Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial

doi:10.1016/S1474-4422(17)30046-7

The Lancet Neurology

Volume 16, Issue 5, May 2017, Pages 360-368

https://doi.org/10.1016/S1474-4422(17)30046-7 Get rights and content

Summary

Background

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery.

Methods

We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18–83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24–48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487.

Findings

The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55–2·09], p=0·83).

Interpretation

Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned.

Funding

Athersys Inc.

Introduction

Intravenous tissue plasminogen activator (tPA; alteplase) and endovascular thrombectomy are effective treatments for stroke. However, the time window for these treatments is limited to 4·5 h for tPA and 6·0 h in the UK and USA for endovascular thrombectomy from symptom onset, and endovascular thrombectomy requires specialised stroke expertise and endovascular skills available mainly at comprehensive stroke centres.1, 2 Less than 5% of patients with ischaemic stroke benefit from these therapies and, even with endovascular thrombectomy, up to 50% of patients cab due or be disabled at 90 days.² Hence, there is a large unmet need for safe, effective, and widely available treatments for acute stroke beyond 6 h from symptom onset.

Cell therapy for stroke has been shown in animal models to be a promising strategy to limit ischaemic injury and promote recovery after ischaemic stroke in extended time windows.3, 4 Cell therapy approaches include different cell types (eg, mesenchymal stem cells, bone marrow mononuclear cells, and neural stem cells), routes of administration (eg, intravenous, intra-arterial, or intracerebral), and time windows (days to months).3, 5 In two small phase 1, single arm, open-label clinical trials in patients with stroke,6, 7 intracerebral delivery of either a neural stem cell line or a mesenchymal stem cell line were shown to be safe. In the first week after stroke, the immune system is activated with splenocytes and other immune cells targeting the ischaemic brain, possibly aggravating ischaemic damage, and preventing remodelling and recovery.4, 8 This period is probably an optimum time window for intravenous administration of bone marrow-derived cell therapies to provide therapeutic benefit given their immunomodulatory effects.³ Intravenous administration of autologous bone marrow-derived cells is safe, but requires expansion time in culture that prohibits administration of a therapeutically relevant number of cells to the patient in the first week.9, 10 A more optimised approach is an allogeneic cell therapy product administered intravenously, that is scalable and universal, and requires no tissue matching. Multipotent adult progenitor cells are a plastic, adherent, bone marrow derived population of adult progenitor cells first characterised more than a decade ago.11, 12 Clinical grade multipotent adult progenitor cells are isolated from a healthy unrelated donor and are an allogenic universal cell therapy with long-term culture expansion and potency.13, 14 Compared with other adherent cells, such as mesenchymal stem cells, multipotent adult progenitor cells have an extended differentiation capability,¹⁵ and distinct phenotype and functional characteristics,¹⁵ transcriptome,¹⁵ secretome,¹⁶ miRNA profiles, and size.¹⁷

Research in context

Evidence before this study

We searched PubMed up to Oct 24, 2016 using the search terms “cell therapy AND stroke”, ‘mesenchymal stem cells AND stroke”, and “bone marrow-derived stem cells AND stroke”; the search was restricted to English language papers. There have been less than ten cell therapy trials of intracerebral injection of neural or neutralised stem cells in stroke, less than ten single centre trials of intravenous autologous bone marrow-derived cells and mesenchymal stem cells, and less than ten small intra-arterial cell therapy trials in stroke. Many of these trials have shown safety and some promise of efficacy in stroke treatment. However, there have been no large multicentre, randomised, placebo-controlled trials of an allogeneic bone marrow-derived cell therapy.

Added value of this study

This randomised, double-blind, phase 2, placebo-controlled trial of an allogeneic cell therapy with no required tissue matching showed feasibility of a multicentre cell-therapy trial in stroke, and the safety and tolerability of multipotent adult progenitor cells treatment. Although the primary efficacy outcome of multivariate global stroke recovery and secondary outcomes showed no difference between groups, post-hoc analyses of patients treated earlier in the time window between 24 h and 36 h suggest benefit in outcome at 1 year follow-up that requires confirmation in future trials.

Implications of all available evidence

Stroke is the leading cause of disability worldwide in adults, yet treatment for stroke is a huge unmet need. Cell therapy is a promising treatment avenue for stroke therapy. This trial indicates that multipotent adult progenitor cells therapy is safe, tolerable, and feasible in multicentre clinical trials. Treatment efficacy of multipotent adult progenitor cells needs to be explored in future trials within the 18–36 h time window after stroke onset.

We did a phase 2, multicentre, double-blind, randomised, parallel group, placebo-controlled trial of multipotent adult progenitor cells treatment in patients with moderately severe acute ischaemic stroke.¹⁸ In the MultiStem in Acute Stroke Treatment to Enhance Recovery Study (MASTERS), we aimed to establish the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells up to a maximum of 1200 million total cells, and if there was efficacy as a treatment for stroke recovery.

Section snippets

Study design

We did a phase 2 multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells compared with placebo.¹⁸ We enrolled and randomly assigned patients in two escalating dose tiers (groups 1 and 2) and then chose the highest well tolerated dose for administration to patients in group 3. The study was done in 33 medical centres in the UK and in the USA, and was approved by local institutional review boards and ethics committees.

Patients

Results

This study was done between Oct 24, 2011, and Dec 7, 2015. Of the nine patients screened for group 1, we randomised eight (six received 400 million cells and two received placebo). One patient did not meet the inclusion criteria and was not randomly allocated to a treatment. After this dose was determined to have no safety concerns, we randomly assigned 129 patients for groups 2 and then group 3 (1200 million cells; figure). Of these, 65 patients in the multipotent adult progenitor cells group

Discussion

Multipotent adult progenitor cell therapy was safe and well tolerated up to a dose of 1200 million cells after a one time intravenous infusion in patients with moderate to moderately severe acute ischaemic stroke. There were no infusion or allergic reactions, no dose limiting toxic events, and adverse events were similar between arms. There was no difference in mortality between arms. In the ITT analysis, there was no difference between the multipotent adult progenitor cells and the placebo

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Oligodendrocytes in human induced pluripotent stem cell-derived cortical grafts remyelinate adult rat and human cortical neurons
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Neuronal loss and axonal demyelination underlie long-term functional impairments in patients affected by brain disorders such as ischemic stroke. Stem cell-based approaches reconstructing and remyelinating brain neural circuitry, leading to recovery, are highly warranted. Here, we demonstrate the in vitro and in vivo production of myelinating oligodendrocytes from a human induced pluripotent stem cell (iPSC)-derived long-term neuroepithelial stem (lt-NES) cell line, which also gives rise to neurons with the capacity to integrate into stroke-injured, adult rat cortical networks. Most importantly, the generated oligodendrocytes survive and form myelin-ensheathing human axons in the host tissue after grafting onto adult human cortical organotypic cultures. This lt-NES cell line is the first human stem cell source that, after intracerebral delivery, can repair both injured neural circuitries and demyelinated axons. Our findings provide supportive evidence for the potential future use of human iPSC-derived cell lines to promote effective clinical recovery following brain injuries.
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Cell therapies have been explored to treat patients with nervous diseases for over 20 years. Even though most kinds of cell therapies demonstrated neurorestorative effects in non-randomized clinical trials; the effects of the majority type cells could not be confirmed by randomized controlled trials. In this review, clinical therapeutic results of neurorestorative cell therapies according to cellular bio-proprieties or cellular functions were introduced. Currently it was demonstrated from analysis of this review that some indications of cell therapies were not appropriate, they might be reasons why their neurorestorative effects could not be proved by multicenter, randomized, double blind, placebo-controlled clinical trials. Theoretically if one kind of cell therapy has neurorestorative effects according to its cellular bio-proprieties, it should have appropriate indications. The cell therapies with special bio-properties is promising if the indication selections are appropriate, such as olfactory ensheathing cells for chronic ischemic stroke, and their neurorestorative effects can be confirmed by higher level clinical trials of evidence-based medicine.
Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial
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Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke.
The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18–80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1–7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6–20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 10⁶ BMMNCs/kg or 5 × 10⁶ BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed.
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Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints.
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ArticlesSafety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design

Patients

Results

Discussion

Lancet

Lancet

Lancet

Neuroscience

Exp Hematol

Cell Immunol

Lancet

Exp Neurol

Stem cell-based tissue replacement after stroke: factual necessity or notorious fiction?

Stroke

Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials

Stroke

Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II

Stroke

Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study

Stroke

Intravenous autologous bone marrow mononuclear cells for ischemic stroke

Ann Neurol

A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke

Stem Cells

Pluripotency of mesenchymal stem cells derived from adult marrow

Nature

Global characterization and genomic stability of human multistem, a multipotent adult progenitor cell

J Stem Cells

Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cellsreflected in their transcriptome and partially influenced by the culture conditions

Stem Cells

Articles
Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial