Clinical trial NCT04181762: Study of Safety, Efficacy and Tolerability of Secukinumab Versus Placebo, in Combination With SoC Therapy, in Patients With Active Lupus Nephritis
Official title: A Two-year, Phase III Randomized, Double-blind, Parallel-group, Placebo-controlled Trial to Evaluate the Safety, Efficacy, and Tolerability of 300 mg s.c. Secukinumab Versus Placebo, in Combination With SoC Therapy, in Patients With Active Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lupus Nephritis
Keywords: Systemic Lupus Erythematosus (SLE)
Lupus Nephritis (LN)
secukinumab
renal biopsy
estimated Glomerular Filtration Rate (eGFR)
Urine Protein-to-Creatinine Ratio (UPCR)
Standard of Care (SoC) background therapy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-11-29
Enrollment: 275
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a pivotal, randomized, double-blind, placebo-controlled trial evaluating at Week 52 the efficacy and safety of secukinumab versus placebo in patients with active lupus nephritis (ISN/RPS Class III or IV, with or without co-existing class V features) also receiving background standard of care therapy (SoC).

Detailed description: The study consisted of the following parts:

* Screening (up to 42 days/6 weeks)
* Run-in period (optional): For subjects who received Mycophenolic acid (MPA) as SoC induction therapy as per investigator's decision and who were not already on MPA at Screening, MPA dosing was initiated during a run-in period before Randomization (for up to 4 weeks prior to the first dose of secukinumab)
* Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in addition to SoC treatment (with last dose given at Week 100)
* Secukinumab dosing was started with initial dosing of 300 mg s.c. injections at Baseline, Weeks 1, 2, 3, and 4, followed by dosing every 4 weeks
* Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of study medication) for all except for subjects entering extension study CAIN457Q12301E1 (NCT05232864).

A total of 275 subjects were enrolled and were randomized to secukinumab 300 mg (n = 137) or placebo (n = 138) until study termination. Recruitment in this study was stopped on 26-May-2023. The CAIN457Q12301 study was terminated early by Novartis due to futile results from interim analysis 1 (IA1). There was no safety related reasons for early termination or concerns for the subjects in the study. The decision was made to terminate both the core and the related extension study in view of treatment futility of the core study.

Eligibility criteria: Key inclusion criteria:

1. Adult male and female subjects aged 18 - 75 years old at the time of Baseline.
2. Confirmed diagnosis of:

   * SLE with documented history of at least 4 of the 11 criteria for SLE as defined by the American College of Rheumatology (ACR) (Tan et al 1982) revised by (Hochberg 1997). \[NOTE: The 4 criteria did not have to be present at the time of Screening\], OR
   * LN as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.
3. Active lupus nephritis, as defined by meeting the 4 following criteria:

   * Biopsy within 6 months prior to Screening visit indicating active glomerulonephritis WHO or ISN/RPS Class III or IV LN \[excluding III (C), IV-S (C) and IV-G (C)\]; patients are permitted to have co-existing Class V. If no biopsy was performed within 6 months of screening, a biopsy was to be performed during the Screening period
   * UPCR ≥ 1 mg/mg at Screening.
   * eGFR \> 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
   * Active urinary sediment (presence of cellular casts (RBC or WBC casts)) or hematuria (\> 5 RBC per high power field or above the laboratory reference range).
4. Subjects must have currently been on MPA, or willing to initiate SoC induction therapy for LN according to the institutional practices using MPA or low-dose CYC in addition to corticosteroids. For guidance, see published guidelines such as by (Bertsias et al 2012, Hahn et al 2012).
5. Subjects must had been treated with anti-malarials (e.g. hydroxychloroquine), unless contra-indicated, and the dose had been stable for at least 10 days prior to Randomization.
6. Able to provide signed informed consent.

Key Exclusion criteria:

1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of oliguria (defined as a documented urine volume \< 400 mL/24 h), or iii.) ESRD required dialysis or transplantation.
2. Known intolerance/hypersensitivity to MPA, or oral corticosteroids, or any component of the study drug(s).
3. Subjects received any other biologic immunomodulatory therapy within 6 months prior to Screening, excluding belimumab where 3 months were acceptable.
4. Previous exposure to secukinumab (AIN457) or any other biologic drug targeting IL-17 or the IL-17 receptor.
5. Subjects received any investigational drug within 1 month or five times the half-life of enrollment, whichever was longer.
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within the 12 weeks prior to Baseline.
7. Treatment with a systemic calcineurin inhibitor (e.g. cyclosporine, tacrolimus) within 12 weeks prior to Baseline
8. CYC use (i.v. or oral) within the month prior to Baseline.
9. Subjects requiring dialysis within the previous 12 months before Screening.
10. History of renal transplant.
11. Any severe progressive or uncontrolled concurrent medical condition, including recent severe thromboembolic events, that, in the opinion of the principal investigator, renders the subject unsuitable for the trial.
12. Active ongoing inflammatory diseases that might confound the evaluation of the benefit of secukinumab therapy, including inflammatory bowel disease.
13. Presence of investigator-identified significant medical problems which at the investigator's discretion would prevent the subject from participating in the study, included but not limited to the following: myocarditis, pericarditis, poorly controlled seizure disorder, acute confusional state, depression, severe manifestations of neuropsychiatric SLE (NPSLE).
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of ongoing infectious or malignant process, obtained within 3 months preceding the Screening visit and evaluated by a qualified physician.
15. History of chronic, recurrent systemic infections, active tuberculosis infection, or active systemic infections during the last two weeks (exception: common cold) prior to Randomization.
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at Screening or Randomization.
17. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system treated or untreated within the past 5 years, regardless of whether there was evidence of local recurrence or metastases (except for skin Bowen's disease or basal cell carcinoma or actinic keratoses that had been treated with no evidence of recurrence in the past 12 weeks, carcinoma in situ of the cervix or non-invasive malignant colon polyps that had been removed).
18. Any of the following abnormal laboratory values on Screening evaluations as reported by Central Laboratory:

    * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase \> 2.5xULN
    * Hemoglobin \< 8g/dL
    * Neutrophils \< 1.0 x 109/L
    * Platelet count \< 50 x 109/L

21. Pregnant or lactating women. 22. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during the entire study or longer if required by locally approved prescribing information (e.g., in European Union (EU) 20 weeks). Of note: the highly effective methods of contraception were mandated due to SoC medications used as per protocol (MPA and CYC).

In case local regulations deviated from the contraception methods listed above, local regulations applied and were described in the informed consent form (ICF).

If stricter female or male contraception requirements were specified in the country-specific label for induction and maintenance standard of care medications, they had to be followed.

Note: Women were considered post-menopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow-up hormone level assessment was she considered not of childbearing potential.

Primary outcomes:
measure: Percentage of Participants Achieving Complete Renal Response (CRR) at Week 52
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Change From Baseline in 24-hour Urine Protein-to Creatinine Ratio (UPCR)
timeFrame: Baseline, Week 52
measure: Percentage of Participants Achieving Partial Renal Response (PRR) at Week 52
timeFrame: Baseline, Week 52
measure: Average Daily Dose of Oral Corticosteroids
timeFrame: Week 16 to Week 52
measure: Percentage of Participants Achieving Partial Renal Response (PRR) at Week 24
timeFrame: Baseline, Week 24
measure: Incidence Rate of Participants Achieving Complete Renal Response (CRR) up to Week 52
timeFrame: Baseline to Week 52
measure: Incidence Rate of Participants Achieving Partial Renal Response (PRR) up to Week 52
timeFrame: Baseline to Week 52
measure: Time to Achieve First Morning Void Urine Protein-to-Creatinine Ratio (UPCR) <= 0.5 mg/mg up to Week 52
timeFrame: Baseline to Week 52
measure: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Mean Change From Baseline up to Week 52
timeFrame: Baseline, Week 12, Week 24, Week 36, Week 52
measure: Short Form Health Survey (SF-36) Version 2 (Acute Form) Mean Change From Baseline in Physical Component Score (PCS) up to Week 52
timeFrame: Baseline, Week 12, Week 24, Week 36, Week 52
measure: Lupus Quality of Life (LupusQoL) Physical Health Score Mean Change From Baseline up to Week 52
timeFrame: Baseline, Week 12, Week 24, Week 36, Week 52
measure: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment up to approximately 2 years
measure: Percentage of Participants With Complete Renal Response (CRR) at Week 104 Within Those Who Had Achieved CRR at Week 52 in the Secukinumab Group
timeFrame: Week 52 to Week 104
measure: Percentage of Participants With Improved or Maintained Response (PRR or CRR) at Week 104 in Those Who Had Achieved at Least PRR at Week 52 in the Secukinumab Group
timeFrame: Week 52 to Week 104
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University Of Alabama
state: Alabama
city: Fontana
country: United States
facility: Kaiser Permanente Fontana
state: California
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: Aventura
country: United States
facility: Arthritis and Rheum Dise Spec
state: Florida
city: Plantation
country: United States
facility: Integral Rheumatology and Immunology Specialists IRIS
state: Florida
city: Atlanta
country: United States
facility: Piedmont Heart Institute
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Hospital
state: Massachusetts
city: Grand Blanc
country: United States
facility: Ahmed Arif Medical Research Center
state: Michigan
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Joinville
country: Brazil
facility: Novartis Investigative Site
state: Santa Catarina
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Valdivia
country: Chile
facility: Novartis Investigative Site
state: Los Rios
city: Santiago
country: Chile
facility: Novartis Investigative Site
state: RM
city: Concepcion
country: Chile
facility: Novartis Investigative Site
city: Santiago
country: Chile
facility: Novartis Investigative Site
city: Nanning
country: China
facility: Novartis Investigative Site
state: Guangxi
city: Shijiazhuang
country: China
facility: Novartis Investigative Site
state: Hebei
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Binzhou
country: China
facility: Novartis Investigative Site
state: Shandong
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Chongqing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Wuhan
country: China
facility: Novartis Investigative Site
city: Medellin
country: Colombia
facility: Novartis Investigative Site
state: Antioquia
city: Barranquilla
country: Colombia
facility: Novartis Investigative Site
city: Cali
country: Colombia
facility: Novartis Investigative Site
city: Cundinamarca
country: Colombia
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Guatemala City
country: Guatemala
facility: Novartis Investigative Site
city: Guatemala
country: Guatemala
facility: Novartis Investigative Site
city: Quetzaltenango
country: Guatemala
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Toyoake city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kitakyushu
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Sendai city
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Kurashiki
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Chuo
country: Japan
facility: Novartis Investigative Site
state: Yamanashi
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Mexicali
country: Mexico
facility: Novartis Investigative Site
state: Baja California Norte
city: Ciudad De Mexico
country: Mexico
facility: Novartis Investigative Site
state: Mexico CP
city: Merida
country: Mexico
facility: Novartis Investigative Site
state: Yucatan
city: Mexico
country: Mexico
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Santiago de Surco
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Lipa City
country: Philippines
facility: Novartis Investigative Site
state: Batangas
city: Iloilo
country: Philippines
facility: Novartis Investigative Site
city: Manila
country: Philippines
facility: Novartis Investigative Site
city: Quezon
country: Philippines
facility: Novartis Investigative Site
city: Coimbra
country: Portugal
facility: Novartis Investigative Site
city: Guimaraes
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Oradea
country: Romania
facility: Novartis Investigative Site
state: Jud Bihor
city: Ramnicu Valcea
country: Romania
facility: Novartis Investigative Site
state: Valcea
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Kemerovo
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov On Don
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Yaroslavl
country: Russian Federation
facility: Novartis Investigative Site
city: Piestany
country: Slovakia
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Vigo
country: Spain
facility: Novartis Investigative Site
state: Pontevedra
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bakırkoy Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
state: VNM
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: