A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients with IgA Nephropathy at Risk of Progressive Loss of Renal Function (The ALIGN Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

19 May 2021 → ongoing

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-513227-16-00

EudraCT number

2020-003084-26

ClinicalTrials.gov

NCT04573478

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the effect of atrasentan versus placebo on proteinuria
Open Label Extension: to futher characterize the safety of atrasentan

Secondary objectives 4

1. To evaluate the effect of atrasentan versus placebo in estimated glomerular filtration rate (eGFR)
2. Additional efficacy outcomes
3. Open Label Extension: to evaluate the effect of atrasentan on proteinuria (endpoint of change in UPRC based on 24-hour urine collection from OL baseline to OLE Week 36
4. Open Label Extension: to evaluate the effect of atrasentan on eGFR

Conditions and MedDRA coding

Immunoglobulin A Nephropathy (IgAN)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male and female subjects aged 18 and older at the time of signing the ICF prior to initiation of any study specific activities/procedures.
2. Biopsy-proven IgAN that, in the opinion of the Investigator, is not due to secondary causes. Biopsy could have occurred at any point in time prior to study. A diagnostic report must be available for review by the Sponsor or designee.
3. Receiving a maximally tolerated and optimized dose of a RAS inhibitor that has been stable for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and optimized dose. Subjects who are intolerant to RAS inhibitors are eligible but will not exceed ~5% of total population randomized (applicable only to non- SGLT2i stratum)
4. Total urine protein ≥1 g/day as measured via 24-hour urine collection at a central laboratory collected at screening.
5. eGFR of at least 30 mL/min/1.73 m2 at screening based on the CKDXML File Identifier: NPqJMh0cM61lInVTZ7wGR8FZHeo= Page 10/23 EPI equation.
6. All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of hormonal contraceptive agents must have been started at least 1 month prior to Baseline.
7. Willing and able to provide written informed consent and comply with all study visits and study procedures.
8. SGLT2i Stable Stratum Only - Receiving a stable dose of an SGLT2i (per Investigator choice) in addition to a maximally tolerated and optimized dose of a RAS inhibitor that have been stable for at least 12 weeks prior to Screening
9. Open Label Extension - Subjects who provided written informed consent for OL extension prior to initiation of any OL-specific activities/procedures and are willing to comply with all study visits and study procedures.
10. Open Label Extension - Subjects from the double-blind portion of study who have completed treatment throguh Week 132 and completed the Week 136 visit. Note: Subjects who were randomized to the non-SGLT2i stratum in the double-blind portion of the study may start SGLT2i during the OL extension
11. Open Label Extension - Subjects entering the OL extension must enroll and have their OLBaseline visit within 14 days of Week 136 (OL Screening visit). Note: If enrollment in the OL extension was not possible due to administrative delays, patients who have completed the EOS visit in the double-blind portion of the study may be able to enroll in the open-label extension if less than 90 days have passed since their EOS visit after approval by Sponsor's Medical Monitor. If enrollment in the OL extension is > 30 days after Week 136, the patient must repeat the Week 136 laboratory assessments to confirm eligibility.
12. Open Label Extension - All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of contraceptive agents must have been continued after completing the double-blind portion of the study.

Exclusion criteria 18

1. Concurrent diagnosis of another cause of chronic kidney disease including diabetic kidney disease or another primary glomerulopathy.
2. Hemoglobin below 9 g/dL at screening or prior history of blood transfusion for anemia within 3 months of screening.
3. History of malignancy unless cancer free for at least 5 years or nonmelanoma skin cancer not requiring ongoing treatment. A subject with curatively treated cervical carcinoma in situ is eligible for this study.
4. Pregnancy, breast feeding, or intent to become pregnant during the study period and at least 1 month afterward for females.
5. Intent to father a child or donate sperm during the study period and at least 1 month afterward for males.
6. Have received any investigational agent or approved treatment for IgAN (other than RAS inhibitor) including SGLT2i (except for subjects in the SGLT2i stable stratum) within 1 month (or 5 half-lives of the agent, whichever is longer) prior to screening. If the investigational agent is a cytotoxic or immunosuppressive agent then this washout period is 6 months
7. Concurrent clinically significant, unstable, or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the Investigator or Sponsor's Medical Monitor (or designee), might confound the results of the study or pose additional risk to the subject by their participation in the study.
8. Refer to Sections 6.10.1 and 6.10.2 for details regarding prohibited and restricted medications, respectively.
9. Open Label Extension - Plan to receive any investigational agent (other than atrasentan) or approved treatment for IgAN (other than a RAS inhibitor or SGLT2i). Other ETA receptor antagonists will not be allowed during OL extension. Additional exclusion criteria included in the study protocol under Appendix 6, Section 3.2
10. Clinical suspicion of rapidly progressive glomerulonephritis (RPGN) based on KDIGO guidelines or clinical suspicion of Henoch-Schonlein Purpura (IgA vasculitis).
11. Clinical diagnosis of nephrotic syndrome.
12. BNP value of > 200 pg/mL at screening.
13. Platelet count <80,000 per μL at screening.
14. History of organ transplantation (subjects with history of corneal transplant are not excluded).
15. Use of systemic immunosuppressant medications including, systemic corticosteroids (e.g. prednisone, prednisolone, nefecon, etc.), mycophenolate, azathioprine, cyclosporine, tacrolimus, etc.; use of herbs such as Tripterygium Wilfordii Hook F, Caulis sinomenii and Sinomenium acutum; for > 2 weeks in the past 3 months. Use of rituximab within the past 6 months.
16. Confirmed blood pressure >150 mmHg systolic or >95 mmHg diastolic based on a mean of 3 measurements obtained at screening.
17. Known history of heart failure or conditions relating to fluid overload such as pulmonary edema, uncontrolled peripheral edema, pleural effusion, or ascites.
18. History of an alcohol or illicit drug-related disorder within the past 3 years.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The change in proteinuria (urine protein:creatinine ratio [UPCR] based on 24-hour urine collection) from baseline to Week 36 (non-SGLT2i stratum).

Secondary endpoints 5

1. Change from baseline to final study visit (Week 136, 4 weeks post end of treatment) in eGFR, using the chronic kidney disease-epidemiology collaboration (CKD-EPI) creatinine equation (non-SGLT2i stratum)
2. Percent of subjects meeting the composite endpoint of experiencing at least one of the following during the study (non-SGLT2i stratum): 1) At least a 30% reduction in eGFR sustained for at least 30 days, 2) eGFR <15 mL/min/1.73m2, sustained for at least 30 days, 3) Chronic dialysis, ≥30 days, 4) Kidney transplantation, 5) All-cause mortality
3. Percent of subjects achieving reduction of proteinuria to < 1 g/day at Week 36 and a 25% decrease in total urine protein from Baseline (non-SGLT2i stratum).
4. Open Label Extension: Change from OL Baseline to OL Week 36 in UPCR based on 24-hour urine collection
5. Open Label Extension: Change from OL Baseline to OL Week 52 in eGFR, using the chronic kidney disease-epidemiology collaboration (CKD-EPI) creatinine equation

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Katharina Boehm

Public contact point

Organisation

Novartis Pharma AG

Contact name

Katharina Boehm

Third parties 8

Locations

6 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 63 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications