A Phase 2a Study to Evaluate Setanaxib in Patients with Alport Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Calliditas Therapeutics Suisse S.A.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

10 Jan 2024 → 26 Jun 2025

Decision date (initial)

2024-11-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-505292-73-00

WHO UTN

U1111-1294-0176

ClinicalTrials.gov

NCT06274489

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic, Therapy, Pharmacogenetic

To evaluate the safety and tolerability of setanaxib compared to placebo in patients with Alport syndrome.

Secondary objectives 8

1. To assess the effect of setanaxib on vital signs compared to placebo.
2. To evaluate the effect of setanaxib on 12-lead ECGs compared to placebo.
3. To evaluate the effect of setanaxib on physical examinations compared to placebo.
4. To evaluate the effect of setanaxib on clinical laboratory parameters compared to placebo.
5. To evaluate the effect of setanaxib on hearing compared to placebo.
6. To assess the effect of setanaxib on UPCR compared to placebo.
7. To assess the effect of setanaxib on eGFR compared to placebo.
8. To assess the plasma exposure of setanaxib and its active metabolite GKT138184.

Conditions and MedDRA coding

Alport syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Male or female patients aged 12 to 50 years inclusive, at the time of informed consent/assent; For sites in the EU: Male or female patients aged 18 to 50 years, inclusive, at the time of informed consent;
2. 2. Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome [ie, COL4A3, COL4A4, or COL4A5]); Patients with a variant of uncertain significance should not be included in the study;
3. 3. Weight ≥40 kg;
4. 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. 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); 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”; b. 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; c. 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. 6. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Visit 3 (after randomization and before dosing);
7. 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. 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. 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. 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. 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
12. 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 and ≤80 mmHg diastolic blood pressure for patients ≥18 years of age.

Exclusion criteria 22

1. 1. Has ongoing chronic hemodialysis or peritoneal dialysis;
2. 10. Has a positive pregnancy test at Study Visit 2 (Screening) and/or Study Visit 3 (Day 1) (WOCBP only) or is breastfeeding;
3. 11. Has evidence of any of the following cardiac conduction abnormalities at Screening or Day 1 (pre-dose): a QTcF interval >450 milliseconds for male patients or >470 milliseconds for female patients, or a PR interval ≥220 milliseconds
4. 12. Has a history of aplastic anemia, or any current marked anemia, defined as hemoglobin <10.0 g/dL;
5. 13. Has uncontrolled hypothyroidism. Patients with subclinical hypothyroidism may be included. Subclinical hypothyroidism is defined biochemically as a normal serum free thyroxine (T4) concentration in the presence of an elevated serum thyroid-stimulating hormone (TSH) concentration;
6. 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;
7. 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;
8. 16. Uses medications known to be potent cytochrome P450 (CYP) 3A4 inhibitors (itraconazole, lopinavir/itonavir, telaprevir, clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, conivaptan, and voriconazole), potent CYP3A4 inducers (avasimibe, carbamazepine, enzalutamide, mitotane, nevirapine, phenobarbital, phenytoin, rifabutin, rifampicin, rifapentine, and St John’s wort), or potent uridine 5'-diphospho-glucuronosyltransferase 1A9 inhibitors and inducers (mefenamic acid and rifampicin) within 21 days prior to study drug administration;
9. 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; or
10. 18. Has known hypersensitivity or intolerance to setanaxib or to any of its excipients.
11. 2. Has a history of kidney transplant;
12. 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;
13. 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;
14. 5. Has had prior treatment with setanaxib;
15. 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;
16. 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;
17. 8. Has an active HIV infection or acute or chronic hepatitis B or C infection, confirmed at Screening;
18. 9. Has had a surgery (eg, gastric bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator);
19. 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. 20. Has plasma alanine aminotransferase and/or aspartate aminotransferase >3 x the upper limit of normal (ULN) at Study Visit 1 or 2 (Screening);
21. 21. Has total bilirubin >2 x ULN at Study Visit 1 or 2 (Screening); or
22. 22. Has international normalized ratio >1.2 at Study Visit 1 or 2 (Screening) (criterion not applicable for patients on anticoagulant therapy).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients with SAEs; and Percentage of patients with treatment-emergent AESIs, ie, anemia.

Secondary endpoints 8

1. Percentage of patients with clinically significant changes in heart rate and blood pressure.
2. Percentage of patients with clinically significant changes in 12-lead ECG.
3. Percentage of patients with clinically significant changes in physical examination.
4. Percentage of patients with clinically significant changes in hematology, serum chemistry, urinalysis, and thyroid function.
5. Percentage of patients with clinically significant changes in hearing audiometric testing (bone- and air-conduction).
6. The ratio of UPCR at 24 weeks compared to baseline; and Percentage of patients with a 25% reduction in UPCR at 24 weeks, compared to baseline.
7. The ratio of eGFR at 24 weeks compared to baseline.
8. Pre-dose and post-dose plasma concentrations of setanaxib and GKT138184 at steady state. The following PK properties will be calculated: Area under the concentration-time curve over 24 hours at steady state (AUC0-24-ss); Minimum plasma concentration at steady state (Cmin-ss); and Maximum plasma concentration at steady state (Cmax-ss).

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Calliditas Therapeutics Suisse S.A.

Sponsor organisation

Calliditas Therapeutics Suisse S.A.

Address

Chemin des Aulx 14

City

Plan-Les-Ouates

Postcode

1228

Country

Switzerland

Scientific contact point

Organisation

Calliditas Therapeutics Suisse S.A.

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Calliditas Therapeutics Suisse S.A.

Contact name

Clinical Trial Information Desk

Third parties 8

Locations

6 EU/EEA countries · 16 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 86 files

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

Application history

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