| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic kidney disease (CKD) with type 2 diabetes mellitus and albuminuria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic kidney disease with diabetes and albuminuria |
|
| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 100000004857 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to compare the effect of AZD1722 versus placebo on the changes in urine albumin-to-creatinine ratio (UACR) from Baseline to Week 12. |
|
| E.2.2 | Secondary objectives of the trial |
• To investigate safety and tolerability of AZD1722
• To investigate the pharmacodynamic effects of AZD1722 on urine albumin-to-creatinine ratio (UACR), eGFR (s-creatinine, and s-cystatin-c), blood pressure, p-NT-proBNP, s-cardiac troponin, u-aldosterone, p-renin activity, and bioimpedance.
• To investigate the pharmacodynamic effects of AZD1722 on u-Na excretion, mean weekly stool consistency (BSFS) and stool frequency
• To investigate the plasma exposure of AZD1722 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| An optional genetic substudy with a separate informed consent will include collection of a DNA sample for potential future research of genes related to the cardio-renal disease area or associated with drug response or drug metabolism. |
|
| E.3 | Principal inclusion criteria |
1. Males or females aged 18 to 80 years, inclusive.
2. Females must be non-pregnant, non-lactating and fulfilling one of the following:
a. Post –menopausal defined as amenorrhoea for at least 12 months following cessation of all exogenous hormonal treatments and with follicle stimulating hormone (FSH) levels in the laboratory defined post-menopausal range.
b. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral
salpingectomy but not tubal ligation.
c. Use of acceptable contraceptive method: IUD with spermicide, a female condom with spermicide, contraceptive
sponge with spermicide, an intravaginal system (e.g., NuvaRing®), a diaphragm with spermicide, a cervical cap with spermicide, or oral, implantable, transdermal, or injectable contraceptives; or sexual abstinence.
3. Males must agree to avoid fathering a child (or donating sperm), and therefore be either sterile or agree to use, from the time of randomization until 45 days after end of study, one of the following approved methods of contraception: a male condom with spermicide; a sterile sexual partner; use by female sexual partner of an IUD with spermicide, a female condom with spermicide, contraceptive sponge with spermicide, an intravaginal system (e.g., NuvaRing®), a diaphragm with spermicide, a cervical cap with spermicide, or oral, implantable, transdermal, or injectable contraceptives.
4. Body mass index between 18 and 45 kg/m2, inclusive.
5. Patients must have a history of type 2 diabetes mellitus and must be receiving 1 glucose lowering medication for at least 3 months prior to randomization
6. Stage 3 CKD where the eGFR value collected at week -1 must be between 30-60 mL/minute/1.73m2 inclusive using the CKDEPI equation (Section 7.4.2)
7. Urinary albumin: mean UACR 200 mg/g (spot urine) collected at Screening and Visit 2 (Week -1)
8. Patient must be receiving an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB) for at least 3 months prior to Screening, where the dose of the ACE inhibitor and/or the ARB is considered appropriate for that patient, and has been stable and maintained on that dose for at least 4 weeks prior to study randomization
9. If treated with diuretics, the prescription should be stable for at least 4 weeks prior to study randomization
10. Systolic blood pressure 130 mmHg
11. Willing and able to sign informed consent.
12. For inclusion in the optional genetic substudy, patients must fulfill all of the inclusion criteria described above and provide informed consent for the genetic sampling and analyses. |
|
| E.4 | Principal exclusion criteria |
1. Urinary albumin: UACR > 3500 mg/g
2. History of a renal transplant
3. Blood pressure (BP) of MSSBP >180 mmHg or a MSDBP of >120 mmHg on two occasions during screening or run-in
periods
4. History of inflammatory bowel disease (IBD) or diarrhea predominant irritable bowel syndrome (IBS-D)
5. Clinical sign of dehydration during screening or run-in periods
6. Poorly controlled diabetes (fasting s-glucose >270 mg/dL) based on results collected at Visit 2 (Day -7)
7. Acidosis (s-bicarbonate < 18 mmol/L) based on results collected at Visit 2 (Day -7) and obtained from the central lab for the study
8. Hepatic dysfunction (alanine aminotransaminase [ALT] or aspartate aminotransaminase [AST]) >3 times the upper limit of normal based on central laboratory reference ranges) based on results collected at Visit 2 (Day -7) and obtained from the central lab for the study
9. Any biopsy or imaging verifying intercurrent kidney disease other than diabetic nephropathy or diabetic nephropathy with nephrosclerosis
10. Any patient with cardiovascular disease as follows:
a. Unstable angina pectoris within 3 months before study randomization;
b. Myocardial infarction, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty/stent within 3 months before study randomization;
c. Transient ischemic attack within 3 months before study randomization;
d. Cerebrovascular accident within 3 months before study randomization;
e. Obstructive valvular heart disease or hypertrophic cardiomyopathy;
f. 2nd degree or 3rd degree atrioventricular block not successfully treated with a pacemaker;
11. Serum sodium value <132mEq/L or >145mEq/L or serum potassium value <3.5mEq/L or >5.5 mEq/L on more than one occasion prior to randomization.
12. Diarrhea or loose stools during the week before randomization defined as BSFS 6 and frequency 3 for 2 or more days.
13. Pregnant or not willing to use appropriate contraception
14. Any evidence of or treatment of malignancy within one year, excluding non melanomatous malignancies of the skin.
15. Positive serology (hepatitis C or B infection, or human immunodeficiency virus) with evidence of significant hepatic
impairment or WBC elevation according to the Investigator
16. History of alcohol abuse, illicit drug use, significant mental illness, or any history of drug abuse or addiction within 12
months of study enrollment.
17. Scheduled for living donor kidney transplant, hemodialysis, peritoneal dialysis, or home HD during the 6 weeks following randomization.
18. Patients taking Kayexalate® or a therapeutic equivalent sodium polystyrene sulfonate, or the phosphate binder Renvela®, (other phosphate binder are allowed), on a regular therapeutic regimen.
19. Use of an investigational agent within 30 days prior to Screening
20. Previous randomization into this study.
21. Involvement in the planning and/or conduct of the study (applies to both Ardelyx staff and/or staff at the study site).
22. Previous allogeneic bone marrow transplant (applicable only for genetic substudy and sampling).
23. Non-leukocyte whole blood transfusion within 120 days of genetic sample collection (applicable only for genetic substudy and sampling).
24. If, in the opinion of the Principal Investigator, the subject is unable or unwilling to fulfill the requirements of the protocol or has a condition which would render the results uninterpretable. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical endpoints:
• UACR (Urine albumin-to-creatinine ratio)
• eGFR (Serum Creatinine and Cystatin-C)
• Blood pressure (MSSBP, MSDBP)
• 24 hr Ambulatory blood pressure
• 24 hr urinary Na
• Mean weekly stool consistency (Bristol Stool Form Scale)
• Mean weekly stool frequency
• NT-proBNP and cardiac troponin (TnT)
• Aldosterone and renin activity
• Bioimpedance (Total body water, intra- and extracellular fluid volume)
• 24 hr urinary Ca, P, pH, Cr, K
• Exploratory biomarker analyses (potentially in future)
• Pharmacogenetic sample analyses (potentially in future) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day -1 to Day 1 (prior to randomization), Weeks 3 and 12:
• Sodium
• Aldosterone
Day 1 prior to randomization, Weeks 1, 3, 8, 12 and 14:
• NT-pro-BNP (plasma), cardiac troponin (serum)
• Renin activity (plasma)
Baseline, 12 weeks:
• Changes in UACR
• Changes in related endpoints, such as eGFR , BP and U-Na |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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