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RAPA-501-Allo Therapy of COVID-19-ARDS

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ClinicalTrials.gov Identifier: NCT04482699
Recruitment Status : Recruiting
First Posted : July 22, 2020
Last Update Posted : April 12, 2021
Sponsor:
Collaborator:
Hackensack Meridian Health
Information provided by (Responsible Party):
Rapa Therapeutics LLC

Brief Summary:

The first-in-human Phase 1 study component will evaluate two dose levels of RAPA-501-ALLO off the shelf cells in patients with COVID-19-related ARDS, with key endpoints of safety, biologic and potential disease-modifying effects. The randomized, double-blind, placebo-controlled Phase 2b study component will evaluate infusion of RAPA-501 ALLO off the shelf cells or a control infusion, with the primary endpoint assessing whether RAPA-501 cells reduce 30-day mortality.

The COVID-19 pandemic is a disaster playing out with progressive morbidity and mortality. As of April 6th, 2021, an estimated 132.1 million people have contracted the virus and 2,866,000 deaths have resulted globally. The United States has the highest totals with an estimated 30.8 million people diagnosed and 556,000 deaths. In stages 1 and 2 of COVID-19, viral propagation within the patient is predominant. As such, therapeutic interventions focus on immune molecules (convalescent serum, monoclonal antibodies) and anti-viral medications (remdesivir). In marked contrast, the most severe and deadly form of COVID-19, stage 3, is driven not by viral propagation, but by an out-of-control immune response (hyperinflammation) caused by increases in immune molecules known as cytokines and chemokines. As such, therapeutic interventions for stage 3 disease focus on anti-inflammatory medications such as anti-cytokine therapy (anti-IL-6 drugs) or corticosteroid therapy. Unfortunately, such interventions do not address the full pathogenesis of stage 3 COVID-19, which includes hyperinflammation due to "cytokine storm" and "chemokine storm," tissue damage, hypercoagulation, and multi-organ failure (including lung, heart, kidney and brain). The pulmonary component of stage 3 disease includes acute respiratory distress syndrome (ARDS), which is a final-common-pathway of patient death due to a myriad of conditions, including pneumonia, sepsis, and trauma. There is a dire need for novel cellular treatments that can deliver both a broad-based immune modulation effect and a tissue regenerative effect, such as RAPA-501-ALLO off-the-shelf allogeneic hybrid TREG/Th2 Cells.

Stage 3 COVID-19 carries an estimated 30-day mortality of over 50% in spite of ICU utilization, mechanical ventilation, and supportive care therapies to manage ARDS and multiorgan failure. Narrowly acting targeted anti-inflammatory approaches such as anti-IL-6 therapeutics have not been particularly effective in stage 3 COVID-19 and the broad anti-inflammatory pharmaceutical approach of corticosteroid therapy, has only modestly tempered stage 3 disease in some studies. Cell therapy is also being evaluated in stage 3 COVID-19, in particular, mesenchymal stromal cells (MSC) and now, with the current RAPA-501-ALLO protocol, regulatory T (TREG) cells. TREG therapy has a mechanism of action that includes a multi-faceted anti-inflammatory effect, which puts TREG therapy at the forefront of future curative therapy of a wide range of autoimmune and neurodegenerative diseases, plus transplant complications, such as graft-versus-host disease (GVHD) and graft rejection. In addition, TREG therapy can provide a tissue regenerative effect, which places TREG cell therapy at the lead of novel regenerative medicine efforts to repair a myriad of tissue-based diseases, such as diseases of the skin, muscle, lung, liver, intestine, heart (myocardial infarction) and brain (stroke). RAPA-501-ALLO off-the-shelf cell therapy offers this potential dual threat mechanism of action that incorporates both anti-inflammatory and tissue repair effects for effective treatment of COVID-19 and multiple lethal conditions.

RAPA-501-ALLO cells are generated from healthy volunteers, cryopreserved, banked, and are then available for off-the-shelf therapy anytime. During manufacturing, T cells are "reprogrammed" ex vivo using a novel, patented 7-day two-step process that involves T cell de-differentiation and subsequent re-differentiation towards the two key anti-inflammatory programs, the TREG and Th2 pathways, thus creating a "hybrid" product. The hybrid phenotype inhibits inflammatory pathways operational in COVID-19, including modulation of multiple cytokines and chemokines, which attract inflammatory cells into tissue for initiation of multi-organ damage. The hybrid TREG and Th2 phenotype of RAPA-501-ALLO cells cross-regulates Th1 and Th17 populations that initiate hyperinflammation of COVID-19. RAPA-501 immune modulation occurs in a T cell receptor independent manner, thus permitting off-the-shelf cell therapy. Finally, in experimental models of viral pneumonia and ARDS, TREG cells mediate a protective effect on the lung alveolar tissue. Because of this unique mechanism of action that involves both anti-inflammatory and tissue protective effects, the allogeneic RAPA-501 T cell product is particularly suited for evaluation in the setting of COVID-19-related ARDS.


Condition or disease Intervention/treatment Phase
Severe COVID-19 Disease Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19 Other: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase I/Phase II Trial of Allogeneic Hybrid TREG/Th2 Cell (RAPA-501-ALLO) Therapy for COVID-19-Related ARDS
Actual Study Start Date : December 30, 2020
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
Experimental: Single agent RAPA-501 cells (dose level 1)
Dose level 1 is 40 x 10^6
Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19
Allogeneic off-the-shelf RAPA-501 cells
Other Name: RAPA-501-Allo cells

Experimental: Single agent RAPA-501 cells (dose level 2)
Dose level 2 is 160 x 10^6
Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19
Allogeneic off-the-shelf RAPA-501 cells
Other Name: RAPA-501-Allo cells

Active Comparator: RAPA-501 cells
RAPA-501 cells at either dose level 1 or dose level 2 (whichever has been deemed safe during phase 1)
Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19
Allogeneic off-the-shelf RAPA-501 cells
Other Name: RAPA-501-Allo cells

Placebo Comparator: Placebo-control Cohort
Placebo
Other: Placebo
RAPA-501-Allo cell placebo




Primary Outcome Measures :
  1. Dose-Limiting Toxicity (DLT) [ Time Frame: Through day 7. ]
    On the phase 1 study component, determine the safety of allogeneic RAPA-501 cells when administered at dose level 1 (Cohort 1, 40 x 106 cells) and dose level 2 (Cohort 2, 160 x 106 cells).

  2. Mortality Rate [ Time Frame: 30 days after the first infusion of allogeneic RAPA-501 cells. ]
    On the phase II study component, determine whether allogeneic RAPA-501 cells result in a mortality rate that is reduced relative to the randomized placebo-control cohort.


Secondary Outcome Measures :
  1. Ventilation Support [ Time Frame: 90 days after the infusion of allogeneic RAPA-501 cells. ]
    Number of days requiring intensive respiratory support (either high-flow nasal cannula or mechanical ventilation).

  2. Days of Hospitalization [ Time Frame: 90 days after the infusion of allogeneic RAPA-501 cells. ]
    Number of days of hospitalization among survivors.

  3. Number of Deaths [ Time Frame: 90 days after the infusion of allogeneic RAPA-501 cells. ]
    Number of deaths due to any cause.

  4. Incidence of Infection [ Time Frame: 90 days after the infusion of allogeneic RAPA-501 cells. ]
    Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection.

  5. GVHD Incidence [ Time Frame: 90 days after the infusion of allogeneic RAPA-501 cells. ]
    GVHD incidence and severity.


Other Outcome Measures:
  1. Viral Load [ Time Frame: Six months after treatment initiation. ]
    COVID-19 viral load, as determined by standard reverse transcriptase polymerase chain reaction (RT-PCR) assay or equivalent test on nasopharyngeal and/or endotracheal tube swab samples.

  2. Host Immunity [ Time Frame: Six months after treatment initiation. ]
    Development of potentially protective host immunity to COVID-19, as determined by serologic studies.

  3. Peripheral Blood Immune Counts [ Time Frame: Six months after treatment initiation. ]
    Peripheral blood immune counts, including CD4+ and CD8+ T cells, NK cells, and B cells.

  4. T Cell Expression [ Time Frame: Six months after treatment initiation. ]
    T cell expression of co-stimulation molecules (including CD28) and checkpoint receptor molecules (including PD-1).

  5. Peripheral Blood Micro-chimerism [ Time Frame: Six months after treatment initiation. ]
    Peripheral blood micro-chimerism, as determined by PCR amplification of donor and host STR loci.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. Male or female participants ≥ 18 years of age.
  2. Participants with SARS-CoV-2 infection, as defined by standard reverse transcriptase polymerase chain reaction (RT-PCR) assay or equivalent test.
  3. Must have pulmonary infiltrate on radiologic examination.
  4. Participant must have a clinical diagnosis of high-risk ARDS (as defined by a PaO2-to-FiO2 ratio of < 150 mm Hg) requiring intensive respiratory support, including non-invasive methods such as high-flow nasal cannula or mechanical ventilation.
  5. AST and ALT ≤ 3 x upper limit of normal (ULN).
  6. Consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn at any time without prejudice to future medical care. Informed consent can be obtained from healthcare proxy if the participant is unable to provide consent due to medical status.

Exclusion Criteria:

  1. Active uncontrolled infection with a non-COVID-19 agent.
  2. Diagnosis of ARDS that is not considered to be high-risk, as defined by PaO2-to-FiO2 ratio of ≥ 150 mm Hg.
  3. Any irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%.
  4. End-stage liver disease with ascites unrelated to COVID-19 (Childs Pugh score > 12).
  5. Uncontrolled or significant cardiovascular disease, including but not limited to: (a) myocardial infarction, stroke, or transient ischemic attack within the past 30 days; (b) uncontrolled angina within the past 30 days; (c) any history of clinically significant arrhythmias such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes; and (d) history of other clinically significant or uncontrolled heart disease, including: cardiomyopathy, congestive heart failure with New York Heart Association functional classification III or IV, myocarditis, pericarditis, or significant pericardial effusion.
  6. Known chronic kidney disease of Stage 4 or 5 severity or requiring hemodialysis.
  7. COVID-19-associated acute kidney injury requiring dialysis.
  8. HIV, hepatitis B, or hepatitis C seropositive.
  9. Patients with baseline QTc interval prolongation, as defined by repeated demonstration of a QTc interval >500 milliseconds.
  10. Patients on hydroxychloroquine (must discontinue at least 2-days before study entry).
  11. Pregnant or breastfeeding participants.
  12. Patients of childbearing age, or males who have a partner of childbearing potential, who are unwilling to practice contraception. Effective forms of birth control, which must be continued through the entire on-study 6-month interval, include: Abstinence; Intrauterine device (IUD); Hormonal (birth control pills, injections, or implants); Tubal ligation; or Vasectomy.
  13. Participants with malignancy requiring active therapy (not including non-melanoma skin cancer).
  14. Recipients of allogeneic hematopoietic cell transplant or solid organ transplant.
  15. History of WHO Class III or IV pulmonary hypertension.
  16. Severe thromboembolic disease, as defined by: administration of thrombolytic agents, insertion of vena cava filter, or pulmonary thrombectomy within one-week interval prior to screening.
  17. Participants may be excluded at the discretion of the PI or if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04482699


Contacts
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Contact: Jennifer Gough Clinical & Regulatory Specialist 617-285-4774 jgough@rapatherapeutics.com

Locations
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United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Michele Donato Principal Investigator    551-996-5855    michele.donato@hackensackmeridian.org   
Principal Investigator: Michele Donato         
Sponsors and Collaborators
Rapa Therapeutics LLC
Hackensack Meridian Health
Investigators
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Study Director: Daniel Fowler, M.D. Rapa Therapeutics LLC
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Responsible Party: Rapa Therapeutics LLC
ClinicalTrials.gov Identifier: NCT04482699    
Other Study ID Numbers: RAPA-501-ALLO-COVID-19
First Posted: July 22, 2020    Key Record Dates
Last Update Posted: April 12, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rapa Therapeutics LLC:
COVID-19
Allogeneic Hybrid TReg/Th2Cells
RAPA-501-ALLO
Off-the-shelf
Pneumonia
Lung Diseases
Acute Respiratory Distress Syndrome
ARDS
Respiratory Distress Syndrome
2019 Novel Coronavirus Pneumonia
Acute Lung Injury
Lung Injury
SARS-CoV-2
Cytokine Storm
Corona Virus Infection
Severe Acute Respiratory Syndrome Coronavirus 2
SARS Coronavirus 2
SARS
Reprogram
COVID-19 Pneumonia
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases