| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunoglobulin A (IgA) Nephropathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| A kidney disease that occurs when antibody deposits build up in the kidneys |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021263 |
| E.1.2 | Term | IgA nephropathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 |
Primary Safety Objective
To evaluate the safety and tolerability of monthly doses of VIS649 at each of 3 dosing levels, administered IV to IgAN participants over the course of 12 months as an add-on to SOC treatment with ACEI/ARB therapy, compared with saline placebo infusions as an add-on to SOC treatment with ACEI/ARB therapy
Primary Efficacy Objective
To evaluate the dose response of monthly doses of VIS649 on proteinuria at each of 3 dosing levels, administered IV to IgAN participants over the course of 12 months as an add-on to SOC treatment with ACEI/ARB herapy, compared with saline placebo infusions as an add-on to SOC treatment with ACEI/ARB therapy |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of repeated doses of VIS649 at 3 dosing levels versus placebo on the following parameters:
- uPCR at Months 9 and 15 (ie, 4 months following the final [12th] monthly dose administration)
- 24-hour urine protein excretion at Months 9, 12, and 15
- ≥ 30% decline from baseline in uPCR at Months 9, 12, and 15.
- Clinical remission, defined as reduction in 24-hour urine protein excretion to < 300 mg/day for at least 3 consecutive months
2. eGFR at Months 12 and 15
3.To evaluate the effect of repeated doses of VIS649 at each dosing level compared with placebo on the following PD parameters: IgA,
IgG, and IgM concentrations
4. To determine the PK profile of repeated dose of VIS649, at each dosing level
5. To determine the PK/PD profile of VIS649, relating VIS649 PK parameters and biomarkers such as changes in IgA to changes in proteinuria and eGFR
6. To screen for ADA responses |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant is a male or female ≥ 18 years of age at the time of signing the informed consent.
2. Participant has biopsy-confirmed IgAN.
3. Participant has medical records showing they have been on stable and maximally tolerated doses of either ACEI or ARB, as per SOC and applicable guidelines, for at least 3 months preceding screening. Participants should be on at least 50% of the maximum recommended dose of these agents to be considered as having adequate RAAS blockade.
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in the study if their overall management of IgAN, including BP control, is as per SOC and applicable guidelines.
4. Participant has screening uPCR ≥ 0.75 g/g measured from a 24-hour urine (or an intended 24-hour urine sample) or 24-hour urine protein ≥ 1.0 g/d, as measured from 24-hour urine collection (or an intended 24-hour urine sample). The proteinuria should be stable, defined as < 25% change when compared to values from ≥ 3 months previously (if
available).
• If previous values are not available or if the change from a prior value is > 25%, a repeat measurement of proteinuria will be done after 15 days and the participant should fulfill the above proteinuria criteria to be eligible for randomization in the study.
• The proteinuria should be assessed when the participant is considered to be in a steady state with no recent heavy exercise, fever, or other potential issues that could impact the result.
5. Participant has eGFR ≥ 45 mL/min/1.73 m2, calculated using the CKD-EPI formula. The eGFR should be stable, as defined by a < 25% change when compared to values from ≥ 3 months previously (if available).
• If previous values are not available or if the change from a prior value is > 25%, a repeat measurement of eGFR will be done after 15 days and the participant should fulfill the eGFR criteria to be eligible for randomization in the study.
• The eGFR should be measured when the participant is considered to be in a steady state without recent changes in volume status, medications that could impact the result (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides, co-trimoxazole), or changes in dietary protein intake.
6. Participant’s serum Ig values must meet the following criteria :
• IgG: ≥ 700 mg/dL
• IgM: ≥ 40 mg/dL
• IgA: ≥ 70 mg/dL
7. Female participants of childbearing potential must have a negative serum pregnancy test prior to the first dose.
8. Participant is willing to adhere to contraceptive requirements outlined in Appendix 4.
9. Participant or a legally authorized representative is able to understand the purpose and risks of the study and is willing to give voluntary written informed consent as described in Appendix 1. |
|
| E.4 | Principal exclusion criteria |
1. Participant has secondary forms of IgAN as defined by the treating physician (eg, Henoch-Schonlein purpura, minimal change disease with IgA deposits, infection associated IgAN, or IgAN-associated with hepatic cirrhosis).
2. Participant has co-existing CKD, other than IgAN.
3. Participant has evidence of additional pathological findings in the kidney biopsy (eg, diabetic kidney disease, membranous nephropathy, or lupus nephritis). However, hypertensive vascular changes are acceptable.
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 from the Oxford IgAN classification schema. If MEST-scoring was not performed, the presence of > 50% tubulo-interstitial fibrosis or crescents in > 25% of glomeruli is exclusionary.
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour urine protein > 3.5 g with concurrent hypoalbuminemia (serum albumin < 2.5 g/dL), hyperlipidemia (total cholesterol > 350 mg/dL), and edema.
6. Participant has received a solid organ transplant, including kidney.
7. Participant has received bone marrow or hematologic stem cell transplantation.
8. Participant is currently receiving systemic immunosuppression (excluding topical, ophthalmic, per rectum, or inhaled corticosteroids).
9. Participant has received systemic steroids within the 24 weeks prior to initial screening.
10. Participant has received treatment with 2 or more systemic immunosuppressive agents within 2 years prior to initial screening.
11. Participant has chronic infectious diseases (eg, chronic urinary tract infection; chronic sinusitis; bronchiectasis; active pulmonary or systemic tuberculosis; chronic viral hepatitis, such as hepatitis C or hepatitis B; or human immunodeficiency virus infection).
12. Participant has acute infectious disease at the time of screening. Participants may be rescreened following resolution of acute infection (such as urinary tract infection or respiratory tract infection), provided there is no evidence of an immunosuppressive condition that predisposed the participant to this infection.
13. Participant has Type 1 diabetes.
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin A1c value > 8%.
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg diastolic), Systolic and diastolic BP should be assessed while the participant is seated or supine for at least 5 minutes in a quiet room without distractions. BP should be measured with a completely automated device. At least 3 readings should be taken and average values from these 3 readings should be calculated.
16. Participant has a history of chronic autoimmune neurodegenerative disorder such as multiple sclerosis.
17. Participant has a known allergy or intolerance to any component of the study intervention.
18. Participant has poorly compensated or controlled ischemic heart disease or cardiomyopathy, as judged by the Investigator.
19. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has required systemic steroid therapy during the prior year. If COPD is present, severity must not exceed Global Initiative for Chronic Obstructive Lung Disease 1 (mild), defined as a forced 1-second expiratory volume (FEV1) > 80% of predicted.
20. Participant has known cirrhosis or liver dysfunction, defined as presence of coagulopathy, platelet count < 100,000/μL or alanine aminotransferase > 3× upper limit of normal.
21. Participant has active malignancy or is receiving chemotherapy for malignancy, except for nonmelanoma skin cancers and cervical carcinoma in situ. Participants with prior malignancy who have been documented to be cancer-free for ≥ 5 years may be enrolled.
22. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is acceptable (if greater than 6 months prior to screening).
23. Participant enrolled in another investigational drug or device study within 3 months prior to initial screening.
24. Participant with a pre-existing illness other than those listed above that, in the opinion of the Investigator, would place the participant at increased risk through participation in this study.
25. Participant is unable to comply with study protocol procedures and/or study visit schedules.
26. Participant with known or suspected alcohol or drug abuse that would compromise their safety or study participation, in the opinion of the Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Safety Endpoint:
- AEs graded by severity, clinical laboratory tests, vital sign measurements, and physical examinations
Primary Efficacy Endpoint
- Change from baseline in uPCR (measured on natural log scale from 24-hour urine collection or the intended 24-hour urine collection) at Month 12 (ie, approximately 30 days after the twelfth dose is administered) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to Month 12 |
|
| E.5.2 | Secondary end point(s) |
1) Change from baseline in uPCR (measured on natural log scale from 24-hour urine collection or the intended 24-hour urine collection) at Months 9 and 15
2) Change in 24-hour urine protein excretion from baseline to Months 9, 12, and 15
3) Number of participants in each group achieving a ≥ 30% decline from baseline in uPCR at Months 9, 12, and 15
4) Number of participants in each group achieving clinical remission
5) Change from baseline in eGFR at Months 12 and 15
6) Change from baseline in total serum IgA, IgG, and IgM concentrations at Months 9, 12, and 15
7) Serum PK parameters
8) Correlation of VIS649 PK parameters with changes in IgA, uPCR, and eGFR
9) Serum ADA levels |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From baseline to Months 9 and 15
2), 3) and 6) From baseline to Months 9, 12, and 15
4) Duration of study
5) At months 12 and 15
7), 8) and 9) refer to schedule of events |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Australia |
| Canada |
| Czech Republic |
| Hong Kong |
| India |
| Japan |
| Korea, Republic of |
| Malaysia |
| Philippines |
| Singapore |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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