A Study to Evaluate Setanaxib in Patients With Alport Syndrome

Alport Syndrome Clinical Trial

Official title:

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the NOX1/4 Inhibitor Setanaxib in Patients With Alport Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06274489
• Other study ID #: GSN000500
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 27, 2023
• Est. completion date: January 27, 2025

Study information

• Verified date: May 2024
• Source: Calliditas Therapeutics AB
• Contact: Maria Norling
• Phone: +46 76 496 2566
• Email: maria.norling[@]calliditas.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to learn about the safety and tolerability of setanaxib in subjects with Alport syndrome, when added to their standard of care treatment. The study will assess how safe setanaxib is when compared to placebo. Study participants will be asked if they are experiencing any side effects at each study visit. In addition, tests in blood, urine and other examinations will be used to look at the safety of setanaxib. The study will also measure how well setanaxib works in comparison to a placebo, by measuring urine protein and certain markers in the blood and urine. The concentration of setanaxib in the blood will also be measured throughout the course of the study.

Setanaxib is planned for use together with the current standard of care to hopefully provide additional therapeutic benefits by preserving kidney function.

The study will be conducted at multiple research sites in the UK, Spain, and Czech Republic. Eligible participants will be randomly assigned to receive either setanaxib or placebo. Setanaxib dose level will depend on age and all participants will receive their standard of care in addition to setanaxib or placebo. The study consists of a Screening period of up to 4 weeks, a 24-week Treatment period and a 4- week Follow-up period.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: January 27, 2025
• Est. primary completion date: January 27, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Male or female patients aged 12 to 40 years inclusive, at the time of informed consent/assent. For sites in the European Union: Male or female patients aged 18 to 40 years, inclusive, at the time of informed consent;

2. Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome [ie, COL4A3, COL4A4, or COL4A5]);

Note: Genetic test results are to be available prior to initiating other Screening procedures. In cases where genetic testing results are not available but the patient is likely to fulfill the other inclusion and exclusion criteria and has provided consent/assent, a sample for genetic testing should be processed locally and the Screening Period duration can be prolonged with the time it takes to receive the genetic test results. All other Screening assessments must be completed within 4 weeks prior to randomization.

3. Weight =40 kg;

4. Willing and able to give informed consent (and assent, where applicable), in accordance with local age requirements, and to comply with the requirements of the study;

5. Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for =4 weeks before randomization and must agree to continue strict contraception (as specified in 5c) up to 90 days after the last dose of investigational medicinal product (IMP);

1. For the purposes of this study, women of childbearing potential (WOCBP) are defined as "fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy";

2. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female patients who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle-stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state; and

3. Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods include the following:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal);

• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable);

• Intrauterine device;

• Intrauterine hormone-releasing system;

• Bilateral tubal occlusion;

• Vasectomized partner; and

• Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments, ie, up to 90 days after the last dose of IMP). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, or post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.

6. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline/Randomization before dosing;

7. Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method (as defined in the list in inclusion criterion 5c). Female condom and male condom should not be used together. This requirement begins at the time of informed consent/assent and ends 90 days after receiving the last dose of IMP;

8. Male patients must be willing not to donate sperm and female study patients must be willing not to donate eggs from baseline until 90 days after the last dose of IMP;

9. Estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 at Study Visit 1 or 2, calculated at the central laboratory using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for patients =18 years of age and the revised bedside Schwartz formula for patients 12 to 17 years of age;

10. Proteinuria (urine protein to creatinine ratio [UPCR] =90 mg/mmol [0.8 g/g]) at 2 consecutive measurements (24-hour urine sampling), separated by at least 2 weeks and calculated by the central laboratory;

11. Receiving maximum allowed dose or maximum-tolerated daily dose of an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II type I receptor blocker (ARB) that has been stable for at least 8 weeks prior to consent/assent; and Note: A stable dose is defined as doses within 25% of the dose at randomization.

Note: Sodium/glucose co-transporter 2 inhibitors are allowed provided they have been given at the same dose for at least 8 weeks prior to randomization and are given at the same dose during the study.

12. Systolic and diastolic blood pressure =95th percentile, based on the patient's age and weight for patients 12 to 17 years of age or with <130 mmHg systolic blood pressure or <80 mmHg diastolic blood pressure for patients =18 years of age. Note: For patients =18 years of age, at least 1 blood pressure measurement during Screening (Study Visit 1 or 2) should be within these limits. Blood pressure will be measured after resting in the supine position for at least 5 minutes and will be measured 3 times with each measurement separated by at least 1 minute (the lowest value will be recorded on the electronic case report form).

Exclusion Criteria:

1. Has ongoing chronic hemodialysis or peritoneal dialysis;

2. Has a history of kidney transplant;

3. Has other causes of chronic kidney disease (CKD) (even if not yet on hemodialysis), including but not limited to other heritable disorders leading to CKD, diabetic nephropathy, hypertensive nephropathy, lupus nephritis, and immunoglobulin A nephropathy;

4. Has been treated with any investigational agent within 12 weeks of signing informed consent/assent or 5 half-lives of the investigational agent (if known), whichever is longer, or current enrollment in an interventional clinical study;

5. Has had prior treatment with setanaxib;

6. Has known malignancy that is progressing or requires active treatment, with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, or malignancy treated with curative intent and with no known active disease =2 years before the first dose of study drug and of low potential risk for recurrence;

7. Positive urine drug screen (if not due to prescription use of a concomitant medication, as confirmed by the Investigator) at Screening. Patients on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not exclusionary and may be allowed if the prescription and diagnosis are reviewed and approved by the Investigator;

8. Has an active HIV infection or acute or chronic hepatitis B or C infection, confirmed at Screening;

9. Has had a surgery (eg, gastric bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator);

10. Has a positive pregnancy test at Study Visit 2 (Screening) and/or Study Visit 3 (Day 1) (WOCBP only) or is breastfeeding; Note: If a randomized patient has a positive pregnancy test at Study Visit 3 (Day 1), they will be considered a patient withdrawn for non-safety reasons.

11. Has evidence of any of the following cardiac conduction abnormalities at Screening or Day 1: a QTc Fridericia interval >450 milliseconds for male patients or >470 milliseconds for female patients, or a PR interval =220 milliseconds; Note: Patients with a second or third degree atrioventricular block are to be excluded.

12. Has a history of aplastic anemia, or any current marked anemia, defined as hemoglobin <10.0 g/dL;

13. Has thyroid-stimulating hormone greater than the upper limit of normal (ULN) at Screening;

14. Has any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a patient's treatment, assessment, or compliance with the Protocol and/or study procedures;

15. Has any other condition that, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the patient in the study, or that could interfere with the study objectives, conduct, or evaluation;

16. Uses medications known to be potent cytochrome P450 3A4 inhibitors (itraconazole, lopinavir/itonavir, telaprevir, clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, conivaptan, and voriconazole) or potent uridine 5'-diphospho-glucuronosyltransferase 1A9 inhibitors and inducers (mefenamic acid and rifampicin) within 21 days prior to study drug administration;

17. Has known psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent/assent;

18. Has known hypersensitivity or intolerance to setanaxib or to any of its excipients;

19. Has a history of chronic liver disease (eg, primary biliary cholangitis, alcoholic liver disease, chronic viral hepatitis including hepatitis B and C, non-alcoholic fatty liver disease, and hemochromatosis);

20. Has plasma alanine aminotransferase and/or aspartate aminotransferase >3 x ULN at Study Visit 1 or 2 (Screening);

21. Has total bilirubin >2 x ULN at Study Visit 1 or 2 (Screening); or

22. Has international normalized ratio >1.2 at Study Visit 1 or 2 (Screening) (criterion not applicable for patients on anticoagulant therapy).

Related Conditions & MeSH terms

• Alport Syndrome
• Nephritis, Hereditary
• Syndrome

Intervention

Drug:
• Setanaxib
Setanaxib (formerly GKT137831) is a first-in-class inhibitor of the human protein NADPH NOX1/4. It is a low molecular weight organic molecule and a member of the pyrazolopyridine dione chemical class.
• Placebo
Matching film-coated placebo tablets, containing only excipients

Locations

Country	Name	City	State
Czechia	Fakultni Nemocnice Hradec Kralove	Hradec Králové
Czechia	Fakultni Nemocnice Olomouc	Olomouc
Czechia	Institut Klinicke a Experimentalni Mediciny	Praha
Czechia	Vseobecna Fakultni Nemocnice v Praze	Praha
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Universitario 12 de Octubre	Madrid	Usera
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Nottingham City Hospital	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Calliditas Therapeutics AB

Countries where clinical trial is conducted

Czechia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of patients with clinically significant changes in heart rate	Clinically significant changes in heart rate from baseline by visit. Heart rate will be measured after resting in the supine position for at least 5 minutes and will be measured 3 times with each measurement separated by at least 1 minute (the lowest value will be recorded)	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Other	Percentage of patients with clinically significant changes blood pressure	Clinically significant changes in blood pressure from baseline by visit. Systolic and diastolic blood pressure will be measured after resting in the supine position for at least 5 minutes and will be measured 3 times with each measurement separated by at least 1 minute (the lowest value will be recorded)	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Other	Percentage of patients with clinically significant changes in 12-lead electrocardiogram (ECG)	Clinically significant changes in ECGs from baseline by visit. ECGs should be collected in triplicate, 1 to 3 minutes apart, and read locally	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Other	Percentage of patients with clinically significant changes in physical examination	Clinically significant changes in physical examinations from baseline by visit. Physical examinations will include general appearance, skin, head, ears, eyes, nose, throat, neck, lungs, heart, abdomen, musculoskeletal, extremities, and neurological systems	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Other	Percentage of patients with clinically significant changes in hematology, serum chemistry, urinalysis, and thyroid function	Clinically significant changes in hematology, serum chemistry, urinalysis, and thyroid function from baseline by visit	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Other	Percentage of patients with clinically significant changes in hearing audiometric testing (bone- and air-conduction)	Clinically significant changes in hearing audiometric testing from baseline by visit. Pure tone audiometry (PTA) air conduction thresholds will be conducted at frequencies 250, 500, 1000, 2000, 4000, and 8000 Hz. Bone conduction thresholds will be conducted at frequencies 500, 1000, 2000, and 4000 Hz.	From baseline by visit up to week 28 (study visit 9, Follow-Up)
Primary	Percentage of patients with Serious Adverse Events (SAEs)	Count and percentage of patients experiencing SAEs	From informed consent up to 30 days post-final dose
Primary	Percentage of patients with treatment-emergent Adverse Events of Special Interest (AESIs)	Count and percentage of patients experiencing treatment-emergent AEISIs. CTCAE Grade =2 anemia will be considered an AESI. During the course of the study, additional AESIs may be identified by the Sponsor	From informed consent up to 30 days post-final dose
Secondary	The ratio of urine protein to creatinine ratio (UPCR) analysed in 24-hour urine sample		At baseline and week 24
Secondary	Percentage of patients with a 25% reduction in UPCR analysed in 24-hour urine sample	The proportions of patients achieving a 25% reduction in UPCR at 24 weeks from baseline in the setanaxib group will be compared to placebo group	At baseline and week 24
Secondary	Pre-dose and post-dose plasma concentrations of setanaxib and GKT138184 measured as the area under the concentration-time curve over 24 hours at steady state (AUC0-24-ss)		within 90 minutes prior to dose and 0-, 1-, 2-, 3-, 4- and 6-hours post-dose at week 2; and prior to dose at weeks 12 and 24
Secondary	Pre-dose and post-dose plasma concentrations of setanaxib and GKT138184 measured as the minimum plasma concentration at steady state (Cmin-ss)		within 90 minutes prior to dose and 0-, 1-, 2-, 3-, 4- and 6-hours post-dose at week 2; and prior to dose at weeks 12 and 24
Secondary	Pre-dose and post-dose plasma concentrations of setanaxib and GKT138184 measured as the maximum plasma concentration at steady state (Cmax-ss)		within 90 minutes prior to dose and 0-, 1-, 2-, 3-, 4- and 6-hours post-dose at week 2; and prior to dose at weeks 12 and 24