E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Immunoglobulin A nephropathy (IgAN) |
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E.1.1.1 | Medical condition in easily understood language |
IgA nephropathy, also known as Berger’s disease, is a kidney disease that occurs when IgA deposits build up in the kidneys, causing inflammation that damages kidney tissues. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of cemdisiran on proteinuria in adult patients with immunoglobulin A nephropathy (IgAN) |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of cemdisiran on additional measures of proteinuria in adult patients with IgAN 2. To evaluate the effect of cemdisiran on hematuria in adult patients with IgAN 3. To evaluate the safety and tolerability of cemdisiran
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent 2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within 60 months of Screening 3. Treated for IgAN with stable, optimal pharmacological therapy. In general, stable and optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB for at least 3 months prior to start of run-in period 4. Urine protein ≥1 g/24-hour at Screening from a valid 24-hour urine collection (see Section 6.4.1.1), and mean urine protein ≥1 g/24-hour from two valid 24-hour urine collections at the end of the run-in period, prior to randomization 5. Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) by microscopy or a positive urine dipstick (2+ [moderate] and above) measured by a central laboratory at Screening 6. Females of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception 14 days before first dose, throughout study participation, and for 90 days after last dose administration 7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine or willingness to receive these vaccinations as well as prophylactic antibiotic treatment if required by local standard of care 8. Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus pneumoniae according to current national/local vaccination guidelines for vaccination use 9. Patient is willing and able to provide written informed consent and to comply with the study requirements
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E.4 | Principal exclusion criteria |
1. Concomitant significant renal disease other than IgAN 2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% over the duration of the run-in phase 3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease) 4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) 5. eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results may be used for assessment of eligibility) 6. Has any of the following laboratory parameter assessments: a. Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin >1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome) 7. Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at Screening 8. Clinical laboratory test results considered clinically relevant and unacceptable in the opinion of the Investigator 9. Positive hepatitis B virus (HBV) surface antigen, HBV core antibody, hepatitis C virus (HCV) antibody (unless HCV viral load demonstrated negative) 10. Treatment with systemic steroids for more than 7 days or other immunosuppressant agents in the 6 months prior to randomization 11. Treatment with dual RAS blockade in the 3 months prior to entry into the run-in phase 12. Received an investigational agent within the last 30 days or 5 half-lives, whichever is longer, prior to the first dose of study drug, or are in follow-up of another clinical study prior to study enrollment 13. Known human immunodeficiency virus (HIV) infection, HCV infection or HBV infection 14. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years 15. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder, or severe depression despite current pharmacological intervention 16. Known medical history or evidence of chronic liver disease or cirrhosis 17. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation 18. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc 19. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study drug administration or evaluation of local tolerability 20. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) required for this study. Refer to the most recent local product information for each vaccine for the current list of contraindications 21. Unable to take antibiotics for meninigococcal prophylaxis, if required by local standard of care 22. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the run-in period, measured in supine position after 10 minutes of rest 23. Receipt of an organ transplant (including hematologic transplant) 24. History of meningococcal infection within 12 months before Screening 25. Patients with systemic bacterial or fungal infections, that require systemic treatment with antibiotics or antifungals 26. Patients with functional or anatomic asplenia 27. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine [125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL])
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from baseline in urine protein/creatinine ratio [UPCR] as measured in 24-hour urine at Week 32. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1-Percent change from baseline in 24-hour proteinuria (g/24-hours) at Week 32 2-Percent of patients with partial clinical remission (urine protein [UP] <1.0 g/24 hours) at Week 32 3-Percent of patients with >50% reduction in 24-hour proteinuria at Week 32 4-Change from baseline in UPCR as measured in a spot urine at Week 32 5-Change from baseline in hematuria at Week 32 6-Frequency of adverse events (AEs)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Malaysia |
Philippines |
Singapore |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |