E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 plus standard of care (SOC) compared to placebo plus SOC in subjects with active proliferative lupus nephritis measured by the relative difference in change from baseline to Week 52 in 24-hour urine protein to creatinine ratio (UPCR) |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of anifrolumab plus SOC compared with placebo plus SOC on the proportion of subjects achieving Complete Renal Response (CRR) at Week 52 |
|
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. Fulfils at least 4 of the 11 criteria of the revised 1982 ACR classification criteria for SLE, at least one of which must be:
a. Positive antinuclear antibody (ANA) test (1:40 or higher) or
b. Elevated anti-dsDNA antibodies at screening (reported as equivocal or positive results), as per the central laboratory; or
c. Anti-Smith antibody at screening elevated to above normal (ie, positive or equivocal results) as per the central laboratory
3.Class III (±class V) or class IV (±class V) LN according to the World Health Organisation (WHO) or 2003 ISN/RPS classification based on a renal biopsy obtained within 12 weeks prior to signing the ICF or during the screening period
4. Urine protein to creatinine ratio >1 mg/mg (113.17 mg/mmol), obtained on a 24-hour urine collection at both:
− The start of screening and
− Within 14 days prior to the expected date of randomisation. Without the results of the second (stratification) sample, subjects cannot be randomised.
5. Estimated glomerular filtration rate ≥35 mL/min/1.73 m2
6. Must not have active or untreated latent TB on either chest radiograph or by Quantiferon gold test
7. Women of childbearing potential must have a negative serum beta-hCG test at screening and negative urine pregnancy test prior to administration of investigational product and prior to the first dose of sponsor-provided MMF
|
|
E.4 | Principal exclusion criteria |
1. Receipt of any investigational product (small molecule or biologic) or commercially
available biologic agent within four weeks or 5 half lives prior to signing of
the ICF, whichever is greater
2. Pure Class V membranous LN on
a renal biopsy obtained within 12 weeks prior to signing ICF or during the
screening period
3. Known intolerance to ≤1.0 gm/day of MMF
4. History of dialysis within 12 months prior to signing the ICF or
expected need for renal replacement therapy (dialysis or renal transplant)
within a 6 month period after enrolment
5. Subjects, who at the time of signing the ICF, received any of the
following immunosuppressive therapies after their qualifying biopsy
(a) Oral corticosteroids >0.5 mg/kg/day for
more than 8 weeks or
(b) Oral or IV pulse methylprednisolone >3.0 gm (cumulative dose) or
(c) IV cyclophosphamide >2 pulses of high dose
(≥0.5 gm/m2) or >4 doses of low-dose (500 mg every 2 weeks) or
(d) Average MMF >2.5 gm/day (or >1800 mg/day of enteric-coated
mycophenolate sodium) for more than 8 weeks or
(e) Tacrolimus >4 mg/day for more than 8 weeks
6. Major surgery within 8 weeks before signing the ICF or major
surgery planned during the study period
7. History of any non-SLE disease that has required treatment with
oral or parenteral corticosteroids for more than a total of 2 weeks within the
last 24 weeks prior to signing the ICF
8. Confirmed positive test for hepatitis B or hepatitis C
9. Any severe herpes infection at any time prior to randomization
10.Opportunistic infection requiring hospitalisation or parenteral
antimicrobial treatment within 3 years prior to randomization
11. History of cancer, apart from:
a. Squamous or basal cell carcinoma of the skin
that has been successfully treated
b. High-grade squamous intraepithelial lesion (CIN III, CIS) treated with apparent success with curative therapy ≥1 year prior to randomisation
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint used to evaluate the effect of anifrolumab compared to placebo on LN disease activity is the relative difference in change from baseline to Week 52 in the 24-hour UPCR. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Complete renal response
To evaluate the effect of anifrolumab compared to placebo on renal response in LN subjects, the proportion of subjects achieving CRR at Week 52 will be used. A subject achieves CRR if all of the following criteria are met:
• Estimated glomerular filtration rate (eGFR):
- ≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline of ≥20%
• 24-hour UPCR ≤ 0.7 mg/mg
• No discontinuation of investigational product or use of restricted medication beyond the protocol-allowed threshold before assessment. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Argentina |
Australia |
Korea, Republic of |
Mexico |
Peru |
Russian Federation |
Serbia |
South Africa |
Taiwan |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United Kingdom |
|
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 60), 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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |