Clinical trial NCT01738035: The Effect of Nefecon® in Patients With Primary IgA Nephropathy at Risk of Developing End-stage Renal Disease
Official title: A Multicentre, Interventional Treatment, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Two Different Doses of Nefecon in Primary IgA Nephropathy Patients at Risk of End-stage Renal Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary IgA Nephropathy
Keywords: IgA nephropathy
Lead sponsor: Calliditas Therapeutics AB
Sponsor class: INDUSTRY
First posted: 2012-11-30
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of the study is to evaluate efficacy and safety of two different doses of NEFECON in the treatment of patients with primary IgA nephropathy (IgAN) at risk of developing end-stage renal disease, under rigorous blood pressure control with an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor I blocker (ARB).

Detailed description: NEFECON is an add-on treatment to other medications for nephropathy symptoms and kidney function, including ACEI and/or ARBs. Rigorous blood pressure control will be achieved over a 6-month Run-in Phase in which ACEI and/or ARB will be dosed to target a blood pressure of \<130/80 mm Hg and UPCR \<0.5 g/g. Patients who complete the Run-in Phase, and despite optimized ACEI and/or ARB therapy, have a UPCR ≥0.5 g/g OR urine protein ≥0.75 g/24hr will be eligible for randomization and entry into the treatment phase of the trial. Patients will remain on their ACEI and/or ARB dosing regimen for the duration of the trial.

Patients entering the treatment phase will be administered NEFECON (8 mg/day OR 16 mg/day) OR placebo for a phase of 9 months. A 3-month follow-up phase will follow on from the treatment phase, of which the first 2 weeks will be used to taper the dose of those patients that received 16 mg/day dosing to 8 mg/day, with the placebo and 8 mg/day groups receiving placebo to retain blinding.

Eligibility criteria: Screening Inclusion Criteria:

1. Female or male patients ≥18 years
2. Biopsy-verified IgA nephropathy
3. Urine protein creatinine ratio ≥0.5 g/g OR urine protein ≥0.75 g/24hr
4. Estimated GFR (using the CKD-EPI formula) OR measured GFR ≥50 mL/min per 1.73 m2 OR ≥45 mL/min per 1.73m2 for patients on a maximum recommended or maximum tolerated dose of an ACEI and/or ARB
5. Willing to change antihypertensive medication regimen if applicable
6. Willing and able to give informed consent

Screening Exclusion Criteria:

1. Secondary forms of IgA nephropathy as defined by the treating physician (for example, Henoch-Schönlein purpura patients and those with associated alcoholic cirrhosis)
2. Presence of crescent formation in ≥50% of glomeruli assessed on renal biopsy
3. Kidney transplanted patients 4. Severe gastrointestinal disorders (including peptic ulcer disease and inflammatory bowel disease) which may impair drug effect, or other conditions which could modify the effect of the trial drug as judged by the Investigator
4. Patients currently treated with systemic immunosuppressive or systemic corticosteroid drugs (excluding topical or nasal steroids) or have been previously treated for more than one week within the last 24 months.
5. Patients currently treated chronically (daily dosing) with inhaled corticosteroid drugs or have previously been treated chronically for more than one month within the last 12 months
6. Patients previously treated with immunosuppressive or systemic corticosteroids for the treatment of IgA nephropathy
7. Patients unable to take oral medication or intolerant to budesonide or other corticosteroid preparations
8. Patients with known allergy or intolerance to ACEI, ARB or to any component of the trial drug formulation
9. Patients with acute or chronic infectious disease incl. hepatitis, HIV positive patients and patients with chronic urinary tract infections
10. Severe liver disease according to the discretion of the Investigator
11. Patients with Type 1 or 2 diabetes
12. Patients with uncontrolled cardiovascular disease as judged by the Investigator
13. Patients with current malignancy or history of malignancy during the last three years
14. For women only; pregnant or breast feeding or unwilling to use adequate contraception during the trial (only women of child bearing potential)

Randomization Inclusion Criteria:

1. Completion of the Run-in Phase
2. Urine protein creatinine ratio ≥0.5 g/g OR urine protein ≥0.75 g/24hr
3. eGFR ≥45 mL/min per 1.73 m2 using CKD-EPI formula OR measured GFR ≥45 mL/min per 1.73 m2

Randomization Exclusion Criteria:

1. Unacceptable blood pressure defined as a systolic value \>160 mm Hg or diastolic \>100 mm Hg
2. eGFR (CKD-EPI) loss \>30% over the entire duration of the Run-in Phase
3. For women only; pregnant or breast feeding or unwilling to use adequate contraception during the trial (only women of child bearing potential)

Primary outcomes:
measure: Change from baseline in urine protein creatinine ratio
timeFrame: 9 months
Secondary outcomes:
measure: Change from baseline in urine albumin creatinine ratio
timeFrame: 9 months
measure: Change from baseline in 24 hour albuminuria
timeFrame: 9 months
measure: Change from baseline in estimated GFR
timeFrame: 9 months
Other outcomes:
measure: Change from baseline in urine protein creatinine ratio
timeFrame: 3-12 months
measure: Change in urine albumin creatinine ratio
timeFrame: 3-12 months
measure: Change from baseline in 24 hour albuminuria
timeFrame: 3-12 months
measure: Change from baseline in estimated GFR
timeFrame: 3-12 months
Locations:
city: Antwerp
country: Belgium
facility: University Hospital of Antwerp
city: Bonheiden
country: Belgium
facility: Imelda Hospital
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Roeselare
country: Belgium
facility: Heilig Hartziekenhuis Roeselare-Menen
city: Olomouc
country: Czech Republic
facility: University Hospital
city: Prague
country: Czech Republic
facility: Charles University & General University Hospital
city: Prague
country: Czech Republic
facility: Institut klinické a experimentální medicíny
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Aachen
country: Germany
facility: RWTH Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Berlin
country: Germany
facility: Charité Hospital
city: Berlin
country: Germany
facility: Charité-Virchow Clinic
city: Berlin
country: Germany
facility: Vivantes Klinikum im Friedrichshain
city: Bremen
country: Germany
facility: Klinikum-Bremen-Mitte
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus
city: Düsseldorf
country: Germany
facility: Studienzentrum Karlstrasse
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Heidelberg
country: Germany
facility: University Hospital
city: Jena
country: Germany
facility: University of Jena
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Munich
country: Germany
facility: Universität München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Wiesbaden
country: Germany
facility: Deutsche Klinik für Diagnostik
city: Würzburg
country: Germany
facility: Würzburg University Hospital
city: Bari
country: Italy
facility: Policlinico di Bari
city: Cagliari
country: Italy
facility: Azienda Ospedaliera G. Brotzu
city: Lecco
country: Italy
facility: Ospedale A Manzoni
city: Milano
country: Italy
facility: Bassini Hospital
city: Torino
country: Italy
facility: Ospedale S. G. Bosco
city: Viterbo
country: Italy
facility: Belcolle Hospital
city: Leiden
country: Netherlands
facility: University Medical Center
city: Barcellona
country: Spain
facility: Fundación Puigver
city: Barcellona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: 12 de Octubre Hospital
city: Madrid
country: Spain
facility: Fundación Jimenez Diaz Hospital
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañon
city: Karlstad
country: Sweden
facility: Central sjukhuset
city: Karlstad
country: Sweden
facility: Karlstad Central Hospital
city: Linköping
country: Sweden
facility: University Hospital
city: Stockholm
country: Sweden
facility: Danderyds Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Belfast
country: United Kingdom
facility: Ulster Hospital
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Western Infirmary
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
Study officials:
affiliation: Professor of Medicine Department of Medical Sciences, Renal Medicine Uppsala University Hospital, Sweden
name: Bengt Fellström, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pharmalink AB, Stockholm, Sweden
name: Alex Mercer, PhD
role: STUDY_DIRECTOR
References:
citation: Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sorensen SS, Tesar V, Del Vecchio L; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0. Epub 2017 Mar 28.
citation: Yeo SC, Liew A, Barratt J. Emerging therapies in immunoglobulin A nephropathy. Nephrology (Carlton). 2015 Nov;20(11):788-800. doi: 10.1111/nep.12527.