at Screening will be tested every 3 months for HBV DNA. To remain eligible for the study, the participant’s HBV DNA levels must remain below the LLOQ as per the central lab.
7. Positive test for hepatitis C antibody as confirmed by the central lab.
8. Any severe case, as defined by study guidelines, 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 (see Section 8.3.8.2 of protocol) requiring hospitalization or IV antimicrobial treatment within 3 years prior to the ICF.
11. Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, etc) 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).
15. Prior receipt of anifrolumab.
16. Previous receipt of >◦2 investigation treatments (other than anifrolumab) for LN or SLE since time of diagnosis and through the ICF.
17. Known intolerance to ≤ 1.0 g/day of MMF.
18. Receipt of any commercially available biologic agent within 5 half-lives (see Appendix O for a complete list) prior to signing of the ICF.
19. Receipt of any of the following prior to signing the ICF (refer to Appendix O of protocol for a complete list): Receipt of B cell-depleting therapy ≤ 26 weeks prior to the ICF or if therapy was administered > 26 weeks ago, if absolute B cell count is below the lower limit of normal or is baseline value prior to receipt of B cell-depleting therapy (whichever is lower)
20. 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.
21. Receipt of any of the following:
- Any live or attenuated vaccine within 8 weeks prior to signing the ICF (killed vaccines are acceptable)
- Any restricted medication listed in Appendix O not discontinued according to the prescribed timeframe prior to ICF
- Blood transfusion within 4 weeks prior to signing the ICF
- Any of the following for the 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 more than 8 weeks or Tacrolimus > 4 mg/day for more than 8 weeks; 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 the ICF.
22. Receipt of any commercially available Janus kinase inhibitor or Bruton’s tyrosine kinase inhibitor ≤ 24 weeks prior to the ICF.
23. 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
24. Lactating or pregnant females or females who intend to become pregnant or begin breastfeeding anytime from initiation of Screening through the Follow-up 12 weeks following last dose of study intervention and 6 weeks after the last dose of MMF (whichever is later). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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% |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
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 (see above; 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. 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 death - through Week 52.
5. Time to renal-related event or death (see definition above) through Week 104
6. aCRR at Week 52 meeting all of the following:
- UPCR ≤ 0.5 mg/mg
- eGFR ≥ 90 mL/min/1.73 m2 or no decrease from baseline of ≥ 10%
7. CRR at Week 52 with sustained OCS reduction
8. CRR at Week 24
9. Time to sustained CRR (see definition above) defined as the time from the first dose of study intervention to achieving CRR that is sustained from that time point through Week 104
10. Time from the first dose of study intervention to achieving 50% reduction in UPCR through Week 52
11. UPCR at Week 52
12. PRR at Week 52 meeting all of the following:
UPCR:
- For participants with a baseline UPCR ≤3 mg/mg: <1.0 mg/mg
- For participants with a baseline UPCR >3 mg/mg: >50% improvement from baseline and ≤3.0 mg/mg
eGFR:
- ≥ 60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline of ≥ 20%
13. Change from baseline in non-renal SLEDAI-2K total score
14. Change from baseline to Week 52 in SF-36v2 (acute) domain scores, physical component summary, and mental health component summary scores; FACIT-Fatigue |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 52
2. Week 52
3. Week 52
4. Week 52
5. Week 104
6. Week 52
7. Week 52
8. Week 24
9. Week 104
10. Week 52
11. Week 52
12. Week 52
13. Week 52
14. Week 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Mexico |
| Peru |
| Thailand |
| Turkey |
| Argentina |
| Belgium |
| Bulgaria |
| China |
| Germany |
| Hungary |
| India |
| Italy |
| Japan |
| Netherlands |
| Poland |
| Russian Federation |
| Taiwan |
| United States |
| Vietnam |
| France |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
An individual subject will be considered to have completed the study if the subject was
followed up until the end of the study (Week 112), regardless of the number of doses of
investigational product that were received. The end of the study (“study completion”) is
defined as the date of the last protocol-specified visit/assessment for the last subject in the
study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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