Clinical trial NCT05834738: Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy
Official title: A Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy on Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: IgA Nephropathy
Immunoglobulin A Nephropathy
Keywords: Kidney Diseases
Kidney Disease, Chronic
Urologic Diseases
Glomerulonephritis
Glomerular Disease
Glomerulonephritis, IGA
Glomerulopathy
Immunoglobulin Disease
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-04-28
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The ASSIST study is a phase 2, double-blind, placebo-controlled crossover study to evaluate the safety and efficacy of atrasentan vs. placebo in subjects with IgA nephropathy (IgAN) while on background standard of care therapy and an SGLT2 inhibitor (SGLT2i).

Detailed description: Approximately 52 patients with biopsy-proven IgAN who are on a background SGLT2i and a maximally tolerated and stable dose of a renin-angiotensin system inhibitor (RASi) \[such as angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor antagonist (ARB)\] as part of standard of care, will be randomized to either sequence AB or sequence BA in which they will receive 0.75 mg atrasentan once daily during one period (period A), complete a 12-week washout period, and then receive matching placebo during the other period (period B) as determined by the randomization schema.

Subjects who are not on background SGLT2i therapy must be willing to undergo a run-in period of 8 weeks with an SGLT2i with a 24-hour total urine protein of \> 0.85 grams/day at screening prior to the run-in period and have 24-hour total urine protein of \> 0.5 grams/day at the end of the run-in period to be eligible for randomization.

Subjects will remain on their maximally tolerated and stable dose of RASi and stable dose of SGLT2i therapies for the duration of the study following randomization.

The primary objective of the study is to evaluate the efficacy of atrasentan vs. placebo while on background therapy with SGLT2i.

Subjects will have safety and efficacy assessments for 1 year (52 weeks).

Eligibility criteria: Inclusion Criteria:

* Legal adults (per local and country specifications) ≥ 18 years of age at the time of signing the informed consent form (ICF) prior to initiation of any study specific activities/procedures.
* Biopsy-proven IgA nephropathy.
* Receiving a maximally tolerated and stable dose of a RASi for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and optimized dose.
* eGFR of at least 30 mL/min/1.73 m\^2 at screening based on the 2021 CKD-EPI equation.
* Willing to agree to highly effective forms of contraception, as specified in the protocol, throughout the study and for up to 1 month afterward. In WOCBP, use of hormonal contraceptive agents must have been started at least 1 month prior to baseline.
* Willing and able to provide informed consent and comply with all study requirements.
* Inclusion Criteria for SGLT2i stable subjects

  * Receiving a stable dose of an SGLT2i for at least 8 weeks prior to screening
  * Must have a 24-hour urine protein of \>0.5 grams/day.
* Inclusion Criteria for Run-In Subjects

  * Must have a 24-hour total urine protein of \>0.85 grams/day at screening
  * Willing to participate in an 8-week run-in period with an SGLT2i (per Investigator choice)
* Additional Inclusion Criteria for Run-in Subjects at the end of Run-In

  * Must have completed the 8-week run-in period on a stable and well tolerated dose of an SGLT2i
  * Must have a 24-hour total urine protein of \>0.5 grams/day confirmed at the Run-in Week 8 visit.
  * Must have an eGFR of ≥ 30 mL/min/1.73 m\^2 based on the CKD-EPI equation at their Run-in Week 8 visit.

Exclusion Criteria:

* Current diagnosis with another chronic kidney disease, including diabetic kidney disease.
* History of kidney transplantation or other organ transplantation.
* Use of systemic immunosuppressant medications, such as steroids, for more than 2 weeks in the past 3 months.
* Blood pressure above 150 mmHg systolic or 95 mmHg diastolic as evaluated by the Investigator.
* Known history of heart failure or prior hospital admissions for conditions relating to fluid overload that in the opinion of the Principal Investigator or Sponsor might confound the results of the study or pose additional risk to the participant by their participation in the study.
* Clinically significant history of liver disease as assessed by the Investigator.
* Hemoglobin below 9 g/dL as measured by the Investigator or prior history of blood transfusion for anemia within the past 3 months.
* Malignancy within the past 5 years. Exceptions to this criteria include nonmelanoma skin cancer and curatively treated cervical carcinoma in situ.
* For women, pregnancy, breast feeding, or intent to become pregnant during the study. and at least 1 month afterward.
* For men, intent to father a child or donate sperm during the study.
* Have received any investigational agent or approved treatment for IgAN (other than a 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.

Primary outcomes:
measure: Change From Baseline in Proteinuria at Week 12 in Both Treatment Periods 1 and 2
timeFrame: Baseline and 12 weeks or approximately 3 months
Secondary outcomes:
measure: Change From Baseline in Proteinuria at Week 24 in Treatment Periods 2
timeFrame: Baseline and 24 weeks or approximately 6 months
measure: Number of Subjects With Adverse Events (AEs)
timeFrame: From informed consent until end of study, approximately 60 weeks
measure: Plasma Concentration of Atrasentan
timeFrame: Treatment Period 1: Pre-dose on Weeks 2, 6 and 12; Treatment Period 2: Pre-dose on Weeks 2, 6, 12 and 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (UAB) - The Kirklin Clinic (TKC) - Nephrology Clinic
state: Alabama
city: Atlanta
country: United States
facility: Fides Clinical Research
state: Georgia
city: Oak Brook
country: United States
facility: NANI Research
state: Illinois
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill - Nephrology and Hypertension
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Kogarah
country: Australia
facility: The St. George Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: Monash Health- Monash Medical Centre
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Belo Horizonte
country: Brazil
facility: NUPEC Cardio
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Universidade Federal de Sao Paulo
state: Sao Paulo
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da USP
state: Sao Paulo
city: Cheonan
country: Korea, Republic of
facility: Soon Chun Hyang Central Medical Center (SCHMC) - Soon Chun Hyang University Hospital
state: Chungnam-Do
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Dong-A University Medical Center (Dong-A University Hospital)
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University College
city: Johor Bahru
country: Malaysia
facility: Hopsital Sultanah Aminah Johor Bharu (HSAJB) - Bangunan Bakawali Heodialysis Centre
state: Johor Darul Takzim
city: Cheras
country: Malaysia
facility: Universiti Kebangsaan Malaysia (UKM) - Medical Centre (Pusat Perubatan) (Hospital Canselor Tuanku Muhriz (HCTM))
state: Kuala Lumpur
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun (HRPB)
state: Perak
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Almería
country: Spain
facility: Hospital Torrecardenas
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital del Vall d´Hebron
city: Lugo
country: Spain
facility: Hospital Ribera Polusa
city: Madrid
country: Spain
facility: Hospital Universitario De Getafe (HUG)
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena
city: Valencia
country: Spain
facility: Hospital Clinico Universitario
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: