Advanced Mesenchymal Enhanced Cell THerapY for SepTic Patients (AMETHYST)

• ClinicalTrials.gov Identifier: NCT04961658
• Recruitment Status: Recruiting
• First Posted: July 14, 2021
• Last Update Posted: November 18, 2022
• Sponsor: Northern Therapeutics
• Information provided by (Responsible Party): Northern Therapeutics

Study Description

Brief Summary:

Bacterial sepsis occurs in patients with severe infections. The condition is caused by toxic substances (toxins) released from bacteria and the patient's elevated inflammatory response to those toxins. In preclinical studies, human mesenchymal stromal cells (MSCs) have been proven to modulate host inflammation in infections, including sepsis. The purpose of the Phase I, open label, dose escalation safety trial is to determine whether escalating doses of enhanced MSCs (GEM00220) are safe and well tolerated in patients with septic shock.

Condition or disease	Intervention/treatment	Phase
Septic Shock	Biological: GEM00220	Phase 1

Detailed Description:

This trial consists of 2 sequential parts using the same trial infrastructure:

Phase 1a: A dose escalating and safety trial with pre-defined stopping rules for safety. Up to 9 participants will receive a single infusion of GEM00220. If no safety issues are identified, we will continue to the Phase 1b trial at the maximum feasible tolerated dose.

Phase 1b: A single-arm, open-label extension of the Phase 1a trial to assess early signs of efficacy (major morbidity and mortality). The Phase 1b trial will enroll up to 12 participants to assess early signals of benefit on mortality and major morbidity in a high risk, high mortality population.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 21 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

A dose-escalation study evaluating GEM00220 cell therapy in 3 cohorts with 3 subjects per cohort. Study will proceed from lower dose to next higher dose if no safety concerns are observed in each cohort. If no safety issues are identified, we will continue to the Phase 1b trial.

Phase 1b: A single-arm, open-label extension of the Phase 1a trial to assess early signs of efficacy (major morbidity and mortality). The Phase 1b trial will enroll up to 12 participants.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Advanced Mesenchymal Enhanced Cell THerapY for SepTic Patients
• Actual Study Start Date: August 11, 2021
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: August 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Arm - Low Dose; Participants will receive a single dose of GEM00220 at 15 million cells	Biological: GEM00220; Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion
Experimental: Treatment arm - Mid dose; Participants will receive a single dose of GEM00220 at 60 million cells	Biological: GEM00220; Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion
Experimental: Treatment arm - High dose; Participants will receive a single dose of GEM00220 at 150 million cells	Biological: GEM00220; Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion

Outcome Measures

Primary Outcome Measures :

1. The safety of GEM00220 will be assessed by monitoring adverse events [ Time Frame: Baseline to 28 days ]
2. Maximum Feasible Tolerated Dose [ Time Frame: Baseline to 28 days ]
   The highest dose which does not meet any of the pre-defined stopping criteria

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult patients age 18 years and older
2. Receipt of appropriate antibiotics for the suspected/confirmed bacterial sepsis as the main diagnosis according to the opinion of the treating critical care staff physician.
3. Refractory hypotension documented within 48 hours prior to enrolment that requires the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, or dopamine >5 mcg/kg/min) for at least 3 hours within 24 hours prior to infusion, despite adequate fluid resuscitation in the opinion of the qualified investigator.

4. At least 1 other new organ dysfunction defined by the following:

   1. Renal: Acute kidney injury with creatinine ≥ 150 µmol/L, or ≥ 1.5x the upper limit of normal or the known baseline creatinine, or < 0.5 ml/kg/hr urine output for 6 hours despite adequate fluid resuscitation (patients on chronic hemodialysis or peritoneal dialysis must meet one of the other organ dysfunction criteria)
   2. Respiratory: Need for invasive mechanical ventilation or a P/F ratio < 250
   3. Hematological: Platelets < 100 x10^9/L, or a drop of 50 x10^9/L in the 3 days prior to enrollment
   4. Metabolic Acidosis: Arterial pH < 7.30 in association with base deficit > 5 mmol/L OR a lactate >/= to 3.0 mmol/L

Exclusion Criteria:

1. Pregnant or lactating
2. Currently receiving extracorporeal life support
3. Documented COVID-19 (SARS-CoV2) or influenza infection (confirmed by laboratory testing)
4. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the past year
5. History of severe heart failure with a New York Heart Association Functional Class of III or IV, or severe ischemic heart disease with a Canadian Cardiovascular Society angina class score of III or IV
6. Moderate to severe chronic liver disease (Childs-Pugh Score > 12)
7. Severe chronic respiratory disease with a baseline PaCO2 > 50 mm Hg or the use of home oxygen
8. Documented deep venous thrombosis or pulmonary embolism within the past 3 months
9. Chronic immunosuppression (any chronic immunotherapy including daily oral steroid use >6months)
10. Uncontrolled HIV infection or end stage HIV/AIDS with CD4+ T-cell counts <50 cells/mm^3, history of hepatitis B, untreated hepatitis C, or active tuberculosis
11. Concurrent use of immunomodulatory biologic drugs or TNF-α inhibitors
12. Participation in another interventional study involving an investigational new drug within 30 days prior to enrolment
13. Moribund patient not expected to survive 24 hours
14. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)

Contacts and Locations

Contacts

Contact: Michael Callahan, MD, DTM&H (UK), MSPH; 343-291-1197; mvcallahan@mgh.harvard.edu

Contact: Jackie Whyte, MSc; 613-859-4849; jwhyte@northernther.com

Locations

Canada, Ontario

Markham Stouffville Hospital - Oak Valley Health; Recruiting

Markham, Ontario, Canada, L3P 7P3

Contact: Valerie Sales, BSc, MD, CM, FRCP(C) vsales@oakvalleyhealth.ca

Principal Investigator: Valerie Sales, BSc, MD, CM, FRCP(C)

Sub-Investigator: Subarna Thirugnanam, BSc Hons., M.D., FRCPC

Sub-Investigator: Anthony LaDelfa, MD, FRCPC

Sub-Investigator: Jeya Nadarajah, MD, MSc, FRCPC

Lakeridge Health; Recruiting

Oshawa, Ontario, Canada, L1G 2B9

Contact: Karim Soliman, MD, FRCP

Principal Investigator: Karim Soliman, MD, FRCP

Sub-Investigator: Shannon Fernando, MD, MSc, FRCPC

St. Michael's Hospital; Recruiting

Toronto, Ontario, Canada, M5B 1W8

Contact: Claudia dos Santos, MD, MSc, BSc, FRCPC

Principal Investigator: Claudia dos Santos, MD, MSc, BSc

Sub-Investigator: Michael Sklar, MD, BSc, FRCPC

Sponsors and Collaborators

Northern Therapeutics

More Information

• Responsible Party: Northern Therapeutics
• ClinicalTrials.gov Identifier: NCT04961658
• Other Study ID Numbers: CT-GEM-001
• First Posted: July 14, 2021
• Last Update Posted: November 18, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Northern Therapeutics:

Sepsis; Bacteria; Septic Shock; Mesenchymal Stromal Cells; Inflammation; Mesenchymal Stem Cells; Infection

Additional relevant MeSH terms:

Shock, Septic; Shock; Pathologic Processes; Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation