A study to assess if two different doses of Nefecon (budesonide) compared to placebo are safe and effective in patients with primary IgA nephropathy at risk of developing end-stage renal disease

• Register: EUCTR
• Last refreshed on: 4 August 2015
• Main ID: EUCTR2012-001923-11-FI
• Date of registration: 15/08/2012
• Prospective Registration: Yes
• Primary sponsor: Pharmalink AB
• Public title: A study to assess if two different doses of Nefecon (budesonide) compared to placebo are safe and effective in patients with primary IgA nephropathy at risk of developing end-stage renal disease
• Scientific title: A Multicentre, Interventional Treatment, Randomised, Double-Blind, Single Group Assignment, Placebo Controlled Study to Evaluate the Efficacy and Safety of Two Different Doses of Nefecon® in Primary IgA Nephropathy Patients at Risk of Developing End-Stage Renal Disease - The NEFIGAN Trial
• Date of first enrolment: 17/10/2012
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001923-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3

Countries of recruitment

Belgium, Czech Republic, Denmark, Finland, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom

Contacts

• Name: Project Director (Alex Mercer)
• Affiliation: Pharmalink

• Name: Project Director (Alex Mercer)
• Affiliation: Pharmalink

Key inclusion & exclusion criteria

Inclusion 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 (56.5 mg/mmol) OR urine protein =0.75 g/24 h
4. Estimated GFR (using 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
Randomisation Inclusion Criteria:
1. Completion of the Run-in Phase
2. Urine protein creatinine ratio =0.5 g/g (56.5 mg/mmol) OR urine protein =0.75 g/24 h
3. Estimated GFR (using CKD-EPI formula) OR measured GFR =45 mL/min per 1.73 m2
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 195
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion criteria:
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
5. Consumption of an investigational drug within 30 days prior to enrolment
6. Hyperlipidaemia defined as unacceptable levels of lipids according to the discretion of the Investigator
7. Morbid obesity defined as a body mass index (BMI) >45 kg/m2
8. 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.
9. 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
10. For the treatment of IgA nephropathy, patients treated within the last 24 months with either immunosuppressive agents or systemic corticosteroid drugs
11. Patients unable to take oral medication or intolerant to budesonide or other corticosteroid preparations
12. Patients with known allergy or intolerance to ACEI and ARB or to any component of the trial drug formulation
13. Patients with acute or chronic infectious disease incl. hepatitis, HIV positive patients and patients with chronic urinary tract infections
14. Severe liver disease according to the discretion of the Investigator
15. Patients with Type 1 or 2 diabetes
16. Patients with uncontrolled cardiovascular disease as judged by the Investigator
17. Patients with current malignancy or history of malignancy during the last three years
18. History or presence of psychological or psychiatric illness (including steroid induced psychosis) which may interfere with the patient´s ability to adhere to the protocol
19. Patients with untreated osteoporosis
20. Patients with glaucoma or cataract
21. Alcohol or drug abuse (present)
22. Patients unwilling to meet the requirements of the protocol
23. Other medical or social reasons for exclusion at the discretion of the Investigator
24. Life expectancy < 1 year
25. For women only; pregnant or breast feeding or unwilling to use adequate contraception during the trial (only women of child bearing potential)

Randomisation Exclusion Criteria:
1. Unacceptable blood pressure defined as a systolic value >160 mm Hg or diastolic >100 mm Hg
2. eGFR (CKD-EPI method of estimation) loss >30% over the entire duration of the Run-in Phase
3. Consumption of an investigational drug after screening
4. Medical or social reasons for exclusion at the discretion of the Investigator
5. For women only; pregnant or breast feeding or unwilling to use adequate contraception during the trial (only women of child bearing potential)
6. For men only; unwilling to use adequate contraception during the treatment and follow-up phase of the trial


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary IgA nephropathy patients at risk of developing end stage renal disease
MedDRA version: 17.1 Level: LLT Classification code 10069341 Term: Berger's disease System Organ Class: 100000004857

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: Nefecon
Pharmaceutical Form: Modified-release capsule, hard
INN or Proposed INN: BUDESONIDE
CAS Number: 51333-22-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-
Pharmaceutical form of the placebo: Modified-release capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Primary Efficacy Endpoint(s):
The primary endpoint is the mean reduction in UPCR at 9 months compared to baseline UPCR values.

Secondary Objective: To evaluate if other urine protein response criteria and other laboratory parameters used to estimate glomerular filtration rate (GFR) are in favour of Nefecon® (budesonide) compared with placebo at 9 months.
Tertiary Objective:
To evaluate if other response criteria and time-points are in favour of Nefecon® (budesonide) compared with placebo.
Safety Objective:
To evaluate safety in terms of adverse events, changes in vital signs and laboratory tests during the trial.

Timepoint(s) of evaluation of this end point: The mean reduction will be measured as ratio of UPCR at 9 months compared to baseline.

Main Objective: To evaluate efficacy and safety of two different doses of Nefecon (budesonide) 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 2 receptor blocker (ARB).
The Primary efficacy objective is to investigate whether patients on Nefecon (budesonide) achieve a lareger mean reduction in urine protein creatinine ratio (UPCR) compared to patients in placebo during a 9 months trial.

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Endpoint(s):
- Mean change in urine protein, urine albumin
creatinine ratio and urine albumin from baseline at
Month 9
- Mean change UPCR, urine protein, UACR, urine
albumin from 9 to 12 months
- Mean change in serum creatinine, chronic kidney
disease epidemiology collaboration equation (CKDEPI)
estimated glomerular filtration rate (eGFR),
modification of diet in renal disease study equation
(MDRD) eGFR and creatinine clearance from baseline
at 9 months

Tertiary Efficacy Endpoint(s)
- Achieving defined reductions (=30%, =40%, =50%) in
UPCR, urine protein, UACR and urine albumin at
Month 9 compared to baseline
- Mean change in UPCR, urine protein, UACR and urine
albumin from baseline at 1, 3, 6, 10.5 and 12 months
- Mean change in CKD-EPI from baseline at 1, 3, 6, 10.5
and 12 months
- Mean change in Cystatin C-based eGFR from baseline
at Months 9
- Proportion of patients with microhematuria at
Months 9 and 12

Exploratory Efficacy Endpoint(s)
The exploratory analyses listed below are planned but may not be conducted if deemed to be obsolete during later stages of the trial; other exploratory analyses may be added.
- Percentage change from baseline at 9 and 12 months on exploratory markers/biomarkers
- Urine and serum total IgA1/2, secretory IgA, IgA kappa/lambda ratios, IgA1 monomer/polymer ratio, IgA1 O-glycosylation, IgA-CD89 immune complex levels
- Urine IL-6/EGF ratio, NAG, NGAL, KIM-1, RBP levels
- Serum or plasma IgA anti-gliadin, IgA anti-ovalbumin, IgA anti-BSA, AOPP, MAdCAM-1, NGAL, hsCRP, PDGF-BB, PDGF-DD, mannose binding lectin levels, 25-hydroxycholesterol levels and non-standard complement assays

Timepoint(s) of evaluation of this end point: Secondary efficacy endpoints will be evaluated at 9 to 12 months.
Tertiary efficacy endpoints will be evaluated from 1 to 12 months depending of the test.
Exploratory efficacy endpoints at 9 and 12 months.

Secondary ID(s)

Nef-202

NCT01738035

Source(s) of Monetary Support

Pharmalink AB