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    Summary
    EudraCT Number:2017-004902-16
    Sponsor's Protocol Code Number:Nef-301
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-13
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2017-004902-16
    A.3Full title of the trial
    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).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study in which the safety and efficacy of Nefecon is compared with placebo in patients with primary IgA Nephropathy.
    A.4.1Sponsor's protocol code numberNef-301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCalliditas Therapeutics AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCalliditas Therapeutics AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCalliditas Therapeutics AB
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressKungsbron 1
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code111 64
    B.5.3.4CountrySweden
    B.5.4Telephone number4676394 98 72
    B.5.6E-mailfredrik.juhlin@calliditas.se
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/139/16 (EMA/COMP/513517/2016)
    D.3 Description of the IMP
    D.3.1Product nameNefecon
    D.3.2Product code Nefecon
    D.3.4Pharmaceutical form Modified-release capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUDESONIDE
    D.3.9.1CAS number 51333-22-3
    D.3.9.3Other descriptive nameNefecon
    D.3.9.4EV Substance CodeSUB05955MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboModified-release capsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary IgA nephropathy patients at risk of developing end stage renal disease
    E.1.1.1Medical condition in easily understood language
    Patients with kidney diseases that have damage to the kidneys associated with Immunoglobulin A
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10069341
    E.1.2Term Berger's disease
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 the Treatment Period and the 3-month Follow-up Period in Part A of the study (contraception only required for women of childbearing potential [WOCBP]); Highly-effective methods of contraception are defined as those that achieve a low failure rate (<1% per year) when used consistently and correctly. Such methods include the use of combined (estrogen and progesterone) hormonal contraceptives (oral, intravaginal, or transdermal), progesterone-only hormonal contraceptives (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence; WOCBP are defined as women who are not surgically or chemically sterilized, including hysterectomy or bilateral oophorectomy (tubal ligation is not acceptable), and who are between menarche and 1 year post-menopause; and Postmenopausal is defined as amenorrhoeic for at least 1 year AND, if aged under 60 years have a serum follicle-stimulating hormone (FSH) level of at least 30 IU/L. Women who are taking hormone replacement therapy (HRT) do not have to have FSH assessments, but the amenorrhea (before starting HRT) must have been naturally (spontaneously) occurring and have been accompanied by an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms); or Staff involved in the conduct of the study.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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)
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints are described within the text in section E.5.1.1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belarus
    Canada
    China
    Korea, Republic of
    Taiwan
    Turkey
    United States
    Belgium
    Finland
    France
    Germany
    Greece
    Italy
    Poland
    Spain
    Sweden
    United Kingdom
    Czechia
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last subject's last
    visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 328
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    F.4.2.2In the whole clinical trial 360
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-06-05
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