Clinical trials of repeated cell therapy in ischaemic or non-ischaemic cardiomyopathy
| Trials . | Phase . | Clinical setting . | Placebo controlled; randomized; double-blind . | Follow-up . | n . | Cell type, dose, and treatment groups . | Delivery method . | Endpoint evaluation . | LVEF . | LV volumes . | Scar size . | NYHA class . | Functional capacity . | QoL . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DanCell-CHF Diederichsen et al.198 | II | Ischaemic HF | Not; not; not | 12 months | 32 | One group: 647 ± 382 × 106 (1st dose) and 889 ± 361 × 106 (2nd dose) BM-MNCs, 4 months apart; variables compared before and after treatment | IC | Echo | NS | NS | NA | ↑ | NS | NA |
| Yao et al.199 | ? | First STEMI with LVEF 20–39% | Yes; yes; ? | 12 months | 39 | Three groups: single dose 1.9 ± 1.2 × 108; two doses of 2.0 ± 1.4 × 108 and 2.1 ± 1.7 × 108 BM-MNCs 3 months apart; one dose of placebo | IC | MRI/SPECT | 2 doses > 1 dose > control | 2 doses > 1 dose > control | 2 doses > 1 dose > control | NA | NA | NA |
| Gu et al.200 | I | Ischaemic HF | Not; ?; not | 12 months | 45 | Control (no intervention) vs. single dose SC G-CSF and single dose (1.5–2 × 108) IV MNCs containing a minimum of 1 × 106 CD34+cells vs. single dose G-CSF and two doses of IV MNCs 6 months apart | IC | Echo/SPECT | 2 doses > 1 dose > control | NA | LVEDV: 2 doses > 1 dose > control | 2 doses > 1 dose or control | NA | NA |
| Mann et al.201 a | NA | Refractory, no-option angina | Not; not; not | 12 months | 23 | One group: 1st dose 93.5 ± 20.1 × 106 BM-MNCs (with 2.0 ± 1.4% CD34+ cells); 2nd dose 98.7 ± 6.3 × 106 BM-MNCs (with 1.8 ± 1.2% CD34+ cells), 4.6 ± 2.5 years apart | TO | MRI/SPECT | NA | NA | NA | NA | ↑ | ↑ |
| Assmus et al.202b | NA | Ischaemic HF | Not; not; not | 36 months | 297 | Two doses of 190 + 110 × 106 BM-MNCs at 3–6 months vs. one dose | IC | SHFM score | NA | NA | NA | NA | NA | NA |
| Vrtovec et al.74 | II/III | Non-ischaemic HF | No; yes; yes | 12 months | 60 | Two doses 6 months apart vs. single dose of 80 × 106 G-CSF-mobilized CD34+ cells | TO | Echo | NS | NS | NA | NA | NS | NA |
| REPEAT121c | II/III | Ischaemic cardiomyopathy, EF ≤45% | No; yes; no | 5 years | 81 | Autologous BM-MNCs, one vs. two doses 4 months apart | IC | Follow-up | NA | NA | NA | NA | NA | NA |
| Trials . | Phase . | Clinical setting . | Placebo controlled; randomized; double-blind . | Follow-up . | n . | Cell type, dose, and treatment groups . | Delivery method . | Endpoint evaluation . | LVEF . | LV volumes . | Scar size . | NYHA class . | Functional capacity . | QoL . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DanCell-CHF Diederichsen et al.198 | II | Ischaemic HF | Not; not; not | 12 months | 32 | One group: 647 ± 382 × 106 (1st dose) and 889 ± 361 × 106 (2nd dose) BM-MNCs, 4 months apart; variables compared before and after treatment | IC | Echo | NS | NS | NA | ↑ | NS | NA |
| Yao et al.199 | ? | First STEMI with LVEF 20–39% | Yes; yes; ? | 12 months | 39 | Three groups: single dose 1.9 ± 1.2 × 108; two doses of 2.0 ± 1.4 × 108 and 2.1 ± 1.7 × 108 BM-MNCs 3 months apart; one dose of placebo | IC | MRI/SPECT | 2 doses > 1 dose > control | 2 doses > 1 dose > control | 2 doses > 1 dose > control | NA | NA | NA |
| Gu et al.200 | I | Ischaemic HF | Not; ?; not | 12 months | 45 | Control (no intervention) vs. single dose SC G-CSF and single dose (1.5–2 × 108) IV MNCs containing a minimum of 1 × 106 CD34+cells vs. single dose G-CSF and two doses of IV MNCs 6 months apart | IC | Echo/SPECT | 2 doses > 1 dose > control | NA | LVEDV: 2 doses > 1 dose > control | 2 doses > 1 dose or control | NA | NA |
| Mann et al.201 a | NA | Refractory, no-option angina | Not; not; not | 12 months | 23 | One group: 1st dose 93.5 ± 20.1 × 106 BM-MNCs (with 2.0 ± 1.4% CD34+ cells); 2nd dose 98.7 ± 6.3 × 106 BM-MNCs (with 1.8 ± 1.2% CD34+ cells), 4.6 ± 2.5 years apart | TO | MRI/SPECT | NA | NA | NA | NA | ↑ | ↑ |
| Assmus et al.202b | NA | Ischaemic HF | Not; not; not | 36 months | 297 | Two doses of 190 + 110 × 106 BM-MNCs at 3–6 months vs. one dose | IC | SHFM score | NA | NA | NA | NA | NA | NA |
| Vrtovec et al.74 | II/III | Non-ischaemic HF | No; yes; yes | 12 months | 60 | Two doses 6 months apart vs. single dose of 80 × 106 G-CSF-mobilized CD34+ cells | TO | Echo | NS | NS | NA | NA | NS | NA |
| REPEAT121c | II/III | Ischaemic cardiomyopathy, EF ≤45% | No; yes; no | 5 years | 81 | Autologous BM-MNCs, one vs. two doses 4 months apart | IC | Follow-up | NA | NA | NA | NA | NA | NA |
Trials are listed in chronological order of publication.
indicates increase; ↓, decrease; BMMNCs, bone marrow mononuclear cells; Echo, echocardiography; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; G-CSF, Granulocyte-colony stimulating factor; HF, heart failure; IC, intracoronary; IV, intravenous; LV, left ventricle; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; n, number of patients; NA, not assessed; NS, not significant; NYHA, New York Heart Association; QoL, quality of life; SHFM, Seattle Heart Failure model; SPECT, single-photon emission tomography; STEMI, ST-elevation myocardial infarction; TE, transendocardial.
Improvement in myocardial perfusion (measured by SPECT), angina, and quality of life score was noted.
Repeated intracoronary infusion of autologous BMMNCs was associated with significantly better 2-year survival compared with a single BMMNC infusion. At the 3-year follow-up, the trend persisted but the mortality reduction was no longer statistically significant between single and repeated treatment. Additionally, mortality was significantly lower at the 2-year follow-up compared with the mortality estimated using the Seattle Heart Failure Model (SHFM) in patients receiving repeated BMMNC infusions.
Study will be completed in 2022. Primary endpoint: mortality at 2 years; secondary endpoint: Morbidity [cardiac and cardiovascular mortality, HF hospitalization, ischaemic cardiac events, coronary revascularization, cardiac transplantation, assisted device implantation, new synchronization therapy, ICD implantation, NYHA status, MLHFQ, bleeding events, all in-hospital events (during hospitalization for BMC therapy), life-threatening arrhythmias, new malignancies].
Clinical trials of repeated cell therapy in ischaemic or non-ischaemic cardiomyopathy
| Trials . | Phase . | Clinical setting . | Placebo controlled; randomized; double-blind . | Follow-up . | n . | Cell type, dose, and treatment groups . | Delivery method . | Endpoint evaluation . | LVEF . | LV volumes . | Scar size . | NYHA class . | Functional capacity . | QoL . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DanCell-CHF Diederichsen et al.198 | II | Ischaemic HF | Not; not; not | 12 months | 32 | One group: 647 ± 382 × 106 (1st dose) and 889 ± 361 × 106 (2nd dose) BM-MNCs, 4 months apart; variables compared before and after treatment | IC | Echo | NS | NS | NA | ↑ | NS | NA |
| Yao et al.199 | ? | First STEMI with LVEF 20–39% | Yes; yes; ? | 12 months | 39 | Three groups: single dose 1.9 ± 1.2 × 108; two doses of 2.0 ± 1.4 × 108 and 2.1 ± 1.7 × 108 BM-MNCs 3 months apart; one dose of placebo | IC | MRI/SPECT | 2 doses > 1 dose > control | 2 doses > 1 dose > control | 2 doses > 1 dose > control | NA | NA | NA |
| Gu et al.200 | I | Ischaemic HF | Not; ?; not | 12 months | 45 | Control (no intervention) vs. single dose SC G-CSF and single dose (1.5–2 × 108) IV MNCs containing a minimum of 1 × 106 CD34+cells vs. single dose G-CSF and two doses of IV MNCs 6 months apart | IC | Echo/SPECT | 2 doses > 1 dose > control | NA | LVEDV: 2 doses > 1 dose > control | 2 doses > 1 dose or control | NA | NA |
| Mann et al.201 a | NA | Refractory, no-option angina | Not; not; not | 12 months | 23 | One group: 1st dose 93.5 ± 20.1 × 106 BM-MNCs (with 2.0 ± 1.4% CD34+ cells); 2nd dose 98.7 ± 6.3 × 106 BM-MNCs (with 1.8 ± 1.2% CD34+ cells), 4.6 ± 2.5 years apart | TO | MRI/SPECT | NA | NA | NA | NA | ↑ | ↑ |
| Assmus et al.202b | NA | Ischaemic HF | Not; not; not | 36 months | 297 | Two doses of 190 + 110 × 106 BM-MNCs at 3–6 months vs. one dose | IC | SHFM score | NA | NA | NA | NA | NA | NA |
| Vrtovec et al.74 | II/III | Non-ischaemic HF | No; yes; yes | 12 months | 60 | Two doses 6 months apart vs. single dose of 80 × 106 G-CSF-mobilized CD34+ cells | TO | Echo | NS | NS | NA | NA | NS | NA |
| REPEAT121c | II/III | Ischaemic cardiomyopathy, EF ≤45% | No; yes; no | 5 years | 81 | Autologous BM-MNCs, one vs. two doses 4 months apart | IC | Follow-up | NA | NA | NA | NA | NA | NA |
| Trials . | Phase . | Clinical setting . | Placebo controlled; randomized; double-blind . | Follow-up . | n . | Cell type, dose, and treatment groups . | Delivery method . | Endpoint evaluation . | LVEF . | LV volumes . | Scar size . | NYHA class . | Functional capacity . | QoL . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DanCell-CHF Diederichsen et al.198 | II | Ischaemic HF | Not; not; not | 12 months | 32 | One group: 647 ± 382 × 106 (1st dose) and 889 ± 361 × 106 (2nd dose) BM-MNCs, 4 months apart; variables compared before and after treatment | IC | Echo | NS | NS | NA | ↑ | NS | NA |
| Yao et al.199 | ? | First STEMI with LVEF 20–39% | Yes; yes; ? | 12 months | 39 | Three groups: single dose 1.9 ± 1.2 × 108; two doses of 2.0 ± 1.4 × 108 and 2.1 ± 1.7 × 108 BM-MNCs 3 months apart; one dose of placebo | IC | MRI/SPECT | 2 doses > 1 dose > control | 2 doses > 1 dose > control | 2 doses > 1 dose > control | NA | NA | NA |
| Gu et al.200 | I | Ischaemic HF | Not; ?; not | 12 months | 45 | Control (no intervention) vs. single dose SC G-CSF and single dose (1.5–2 × 108) IV MNCs containing a minimum of 1 × 106 CD34+cells vs. single dose G-CSF and two doses of IV MNCs 6 months apart | IC | Echo/SPECT | 2 doses > 1 dose > control | NA | LVEDV: 2 doses > 1 dose > control | 2 doses > 1 dose or control | NA | NA |
| Mann et al.201 a | NA | Refractory, no-option angina | Not; not; not | 12 months | 23 | One group: 1st dose 93.5 ± 20.1 × 106 BM-MNCs (with 2.0 ± 1.4% CD34+ cells); 2nd dose 98.7 ± 6.3 × 106 BM-MNCs (with 1.8 ± 1.2% CD34+ cells), 4.6 ± 2.5 years apart | TO | MRI/SPECT | NA | NA | NA | NA | ↑ | ↑ |
| Assmus et al.202b | NA | Ischaemic HF | Not; not; not | 36 months | 297 | Two doses of 190 + 110 × 106 BM-MNCs at 3–6 months vs. one dose | IC | SHFM score | NA | NA | NA | NA | NA | NA |
| Vrtovec et al.74 | II/III | Non-ischaemic HF | No; yes; yes | 12 months | 60 | Two doses 6 months apart vs. single dose of 80 × 106 G-CSF-mobilized CD34+ cells | TO | Echo | NS | NS | NA | NA | NS | NA |
| REPEAT121c | II/III | Ischaemic cardiomyopathy, EF ≤45% | No; yes; no | 5 years | 81 | Autologous BM-MNCs, one vs. two doses 4 months apart | IC | Follow-up | NA | NA | NA | NA | NA | NA |
Trials are listed in chronological order of publication.
indicates increase; ↓, decrease; BMMNCs, bone marrow mononuclear cells; Echo, echocardiography; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; G-CSF, Granulocyte-colony stimulating factor; HF, heart failure; IC, intracoronary; IV, intravenous; LV, left ventricle; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; n, number of patients; NA, not assessed; NS, not significant; NYHA, New York Heart Association; QoL, quality of life; SHFM, Seattle Heart Failure model; SPECT, single-photon emission tomography; STEMI, ST-elevation myocardial infarction; TE, transendocardial.
Improvement in myocardial perfusion (measured by SPECT), angina, and quality of life score was noted.
Repeated intracoronary infusion of autologous BMMNCs was associated with significantly better 2-year survival compared with a single BMMNC infusion. At the 3-year follow-up, the trend persisted but the mortality reduction was no longer statistically significant between single and repeated treatment. Additionally, mortality was significantly lower at the 2-year follow-up compared with the mortality estimated using the Seattle Heart Failure Model (SHFM) in patients receiving repeated BMMNC infusions.
Study will be completed in 2022. Primary endpoint: mortality at 2 years; secondary endpoint: Morbidity [cardiac and cardiovascular mortality, HF hospitalization, ischaemic cardiac events, coronary revascularization, cardiac transplantation, assisted device implantation, new synchronization therapy, ICD implantation, NYHA status, MLHFQ, bleeding events, all in-hospital events (during hospitalization for BMC therapy), life-threatening arrhythmias, new malignancies].
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