Clinical Trials Register

Summary
EudraCT Number:	2016-000661-23
Sponsor's Protocol Code Number:	NEPHSTROM
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-05-10
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

UK - MHRA

A.2

EudraCT number

2016-000661-23

A.3

Full title of the trial

NOVEL STROMAL CELL THERAPY FOR DIABETIC KIDNEY DISEASE
(NEPHSTROM Study)

A.3.1

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

Nephstrom for Diabetic Kidney Disease

A.3.2

Name or abbreviated title of the trial where available

NEPHSTROM Study

A.4.1

Sponsor's protocol code number

NEPHSTROM

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02585622

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	IRCCS - Istituto di Ricerche Farmacologiche Mario Negri
B.1.3.4	Country	Italy
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	HORIZON 2020
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRFMN - Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò
B.5.2	Functional name of contact point	Lab. Regulatory Acitivities
B.5.3	Address:
B.5.3.1	Street Address	Via G.B. Camozzi, 3
B.5.3.2	Town/ city	Ranica
B.5.3.3	Post code	24020
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390354535307
B.5.5	Fax number	+390354535371
B.5.6	E-mail	paola.boccardo@marionegri.it

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	NEPHSTROM ORBCEL-M
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NEPHSTROM ORBCEL-M
D.3.9.3	Other descriptive name	Expanded bone marrow-derived human mesenchymal stromal cells
D.3.9.4	EV Substance Code	SUB27304
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms million organisms
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	80 to 240
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous 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 clinically-diagnosed progressive diabetic kidney disease.

E.1.1.1

Medical condition in easily understood language

Patients with type 2 diabetes and clinically-diagnosed progressive diabetic kidney disease.

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10012687
E.1.2	Term	Diabetic renal disease
E.1.2	System Organ Class	100000004857

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	10012601
E.1.2	Term	Diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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

The primary objective of this trial is to establish the safety and tolerability of a single intravenous infusion of NEPHSTROM ORBCEL-M in study participants with type 2 diabetes (T2D) and progressive Diabetic Kidney Disease (DKD).

E.2.2

Secondary objectives of the trial

i. To evaluate the potential efficacy of an intravenous infusion of NEPHSTROM ORBCEL-M to slow or halt the progression of DKD.
ii. To evaluate the effect of NEPHSTROM ORBCEL-M on other diabetes-relevant clinical parameters such as glycaemic control, lipid and arterial blood pressure control.
iii. To estimate the impact of NEPHSTROM ORBCEL-M treatment on health related quality of life.
iv. To acquire mechanistic data regarding the anti-inflammatory and immune-modulatory activity of NEPHSTROM ORBCEL-M in study participants.
v. To investigate the potential cost-effectiveness of NEPHSTROM ORBCEL-M therapy approach compared to conventional pharmacological intervention.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male and female ≥ 40 years and <85 years old;
2.T2D for 3 or more years under a clinician with mandated responsibility for management of the patients to national guidelines;
3.Urine albumin-to-creatinine ratio (UACR) ≥ 88 mg/g (≥ 10 mg/mmol) (in a spot morning urine collection);
4.Estimated GFR (eGFR) 25-55 ml/min/1.73 m^2 by the CKD-EPI equation on 2 or more consecutive measurements at least 30 days apart within the past 6 months;
5.A documented decline of eGFR of ≥ -10ml/min/1.73 m^2 over the past 3 years or documented rate of eGFR decline of ≥ -5 ml/min/1.73 m^2 year based on 3 or more consecutive readings at least 90 days within the past 18 months up to date of consent, or an intermediate or high 5-year risk of progression to end-stage kidney failure (dialysis or transplantation)based on the validated TANGRI 4-variable (age, sex, eGFR, urinary albumin/creatinine ratio) kidney failure risk equation (KFRE) http://kidneyfailurerisk.com/) for subjects with CKD stage 3-5;
6.Lack of suspicion of renal diagnosis other than DKD;
7.Willing and able to provide written informed consent.

E.4

Principal exclusion criteria

Exclusion criteria related to blood pressure:
1.Current resting systolic BP ≥ 150 mmHg and current resting diastolic BP ≥ 90 mmHg in a clinical setting, despite treatment with 3 hypertensive agents of different classes (including one diuretic), measured in a quiet environment with morning medications already taken;
2.Initiation of a new anti-hypertensive agent within the past 3 months
3.Increase the dose of an anti-hypertensive agent by > 100% of the previous dose within the past 3 months

Exclusion criteria related to glycaemic control:
4.Current HbA1c > 75 mmol/mol (> 9%)
5.Initiation of a new hypoglycaemic agent within the past 3 months
6.Increase the dose of a hypoglycaemic agent by > 100% of the previous dose within the past 3 months

Exclusion criteria related to dyslipidaemia:
7.Current fasting total cholesterol > 7 mmol/l
8.Current fasting total triglycerides > 3.5 mmol/l
9.Initiation of a new lipid lowering agent within the past 3 months

Other exclusion criteria:
10.Chronic lung or liver disease;
11.Cardiovascular events (myocardial infarction, stroke or acute limb ischemia) within 6 months prior to enrolment;
12.Current or history within 6 months prior to enrolment of NYHA class III or IV heart failure;
13.Other concomitant disease or conditions in the opinion of the investigator that are likely to pose risk to the patient and that would render the patient unsuitable for participation or that could impair patient safety or ability to participate in the study, such as active malignancy;
14.Irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%;
15.Positive screening test for clinically significant anti-HLA antibodies. An initial antibody screening with Luminex® multi-antigen beads to detect class I and class II MHC antibodies followed by a Luminex single antigen bead assay to determine the specificity of any antibody detected. Potential study subjects with positive screening for any clinically significant anti-HLA antibody will be excluded and will not be eligible to participate in the NEPHSTROM clinical study (MFI>1500);
16.History or presence of any medical condition or disease which, in the opinion of the Investigator may place the participant at unacceptable risk for study participation;
17.Childbearing potential without use of effective acceptable methods of contraception. Women of childbearing potential can only be included in the study if a pregnancy test is negative at the screening visit (V1) and at baseline visit (V2) if they agree to use adequate contraception. Adequate contraception is defined as any combination of at least two effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate) or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical treatment such as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
18.Pregnancy or lactating;
19.Participation in other investigational medicinal product (IMP) trials within 30 days before the inclusion or concurrent to this study (18 month follow-up);
20.Inability to understand the potential risks and benefits of the study;
21.Legal incapacity.

E.5 End points

E.5.1

Primary end point(s)

- Number and severity of pre-specified cell-infusion associated events
- Overall number and frequency of adverse events and unexpected severe adverse events compared to placebo

E.5.1.1

Timepoint(s) of evaluation of this end point

Number and frequency of adverse events (SAEs and AEs) will be recorded from the time of infusion until the end of the 18 months follow-up period or, in the case of early withdrawal, to the time of study withdrawal.

E.5.2

Secondary end point(s)

1) - GFR changes (ΔGFR and slope of GFR decline) evaluated by iohexol plasma clearance;
- Estimated GFR (by CKD-EPI and MDRD equations);
- Urinary ACR on spot morning urine samples;
- Urinary albumin excretion in 24h urine collection;

2 ) - Glycaemic control as assessed by fasting blood glucose and HbA1c;
- Lipid control measured as total cholesterol, LDL cholesterol and triglycerides;
- Arterial blood pressure control;

3) - Quality of life (evaluated by SF36 and EQ-5D-5L questionnaires);

4) - Anti-HLA antibody development;
- Blood and urine bio-chip-based multiplex assay of inflammation- and fibrosis-related soluble mediators;
- Immunoassay-derived concentrations of biomarkers of inflammation and CKD progression in plasma/serum and urine;
- Proportion/total number of circulating lymphocyte (T cells, B cells and NK cells) and myeloid cell (monocyte, dendritic cells) subsets;

5) - Potential impact of cost-effectiveness of cell therapy approach compared to conventional pharmacologic intervention.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) At baseline, 6, 12 and 18 months.
2) At each study time-point (screening, baseline, 7 day, 1,3,6,12,18 months)
3) At baseline, 6, 12 and 18 months.
4) Anti-HLa antibody development: at baseline, 3, 12 and 18 months;
Inflammation and fibrosis mediators, biomarkers of inflammation and proportional number of circulating T cells, B cells, NK cells , monocytes and dendritic cells: at baseline, 7 days, 1, 6, 12 and 18 months;
5) At baseline and 1, 3, 6, 12 and 18 months.

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

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability and potential efficacy.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The end of the trial is the time in which the database is closed.

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

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

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)

At the end of the 18 month clinical trial period, the participants will continue in an open 5-year long-term follow-up to monitor outcomes including ESRD, CVD events, malignancies and survival.

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

2017-05-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-17

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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