Clinical trial NCT02585622: NEPHSTROM for Diabetic Kidney Disease
Official title: Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Diabetic Kidney Disease
Keywords: Diabetic Kidney Disease
Mesenchymal Stromal Cells (MSC)
immune response
allogeneic
disease progression
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: Leiden University Medical Center
name: Papa Giovanni XXIII Hospital
name: Istituto Di Ricerche Farmacologiche Mario Negri
name: Belfast Health and Social Care Trust
name: National University of Ireland, Galway, Ireland
name: University Hospital Birmingham, NHS Foundation Trust, Hospital, Birmingham, UK
name: NHS Blood and Transplant
First posted: 2015-10-23
Enrollment: 29
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The study will investigate, primarily, the safety, feasibility and tolerability and, secondarily, the preliminary efficacy of an allogeneic bone marrow-derived Mesenchymal Stromal Cell (MSC) therapy (ORBCEL-M) in study subjects with type 2 diabetes (T2D) and progressive diabetic kidney disease (DKD).


Eligibility criteria: Inclusion Criteria:

* Male and female ≥ 40 years and \<85 years old. ;
* T2D for 3 or more years under a clinician with mandated responsibility for management of the patients to national guidelines;
* Urinary albumin excretion (UAE) ≥ 60 µg/min (in a 24 hour urine collection) and urine albumin-to-creatinine ratio (UACR) ≥ 88 mg/g (≥ 10 mg/mmol) (in a spot morning urine collection);
* Estimated GFR (eGFR) 30-50 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;
* 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 apart in the past 18 months;
* Lack of suspicion of renal diagnosis other than DKD;
* Willing and able to provide written informed consent.

Exclusion Criteria:

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 6 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 6 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 6 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.

Primary outcomes:
measure: Number and severity of all pre-specified infusion-associated events and the overall number and frequency of adverse events.
timeFrame: Changes from baseline to study completion, up to 18 months after cell or placebo infusion.
Secondary outcomes:
measure: Glomerular filtration rate (GFR)
timeFrame: Changes from baseline up to 18 months after cell or placebo infusion.
measure: Urinary Albumin/Creatinine Ratio (ACR)
timeFrame: Changes from baseline at 6 months and then every six months to study completion,up to 18 months after cell or placebo infusion.
measure: Urinary albumin excretion (UAE).
timeFrame: Changes from baseline at 6 months and then every six months to study completion,up to 18 months after cell or placebo infusion.
measure: Fasting blood glucose (target <126mg/dL)
timeFrame: Proportion of study participants within target range (<126mg/dL) at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: HbA1c (target <75mmol/mol or <9%)
timeFrame: Proportion of study participants within target range (<75mmol/mol or <9%) at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: Total cholesterol (target <200 mg/dl)
timeFrame: Proportion of study participants within target range (<200 mg/dl) at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: LDL cholesterol (target <100 mg/dl)
timeFrame: Proportion of study participants within target range (<100 mg/dl) at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: Triglycerides (target <170 mg/dl)
timeFrame: Proportion of study participants within target range (<170 mg/dl) at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: Arterial blood pressure (the target value <130/80 mmHg)
timeFrame: Proportion of study participants within target range (<130/80 mmHg)at baseline and at each time point (day 1, day 7, month 1,3,6,12,18 after cell or placebo infusion).
measure: Quality of life
timeFrame: Changes from baseline to 1,3,6,12 and 18 months after cell or placebo infusion.
measure: Quality of life
timeFrame: Changes from baseline to 1,3,6,12 and 18 months after cell or placebo infusion.
measure: Anti-HLA antibody development
timeFrame: Changes from baseline to 3,12 and 18 months after cell or placebo infusion.
measure: Inflammation and fibrosis related soluble mediators
timeFrame: Changes from baseline to 7 days, 1,6,12 and 18 months after cell or placebo infusion.
measure: Serum/plasma concentrations (pg/ml) of biomarkers of inflammation.
timeFrame: Changes from baseline to 7 days, 1,6,12 and 18 months after cell or placebo infusion.
measure: Serum/plasma concentrations (ng/ml) of biomarkers of CKD progression.
timeFrame: Changes from baseline to 7 days, 1,6,12 and 18 months after cell or placebo infusion.
measure: Urine concentrations (pg/ml adjusted to urine creatinine concentration) of biomarkers of inflammation.
timeFrame: Changes from baseline to 7 days, 1,6,12 and 18 months after cell or placebo infusion.
measure: Proportion/total number of circulating T cells, B cells, NK cells, monocytes, dendritic cells
timeFrame: Changes from baseline to 7 days, 1,6,12 and 18 months after cell or placebo infusion.
measure: Cost-effectiveness of cell therapy
timeFrame: Changes from baseline to 1,3,6,12 and 18 months after cell or placebo infusion.
Other outcomes:
Locations:
city: Galway
country: Ireland
facility: National University of ireland - Galway University Hospital -Regenerative Medicine Institute
city: Bergamo
country: Italy
facility: ASST - Papa Giovanni XXIII - U.O. Nefrologia e Dialisi/ Mario Negri Institute for Pharmacological Research - Clinical Research Center for Rare Diseases Aldo e Cele Daccò
state: BG
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust - Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham NHS Foundation Trust - Queen Elizabeth Medical Centre
Study officials:
affiliation: ASST Papa Giovanni XXIII, Bergamo, Italy/IRCCS - Mario Negri Institute for Pharmacological Research
name: Giuseppe Remuzzi, MD
role: STUDY_CHAIR
affiliation: National University of ireland - Galway University Hospital -Regenerative Medicine Institute
name: Mattew Griffin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Birmingham NHS Foundation Trust
name: Paul Cockwell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Belfast Health and Social Care Trust - Belfast City Hospital
name: Peter Maxwell, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Perico N, Remuzzi G, Griffin MD, Cockwell P, Maxwell AP, Casiraghi F, Rubis N, Peracchi T, Villa A, Todeschini M, Carrara F, Magee BA, Ruggenenti PL, Rota S, Cappelletti L, McInerney V, Griffin TP, Islam MN, Introna M, Pedrini O, Golay J, Finnerty AA, Smythe J, Fibbe WE, Elliman SJ, O'Brien T; NEPHSTROM Trial Consortium. Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM). J Am Soc Nephrol. 2023 Oct 1;34(10):1733-1751. doi: 10.1681/ASN.0000000000000189. Epub 2023 Aug 10.