A study in which the safety and efficacy of Nefecon is compared with placebo in patients with primary IgA Nephropathy.

• Register: EUCTR
• Last refreshed on: 9 October 2023
• Main ID: EUCTR2017-004902-16-SE
• Date of registration: 13/02/2018
• Prospective Registration: Yes
• Primary sponsor: Calliditas Therapeutics AB
• Public title: A study in which the safety and efficacy of Nefecon is compared with placebo in patients with primary IgA Nephropathy.
• Scientific title: A Randomized, Double-Blind, Placebo Controlled Study to Evaluate Efficacy and Safety of Nefecon in Patients with Primary IgA Nephropathy at Risk of Progressing to End-Stage Renal Disease (NefIgArd).
• Date of first enrolment: 28/03/2018
• Target sample size: 360
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004902-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belarus, Belgium, Canada, China, Czech Republic, Czechia, Finland, France, Germany, Greece, Italy, Korea, Republic of, Poland, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Clinical Operations
• Affiliation: Calliditas Therapeutics AB

• Name: Clinical Operations
• Affiliation: Calliditas Therapeutics AB

Key inclusion & exclusion criteria

Inclusion criteria:
Patients must meet all of the following inclusion criteria at screening to be eligible for admission into the study:
1. Female or male patients =18 years of age;
2. Diagnosed IgAN with biopsy verification within the past 10 years;
3. On a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) at the maximum allowed dose or MTD according to the 2012 KDIGO guidelines for the 3 months prior to randomization (see Appendix D). In this instance, a stable dose is defined as doses within 25% of the dose at randomization. Patients on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) below the maximum allowed dose or MTD according to the 2012 KDIGO guidelines will be permitted into the study if an attempt to reach the maximum allowed dose or MTD has been performed21 or if such attempt is deemed unsafe for the patient by the Investigator; and
Note: It is recommended that patients achieve a target systolic blood pressure <125 mmHg and target diastolic blood pressure <75 mmHg according to the 2012 KDIGO guidelines.
4. Willing and able to provide written informed consent at screening.
In addition, patients must meet the following inclusion criteria before randomization into the study:
5. Proteinuria based on 2 consecutive measurements (24-hour urine sampling) after informed consent, separated by at least 2 weeks and calculated by the central laboratory. Both samples of the same parameter must show either of the following:
o Proteinuria =1 g per day (=1000 mg per day) in 2 consecutive measurements, or
o UPCR =0.8 g/gram (=90 mg/mmol) in 2 consecutive measurements; and
6. eGFR =35 mL/min per 1.73 m2 and =90 mL/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, confirmed by the central laboratory at Study Visit 1 or Study Visit 3.

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 328
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 32

Exclusion criteria:
Systemic diseases that may cause mesangial IgA deposition including, but not limited to, Henoch Schönlein purpura, systemic lupus erythematosus, dermatitis herpetiformis, and ankylosing spondylitis; Patients who have undergone a kidney transplant;Patients with presence of other glomerulopathies (e.g.C3 glomerulopathy and/or diabetes nephropathy) and with nephrotic syndrome (i.e.proteinuria >3.5 g per day and with serum albumin <3.0 g/dL, with or without edema); Patients with acute, chronic or latent infectious disease including hepatitis, tuberculosis, human immunodeficiency virus , and chronic urinary tract infections; Patients with liver cirrhosis, as assessed by the Investigator; Patients with a diagnosis of type 1 or type 2 diabetes mellitus which is poorly controlled (defined as hemoglobin A1c [HbA1c] >8% [64 mmol/mol]); Patients with history of unstable angina, class III or IV congestive heart failure, and/or clinically significant arrhythmia, as judged by the Investigator; Patients with unacceptable blood pressure control defined as a blood pressure consistently above national guidelines for proteinuric renal disease, as assessed by the Investigator. Patients with =140 mmHg systolic blood pressure or =90 mmHg diastolic blood pressure are not eligible. At least one blood pressure measurement at either Study Visit 1 or Study Visit 3 should be within these limits (based on up to 3 measurements, measured 1 minute apart, after resting in the supine position for at least 5 minutes); Patients with diagnosed malignancy within the past 5 years, except for treated basal cell carcinoma of the skin, curatively resected squamous cell carcinoma of the skin, colon polyps, or cervical carcinoma in situ; Patients with known osteoporosis in medium- or high-risk category according to the 2010 American College of Rheumatology recommendations. For patients in China, the medium- or high-risk category is defined according to the Osteoporosis Self Assessment Tool for Asians (OSTA) index; Patients with known glaucoma, known cataract(s), and/or history of cataract surgery, unless the surgery was performed on both eyes; Gastrointestinal disorders (e.g., peptic ulcer disease, inflammatory bowel disease, and chronic diarrhea) that may interfere with the effects or release of the study drug; Patients with hypersensitivity to budesonide or any component of the study drug formulation; Patients with previous severe adverse reactions to steroids, at the discretion of the Investigator, including psychotic symptoms; Patients who have been treated with systemic immunosuppressive medications, other than GCSs, within the 12 months before randomization; Patients who have been treated with any systemic GCSs within the 3 months before randomization; Patients who have been treated with any systemic GCSs within the 12 months before randomization except for a maximum of 3 periods of 2 weeks with the equivalent of 0.5 mg/kg/day prednisolone or less for non-IgAN indications; Patients taking potent inhibitors of cytochrome P450 3A4 (CYP3A4);Current or prior (within the past 2 years) alcohol or drug abuse; Intake of an investigational drug within 30 days and at least 5 half-lives before randomization; Patients unwilling or unable to meet the requirements of the protocol; Other medical or social reasons for exclusion at the discretion of the Investigator; Life expectancy <5 years; Females who are pregnant, breastfeeding, or unwilling to use highly-effective contraception during

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

Health Condition(s) or Problem(s) studied

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

Primary IgA nephropathy patients at risk of developing end stage renal disease
MedDRA version: 20.0 Level: LLT Classification code 10069341 Term: Berger's disease System Organ Class: 100000004857

Intervention(s)

Product Name: Nefecon
Product Code: Nefecon
Pharmaceutical Form: Modified-release capsule, hard
INN or Proposed INN: BUDESONIDE
CAS Number: 51333-22-3
Other descriptive name: Nefecon
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)

Timepoint(s) of evaluation of this end point: The data cut-off for the Part A analysis will occur once the first 201 patients randomized have had the opportunity to complete their 9-month visit. Therefore it is expected the data-cut off will occur at the latest 9,5 months after the 201st patient randomized closed.
Supportive analyses of the above endpoints will also be performed at other time points up to 12 months to describe the time course of effect.
The Part B analysis will be performed when the 360th/last patient randomized has had the opportunity to complete Visit 17b, which can occur up to 35 days after Visit 17a (the 24 month visit)

Main Objective: Part A:
The primary objective of Part A is to assess the effect of Nefecon 16 mg treatment on urine protein to creatinine ratio (UPCR) over 9 months compared to placebo.
Part B:
The primary objective of Part B is to assess the effect of the Nefecon 16 mg treatment given in Part A on clinical consequences of any proteinuria reduction as measured by estimated glomerular filtration rate (eGFR) recorded over 2 years compared to placebo.

Primary end point(s): The primary efficacy endpoint for the Part A analysis is defined as the ratio of UPCR (based on 24 hour urine collections) at 9 months following the first dose of study drug compared to baseline.
The primary efficacy endpoint for the Part B analysis is an area under the curve (AUC)-based endpoint of eGFR calculated as a time-weighted average of eGFR recordings observed at each time point over 2 years.
The eGFR (CKD EPI) at 2 years (which must be repeated to provide by a second value obtained within 14 to 35 days) will be the geometric mean of the 2 assessments. A supportive analysis of 2-year eGFR slope will also be performed.

Secondary Objective: Part A:
The secondary objectives of Part A are:
• To assess the effect of Nefecon 16 mg treatment on eGFR at 9 and 12 months compared to placebo, and
• To evaluate additional aspects of renal function, and safety and tolerability of Nefecon 16 mg treatment over 9 months compared to placebo.
Part B:
The secondary objectives of Part B are to assess the effects of the Nefecon 16 mg treatment given in Part A on different aspects of renal function and safety compared to placebo over 2 years.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Timepoints are described within the text in section E.5.1.1

Secondary end point(s): The secondary efficacy endpoints for the Part A analysis are:
• Ratio of eGFR at 9 and 12 months compared to baseline calculated using the CKD-EPI formula, and
Note: A supportive analysis of 1 -year eGFR slope will also be performed
• Ratio of urine albumin to creatinine ratio (UACR) at 9 months compared to baseline.

The secondary efficacy endpoints for the Part B analysis are:
• Time to 30% reduction from baseline in eGFR (CKD-EPI) confirmed by a second value, with 4 weeks of separation between the 2 sampling time
points;
• Time from the first dose of study drug until receiving rescue medication;
• Ratio of UPCR, UACR, and eGFR (CKD-EPI) compared to baseline averaged over time points between 12 and 24 months, inclusive, following the first dose of study drug;
• Proportion of patients without microhematuria in at least 2 of the following time points: 12, 18, and 24 months following the first dose of study drug;
• Proportion of patients receiving rescue treatment; and
• Short Form 36 (SF-36) quality of life assessment at 9 and 24 months.

Secondary ID(s)

2017-004902-16-CZ

Nef-301

Source(s) of Monetary Support

Calliditas Therapeutics AB

Ethics review

Status: Approved
Approval date: 21/03/2018
Contact: