Alport Syndrome
Conditions
Brief 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.
Interventions
DRUGSetanaxib
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.
DRUGPlacebo
Matching film-coated placebo tablets, containing only excipients
Sponsors
Calliditas Therapeutics AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged 12 to 50 years inclusive, at the time of informed consent/assent. For sites in the European Union: Male or female patients aged 18 to 50 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 \[ie, COL4A3, COL4A4, or COL4A5\]); Patients with a variant of uncertain significance should not be included in the study; 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 (± 7 days) 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 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 Visit 3 (after randomization and 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 a dose within 25% of the dose at randomization. Note: Patients with proven intolerance to ACEi and ARB are allowed in the study. 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 Screening 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 height 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. Note: 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Serious Adverse Events (SAEs) | From informed consent up to 30 days post-final dose, up to 32 weeks | Count and percentage of patients experiencing SAEs |
| Percentage of Patients With Treatment-emergent Adverse Events of Special Interest (AESIs) | From informed consent up to 30 days post-final dose | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Ratio of Urine Protein to Creatinine Ratio (UPCR) Analysed in 24-hour Urine Sample | At baseline and week 24 | The ratio of UPCR at 24 weeks compared to baseline |
| Percentage of Patients With a 25% Reduction in UPCR Analysed in 24-hour Urine Sample | At baseline and week 24 | 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 |
| The Ratio of Estimated Glomerular Filtration Rate (eGFR) at 24 Weeks Compared to Baseline. | At baseline and Week 24. | — |
| 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 | — |
| 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 | — |
| 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 | — |
Countries
Austria, Czechia, France, Spain, United Kingdom
Participant flow
Pre-assignment details
Overall, 34 participants were screened. 20 of them were randomized: 13 to the setanaxib group and 7 to the placebo group. 2 participants in the placebo group discontinued early from the study: * 1 participant in the placebo group did not start the study treatment. * 1 participant in the placebo group who received study drug discontinued early due to pregnancy.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 29.7 years STANDARD_DEVIATION 8.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 6 |
| other Total, other adverse events | 8 / 13 | 4 / 6 |
| serious Total, serious adverse events | 1 / 13 | 0 / 6 |
Outcome results
None listed