Clinical trial NCT03610516: Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Lupus Nephritis.
Official title: A Randomized, Placebo-controlled, Patient and Investigator Blinded, Study Investigating the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Multiple Doses of CFZ533 in Patients With Moderately Active Proliferative Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lupus Nephritis
Keywords: anti-CD40
CFZ533
moderately active lupus nephritis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-08-01
Enrollment: 57
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 study was to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic efficacy of multiple doses of CFZ533 anti-CD40 monoclonal antibody in patients with moderately active lupus nephritis.

Detailed description: This was a randomized, subject and investigator blind, placebo controlled multicenter study with multiple doses of CFZ533 administered by 1-hour intravenous infusion over a 24 week treatment period, as compared to matched placebo infusion. The treatment period was followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient was approximately 53 weeks. The investigational drug or placebo was administered on top of standard of care therapy for lupus nephritis.

Patients were screened within 29 days of the first study drug infusion. Eligibility was confirmed at the baseline visit within one week before the first dose. Eligible patients were assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.

Eligibility criteria: Key Inclusion Criteria:

* Men and women with systemic lupus erythematosus (SLE) aged ≥ 18 years and ≤ 75 years at screening, fulfilling at least 4 out of 11 criteria for SLE as defined by the American College of Rheumatology (Tan at al 1982, revised by Hochberg 1997)
* Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at screening visit
* Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV within 5 years of screening
* Presence of antinuclear autoantibody (ANA titer ≥ 1:80) at screening
* Morning UPCR ≥ 0.5 at screening visit and baseline visit
* At least one of the following:

  1. low complement level (C3 ˂ 0.9 g/L) or (C4 ˂ 0.1 g/L), and/or
  2. elevated anti-dsDNA (≥ 30 IU/mL), and/or
  3. urine sediment consistent with active proliferative LN such as presence of cellular (granular or red blood cell) casts or hematuria ( ˃5 red blood cells per high power field) if other causes such as menstrual bleeding are excluded
* Patient must have sufficient kidney function as estimated by eGFR ˃ 30mL/min/1.73 m2 at screening and baseline visits (Levey et al 2009)
* Patient must have active disease as defined by proteinuria and additional symptoms as above despite standard of care therapy for LN as considered appropriate by the treating physician (e.g., corticosteroids and/or immunosuppressive or immunomodulatory treatments such as mycophenolate, azathioprine, methotrexate or hydroxychloroquine). For guidance, see published guidelines such as Bertsias et all 2012 and Hahn et al 2012.
* Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must use highly effective methods of contraception during dosing and until study completion.

Key Exclusion Criteria:

* Any glomerulonephritis other than WHO Class III or IV lupus nephritis. Patients with proliferative nephritis (Class III or IV) who, in addition, have overlapping histological signs for other glomerulonephritis, e.g., Class V, are eligible at the investigator´s discretion.
* Hypoalbuminemia (serum albumin of less than 2.0 g/dL)
* Patients who have received:

  1. oral or i.v. cyclophosphamide within 3 months prior to randomization
  2. i.v. corticosteroid bolus (dose ˃ 1 mg/kg) within 3 months prior to randomization
  3. rituximab or other B cell depleting agent within 12 months. for patients who received such treatment earlier, B cell count should be within normal ranges prior to randomization
  4. belimumab within 6 months prior to randomization
  5. any other biologic drug or an investigational drug within one months or five times the half-life, whichever is longer prior to randomization
  6. any calcineurin inhibitor (e.g., tacrolimus or cyclosporin A) within 3 months prior to randomization
* Patients who are at significant risk for the thromboembolic events based on the following:

  1. history of either thrombosis or 3 or more spontaneous abortions
  2. presence of lupus anticoagulant or prolonged activated partial thromboplastin time (aPTT) and no prophylactic treatment with aspirin or anticoagulants as per local standard of care
* Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to randomization
* Live vaccines within 4 weeks of the first study drug infusion

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 49 weeks.
measure: Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR)
timeFrame: Baseline, Day 169
Secondary outcomes:
measure: Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR)
timeFrame: Day 197, Day 225, Day 253, Day 281, Day 309, Day 337 (End of Study)
measure: Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of CFZ533
timeFrame: Day 141: pre dose and 1 hour post dose
measure: Pre-dose Trough Concentration (Ctrough) of CFZ533
timeFrame: Pre-dose at: Day 1, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 141
measure: The Observed Maximum Plasma Concentration Following CFZ533 Administration at Steady State (Cmax,ss)
timeFrame: Day 141: pre dose and 1 hour post dose
measure: Total Soluble CD40 Plasma Concentrations
timeFrame: Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of Study)
measure: Number of Participants With Anti-CFZ533 Antibodies
timeFrame: Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of study)
measure: Hematuria Casts- Urine White Blood Cell Casts
timeFrame: Baseline, Day 1 (Pre dose), and Day 309
measure: Hematuria Casts- Casts Granular
timeFrame: Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 253, and Day 337 (end of study)
measure: Change From Baseline in Urine Hyaline Casts
timeFrame: Baseline, Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 57 (Pre dose), Day 85 (Pre dose), Day 113 (Pre dose), Day 141 (Pre dose), Day 169, Day 197, Day 225, Day 253, Day 281, Day 309 and Day 337 (end of study)
measure: Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR)
timeFrame: Baseline, up to Day 169
Other outcomes:
Locations:
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Urumqi
country: China
facility: Novartis Investigative Site
state: Xinjiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: HongKong
country: Hong Kong
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
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: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Yaroslavl
country: Russian Federation
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Tunis
country: Tunisia
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: