Clinical Trials Register

Summary
EudraCT Number:	2014-005142-21
Sponsor's Protocol Code Number:	MLN1202-2005
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-04-21
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2014-005142-21

A.3

Full title of the trial

A Multicenter, Randomized, Double Blind, Placebo Controlled, Proof of Concept, Phase 2 Study to Evaluate the Efficacy and Safety of Weekly Subcutaneous MLN1202, in Improving Diabetic Nephropathy Subjects with Macroalbuminuria

A.3.1

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

MLN1202 75, 105, 150 mg as add-on to ACE/ARB to treat Diabetic Nephropathy

A.3.2

Name or abbreviated title of the trial where available

MLN1202 75, 105, 150 mg as add-on to ACE/ARB to treat Diabetic Nephropathy

A.4.1

Sponsor's protocol code number

MLN1202-2005

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	Takeda Development Centre Europe Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Takeda Development Centre Americas, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Development Centre Americas, Inc.
B.5.2	Functional name of contact point	Medical Director, Clinical Science
B.5.3	Address:
B.5.3.1	Street Address	One Takeda Parkway
B.5.3.2	Town/ city	Deerfield
B.5.3.3	Post code	IL60015
B.5.3.4	Country	United States
B.5.4	Telephone number	001224554 6500

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	MLN1202
D.3.2	Product code	MLN1202
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	plozalizumab
D.3.9.1	CAS number	1610761-46-0
D.3.9.2	Current sponsor code	MLN1202
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diabetic Nephropathy:
Adults (age 18 - 90 years inclusive) with type 2 diabetes, an eGFR of 25-59 mL/min/1.73 m2, and with macroalbuminuria (>300 mg/g) will be randomized.

E.1.1.1

Medical condition in easily understood language

Diabetic kidney disease (patients with type 2 diabetes)

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

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 characterize the effects of 85 days treatment with MLN1202 on urinary albumin-creatinine ratio (UACR) in subjects with type 2 diabetes, advanced kidney disease (diabetic nephropathy) and macro-albuminuria (UACR>300 mg/g) based on an average of 3 consecutive days first morning void sample collection.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
To characterize the effect of MLN1202 on urinary albumin-creatinine ratio over time.

To characterize the effect of MLN1202 on total protein-creatinine ratio over time.

Additional Objectives:
To characterize the effect of study drug on glycosylated hemoglobin fraction (HbA1c); high sensitivity C-reactive protein (hs-CRP); homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function HOMA-BCF; and renal function, as measured by creatinine.
To assess the safety and tolerability of study drug; evaluate the PK of MLN1202 given by SC injection in patients with CKD.
To evaluate the correlation between genetic markers and the effect of MLN1202 on UACR; subject’s pain during weekly SC injections; the role of baseline urinary MCP-1 as a biomarker for the effect of MLN1202 on albuminuria.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subject eligibility is determined according to the following criteria:

1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.

2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. At the time of Screening the subject is male or female and aged 18-90 years inclusive at first dose of study medication.

4. The subject was previously diagnosed with type 2 diabetes mellitus per ADA criteria.

5. The subject has an estimated glomerular filtration rate based on serum creatinine (eGFR, determined by MDRD equation) of 25-59 mL/min/1.73 m(2) at Screening.

6. The subject has been on a stable dose of ACE inhibitor or ARB for 8 weeks prior to Screening.

7. The subject has residual albuminuria despite stable treatment with an ACE inhibitor or an ARB for at least 8 weeks prior to Screening (urine albumin:creatinine ratio [UACR] of > 300 mg/g creatinine, inclusive at Screening).

8. The subject has HbA1c test result less than or equal to 10.5% at screening.

9. Subject regularly using DPP4i or SGLT2 to treat diabetes has been on a stable dose and regimen within 2 months prior to Screening.

10. All patients who are not surgically sterile or post-menopausal, or whose partners are not surgically-sterile or postmenopausal, must use two effective birth control methods or abstain from intercourse during this study.

E.4

Principal exclusion criteria

Any subject who meets any of the following criteria will not qualify for entry into the study:

1. Subject has received any investigational compound within 90 days prior to Screening.

2. The subject is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

3. Subject is taking any combination of dual RAS inhibition (such as an ACE inhibitor and an ARB or an ACE inhibitor and a mineralocorticoid receptor antagonist).

4. Subject has type 1 diabetes mellitus or a history of ketoacidosis.

5. Subject has poorly-controlled blood pressure (systolic blood pressure >160 or diastolic blood pressure >110, with blood pressure measured in the seated position after at least 5 minutes of rest) at Screening and Day 1.

6. Subject has received dialysis within 3 months of Screening.

7. Subject has infectious diseases or leg ulcers at Screening (all per discretion of Principal Investigator [PI]).

8. Subject has severe concurrent disease which, in the judgment of the investigator, would interfere significantly with the assessments of safety and efficacy during this study.

9. Subject with known infection with human immunodeficiency virus (HIV), or a positive test for Hepatitis B, Hepatitis C, or TB at Screening.

10. Subject has used long-term immune suppressants, steroid therapy (except for topical use or inhalation), chronic use of non-steroidal anti-inflammatory drug (NSAIDs), cyclooxygenase type 2 (COX-2) inhibitors within 2 weeks prior to Screening. Short-term use is defined as a duration of ≤4 weeks of continuous use.

11. In the judgment of the principal investigator, patients who are likely to be non-compliant or uncooperative during the study.

12. Subjects with known non-diabetic kidney disease (such as autosomal dominant polycystic kidney disease (ADPCKD), IgA nephropathy, focal segmental glomerulosclerosis, or obstructive uropathy). Hypertensive nephrosclerosis superimposed on diabetic kidney disease is acceptable.

13. Subject had a previous renal transplant.

14. Subject has hypersensitivity to other monoclononal antibodies (mAb) or to any component of the formulation of MLN1202.

15. The subject has history of malignancy within the previous 5 years (with the exception of adequately treated basal cell or squamous cell carcinoma of the skin).

16. Subject is symptomatic with dysuria, and has a positive urine culture at screening.

E.5 End points

E.5.1

Primary end point(s)

Efficacy: The primary endpoint for this study is UACR at 85 days, relative to the baseline (average of 3 consecutive first in the morning urine voids).

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 85, relative to baseline average of 3 consecutive first in the morning voids

E.5.2

Secondary end point(s)

Secondary endpoints for this study are:

• UACR change from baseline over time at Day 29, 57, 85, and 113, (these collections will be single first morning void with the exception of Day 85 and 113 which will use the average of 3 consecutive first morning voids).

• Urinary protein:creatinine change from baseline over time at Day 29, 57, 85, and 113, relative to baseline.

Additional Endpoints:
• UACR change from baseline over time at Day 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 113 (these collections will be single first morning voids with the exception of Days 85 and 113 which will use the average of 3 consecutive first morning voids).
• Change from Baseline in plasma glycosylated hemoglobin at Day 29, 57, 85, and 113.
• Percent change from Baseline in serum hs-CRP at Day 29, 57, 85, and 113.
• Change from Baseline in HOMA-IR and HOMA-BCF at Day 85.
• Change from Baseline in serum creatinine at Day 29, 57, 85, and 113.
• Change from Baseline in eGFR at Day 29, 57, 85, and 113.
• The safety and tolerability of therapy will be assessed by collected AEs, labs, vital signs, physical examination, and electrocardiogram (ECG).
• Pharmacokinetic parameters of MLN1202 in subjects with chronic kidney disease.
• A 1-10 pain scale measures [Pain Assessment Scale, Appendix G] will be used to evaluate subject’s pain during weekly SC injections.

Pharmacodynamic Endpoints:
The following pharmacodynamic (PD) parameters will be determined:
• Concentrations of MCP-1 in serum and urine.
• Counts and relative percentages of monocyte and neutrophil populations (from differential white blood cell counts and flow cytometry of classical, inflammatory and intermediate monocytes, and mature, intermediate, and immature neutrophils in peripheral blood).
• Change from Baseline in renal tumor necrosis factor alpha [TNF-α].

Immunogenicity Endpoints:
• Proportion of patients with positive ADA (monthly) during the study.
• Proportion of patients with positive neutralizing ADA during the study.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary Endpoints:
UACR at Day 29, 57, 85, and 113, change from baseline over time
(Day 85 and 113 will use the average of 3 consecutive first morning voids)

UPC change from baseline over time at Day 29, 57, 85, and 113.

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

Yes

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.6

Cross over

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

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

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

Austria

Denmark

Mexico

Peru

Serbia

Slovakia

South Africa

United States

E.8.7

Trial has a data monitoring committee

Yes

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

E.8.9.2

In all countries concerned by the trial months

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-04-21.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

156

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)

The study medication will not be available upon completion of the subject’s participation in the study. The subject should be returned to the care of a physician and standard therapies as required.

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

2015-07-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-11-17

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