Stem Cell Therapy for Septic Shock

(UC-CISSII Trial)

Recruiting at 1 trial location

Overseen By Josee Champagne

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ottawa Hospital Research Institute

Disqualifiers: Other shock, Pulmonary hypertension, Cardiac disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

Duration: 28 days

296 Participants Needed

Trial Summary

What is the purpose of this trial?

Septic shock is associated with substantial burden in terms of both mortality and morbidity for survivors of this illness. Pre-clinical sepsis studies suggest that mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance pathogen clearance and tissue repair and reduce death. Our team has completed a Phase I dose escalation and safety clinical trial that evaluated MSCs in patients with septic shock. The Cellular Immunotherapy for Septic Shock Phase I (CISS) trial established that MSCs appear safe and that a randomized controlled trial (RCT) is feasible. Based on these data, the investigators have planned a phase II RCT (UC-CISS II) at several Canadian academic centres which will evaluate intermediate measures of clinical efficacy (primary outcome), as well as biomarkers, safety, clinical outcome measures, and a health economic analysis (secondary outcomes).

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Allogeneic umbilical cord-derived human mesenchymal stromal cells for septic shock?

Research shows that umbilical cord-derived mesenchymal stem cells (UC-MSCs) improved survival and bacterial clearance in neonatal sepsis in rats, and clinical-grade UC-MSCs improved septic shock outcomes in pigs, suggesting potential benefits for septic shock treatment. ^{1 2 3 4 5}

Is stem cell therapy using umbilical cord-derived mesenchymal stem cells safe for humans?

Research shows that umbilical cord-derived mesenchymal stem cells have been tested for safety in conditions like acute respiratory distress syndrome, and they do not turn into cancerous cells during long-term lab growth. These findings suggest that they are generally safe for use in humans. ^{1 4 6 7 8}

How is the treatment with umbilical cord-derived mesenchymal stem cells different from other treatments for septic shock?

This treatment is unique because it uses stem cells from the umbilical cord, which have shown potential to improve organ function and survival in septic shock by enhancing the body's immune response and promoting blood vessel growth. Unlike standard treatments, which mainly focus on managing symptoms, this approach targets the underlying immune and inflammatory processes. ^{1 3 4 9 10}

Research Team

Lauralyn McIntyre, MD

Principal Investigator

The Ottawa Hospital Research Institute

Eligibility Criteria

This trial is for adults over 18 in intensive care with septic shock, needing certain levels of drugs to maintain blood pressure, respiratory or kidney support, or showing signs of organ failure due to infection. They must be within the first 48 hours of these conditions being identified upon ICU admission.

Inclusion Criteria

My heart issues are thought to be caused by an infection.

You are experiencing respiratory failure requiring invasive or non-invasive mechanical ventilation with a PEEP of 5 cm H2O minimum, high flow nasal canula oxygen therapy of 40 lpm minimum, and have a P/F ratio below 200; OR you have hematological failure evidenced by platelet count lower than 100 X 10^9/L; OR acute kidney injury manifested as creatinine higher than 200 umol/L or the need for renal replacement therapy even if having chronic renal failure but not on dialysis yet showing 50% increase in baseline creatinine concentration; OR organ hypoperfusion marked by lactate greater

I need to be admitted to the ICU.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells or placebo

28 days

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of biomarkers, safety, and clinical outcomes

1 year

Regular follow-up visits at 30 days, 6 months, and 1 year

Long-term Follow-up

Extended monitoring for patient-reported outcomes and health economic analysis

Up to 1 year

Treatment Details

Interventions

• Allogeneic umbilical cord-derived human mesenchymal stromal cells

Trial Overview The study tests if mesenchymal stromal cells from umbilical cords can help treat septic shock by modulating inflammation and enhancing recovery. It's a phase II randomized controlled trial comparing these cells' effects against a placebo.

Participant Groups

Group I: Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs) Experimental Treatment 1 Intervention

Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells

Group II: Placebo Placebo Group 1 Intervention

Intravenous infusion of placebo, with excipients

Who Is Running the Clinical Trial?

Ottawa Hospital Research Institute

Lead Sponsor

Trials

585

Recruited

3,283,000+

Technische Universität Dresden

Collaborator

Trials

292

Recruited

2,275,000+

Canadian Critical Care Trials Group

Collaborator

Trials

32

Recruited

227,000+

Stem Cell Network

Collaborator

Trials

9

Recruited

600+

Center for Regenerative Therapies Dresden (CRTD)

Collaborator

Trials

1

Recruited

300+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

Both amniotic fluid-derived mesenchymal stem cells (AF-MSCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) are safe and effective in treating sepsis in a rat model, significantly improving survival rates and reversing harmful changes caused by sepsis.

AF-MSCs and UC-MSCs have different therapeutic effects on various organs; UC-MSCs are more effective in reducing inflammation in the lungs and liver, while AF-MSCs better protect kidney function by reducing cell death and lowering blood urea nitrogen levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MSCs derived from amniotic fluid and umbilical cord require different administration schemes and exert different curative effects on different tissues in rats with CLP-induced sepsis. Chen, R., Xie, Y., Zhong, X., et al.[2021]

A 59-year-old man with acute respiratory distress syndrome (ARDS) showed immediate improvement in lung function and mental status after receiving a dose of umbilical cord blood-derived mesenchymal stem cells (MSCs) via intratracheal administration on hospital day 114.

This case represents the first reported use of UCB-derived MSC therapy in ARDS, suggesting potential for this treatment approach, despite the patient ultimately succumbing to pulmonary infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intratracheal administration of umbilical cord blood-derived mesenchymal stem cells in a patient with acute respiratory distress syndrome. Chang, Y., Park, SH., Huh, JW., et al.[2022]

In a study involving 184 septic rats, treatment with human umbilical cord mesenchymal stem cells (UC-MSCs) significantly reduced pro-inflammatory factors like TNF-α and HMGB1 while increasing the anti-inflammatory factor IL-10, suggesting a potential mechanism for improving immune function during sepsis.

Although UC-MSCs treatment improved immune cell profiles, such as normalizing CD4+ T cell percentages and Th1/Th2 ratios, it did not significantly enhance the survival rate of the septic rats compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immune intervention of human umbilical cord mesenchymal stem cells on sepsis rats]. Zhang, H., Cui, X., Fang, T., et al.[2019]

In a study involving 12 male pigs with septic shock induced by fecal peritonitis, the administration of umbilical cord-derived mesenchymal stem cells (UCMSCs) significantly improved survival rates (60% survival vs. 0% in the placebo group) and reduced cardiovascular failure.

UCMSCs treatment led to better hemodynamic stability, evidenced by improved mean arterial pressure and lower lactate levels, while also decreasing the need for norepinephrine, indicating a potential therapeutic benefit in managing septic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs. Laroye, C., Lemarié, J., Boufenzer, A., et al.[2023]

Treatment with human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) significantly improved survival rates in neonatal sepsis models, with survival rates of 81% for hUC-MSCs and 89% for preconditioned hUC-MSCs compared to 51% for saline.

Both hUC-MSCs and preconditioned hUC-MSCs enhanced bacterial clearance and reduced splenocyte apoptosis, suggesting they may serve as effective adjunct therapies to lower morbidity and mortality associated with neonatal sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord Mesenchymal Stromal Cells Improve Survival and Bacterial Clearance in Neonatal Sepsis in Rats. Zhu, Y., Xu, L., Collins, JJP., et al.[2022]

Lentivirus-GFP labeling of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) proved to be the most effective method for long-term tracking, remaining detectable up to 14 passages, while other methods like BrdU and PKH26 showed significant decreases in labeling efficiency over time.

All labeled hUCMSCs, regardless of the labeling method, maintained their ability to differentiate into adipocytes and osteoblasts, indicating that the labeling process does not negatively impact their functional capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of in vitro cell labeling methods for human umbilical cord-derived mesenchymal stem cells. Tao, R., Sun, TJ., Han, YQ., et al.[2018]

In a phase I clinical trial involving 9 patients with moderate-to-severe acute respiratory distress syndrome, a single-dose infusion of human umbilical cord-derived mesenchymal stem cells was found to be safe, with no serious treatment-related adverse events reported.

The treatment showed promising effects on inflammatory biomarkers and immune cell markers, indicating a potential beneficial impact on the immune response in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome. Yip, HK., Fang, WF., Li, YC., et al.[2021]

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can be safely cultured in serum-free medium for up to 15 passages without signs of malignant transformation, making them suitable for cell therapy.

The study confirmed that hUC-MSCs maintained their ability to differentiate into various cell types (osteocytes, chondrocytes, and adipocytes) and met the International Society for Cellular Therapy standards, indicating their potential for therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human umbilical cord-derived mesenchymal stem cells do not undergo malignant transformation during long-term culturing in serum-free medium. Chen, G., Yue, A., Ruan, Z., et al.[2022]

UC-MSCs (mesenchymal stromal/stem cells from human umbilical cord) demonstrate pro-angiogenic properties by promoting the proliferation and migration of endothelial cells, even without producing detectable levels of VEGF-A, indicating a VEGF-A-independent mechanism.

The study shows that UC-MSCs can differentiate into endothelial-like cells and form tubular structures, suggesting their potential for therapeutic angiogenesis in cell therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of VEGF-A in angiogenesis promoted by umbilical cord-derived mesenchymal stromal/stem cells: in vitro study. Arutyunyan, I., Fatkhudinov, T., Kananykhina, E., et al.[2022]

Human umbilical cord mesenchymal stromal cells significantly improved survival rates in a rat model of fecal sepsis, with the most effective dose being 10 million cells/kg, increasing survival from 48% to 88%.

The therapeutic effects of these cells are partly mediated by the upregulation of heme oxygenase-1 in macrophages, which enhances their ability to kill bacteria, highlighting the importance of lipoxin A4 and prostaglandin E2 in this interaction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats. Jerkic, M., Gagnon, S., Rabani, R., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

MSCs derived from amniotic fluid and umbilical cord require different administration schemes and exert different curative effects on different tissues in rats with CLP-induced sepsis. [2021]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Intratracheal administration of umbilical cord blood-derived mesenchymal stem cells in a patient with acute respiratory distress syndrome. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Immune intervention of human umbilical cord mesenchymal stem cells on sepsis rats]. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord Mesenchymal Stromal Cells Improve Survival and Bacterial Clearance in Neonatal Sepsis in Rats. [2022]

6. Italy pubmed.ncbi.nlm.nih.gov

Optimization of in vitro cell labeling methods for human umbilical cord-derived mesenchymal stem cells. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Human umbilical cord-derived mesenchymal stem cells do not undergo malignant transformation during long-term culturing in serum-free medium. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Role of VEGF-A in angiogenesis promoted by umbilical cord-derived mesenchymal stromal/stem cells: in vitro study. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats. [2020]