Stem Cell Therapy in Non-IschEmic Non-treatable Dilated CardiomyopathiEs II: a Pilot Study

Study design

The primary objective of the study is to investigate safety and regenerative capacity of direct intra-myocardial injection of 100 million allogeneic CSCC_ASCs in NIDCM patients with reduced left ventricular EF (≤ 40%) and heart failure.

It is a proof of concept study enrolling a total of 30 NIDCM patients with heart failure who will be randomly allocated in a 2:1 ratio to either CSCC_ASC cell therapy (Stem Cell Group) or no cell therapy (Control Group). The treatment period is estimated to be 6 months (efficacy end-point) with a 12-month follow-up period for safety end-points.

Patient treatment and follow-up

• The cell IMP will be delivered by a courier service to from REGIONH to UKCL using validated portable dry liquid nitrogen shipping containers. It will then be stored in nitrogen vapour containers until treatment.
• The preparation of the IMP will be performed as described in the treatment manual. The IMP will be thawed and prepared for injection immediately before treatment.
• A 3-D map of the left ventricle will be created using the NOGA XP® system (Biological Delivery System, Cordis, Johnson \& Johnson, USA). The delivery of the IMP (100 million ASCs) into the myocardium will be performed by 10-15 injections of 0.2 cc, as described in the treatment manual.
• The post cell therapy surveillance will include clinical and laboratory safety follow-up with monitoring of cardiac enzymes, hemodynamic and rhythm stability. The clinical follow-up will be obtained at pre-defined time points. The presence of allogeneic HLA anti-bodies will be monitored three and six months after treatment. End-points will be monitored continuously and reported as occurring throughout the 12 months follow-up period.

Primary and secondary endpoints

The primary endpoint is change in left ventricle end-systolic volume (LVESV) at 6 months follow-up measured by Echocardiography.

The secondary endpoints are safety evaluated by development of allogeneic antibodies and laboratory safety measurements 1, 3 and 6 months after treatment and changes in left ventricular ejection fraction (LVEF), end-diastolic volume and myocardial mass at 6 months follow-up.

Additional secondary endpoints are changes in NYHA, Kansas City Cardiomyopathy Questionnaire, EQ-5D3L Questionnaire, 6 min walking test, additional echocardiographic measures (Global strain %) and NT-pro-BNP.

Safety of allogeneic CSCC_ASCs with respect to incidence and severity of serious adverse events and suspected unrelated serious adverse events will be evaluated at 12 months follow-up.

Outcome measures for safety Safety endpoints will be collected, reported to the authorities and monitored according to legislation during the entire study period.

Adverse event (AE) is defined as any untoward medical occurrence in a subject who was treated with an investigational product, and does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease, whether or not related to the investigational product.

Serious adverse event (SAE) is defined as any untoward medical occurrence that:

1. results in death
2. is life-threatening
3. requires inpatient hospitalisation or prolongation of existing hospitalisation
4. results in persistent or significant disability/incapacity
5. is a congenital anomaly/birth defect
6. is medically important

Suspected unexpected serious adverse event reactions (SUSAR) is defined as a SAE occurring in a subject in an interventional study that is assessed as both causally related to the suspect product under clinical investigation and unexpected per the Investigator's Brochure (IB).

An independent Data Safety Monitoring Board (DSMB) will be established to evaluate the safety of the treatment. The DSMB will report directly to the director of the Project Management Board, which will take the necessary action upon the DSMB's recommendations.

Study medication The investigational cell product, CSCC_ASC, will be produced in an approved GMP facility in Cardiology Stem Cell Centre at Rigshospitalet University Hospital, Copenhagen, Denmark.

The production of the allogeneic CSCC_ASCs will follow the description in an approved Investigational Medicinal Product Dossier. The cell product will come from healthy donors.

The production unit will label the investigational medicinal product (IMP) in accordance with the legislation and keep the randomisation code until finalisation of the clinical trial. The final cell products will be stored in nitrogen vapour containers until clinical use.

Allogeneic MSCs and ASCs have been administered to more than 600 patients with heart disease. In the conducted clinical trials there has not been any serious adverse event due to the treatment. A few patients have developed transient donor specific HLA-antibodies in serum within the first months after treatment. However, none of the patients had any symptoms related to the presence of antibodies. Transient fever was registered in a few patients, but it could as well be due to the treatment procedure or the disease for treatment.

Based on the accumulated safety and efficacy evidence with clinical use of allogeneic MSCs and ASCs in conducted clinical trials and the safety data from the CSCC_ASC phase I trial and the two ongoing phase II trials then it is concluded that it is safe to conduct a pilot CSCC_ASC trial in patients with NIDCM and HF.

Echocardiography

The echocardiography data will be recorded at pre-defined intervals according to American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) recommendations. For each patient at least five end-expiratory full cardiac cycles will be recorded for each protocol specified view. All acquired images will be de-identified and transferred to independent imaging core-lab (Stanford Cardiovascular Institute Clinical Biomarker \& Phenotyping Core Lab). The recordings will be analyzed at the end of the study by an independent echocardiographer who will be blinded to the patient's treatment status and the timing of the recordings. All measurements will be performed according to ASE/EACVI recommendations. All echocardiographic measurements will be averaged over 5 cardiac cycles. Left ventricular end-systolic dimension (LVESD) and end-diastolic dimension (LVEDD) will be measured in the parasternal long-axis view. Left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and LVEF will be estimated using the Simpson's biplane method. Peak longitudinal strains will be computed automatically to generate regional data from each of the 17 segments and then averaged to calculate global longitudinal strain.