Clinical Trials Register

Summary
EudraCT Number:	2021-001324-18
Sponsor's Protocol Code Number:	202100178
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-01-11
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2021-001324-18

A.3

Full title of the trial

A Study to Assess the Effects of the Endothelin Receptor Antagonist
Zibotentan and the SGLT2 Inhibitor Dapagliflozin in Patients with Type 2 Diabetes and elevated Albuminuria: a Randomized Double Blind Cross-Over Trial

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study to Assess the Effects of the drugs Zibotentan and Dapagliflozin in Patients with Type 2 Diabetes and Elevated Levels of Protein in Urine

A.3.2

Name or abbreviated title of the trial where available

ZODIAC trial

A.4.1

Sponsor's protocol code number

202100178

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Center Groningen
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Astra Zeneca
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Hiddo Lambers Heerspink
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9700 RB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00311503617859
B.5.6	E-mail	h.j.lambers.heerspink@umcg.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	zibotentan
D.3.2	Product code	ZD4054
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZIBOTENTAN
D.3.9.1	CAS number	186497-07-4
D.3.9.2	Current sponsor code	ZD4054
D.3.9.4	EV Substance Code	SUB32097
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Forxiga
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dapagliflozin
D.3.2	Product code	Dapagliflozin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DAPAGLIFLOZIN PROPANEDIOL
D.3.9.1	CAS number	Dapa
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN PROPANEDIOL
D.3.9.4	EV Substance Code	SUB185982
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Type 2 Diabetes and elevated Albuminuria

E.1.1.1

Medical condition in easily understood language

Patients with type two diabetes and protein in the urine

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.1
E.1.2	Level	PT
E.1.2	Classification code	10061835
E.1.2	Term	Diabetic nephropathy
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.0
E.1.2	Level	PT
E.1.2	Classification code	10016807
E.1.2	Term	Fluid retention
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10001580
E.1.2	Term	Albuminuria
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the change from baseline in albuminuria after 4 weeks combined zibotentan (ZIBO) and dapagliflozin (DAPA) treatment versus four weeks treatment with ZIBO alone in patients with type 2 diabetes and albumin: creatinine ratio >100 mg/g on stable ACEi or ARB treatment.

E.2.2

Secondary objectives of the trial

To assess the effect of combined ZIBO/DAPA treatment versus ZIBO alone on:
o Extracellular Fluid measured by bioimpedance spectroscopy
o Body weight
o NT-proBNP and BNP
o Glomerular Filtration Rate (GFR) and extracellular volume (ECV) using iohexol clearance techniques.
o Hematocrit
o Systolic and diastolic blood pressure

To assess the effect of ZIBO/DAPA versus ZIBO on selected neurohormones/biomarkers:
o Renin-angiotensin-aldosterone system markers (plasma and urine)
o Copeptin (surrogate of vasopressin)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 and ≤75 years
2. Hba1c ≥ 6.0%
3. Urinary albumin:creatinine ratio > 100 mg/g and ≤ 3500 mg/g in a first morning void urine collection
eGFR ≥ 30 mL/min/1.73m2
4. On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization
5. Willing to sign informed consent

E.4

Principal exclusion criteria

1. Diagnosis of type 1 diabetes
2. Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease
3. Hba1c > 12.5%
4. Urinary albumin excretion > 3500 mg/day
5. Heart Failure NYHA Class III or IV
6. NT-proBNP > 600 pg/ml
7. Acute coronary syndrome event within the preceding 6 months
8. Severe peripheral edema according to investigators opinion
9. Women of childbearing potential (WOCBP). WOCBP is defined as women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal
10. Pregnancy or breastfeeding
11. Indication for high dose immunosuppressants as per the treating physician’s judgment.
12. Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin within the last 5 years.
13. Use of the co-interventional treatments within 6 weeks of screening will not be allowed.
14. Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:
o History of active inflammatory bowel disease within the last six months;
o Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
o Pancreatic injury or pancreatitis within the last six months;
o Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
o Evidence of urinary obstruction or difficulty in voiding at screening
o Severe hepatic impairment
o History of epilepsy syndrome
o History of severe hypersensitivity or contraindications to dapagliflozin
o History of hypersensitivity or contraindications to iodinated contrast media
15.Subject who, in the assessment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data
16. Participation in any clinical investigation within 3 months prior to initial dosing.
17. Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing
18. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening or according to investigator’s assessment.
19. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
20. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.

E.5 End points

E.5.1

Primary end point(s)

Geometric mean ratio of three consecutive albumin:creatinine ratio derived from a first morning void collection

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 22 of the trial (end of treatment period 3)

E.5.2

Secondary end point(s)

Extracelluar volume measured by bioimpedance spectroscopy
Body weight
NT-proBNP and BNP
Glomerular Filtration Rate (GFR) using iohexol clearance.
hematocrit
Systolic blood pressure
Renin-angiotensin-aldosterone system markers (plasma and urine)
Copeptin (surrogate marker of vasopressin)

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 22 of the trial (end of treatment period 3)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Canada

United Kingdom

United States

Netherlands

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-04-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Other

Date of Ethics Committee Opinion

2024-04-30

P. End of Trial
P.	End of Trial Status	Completed

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