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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy

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SLCTR Registration Number

SLCTR/2021/004


Date of Registration

21 Feb 2021

The date of last modification

Feb 21, 2021



Application Summary


Scientific Title of Trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy


Public Title of Trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy


Disease or Health Condition(s) Studied

Immunoglobulin A (IgA) Nephropathy


Scientific Acronym

IgAN


Public Acronym

IgAN


Brief title

None


Universal Trial Number

U1111-1263-1268


Any other number(s) assigned to the trial and issuing authority

ClinicalTrials.gov-NCT04287985 and P/138/11/2020:Faculty of Medicine, UoK


Trial Details


What is the research question being addressed?

‘Is VIS649 efficacious, safe and tolerable in participants with immunoglobulin A (IgA) nephropathy?’


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Double blinded


Control

Placebo


Assignment

Parallel


Purpose

Treatment


Study Phase

Phase 2


Intervention(s) planned

In Sri Lanka, this study will be conducted at the following centers • Sri Jayawardenapura General Hospital • National Hospital of Sri Lanka.

Randomization will be a stratified randomization. All eligible participants will be centrally assigned to randomized study intervention using an Interactive Voice/Web Response System (IVRS/IWRS). Participants will be randomly assigned in a 1:1:1:1 allocation ratio to receive VIS649 at 2, 4, or 8 mg/kg or placebo, with approximately 36 participants randomized to each intervention group.

VIS649 will be intravenously (IV) administered monthly over a 12-month treatment course in participants with IgAN. VIS649 will be administered as a mg/kg dosage determined by dose assigned at time of randomization. VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL infusion in normal saline (0.9% NaCl). Dosage frequency is once a month for a period of 12 months.

Control group will be receiving normal saline (0.9% NaCl) IV infusion which will be administered over 1 hour as a single 100 mL infusion, once a month over a 12 month treatment course.

Both groups will receive standard of care treatment with ACEI (angiotensin-converting enzyme inhibitor) /ARB (angiotensin receptor blocker) therapy.


Inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply: 1. Participant is a male or female greater than or equal 18 years of age at the time of signing the informed consent.

  1. Participant has biopsy-confirmed IgAN.

  2. 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.

  3. Participant has screening uPCR greater than or equal to 0.75 g/g measured from a 24-hour urine (or an intended 24-hour urine sample) or 24-hour urine protein greater than or equal to 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 greater than or equal to 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.

  1. Participant has eGFR greater than or equal to 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 greater than or equal to 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: greater than or equal 700 mg/dL •IgM: greater than or equal 40 mg/dL •IgA: greater than or equal 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 specified.


Exclusion criteria

Participants are excluded from the study if they meet any of the following 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 OxfordIgAN 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; chronicsinusitis; bronchiectasis; active pulmonary or systemic tuberculosis; chronic viralhepatitis, such as hepatitis C or hepatitis B; or human immunodeficiency virus infection).

  1. Participant has acute infectious disease at the time of screening. Participants may be re-screened 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.

  2. Participant has Type 1 diabetes.

  3. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin A1c value > 8%.

  4. 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.

  5. Participant has a history of chronic autoimmune neurodegenerative disorder such as multiple sclerosis.

  6. Participant has a known allergy or intolerance to any component of the study intervention.

  7. Participant is breastfeeding.

  8. Participant has poorly compensated or controlled ischemic heart disease or cardiomyopathy, as judged by the Investigator.

  9. 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.

  10. Participant has known cirrhosis or liver dysfunction, defined as presence of coagulopathy, platelet count < 100,000/micro-litre or alanine aminotransferase > 3× upper limit of normal.

  11. 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 greater than or equal to 5 years may be enrolled.

  12. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is acceptable (if greater than 6 months prior to screening).

  13. Participant has enrolled in another investigational drug or device study within 3 months prior to initial screening.

  14. 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.

  15. Participant is unable to comply with study protocol procedures and/or study visit schedules.

  16. Participant with known or suspected alcohol or drug abuse that would compromise their safety or study participation, in the opinion of the Investigator.



Primary outcome(s)

1.

Significant difference among the three groups receiving three doses of the interventional drug on following parameter

  • Adverse events graded by severity, clinical laboratory tests, vital sign measurements, and physical examinations

A complete physical examination, including assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems will be completed at the screening, Month 12 visit, and Month 16 visits.

Vital signs include weight, temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure which will be taken at each visit (screening visit, month 0-16 visits)

Laboratory tests include: • Hepatitis B virus, Hepatitis C virus, HIV serology- at screening visit • Serum beta-human chorionic gonadotropin (females only)- at screening visit • Urine ?- beta-human chorionic gonadotropin (females only)- at month 0 (day 1 prior to IV infusion) and at month 1-12 visits, month 16 • Hemoglobin A1c- at screening visit • Serum chemistry- screening visit, at month 0 (day 1 prior to IV infusion) and at month 1-12 visits, month 16 • Hematology- screening visit, at month 0 (day 1 prior to IV infusion) and at month 1-12 visits, month 16 • Urinalysis (dipstick and microscopy)- screening visit, at month 0 (day 1 prior to IV infusion) and at month 1-12 visits, month 16 • 24-hour urine collection- screening visit, month 9,12 & 16 visit • Urine sample for uPCR determination- screening visit, at month 0 (day 1 prior to IV infusion) and at month 1-12 visits, month 16 • Blood sample for lymphocytes- at month 0 (day 1 prior to IV infusion), month 6, 12 & 16 visit • Serum for PK13- month 0 (day 1 pre IV infusion, post IV infusion, day 8, 18, 30) visit, and at month 1-12 visits, month 16
• Blood for total IgA, IgG, and IgM- screening visit, month 0-16 visits • Blood for IgA subtypes- month 0 (day 1 pre IV infusion), month 3,6,9,12,16 visits • Serum for APRIL-month 0 (pre IV infusion & post IV infusion), month 1-12 visits and month 16 visit • Serum for a-g IgA and anti-IgA- screening visit, month 0 (pre IV infusion), month 3,6,9,12 & 16 visits • Serum for ADA (adenosine deaminase)- month 0 (pre IV infusion), month 1, 2 4,6,8,11, 12 & 16 visits

[

During the 16 month period

]
2.

Significant difference among the three groups receiving three doses of the interventional drug on following parameter

-The change in uPCR (Urine protein/creatinine ratio) against baseline measured on natural log scale from 24-hour urine collection or the intended 24-hour urine collection at month 12,

[

Approximately 30 days after the 12th dose is administered

]

Secondary outcome(s)

1.

Significant differences among interventional group and control group in the following parameter.

• The change in uPCR measured on natural log scale from 24-hour urine collection or the intended 24-hour urine collection

[

At months 9 and 16 (ie, 5 months following the final [12th] monthly dose administration)

]
2.

Significant differences among interventional group and control group in the following parameter.

  • The change in 24-hour urine protein excretion
[

At months 9, 12, and 16

]
3.

Significant differences among interventional group and control group in the following parameter.

•Number of participants in each group achieving greater than or equal to 30% decline from baseline in uPCR

[

At months 9, 12, and 16

]
4.

Significant differences among interventional group and control group in the following parameter.

•Number of participants in each group with clinical remission, defined as reduction in 24-hour urine protein excretion to < 300 mg/day for at least 3 consecutive months

[

During 12 months

]
5.

Significant differences among interventional group and control group in the following parameter.

The change from baseline eGFR

[

At months 12 and 16

]

Target number/sample size

144 (36 in a group)


Countries of recruitment

Aland Islands


Anticipated start date

2021-02-21


Anticipated end date

2021-03-31


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source

Visterra, Inc. 275 2nd Avenue Waltham,MA 02451,USA


Regulatory approvals

Pending



State of Ethics Review Approval


Status

Approved


Date of Approval

2021-01-08


Approval number

P/138/11/2020


Details of Ethics Review Committee

Name: Ethics- Review Committee, Faculty of Medicine, University of Kelaniya
Institutional Address:Ethics- Review Committee, Faculty of Medicine, University of Kelaniya
Telephone:011-2961267
Email: ercmed@kln.ac.lk

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr. C.A. Herath
Consultant Nephrologist
Department of Nephrology, Sri Jayawardenapura General Hospital, Thalapathpitiya, Nugegoda, Sri Lanka

0773017025

chulaherath@gmail.com

Contact Person for Public Queries

Dr. C.A. Herath
Consultant Nephrologist
Department of Nephrology, Sri Jayawardenapura General Hospital, Thalapathpitiya, Nugegoda, Sri Lanka

0773017025

chulaherath@gmail.com


Primary study sponsor/organization

Visterra, Inc.

275, 2nd Avenue Waltham, MA 02451, USA



Secondary study sponsor (If any)







Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description


Study protocol available

No


Protocol version and date

Not Available


Protocol URL

Not Available


Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results