Clinical trial NCT04513470: Allocetra-OTS in COVID-19
Official title: A Multi-Center, Open-Label Study, Evaluating Safety of Allocetra-OTS for the Prevention of Organ-Failure Deterioration in Severe Patients With COVID-19 and Respiratory Dysfunction
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: COVID-19
Lead sponsor: Hadassah Medical Organization
Sponsor class: OTHER
First posted: 2020-08-14
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This is a multi-center, open-label study evaluating the safety of Allocetra-OTS, in 5 subjects with severe COVID-19 and respiratory dysfunction. Subjects, who will be identified as suffering from COVID-19, will be recruited.

After signing an informed consent by the patient and, within 24+6 hours following the time of eligibility (time 0), on Day 1, eligible recipient subjects will receive single intravenous (IV) administration of investigational product as described below.

Subjects will be hospitalized for COVID-19, and later as medically indicated. Following investigational product (IP) administration (Day 1), subjects will be followed for efficacy and safety assessments through 28 days.

Detailed description: Study Rationale

COVID-19, the name given to the clinical syndrome associated with the newly recognized virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become pandemic with a mortality estimated based on reports from China between 1-3% and complications among hospitalized patients leading to up to 15-25% admissions to the Intensive Care Unit (ICU). The clinical presentation includes both upper and lower respiratory tract infection, but patients may also be asymptomatic.

The term "cytokine storm" calls up vivid images of an immune system gone awry and an inflammatory response flaring out of control. The term has captured the attention of the public and the scientific community alike and is increasingly being used in both the popular media and the scientific literature. Indeed, a few publications have indicated an important part of the complications in COVID-19 are related to a cytokine storm.

In that regard, the investigators have recently completed a successful phase 1b clinical trial of immune-modulation in patients with sepsis (NCT03925857).

Taken together, in patients with moderate to severe COVID-19, there may be a comparable underlying immunological mechanism of action that may be similar to the one that was recently shown by us in sepsis, which is a hyper-inflammatory pathway associated with increased death. 40 previous trials using monoclonal antibodies against a single cytokine in septic patients have failed in sepsis pointing out that there is a need to modify the cytokine storm rather than treating with a single anti-cytokine.

This solution is provided by Allocetra-OTS, which targets macrophages and dendritic cells that produce most of the cytokine storm.

Study Design This is a multi-center, open-label study evaluating the safety of Allocetra-OTS, in five subjects with severe COVID-19 and respiratory dysfunction. Subjects, who will be identified as suffering from COVID-19, will be recruited.

After signing an informed consent by the patient and, within 24+6 hours following the time of eligibility (time 0), on Day 1, eligible recipient subjects will receive single intravenous (IV) administration of investigational product as described below:

● Allocetra-OTS treatment at 140 x 106 ±20% cells/kg body weight (screening body weight) in 375 mL of Ringer's lactate solution.

Subjects will be followed for efficacy and safety assessments over 28 days following investigational product administration.

Subjects will be hospitalized for COVID-19, and later as medically indicated. Following IP administration (Day 1), subjects will be followed for efficacy and safety assessments through 28 days. The number of visits for subjects participating in this study will be on Days 3, 5, 7, 14, and 28.

Study Intervention, Route of Administration, and Dosage Form Allocetra-OTS is a cell-based therapeutic composed of donor early apoptotic cells.

Patient Classification \[National Institutes of Health (NIH)\]- www.covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/

In general, adults with COVID-19 can be grouped into the following severity of illness categories:

* Asymptomatic or Pre-symptomatic Infection: Individuals who test positive for SARS-CoV-2 by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or antigen test, but have no symptoms.
* Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal chest imaging.
* Moderate Illness: Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and saturation of oxygen (SpO2) ≥94% on room air at sea level.
* Severe Illness: Individuals who have respiratory frequency \>30 breaths per minute, SpO2 \<94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) \<300 mmHg, or lung infiltrates \>50%
* Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.

Standard of Care (SOC) The SOC for COVID-19 will be according to institutional standards. Institutional SOC may include Clexane, anti-viral agents such as Remdesivir, Dexamethasone, or other agents.

Concomitant Medications Prohibited medications: Significant immune-suppressing agents including Azathioprine, Cyclosporine, Cyclophosphamide, and any biological treatment.

Concomitant Medical Conditions Apart from patients with a tumor or end-stage organ condition, chronic diseases like cardiovascular or diabetes are allowed.

Eligibility criteria: Inclusion Criteria:

Five subjects, male or female \> 18 and \< 80-year-old diagnosed with respiratory dysfunction and COVID-19, as defined below:

1. Laboratory confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source.
2. Patients classified as severe according to NIH severity classification.
3. All patients will be treated by treating physicians with subcutaneous (S.C.) Clexane, at a minimal dose of 40 mg a day

Exclusion Criteria:

1. Pregnancy, lactation, and childbearing potential woman who are not willing to use acceptable contraceptives measures for the entire study duration.
2. Combined with other organ failures (need organ support not including respirator), including Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular filtration rate (eGFR) \< 30)
3. Patients with malignant tumor, other serious systemic diseases and psychosis.
4. Patients who are participating in other clinical trials or treated with any experimental agents that may contradict this trial (i.e, biologics)
5. Co-Infection of HIV, tuberculosis.
6. Known immunocompromised state or medications known to be immunosuppressive (see concomitant prohibited medications).
7. Intubated patients (due to inability to sign an informed consent)
8. Patients with P/F ratio of \<150 or a change in status of eligibility manifested by a rapid decline of P/F ratio between eligibility status and actual drug delivery.

Primary outcomes:
measure: Assessment of safety by determining the number of participants with any Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: 28 days follow up
Secondary outcomes:
measure: Preliminary Efficacy: Recovery from COVID-19 as determined by negative PCR or asymptomatic by the NIH classification for the severity of illness
timeFrame: 28 days follow up
measure: Mortality
timeFrame: 28 days follow up
measure: Preliminary Efficacy: To assess prevention of respiratory deterioration associated with COVID-19 by measuring the PaO2/FiO2 ratio
timeFrame: On days, 3, 5, 7, 14, and 28 during 28 days follow up
measure: Hospitalization
timeFrame: 28 days follow up
measure: Life support
timeFrame: 28 days follow up
measure: Clinical status by the new NIH Patient Classification for the severity of illness
timeFrame: 28 days follow up
measure: Clinical status by NEWS2
timeFrame: 28 days follow up
measure: Support measurements: percentage of subjects reporting each severity rating on a 7-point ordinal scale
timeFrame: 28 days follow up
measure: Support measurements: improvement of severity rating on a 7-point ordinal scale
timeFrame: 28 days follow up
measure: Virus Clearance
timeFrame: Within the 28 days follow up, tested on days 14 and 28
measure: Exploratory: Serum cytokines/chemokines and immunomodulating factors
timeFrame: 28 days follow up
measure: Exploratory: complete blood counts
timeFrame: 28 days follow up
measure: Exploratory: Histone and cell-free DNA levels
timeFrame: 28 days follow up
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
Study officials:
affiliation: Hadassah Medical Organization
name: Dror Mevorach, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hadassah Medical Organization
name: Peter V van Heerden, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baden LR, Rubin EJ. Covid-19 - The Search for Effective Therapy. N Engl J Med. 2020 May 7;382(19):1851-1852. doi: 10.1056/NEJMe2005477. Epub 2020 Mar 18. No abstract available.
citation: Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
citation: Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
citation: Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.