A Phase 2b Multicentre, Randomised, Double-Blind, Active Controlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin in Patients with Chronic Kidney Disease with Estimated Glomerular Filtration Rate (eGFR) Between 20 and 60 mL/min/1.73 m2
- Conditions
- Chronic Kidney DiseaseKidney Failure10038430
- Registration Number
- NL-OMON52170
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Trial is onging in other countries
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 9
Participants are eligible to be included in the study only if all of the
following criteria apply:
Age
1 Participant must be 18 years of age or older at the time of signing the
informed consent.
Type of Participant and Disease Characteristics / Laboratory Parameters
2 Diagnosis of CKD, defined as:
(a) eGFR (CKD-EPI) >= 20 mL/min/1.73 m2 (by CKD-EPI formula, see Section 8.1.2.2)
AND
(b) Urine albumin to creatinine ratio (UACR) >= 150 and <= 5000 mg albumin/g
creatinine,
based on a single first morning void spot urine sample at screening.
Medical Treatment
3 No current or prior (within 1 month of screening) medical treatment with an
SGLT2i or
any FDC with SGLT2i (such as SGLT2i + metformin).
4 If ACEi and/or ARB and/or MRA are prescribed, the dose must be stable >= 4
weeks
before screening. Participants who have been deemed unable to tolerate ACEi or
ARB therapy due to allergy or complications can be enrolled.
5 No current or prior treatment within 6 months prior to screening with
cytotoxic therapy,
immunosuppressive therapy or other immunotherapy for primary or secondary
kidney disease.
Weight
6 Body mass index (BMI) <= 40 kg/m2.
Sex
7 Male or female of non-childbearing potential.
Reproduction
8 Female participants must have a negative pregnancy test at screening, must
not be
lactating, and must be of non-childbearing potential, confirmed at screening by
fulfilling one of the following criteria:
(a) Postmenopausal defined as amenorrhoea for at least 12 months or more
following
cessation of all exogenous hormonal treatments and FSH and LH levels in the
postmenopausal range.
(b) Documentation of irreversible surgical sterilisation by hysterectomy,
bilateral
oophorectomy, or bilateral salpingectomy but not tubal ligation.
9 Male participants must be surgically sterile, abstinent, or in conjunction
with a female
sexual partner, using a highly effective method of contraception for the
duration of the study (from the time they sign consent) and for 3 months after
the last dose of investigational product to prevent any pregnancies. Male study
participants must not donate or bank sperm during this same time period (see
Section 8.3.8.2).
Methods that can achieve a failure rate of less than 1% per year when used
consistently and correctly are considered highly effective birth control
methods such as:
• Combined (oestrogen and progesterone containing) hormonal contraception
associated
with inhibition of ovulation:
* Oral.
* Intravaginal.
* Transdermal.
• Progesterone-only hormonal contraception associated with inhibition of
ovulation:
* Oral.
* Injectable.
* Implantable.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Bilateral tubal occlusion of female partner.
• Male vasectomy.
• True sexual abstinence.
True abstinence refers to: when this is in line with the preferred and usual
lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation,
symptom-thermal, post-ovulation methods), declaration of abstinence for the
duration of a trial, and withdrawal are not acceptable methods of contraception.
Informed Consent
10 Capable of giving signed informed consent, as described in Appendix A, which
includes
compliance with the requirements and restrictions liste
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1 Minimal change disease, unstable rapidly progressing renal disease, and/or
renal disease
requiring significant immunosuppression, autosomal dominant or autosomal
recessive polycystic kidney disease.
2 Participants with NYHA functional HF class III or IV.
3 Acute coronary syndrome (ACS) events within 3 months prior to screening.
4 Participants with a BNP >= 200 pg/mL or NT-proBNP >= 600 pg/mL (BNP >= 400 pg/mL
or NT-proBNP >= 1200 pg/mL, respectively, if associated with atrial
fibrillation) measured by local laboratory at screening (Visit 1).
5 Participants with unstable HF requiring hospitalisation for optimisation of
HF treatment
and/or who have not been stable on HF therapy within 6 months prior to
screening.
6 Heart failure due to cardiomyopathies that would primarily require other
specific
treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other
infiltrative diseases, cardiomyopathy related to congenital heart disease,
primary hypertrophic cardiomyopathy, cardiomyopathy related to toxic or
infective conditions (ie, chemotherapy, infective myocarditis, septic
cardiomyopathy).
7 High output HF (eg, due to hyperthyroidism or Paget*s disease).
8 Heart failure due to primary cardiac valvular disease/dysfunction, severe
functional mitral
or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
9 Participants with uncontrolled diabetes mellitus (HbA1c > 12%).
10 Participants with T1DM.
11 Hyponatremia, defined as serum Na+ < 135 mmol/L at the time of screening
(Visit 1).
12 Intermittent or persistent second or third degree atrioventricular (AV)
block after sinus
node dysfunction, with clinically significant bradycardia or sinus pause when
not treated with pacemaker.
13 Prolonged QT interval (QTcF > 470ms) on ECG at screening (Visit 1) or
randomisation
visit (Visit 2), known congenital long QT syndrome or history of QT
prolongation associated with other medications.
14 History of any life-threatening cardiac dysrhythmia (continuous or
paroxysmal or
uncontrolled ventricular rate in participants with atrial fibrillation or
atrial flutter).
15 Cardiac surgery or non-elective percutaneous coronary interventions
(PCI/TAVI) (within
3 months) or open chest coronary artery bypass grafting or valvular
repair/replacement (within 3 months) prior to screening or is planned to
undergo any of these procedures after randomisation.
16 Heart transplantation or left ventricular assist device at any time.
17 Kidney or any organ transplantation.
18 History or ongoing allergy/hypersensitivity, as judged by the investigator,
to SGLT2i (eg,
dapagliflozin, canagliflozin, empagliflozin) or drugs with a similar chemical
structure to zibotentan.
19 Any clinically significant disease or disorder (eg, cardiovascular,
gastrointestinal, liver,
renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major
physical impairment) which, as judged by the investigator, might put the
participant at risk because of participation in the study, or probable
alternative primary reason for participant*s symptoms in judgment of
investigator, including but not limited to:
(a) Isolated pulmonary arterial hypertension (de
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>· Change in log-transformed UACR from<br /><br>baseline to Week 12.<br /><br>The primary estimand is a hypothetical estimand such that the treatment effect<br /><br>is quantified in the optimal situation where any potential confounder is<br /><br>avoided.<br /><br>The population of interest is the Full Analysis population. Participants will<br /><br>be included in the analysis if they have a non-missing baseline and at least<br /><br>one post-treatment visit UACR measurement.<br /><br>For the intercurrent events, if a participant is lost to follow up, prematurely<br /><br>discontinues study treatment or uses a prohibited medication, the<br /><br>UACR data are treated as missing after the event and no imputation is<br /><br>performed. The summary measure being evaluated is the geometric mean reduction<br /><br>of<br /><br>UACR from baseline to Week 12.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Change in log-transformed UACR from baseline to Week 12.<br /><br>Change in BP from baseline (Visit 2) to Week 12.<br /><br><br /><br>The least squares mean change of UACR at<br /><br>Week 12 from the Zibo/Dapa dose arms and the dapagliflozin monotherapy arm.<br /><br><br /><br>Change in eGFR from baseline to Week 1.<br /><br>Change in eGFR from baseline to Week 12.<br /><br>Change in eGFR from baseline to Week 14.<br /><br>Change in eGFR from Week 1 to Week 12.</p><br>