<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04482699</url>
  </required_header>
  <id_info>
    <org_study_id>RAPA-501-ALLO-COVID-19</org_study_id>
    <nct_id>NCT04482699</nct_id>
  </id_info>
  <brief_title>RAPA-501-Allo Therapy of COVID-19-ARDS</brief_title>
  <official_title>Phase I/Phase II Trial of Allogeneic Hybrid TREG/Th2 Cell (RAPA-501-ALLO) Therapy for COVID-19-Related ARDS</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rapa Therapeutics LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hackensack Meridian Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rapa Therapeutics LLC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The first-in-human Phase 1 study component will evaluate two dose levels of RAPA-501-ALLO off&#xD;
      the shelf cells in patients with COVID-19-related ARDS, with key endpoints of safety,&#xD;
      biologic and potential disease-modifying effects. The randomized, double-blind,&#xD;
      placebo-controlled Phase 2b study component will evaluate infusion of RAPA-501 ALLO off the&#xD;
      shelf cells or a control infusion, with the primary endpoint assessing whether RAPA-501 cells&#xD;
      reduce 30-day mortality.&#xD;
&#xD;
      The COVID-19 pandemic is a disaster playing out with progressive morbidity and mortality. As&#xD;
      of April 6th, 2021, an estimated 132.1 million people have contracted the virus and 2,866,000&#xD;
      deaths have resulted globally. The United States has the highest totals with an estimated&#xD;
      30.8 million people diagnosed and 556,000 deaths. In stages 1 and 2 of COVID-19, viral&#xD;
      propagation within the patient is predominant. As such, therapeutic interventions focus on&#xD;
      immune molecules (convalescent serum, monoclonal antibodies) and anti-viral medications&#xD;
      (remdesivir). In marked contrast, the most severe and deadly form of COVID-19, stage 3, is&#xD;
      driven not by viral propagation, but by an out-of-control immune response (hyperinflammation)&#xD;
      caused by increases in immune molecules known as cytokines and chemokines. As such,&#xD;
      therapeutic interventions for stage 3 disease focus on anti-inflammatory medications such as&#xD;
      anti-cytokine therapy (anti-IL-6 drugs) or corticosteroid therapy. Unfortunately, such&#xD;
      interventions do not address the full pathogenesis of stage 3 COVID-19, which includes&#xD;
      hyperinflammation due to &quot;cytokine storm&quot; and &quot;chemokine storm,&quot; tissue damage,&#xD;
      hypercoagulation, and multi-organ failure (including lung, heart, kidney and brain). The&#xD;
      pulmonary component of stage 3 disease includes acute respiratory distress syndrome (ARDS),&#xD;
      which is a final-common-pathway of patient death due to a myriad of conditions, including&#xD;
      pneumonia, sepsis, and trauma. There is a dire need for novel cellular treatments that can&#xD;
      deliver both a broad-based immune modulation effect and a tissue regenerative effect, such as&#xD;
      RAPA-501-ALLO off-the-shelf allogeneic hybrid TREG/Th2 Cells.&#xD;
&#xD;
      Stage 3 COVID-19 carries an estimated 30-day mortality of over 50% in spite of ICU&#xD;
      utilization, mechanical ventilation, and supportive care therapies to manage ARDS and&#xD;
      multiorgan failure. Narrowly acting targeted anti-inflammatory approaches such as anti-IL-6&#xD;
      therapeutics have not been particularly effective in stage 3 COVID-19 and the broad&#xD;
      anti-inflammatory pharmaceutical approach of corticosteroid therapy, has only modestly&#xD;
      tempered stage 3 disease in some studies. Cell therapy is also being evaluated in stage 3&#xD;
      COVID-19, in particular, mesenchymal stromal cells (MSC) and now, with the current&#xD;
      RAPA-501-ALLO protocol, regulatory T (TREG) cells. TREG therapy has a mechanism of action&#xD;
      that includes a multi-faceted anti-inflammatory effect, which puts TREG therapy at the&#xD;
      forefront of future curative therapy of a wide range of autoimmune and neurodegenerative&#xD;
      diseases, plus transplant complications, such as graft-versus-host disease (GVHD) and graft&#xD;
      rejection. In addition, TREG therapy can provide a tissue regenerative effect, which places&#xD;
      TREG cell therapy at the lead of novel regenerative medicine efforts to repair a myriad of&#xD;
      tissue-based diseases, such as diseases of the skin, muscle, lung, liver, intestine, heart&#xD;
      (myocardial infarction) and brain (stroke). RAPA-501-ALLO off-the-shelf cell therapy offers&#xD;
      this potential dual threat mechanism of action that incorporates both anti-inflammatory and&#xD;
      tissue repair effects for effective treatment of COVID-19 and multiple lethal conditions.&#xD;
&#xD;
      RAPA-501-ALLO cells are generated from healthy volunteers, cryopreserved, banked, and are&#xD;
      then available for off-the-shelf therapy anytime. During manufacturing, T cells are&#xD;
      &quot;reprogrammed&quot; ex vivo using a novel, patented 7-day two-step process that involves T cell&#xD;
      de-differentiation and subsequent re-differentiation towards the two key anti-inflammatory&#xD;
      programs, the TREG and Th2 pathways, thus creating a &quot;hybrid&quot; product. The hybrid phenotype&#xD;
      inhibits inflammatory pathways operational in COVID-19, including modulation of multiple&#xD;
      cytokines and chemokines, which attract inflammatory cells into tissue for initiation of&#xD;
      multi-organ damage. The hybrid TREG and Th2 phenotype of RAPA-501-ALLO cells cross-regulates&#xD;
      Th1 and Th17 populations that initiate hyperinflammation of COVID-19. RAPA-501 immune&#xD;
      modulation occurs in a T cell receptor independent manner, thus permitting off-the-shelf cell&#xD;
      therapy. Finally, in experimental models of viral pneumonia and ARDS, TREG cells mediate a&#xD;
      protective effect on the lung alveolar tissue. Because of this unique mechanism of action&#xD;
      that involves both anti-inflammatory and tissue protective effects, the allogeneic RAPA-501 T&#xD;
      cell product is particularly suited for evaluation in the setting of COVID-19-related ARDS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The first-in-human Phase 1 study component will evaluate two dose levels of RAPA-501-ALLO off&#xD;
      the shelf cells in patients with COVID-19-related ARDS, with key endpoints of safety,&#xD;
      biologic and potential disease-modifying effects. The randomized, double-blind,&#xD;
      placebo-controlled Phase 2b study component will evaluate infusion of RAPA-501 ALLO off the&#xD;
      shelf cells or a control infusion, with the primary endpoint assessing whether RAPA-501 cells&#xD;
      reduce 30-day mortality.&#xD;
&#xD;
      The COVID-19 pandemic is a disaster playing out with progressive morbidity and mortality. As&#xD;
      of April 6th, 2021, an estimated 132.1 million people have contracted the virus and 2,866,000&#xD;
      deaths have resulted globally. The United States has the highest totals with an estimated&#xD;
      30.8 million people diagnosed and 556,000 deaths. The United States has the highest totals&#xD;
      with an estimated 22.4 million people diagnosed and 375,000 deaths. In stages 1 and 2 of&#xD;
      COVID-19, viral propagation within the patient is predominant. As such, therapeutic&#xD;
      interventions focus on immune molecules (convalescent serum, monoclonal antibodies) and&#xD;
      anti-viral medications (remdesivir). In marked contrast, the most severe and deadly form of&#xD;
      COVID-19, stage 3, is driven not by viral propagation, but by an out-of-control immune&#xD;
      response (hyperinflammation) caused by increases in immune molecules known as cytokines and&#xD;
      chemokines. As such, therapeutic interventions for stage 3 disease focus on anti-inflammatory&#xD;
      medications such as anti-cytokine therapy (anti-IL-6 drugs) or corticosteroid therapy.&#xD;
      Unfortunately, such interventions do not address the full pathogenesis of stage 3 COVID-19,&#xD;
      which includes hyperinflammation due to &quot;cytokine storm&quot; and &quot;chemokine storm,&quot; tissue&#xD;
      damage, hypercoagulation, and multi-organ failure (including lung, heart, kidney and brain).&#xD;
      The pulmonary component of stage 3 disease includes acute respiratory distress syndrome&#xD;
      (ARDS), which is a final-common-pathway of patient death due to a myriad of conditions,&#xD;
      including pneumonia, sepsis, and trauma. There is a dire need for novel cellular treatments&#xD;
      that can deliver both a broad-based immune modulation effect and a tissue regenerative&#xD;
      effect, such as RAPA-501-ALLO off-the-shelf allogeneic hybrid TREG/Th2 Cells.&#xD;
&#xD;
      The mechanism of fatal pneumonia in experimental murine coronavirus infection is mediated by&#xD;
      innate inflammasome activation, a resultant robust infiltration of inflammatory monocytes and&#xD;
      macrophages, and a subsequent increase in multiple pro-inflammatory cytokines and chemokines.&#xD;
      Importantly, the CD4+ and CD8+ adaptive T cell response to experimental coronavirus infection&#xD;
      can be either curative or disease propagating. Viral-induced pulmonary inflammation has also&#xD;
      been evaluated in non-human primate models, which have confirmed that dysregulated immune&#xD;
      activation during viral pneumonia involves T cell subset imbalance, a downstream&#xD;
      monocyte-derived inflammatory cascade, and resultant epithelial cell injury. In humans,&#xD;
      severity of viral-induced lower respiratory tract infection correlates with increased numbers&#xD;
      of effector memory CD8+ T cells in the airway. As recently reviewed, human coronavirus&#xD;
      infection represents an ongoing battle between virus and host, with the nature of the&#xD;
      response dictating disease cure or alternatively, aggravated lung disease. Evidence exists&#xD;
      that the adaptive immune system contributes to pulmonary inflammation during SARS-associated&#xD;
      Coronavirus (SARS-CoV) disease: that is, bronchoalveolar fluid from such subjects had&#xD;
      increased T cell numbers and increased Th1-associated molecules IL-12, IFN-gamma, and IP-10.&#xD;
      This downstream adaptive T cell-mediated inflammatory response is driven in part by the&#xD;
      SARS-Co-V protein viroporin 3a. Specifically, viroporin molecules activate the NLRP3&#xD;
      inflammasome that links innate-to-adaptive inflammatory responses. Furthermore, both SARS-CoV&#xD;
      and SARS-CoV-2 express an open-reading-frame ORF3a molecule, which also activate the NLRP3&#xD;
      inflammasome.&#xD;
&#xD;
      The nature of immunity during resolution of symptomatic COVID-19 infection has recently been&#xD;
      reported, namely: emergence of antibody-secreting cells and CD4+ T follicular helper cells;&#xD;
      increase in perforin- and granzyme-expressing CD8+ T cells; and relative lack of an increase&#xD;
      in pro-inflammatory cytokines and chemokines. In marked contrast, patients with severe&#xD;
      COVID-19 disease had greatly increased plasma levels of cytokines (including IL-2 and&#xD;
      TNF-alpha) and chemokines (including IP-10 and MIP-1-alpha) (Huang et al., Lancet, 2020).&#xD;
      Collectively, these results indicate that pro-inflammatory cytokine and chemokine responses&#xD;
      that occur in severe COVID-19 is detrimental and that effective anti-inflammatory approaches&#xD;
      may ultimately prove to be therapeutic. However, as previously detailed, the more advanced&#xD;
      Stage 3 COVID-19 disease is characterized by an ARDS component, and cytokine storm, as such,&#xD;
      novel approaches to treat the COVID-19 viral pneumonia should optimally incorporate both an&#xD;
      anti-inflammatory element and a tissue protection/tissue repair element.&#xD;
&#xD;
      Stage 3 COVID-19 carries an estimated 30-day mortality of over 50% in spite of ICU&#xD;
      utilization, mechanical ventilation, and supportive care therapies to manage ARDS and&#xD;
      multiorgan failure. Narrowly acting targeted anti-inflammatory approaches such as anti-IL-6&#xD;
      therapeutics have not been particularly effective in stage 3 COVID-19 and the broad&#xD;
      anti-inflammatory pharmaceutical approach of corticosteroid therapy, has only modestly&#xD;
      tempered stage 3 disease in some studies. Cell therapy is also being evaluated in stage 3&#xD;
      COVID-19, in particular, mesenchymal stromal cells (MSC) and now, with the current&#xD;
      RAPA-501-ALLO protocol, regulatory T (TREG) cells. TREG therapy has a mechanism of action&#xD;
      that includes a multi-faceted anti-inflammatory effect, which puts TREG therapy at the&#xD;
      forefront of future curative therapy of a wide range of autoimmune and neurodegenerative&#xD;
      diseases, plus transplant complications, such as graft-versus-host disease (GVHD) and graft&#xD;
      rejection. In addition, TREG therapy can provide a tissue regenerative effect, which places&#xD;
      TREG cell therapy at the lead of novel regenerative medicine efforts to repair a myriad of&#xD;
      tissue-based diseases, such as diseases of the skin, muscle, lung, liver, intestine, heart&#xD;
      (myocardial infarction) and brain (stroke). RAPA-501-ALLO off-the-shelf cell therapy offers&#xD;
      this potential dual threat mechanism of action that incorporates both anti-inflammatory and&#xD;
      tissue repair effects for effective treatment of COVID-19 and multiple lethal conditions.&#xD;
&#xD;
      RAPA-501-ALLO cells are generated from healthy volunteers, cryopreserved, banked, and are&#xD;
      then available for off-the-shelf therapy anytime. During manufacturing, T cells are&#xD;
      &quot;reprogrammed&quot; ex vivo using a novel, patented 7-day two-step process that involves T cell&#xD;
      de-differentiation and subsequent re-differentiation towards the two key anti-inflammatory&#xD;
      programs, the TREG and Th2 pathways, thus creating a &quot;hybrid&quot; product. The hybrid phenotype&#xD;
      inhibits inflammatory pathways operational in COVID-19, including modulation of multiple&#xD;
      cytokines and chemokines, which attract inflammatory cells into tissue for initiation of&#xD;
      multi-organ damage. The hybrid TREG and Th2 phenotype of RAPA-501-ALLO cells cross-regulates&#xD;
      Th1 and Th17 populations that initiate hyperinflammation of COVID-19. RAPA-501 immune&#xD;
      modulation occurs in a T cell receptor independent manner, thus permitting off-the-shelf cell&#xD;
      therapy. Finally, in experimental models of viral pneumonia and ARDS, TREG cells mediate a&#xD;
      protective effect on the lung alveolar tissue. Because of this unique mechanism of action&#xD;
      that involves both anti-inflammatory and tissue protective effects, the allogeneic RAPA-501 T&#xD;
      cell product is particularly suited for evaluation in the setting of Stage 3 COVID-19-related&#xD;
      ARDS.&#xD;
&#xD;
      In general, classical autoimmune disease, neurodegenerative disease, and viral-induced&#xD;
      inflammatory disease are driven by predominance of Th1/Th17-type responses with a relative&#xD;
      insufficiency of the counter-regulatory immune suppressive Th2 and TREG subsets. TREG cells,&#xD;
      which are defined in part by their expression of FOXP3 transcription factor, have been&#xD;
      extensively studied in experimental models for their capacity to modulate autoimmune disease,&#xD;
      neurodegenerative disease, and transplantation complications, including graft-versus-host&#xD;
      disease (GVHD) and graft rejection. Importantly, T cell production of IL-2 or exogenous IL-2&#xD;
      administration drives lung inflammation during experimental viral infection; therefore, given&#xD;
      the known role of TREG cells as a consumer of IL-2, there is a strong mechanistic rationale&#xD;
      for a beneficial contribution of TREG cells during viral-driven lung inflammation.&#xD;
      Furthermore, in an experimental murine models of virus-induced lung inflammation and lung&#xD;
      injury, interventions that augmented TREG cell number and function accelerated the repair of&#xD;
      lung injury. And, Th2 cells, which are defined in part by their expression of GATA3&#xD;
      transcription factor, were described thirty years ago as a powerful counter-regulatory&#xD;
      population to prevent Th1 cell predominance. It is important to note that clinical data&#xD;
      indicates that maneuvers that increase immune suppressive cell populations, including TREG&#xD;
      cells, can reduce severe inflammatory disease such as graft-versus-host disease without&#xD;
      impairing anti-viral immunity. In addition, in both experimental models and clinical studies,&#xD;
      an appropriate level of TREG cells can result in an overall improvement in pulmonary&#xD;
      inflammation during viral bronchiolitis. Collectively, these findings indicate that T cells&#xD;
      expressing a combined TREG/Th2 phenotype would predictably yield beneficial effects in the&#xD;
      setting of viral-induced pulmonary inflammation and injury associated with severe Stage 3&#xD;
      COVID-19 disease.&#xD;
&#xD;
      Clinical trials have evaluated both TREG and Th2-type cells for various conditions, most&#xD;
      prominently transplantation complications. In general, thymic-derived natural (n)TREG cells&#xD;
      are thought to express a more stable phenotype than post-thymic induced (i)TREG cells; by&#xD;
      comparison, iTREG cells can mediate more potent suppression. Nonetheless, both nTREG and&#xD;
      iTREG cells are susceptible to differentiation plasticity, which creates concern that a&#xD;
      potentially therapeutic TREG population might convert to pathogenic Th1/Th17 phenotypes in&#xD;
      vivo. Ex vivo expanded (n)TREG cells were evaluated in the setting of allogeneic&#xD;
      hematopoietic cell transplantation (HCT) using cord blood donors; more recently, the same&#xD;
      research group has developed ex vivo expanded (i)TREG cell therapy to limit transplant&#xD;
      complications. In addition, ex vivo expanded nTREG cells have been evaluated in the setting&#xD;
      of type I diabetes mellitus; this clinical trial found that TREG therapy was safe and at&#xD;
      least transiently effective in improving disease control. Furthermore, in the setting of&#xD;
      amyotrophic lateral sclerosis (ALS), which is a disease propagated by a severe Th1-driven&#xD;
      peripheral and central inflammatory response, a clinical trial of nTREG cell adoptive&#xD;
      transfer identified that the intervention was safe and showed promise in terms of ALS disease&#xD;
      amelioration. Finally, in a phase II study of rapamycin-resistant Th2 cell therapy in the&#xD;
      setting of low-intensity allogeneic HCT, adoptive Th2 cell transfer was safe and associated&#xD;
      with a shift towards Th2 polarization in vivo, preservation of donor engraftment,&#xD;
      stabilization of mixed chimerism, a low rate of GVHD, and potent anti-tumor effects in&#xD;
      patients with refractory hematologic malignancy. Collectively, these clinical trial results&#xD;
      indicate that the adoptive transfer of TREG and Th2-type populations can be safely&#xD;
      administered, even in the allogeneic HCT setting, and can mediate beneficial modulation of&#xD;
      inflammatory conditions.&#xD;
&#xD;
      Ex vivo manufacturing can be utilized to generate induced (i)TREG cells from the post-thymic&#xD;
      pool of peripheral T cells. In the current protocol, the manufacturing method will focus upon&#xD;
      mTOR inhibition, which is an established intervention that promotes the induction of TREG&#xD;
      cells. In combination with mTOR inhibition, the culture system that is utilized incorporates&#xD;
      cytokines that promote both a Th2 and a TREG phenotype, namely, IL-4, TGF-beta, and IL-2.&#xD;
      Finally, the protocol will include a TREG/Th2 cell product comprised of both CD4+ and CD8+ T&#xD;
      cell subsets, as these counter-regulatory T cell subsets express differential T cell receptor&#xD;
      (TCR) repertoires and a diversity of effector mechanisms that can potentially enhance an&#xD;
      anti-inflammatory effect. For RAPA-501 manufacture, peripheral blood mononuclear cells are&#xD;
      collected from a steady-state apheresis and subjected to the following two-step culture&#xD;
      intervention: in step 1, a severe starvation step results in T cell de-differentiation, which&#xD;
      is realized through both selective media utilization and the addition of FDA-approved&#xD;
      pharmaceutical agents that potently inhibit mTOR signaling; and in step 2, re-differentiation&#xD;
      of T cells occurs using co-stimulation agents and Th2- and TREG-type polarizing cytokines.&#xD;
      After 6-days in culture, the resultant TREG/Th2 population is cryopreserved in single-use&#xD;
      aliquots at protocol-driven therapeutic doses. T cells of type II cytokine phenotype are&#xD;
      characterized in part by their expression of the transcription factor GATA3 whereas&#xD;
      regulatory T cell populations are identified in part by their expression of FOXP3&#xD;
      transcription factor. At culture initiation, a very low frequency of T cells express either&#xD;
      GATA3 or FOXP3. In contrast, the RAPA-501 cell product manufactured in the TREG/Th2 culture&#xD;
      conditions expresses a high frequency of T cells that are either single-positive for GATA3,&#xD;
      single-positive for FOXP3, or double-positive for both GATA3 and FOXP3. Importantly, this&#xD;
      transcription factor profile is expressed in both manufactured CD4+ and CD8+ T cells. It is&#xD;
      important to note that both CD4+ and CD8+ T cell populations with TREG function have been&#xD;
      defined, including a CD8+ TREG population that potently suppresses GVHD; it is potentially&#xD;
      advantageous to have both subsets represented in a therapeutic product because CD4+ and CD8+&#xD;
      TREG cells utilize differential effector mechanisms.&#xD;
&#xD;
      Regulatory T cell populations can suppress pathogenic effector T cell populations by several&#xD;
      defined mechanisms, including through expression of CD39 and CD73 ectonucleotidase molecules,&#xD;
      which act to hydrolyse pro-inflammatory ATP towards the immune suppressive adenosine&#xD;
      substrate . Indeed, TREG cells that express CD39 possess increased suppressive function and&#xD;
      have been associated with resolution of inflammatory bowel disease. Furthermore, suppressive&#xD;
      function of human TREG cells is mediated in part by CD73. T cells manufactured in the&#xD;
      TREG/Th2 culture condition have an increase in expression of the TREG-associated effector&#xD;
      molecules, CD39 and CD73. In addition to the CD39/CD73 ectonucleotidases, TREG cell function&#xD;
      has also been correlated with expression of CD103, which is an integrin that dictates&#xD;
      epithelial lymphocyte localization. Indeed, CD103 and IL-2 receptor signaling cooperate to&#xD;
      maintain immune tolerance in the gut mucosa; furthermore, CD103-expressing TREG cells are&#xD;
      critical for amelioration of experimental chronic GVHD . T cells manufactured in the TREG/Th2&#xD;
      culture condition have increased expression of the TREG effector molecule CD103.&#xD;
&#xD;
      In experimental models, the efficacy of adoptive T cell therapy is dependent upon successful&#xD;
      engraftment and in vivo T cell persistence. Importantly, the T cell differentiation state&#xD;
      helps dictate in vivo persistence, with less differentiated cells having increased&#xD;
      persistence. Murine rapamycin-resistant T cells, which expressed a T central memory (TCM)&#xD;
      phenotype, had increased in vivo engraftment potential relative to control T cells. In&#xD;
      addition, human rapamycin-resistant T cells also had increased engraftment in a&#xD;
      human-into-murine model of xenogeneic graft-versus-host disease. T cells with reduced&#xD;
      differentiation relative to the T effector memory (TEM) population have increased in vivo&#xD;
      persistence and mediate increased in vivo effects, including the TCM subset, the naïve T cell&#xD;
      subset, and more recently, the T stem cell memory (TSCM) subset. This relationship between T&#xD;
      cell differentiation status and in vivo T cell function is relevant to TREG cells, as: (1)&#xD;
      TREG cells of TCM phenotype were more effective at reducing experimental GVHD relative to&#xD;
      TREG cells of TEM phenotype; and (2) TREG cells that expressed the stem cell marker CD150&#xD;
      were highly effective for the prevention of stem cell graft rejection. T cells manufactured&#xD;
      in the TREG/Th2 culture condition are enriched for cells having a reduced differentiation&#xD;
      state consistent with a T stem cell subset, including expression of the CD150 marker.&#xD;
&#xD;
      It is also important to assess the cytokine secretion profile of the manufactured RAPA-501&#xD;
      cells. First, it is critical that the cell product is capable of IL-4 secretion, which is the&#xD;
      driver cytokine for subsequent Th2 differentiation. Second, it is desirable that an&#xD;
      adoptively transferred T cell population is capable of secreting IL-2, as this capacity&#xD;
      indicates a progenitor function that permits T cells to expand more readily in vivo without&#xD;
      the need for exogenous IL-2 . Finally, it is important that the RAPA-501 cell population has&#xD;
      reduced secretion of the Th1- or Th17-type cytokines IFN-gamma, TNF-alpha, IL-17, and GM-CSF.&#xD;
      The manufactured RAPA-501 cell product secretes IL-4 and IL-2 with minimal secretion of Th1-&#xD;
      or Th17-type cytokines.&#xD;
&#xD;
      Regulatory T cells can also be defined in part by their ability to suppress the proliferation&#xD;
      or function of effector T cells. Importantly, manufactured TREG/Th2 cells potently suppress&#xD;
      Th1/Tc1 cell secretion of multiple inflammatory cytokines, including IFN-gamma, GM-CSF, and&#xD;
      TNF-alpha. To assess the mechanism of suppression, experiments were performed using the&#xD;
      transwell assay, whereby effector T cells and RAPA-501 cells are separated by a filter that&#xD;
      prevents cell-to-cell contact but allows cell communication by small soluble mediators such&#xD;
      as cytokines. RAPA-501 cells acted in a TCR-independent manner to suppress the cytokine&#xD;
      secretion capacity of effector T cells. Because no co-stimulation was provided to the&#xD;
      transwell chamber containing RAPA-501 cells, RAPA-501 cells did not require co-stimulation to&#xD;
      modulate inflammatory cytokine levels, including IL-2, IFN-gamma, GM-CSF, and TNF-alpha. The&#xD;
      following cytokines and chemokines were reduced by RAPA-501 cells in this transwell assay,&#xD;
      with relatively equal suppression mediated by CD4+ and CD8+ subsets of RAPA-501 cells: CCL1,&#xD;
      CCL2, CCL7, CCL11, CCL13, CCL17, CCL20, CCL22, CCL26, CXCL1, CXCL10, CXCL11, CXCL12, IL-6,&#xD;
      IFN-gamma, GM-CSF, and IL-10. The ability of TREG cells to consume IL-2 is a commonly&#xD;
      described phenomenon, although previous studies identified the requirement of cell-to-cell&#xD;
      contact for IL-2 consumption. As such, RAPA-501 cells are uniquely capable of modulating the&#xD;
      level of multiple inflammatory cytokines in a contact-independent manner. These results&#xD;
      suggest that RAPA-501 cells represent a suitable candidate for neutralization of multiple&#xD;
      cytokines and chemokines associated with various diseases, including viral-induced lung&#xD;
      inflammation. In light of this capacity of the RAPA-501 cell product to suppress T&#xD;
      cell-mediated inflammation in a TCR-independent manner, RAPA-501 therapy is highly suitable&#xD;
      for allogeneic, off-the-shelf treatment applications.&#xD;
&#xD;
      Further experiments were performed to evaluate whether the RAPA-501 cell product might also&#xD;
      regulate human CNS microglial cells, which are myeloid-derived cells that are analogous to&#xD;
      the peripheral monocyte population. To evaluate whether the RAPA-501 cell product might&#xD;
      modulate pro-inflammatory microglial cells in a contact-independent manner, the ability of&#xD;
      RAPA-501 cells to reduce the inflammatory state of the microglial cell line HMC3 was tested&#xD;
      in a transwell assay. RAPA-501 cells reduced the HMC3 cell secretion of the pro-inflammatory&#xD;
      cytokines IL-6 and IFN-gamma and the pro-inflammatory chemokine IP-10 at the relatively low&#xD;
      ratio of RAPA-501 cells to microglial cells of 1:40. These results demonstrate that the&#xD;
      RAPA-501 product is capable of inhibiting cytokine and chemokine secretion from&#xD;
      myeloid-derived populations in a contact- and TCR-independent manner, thereby providing a&#xD;
      further rationale for allogeneic, off-the-shelf utilization of the RAPA-501 product.&#xD;
&#xD;
      RAPA-501 cell product for stability of T cell phenotype was also evaluated. That is, it has&#xD;
      been determined that a limiting factor of TREG cell therapy may be differentiation&#xD;
      plasticity, for example, whereby TREG cells can be influenced by inflammatory cytokines to&#xD;
      lose their TREG characteristics and adopt a Th1-type inflammatory state, which may then&#xD;
      promote disease pathogenesis. To address this possibility, the RAPA-501 cell capacity to&#xD;
      modulate T cell differentiation transcription factors after an extended culture interval that&#xD;
      involved T cell co-stimulation, the absence of mTOR inhibitors, and the presence of the&#xD;
      polarizing inflammatory cytokines IFN-alpha and IL-6 was studied. These experiments&#xD;
      demonstrated that the RAPA-501 cell product had remarkable differentiation stability&#xD;
      (continued expression of FOXP3 and GATA3 in CD4+ and CD8+ subsets; lack of up-regulation of&#xD;
      TBET).&#xD;
&#xD;
      In summary, RAPA-501 cells express a phenotype consistent with a regulatory T cell&#xD;
      population, including: stable expression of the TREG and Th2 transcription factors FOXP3 and&#xD;
      GATA3; expression of the TREG functional molecules CD39, CD73, and CD103; expression of a&#xD;
      reduced state of T cell differentiation, including expression of the stem cell marker CD150;&#xD;
      secretion of a Th2 pattern of cytokines with minimal secretion of Th1/Th17-type cytokines;&#xD;
      functional suppressive capacity against both effector Th1/Tc1 cells and pro-inflammatory&#xD;
      myeloid cells, including reduced levels of multiple inflammatory cytokines and chemokines;&#xD;
      and a capacity to inhibit inflammatory effectors in a contact- and TCR-independent manner.&#xD;
      Collectively, these characteristics of the RAPA-501 product predicts that this therapy&#xD;
      represents a novel and promising candidate to treat COVID-19-related ARDS.&#xD;
&#xD;
      This is a first-in-human phase 1/phase 2b study evaluating allogeneic RAPA-501 cell therapy&#xD;
      in participants with COVID-19-related ARDS. Two phase 1 cohorts will be evaluated, namely, a&#xD;
      low-dose Cohort 1 (40 x 10^6 cells/infusion) and a high-dose Cohort 2 (160 x 10^6&#xD;
      cells/infusion); this phase 1 component will utilize dose-limiting-toxicity (DLT) as a&#xD;
      primary endpoint. Provided that safety is demonstrated in the phase 1 study component, each&#xD;
      RAPA-501 dose cohort can be evaluated in the randomized phase 2b component. In the phase 2b&#xD;
      component, for each RAPA-501 dose level determined to be safe, patients will be randomized to&#xD;
      receive RAPA-501 cells (n=19) or placebo (n=19). After infusion of either RAPA-501 cells or&#xD;
      placebo, these randomized cohorts will continue on standard-of-care therapy (not&#xD;
      protocol-driven). The primary endpoint of the phase 2b study is 30-day mortality, with the&#xD;
      statistical goal of reducing mortality in RAPA-501 recipients relative to the randomized,&#xD;
      placebo-control cohort.&#xD;
&#xD;
      Study participants must be hospitalized patients with COVID-19-related ARDS, specifically:&#xD;
      SARS-CoV-2 infection, as determined by RT-PCR or equivalent test; pulmonary infiltrate on&#xD;
      radiologic examination; and a diagnosis of ARDS requiring intensive respiratory support&#xD;
      including non-invasive ventilation such as high-flow nasal cannula or mechanical ventilation.&#xD;
      The study consists of: (1) a study enrollment step (screening); and (2) after eligibility is&#xD;
      confirmed, infusion of RAPA-501 cells will be performed. On Cohort 1, infusion of RAPA-501&#xD;
      cells will be at a dose of 40 x 10^6 cells/infusion; three participants will be initially&#xD;
      treated, with one week separating participants in this phase 1 component to evaluate for DLT,&#xD;
      which will be defined as grade 3 or greater toxicity attributable to RAPA-501 cells within&#xD;
      7-days of infusion. At any point that Cohort 1 therapy is deemed to be safe (either 0/3 or&#xD;
      1/6 having a DLT), then Cohort 1 RAPA-501 therapy can be evaluated in the randomized phase 2b&#xD;
      study component to address the primary study objective relating to 30-day mortality. At any&#xD;
      point that Cohort 1 therapy is deemed to be safe, treatment on Cohort 2 can be initiated,&#xD;
      which will evaluate the infusion of RAPA-501 cells at a dose of 160 x 10^6 cells/infusion. In&#xD;
      the same manner as Cohort 1, if Cohort 2 therapy is deemed to be safe, Cohort 2 RAPA-501&#xD;
      therapy can be evaluated in the randomized phase 2b study component to address the primary&#xD;
      study objective relating to 30-day mortality. The study will be comprised of three main&#xD;
      stages: (1) the above-detailed 30-day interval relating to the primary study objectives; (2)&#xD;
      an extended, total 90-day interval to continue relatively intensive clinical monitoring of&#xD;
      potential efficacy and safety endpoints; and (3) an extended, total 6-month interval to&#xD;
      provide long-term clinical follow-up and to continue to monitor for laboratory parameters&#xD;
      relating to immune and viral endpoints.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Change in eligible patient population&#xD;
  </why_stopped>
  <start_date type="Actual">December 30, 2020</start_date>
  <completion_date type="Actual">September 13, 2021</completion_date>
  <primary_completion_date type="Actual">September 13, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose-Limiting Toxicity (DLT)</measure>
    <time_frame>Through day 7.</time_frame>
    <description>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).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mortality Rate</measure>
    <time_frame>30 days after the first infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ventilation Support</measure>
    <time_frame>90 days after the infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>Number of days requiring intensive respiratory support (either high-flow nasal cannula or mechanical ventilation).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days of Hospitalization</measure>
    <time_frame>90 days after the infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>Number of days of hospitalization among survivors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Deaths</measure>
    <time_frame>90 days after the infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>Number of deaths due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Infection</measure>
    <time_frame>90 days after the infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GVHD Incidence</measure>
    <time_frame>90 days after the infusion of allogeneic RAPA-501 cells.</time_frame>
    <description>GVHD incidence and severity.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Viral Load</measure>
    <time_frame>Six months after treatment initiation.</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Host Immunity</measure>
    <time_frame>Six months after treatment initiation.</time_frame>
    <description>Development of potentially protective host immunity to COVID-19, as determined by serologic studies.</description>
  </other_outcome>
  <other_outcome>
    <measure>Peripheral Blood Immune Counts</measure>
    <time_frame>Six months after treatment initiation.</time_frame>
    <description>Peripheral blood immune counts, including CD4+ and CD8+ T cells, NK cells, and B cells.</description>
  </other_outcome>
  <other_outcome>
    <measure>T Cell Expression</measure>
    <time_frame>Six months after treatment initiation.</time_frame>
    <description>T cell expression of co-stimulation molecules (including CD28) and checkpoint receptor molecules (including PD-1).</description>
  </other_outcome>
  <other_outcome>
    <measure>Peripheral Blood Micro-chimerism</measure>
    <time_frame>Six months after treatment initiation.</time_frame>
    <description>Peripheral blood micro-chimerism, as determined by PCR amplification of donor and host STR loci.</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Severe COVID-19 Disease</condition>
  <arm_group>
    <arm_group_label>Single agent RAPA-501 cells (dose level 1)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose level 1 is 40 x 10^6</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Single agent RAPA-501 cells (dose level 2)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose level 2 is 160 x 10^6</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RAPA-501 cells</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>RAPA-501 cells at either dose level 1 or dose level 2 (whichever has been deemed safe during phase 1)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-control Cohort</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>RAPA-501-Allo off-the-shelf Therapy of COVID-19</intervention_name>
    <description>Allogeneic off-the-shelf RAPA-501 cells</description>
    <arm_group_label>RAPA-501 cells</arm_group_label>
    <arm_group_label>Single agent RAPA-501 cells (dose level 1)</arm_group_label>
    <arm_group_label>Single agent RAPA-501 cells (dose level 2)</arm_group_label>
    <other_name>RAPA-501-Allo cells</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>RAPA-501-Allo cell placebo</description>
    <arm_group_label>Placebo-control Cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female participants ≥ 18 years of age.&#xD;
&#xD;
          2. Participants with SARS-CoV-2 infection, as defined by standard reverse transcriptase&#xD;
             polymerase chain reaction (RT-PCR) assay or equivalent test.&#xD;
&#xD;
          3. Must have pulmonary infiltrate on radiologic examination.&#xD;
&#xD;
          4. Participant must have a clinical diagnosis of high-risk ARDS (as defined by a&#xD;
             PaO2-to-FiO2 ratio of &lt; 150 mm Hg) requiring intensive respiratory support, including&#xD;
             non-invasive methods such as high-flow nasal cannula or mechanical ventilation.&#xD;
&#xD;
          5. AST and ALT ≤ 3 x upper limit of normal (ULN).&#xD;
&#xD;
          6. Consent must be given before performance of any study related procedure not part of&#xD;
             standard medical care, with the understanding that consent may be withdrawn at any&#xD;
             time without prejudice to future medical care. Informed consent can be obtained from&#xD;
             healthcare proxy if the participant is unable to provide consent due to medical&#xD;
             status.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Active uncontrolled infection with a non-COVID-19 agent.&#xD;
&#xD;
          2. Diagnosis of ARDS that is not considered to be high-risk, as defined by PaO2-to-FiO2&#xD;
             ratio of ≥ 150 mm Hg.&#xD;
&#xD;
          3. Any irreversible disease or condition for which 6-month mortality is estimated to be&#xD;
             greater than 50%.&#xD;
&#xD;
          4. End-stage liver disease with ascites unrelated to COVID-19 (Childs Pugh score &gt; 12).&#xD;
&#xD;
          5. Uncontrolled or significant cardiovascular disease, including but not limited to: (a)&#xD;
             myocardial infarction, stroke, or transient ischemic attack within the past 30 days;&#xD;
             (b) uncontrolled angina within the past 30 days; (c) any history of clinically&#xD;
             significant arrhythmias such as ventricular tachycardia, ventricular fibrillation, or&#xD;
             torsades de pointes; and (d) history of other clinically significant or uncontrolled&#xD;
             heart disease, including: cardiomyopathy, congestive heart failure with New York Heart&#xD;
             Association functional classification III or IV, myocarditis, pericarditis, or&#xD;
             significant pericardial effusion.&#xD;
&#xD;
          6. Known chronic kidney disease of Stage 4 or 5 severity or requiring hemodialysis.&#xD;
&#xD;
          7. COVID-19-associated acute kidney injury requiring dialysis.&#xD;
&#xD;
          8. HIV, hepatitis B, or hepatitis C seropositive.&#xD;
&#xD;
          9. Patients with baseline QTc interval prolongation, as defined by repeated demonstration&#xD;
             of a QTc interval &gt;500 milliseconds.&#xD;
&#xD;
         10. Patients on hydroxychloroquine (must discontinue at least 2-days before study entry).&#xD;
&#xD;
         11. Pregnant or breastfeeding participants.&#xD;
&#xD;
         12. Patients of childbearing age, or males who have a partner of childbearing potential,&#xD;
             who are unwilling to practice contraception. Effective forms of birth control, which&#xD;
             must be continued through the entire on-study 6-month interval, include: Abstinence;&#xD;
             Intrauterine device (IUD); Hormonal (birth control pills, injections, or implants);&#xD;
             Tubal ligation; or Vasectomy.&#xD;
&#xD;
         13. Participants with malignancy requiring active therapy (not including non-melanoma skin&#xD;
             cancer).&#xD;
&#xD;
         14. Recipients of allogeneic hematopoietic cell transplant or solid organ transplant.&#xD;
&#xD;
         15. History of WHO Class III or IV pulmonary hypertension.&#xD;
&#xD;
         16. Severe thromboembolic disease, as defined by: administration of thrombolytic agents,&#xD;
             insertion of vena cava filter, or pulmonary thrombectomy within one-week interval&#xD;
             prior to screening.&#xD;
&#xD;
         17. Participants may be excluded at the discretion of the PI or if it is deemed that&#xD;
             allowing participation would represent an unacceptable medical or psychiatric risk.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daniel Fowler, M.D.</last_name>
    <role>Study Director</role>
    <affiliation>Rapa Therapeutics LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hackensack University Medical Center</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 22, 2020</study_first_posted>
  <last_update_submitted>November 3, 2021</last_update_submitted>
  <last_update_submitted_qc>November 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Allogeneic Hybrid TReg/Th2Cells</keyword>
  <keyword>RAPA-501-ALLO</keyword>
  <keyword>Off-the-shelf</keyword>
  <keyword>Pneumonia</keyword>
  <keyword>Lung Diseases</keyword>
  <keyword>Acute Respiratory Distress Syndrome</keyword>
  <keyword>ARDS</keyword>
  <keyword>Respiratory Distress Syndrome</keyword>
  <keyword>2019 Novel Coronavirus Pneumonia</keyword>
  <keyword>Acute Lung Injury</keyword>
  <keyword>Lung Injury</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Cytokine Storm</keyword>
  <keyword>Corona Virus Infection</keyword>
  <keyword>Severe Acute Respiratory Syndrome Coronavirus 2</keyword>
  <keyword>SARS Coronavirus 2</keyword>
  <keyword>SARS</keyword>
  <keyword>Reprogram</keyword>
  <keyword>COVID-19 Pneumonia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>November 10, 2022</submitted>
    <returned>December 7, 2022</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04482699
org study id: RAPA-501-ALLO-COVID-19
nct id: NCT04482699
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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. The United States has the highest totals
      with an estimated 22.4 million people diagnosed and 375,000 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.

      The mechanism of fatal pneumonia in experimental murine coronavirus infection is mediated by
      innate inflammasome activation, a resultant robust infiltration of inflammatory monocytes and
      macrophages, and a subsequent increase in multiple pro-inflammatory cytokines and chemokines.
      Importantly, the CD4+ and CD8+ adaptive T cell response to experimental coronavirus infection
      can be either curative or disease propagating. Viral-induced pulmonary inflammation has also
      been evaluated in non-human primate models, which have confirmed that dysregulated immune
      activation during viral pneumonia involves T cell subset imbalance, a downstream
      monocyte-derived inflammatory cascade, and resultant epithelial cell injury. In humans,
      severity of viral-induced lower respiratory tract infection correlates with increased numbers
      of effector memory CD8+ T cells in the airway. As recently reviewed, human coronavirus
      infection represents an ongoing battle between virus and host, with the nature of the
      response dictating disease cure or alternatively, aggravated lung disease. Evidence exists
      that the adaptive immune system contributes to pulmonary inflammation during SARS-associated
      Coronavirus (SARS-CoV) disease: that is, bronchoalveolar fluid from such subjects had
      increased T cell numbers and increased Th1-associated molecules IL-12, IFN-gamma, and IP-10.
      This downstream adaptive T cell-mediated inflammatory response is driven in part by the
      SARS-Co-V protein viroporin 3a. Specifically, viroporin molecules activate the NLRP3
      inflammasome that links innate-to-adaptive inflammatory responses. Furthermore, both SARS-CoV
      and SARS-CoV-2 express an open-reading-frame ORF3a molecule, which also activate the NLRP3
      inflammasome.

      The nature of immunity during resolution of symptomatic COVID-19 infection has recently been
      reported, namely: emergence of antibody-secreting cells and CD4+ T follicular helper cells;
      increase in perforin- and granzyme-expressing CD8+ T cells; and relative lack of an increase
      in pro-inflammatory cytokines and chemokines. In marked contrast, patients with severe
      COVID-19 disease had greatly increased plasma levels of cytokines (including IL-2 and
      TNF-alpha) and chemokines (including IP-10 and MIP-1-alpha) (Huang et al., Lancet, 2020).
      Collectively, these results indicate that pro-inflammatory cytokine and chemokine responses
      that occur in severe COVID-19 is detrimental and that effective anti-inflammatory approaches
      may ultimately prove to be therapeutic. However, as previously detailed, the more advanced
      Stage 3 COVID-19 disease is characterized by an ARDS component, and cytokine storm, as such,
      novel approaches to treat the COVID-19 viral pneumonia should optimally incorporate both an
      anti-inflammatory element and a tissue protection/tissue repair element.

      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 Stage 3 COVID-19-related
      ARDS.

      In general, classical autoimmune disease, neurodegenerative disease, and viral-induced
      inflammatory disease are driven by predominance of Th1/Th17-type responses with a relative
      insufficiency of the counter-regulatory immune suppressive Th2 and TREG subsets. TREG cells,
      which are defined in part by their expression of FOXP3 transcription factor, have been
      extensively studied in experimental models for their capacity to modulate autoimmune disease,
      neurodegenerative disease, and transplantation complications, including graft-versus-host
      disease (GVHD) and graft rejection. Importantly, T cell production of IL-2 or exogenous IL-2
      administration drives lung inflammation during experimental viral infection; therefore, given
      the known role of TREG cells as a consumer of IL-2, there is a strong mechanistic rationale
      for a beneficial contribution of TREG cells during viral-driven lung inflammation.
      Furthermore, in an experimental murine models of virus-induced lung inflammation and lung
      injury, interventions that augmented TREG cell number and function accelerated the repair of
      lung injury. And, Th2 cells, which are defined in part by their expression of GATA3
      transcription factor, were described thirty years ago as a powerful counter-regulatory
      population to prevent Th1 cell predominance. It is important to note that clinical data
      indicates that maneuvers that increase immune suppressive cell populations, including TREG
      cells, can reduce severe inflammatory disease such as graft-versus-host disease without
      impairing anti-viral immunity. In addition, in both experimental models and clinical studies,
      an appropriate level of TREG cells can result in an overall improvement in pulmonary
      inflammation during viral bronchiolitis. Collectively, these findings indicate that T cells
      expressing a combined TREG/Th2 phenotype would predictably yield beneficial effects in the
      setting of viral-induced pulmonary inflammation and injury associated with severe Stage 3
      COVID-19 disease.

      Clinical trials have evaluated both TREG and Th2-type cells for various conditions, most
      prominently transplantation complications. In general, thymic-derived natural (n)TREG cells
      are thought to express a more stable phenotype than post-thymic induced (i)TREG cells; by
      comparison, iTREG cells can mediate more potent suppression. Nonetheless, both nTREG and
      iTREG cells are susceptible to differentiation plasticity, which creates concern that a
      potentially therapeutic TREG population might convert to pathogenic Th1/Th17 phenotypes in
      vivo. Ex vivo expanded (n)TREG cells were evaluated in the setting of allogeneic
      hematopoietic cell transplantation (HCT) using cord blood donors; more recently, the same
      research group has developed ex vivo expanded (i)TREG cell therapy to limit transplant
      complications. In addition, ex vivo expanded nTREG cells have been evaluated in the setting
      of type I diabetes mellitus; this clinical trial found that TREG therapy was safe and at
      least transiently effective in improving disease control. Furthermore, in the setting of
      amyotrophic lateral sclerosis (ALS), which is a disease propagated by a severe Th1-driven
      peripheral and central inflammatory response, a clinical trial of nTREG cell adoptive
      transfer identified that the intervention was safe and showed promise in terms of ALS disease
      amelioration. Finally, in a phase II study of rapamycin-resistant Th2 cell therapy in the
      setting of low-intensity allogeneic HCT, adoptive Th2 cell transfer was safe and associated
      with a shift towards Th2 polarization in vivo, preservation of donor engraftment,
      stabilization of mixed chimerism, a low rate of GVHD, and potent anti-tumor effects in
      patients with refractory hematologic malignancy. Collectively, these clinical trial results
      indicate that the adoptive transfer of TREG and Th2-type populations can be safely
      administered, even in the allogeneic HCT setting, and can mediate beneficial modulation of
      inflammatory conditions.

      Ex vivo manufacturing can be utilized to generate induced (i)TREG cells from the post-thymic
      pool of peripheral T cells. In the current protocol, the manufacturing method will focus upon
      mTOR inhibition, which is an established intervention that promotes the induction of TREG
      cells. In combination with mTOR inhibition, the culture system that is utilized incorporates
      cytokines that promote both a Th2 and a TREG phenotype, namely, IL-4, TGF-beta, and IL-2.
      Finally, the protocol will include a TREG/Th2 cell product comprised of both CD4+ and CD8+ T
      cell subsets, as these counter-regulatory T cell subsets express differential T cell receptor
      (TCR) repertoires and a diversity of effector mechanisms that can potentially enhance an
      anti-inflammatory effect. For RAPA-501 manufacture, peripheral blood mononuclear cells are
      collected from a steady-state apheresis and subjected to the following two-step culture
      intervention: in step 1, a severe starvation step results in T cell de-differentiation, which
      is realized through both selective media utilization and the addition of FDA-approved
      pharmaceutical agents that potently inhibit mTOR signaling; and in step 2, re-differentiation
      of T cells occurs using co-stimulation agents and Th2- and TREG-type polarizing cytokines.
      After 6-days in culture, the resultant TREG/Th2 population is cryopreserved in single-use
      aliquots at protocol-driven therapeutic doses. T cells of type II cytokine phenotype are
      characterized in part by their expression of the transcription factor GATA3 whereas
      regulatory T cell populations are identified in part by their expression of FOXP3
      transcription factor. At culture initiation, a very low frequency of T cells express either
      GATA3 or FOXP3. In contrast, the RAPA-501 cell product manufactured in the TREG/Th2 culture
      conditions expresses a high frequency of T cells that are either single-positive for GATA3,
      single-positive for FOXP3, or double-positive for both GATA3 and FOXP3. Importantly, this
      transcription factor profile is expressed in both manufactured CD4+ and CD8+ T cells. It is
      important to note that both CD4+ and CD8+ T cell populations with TREG function have been
      defined, including a CD8+ TREG population that potently suppresses GVHD; it is potentially
      advantageous to have both subsets represented in a therapeutic product because CD4+ and CD8+
      TREG cells utilize differential effector mechanisms.

      Regulatory T cell populations can suppress pathogenic effector T cell populations by several
      defined mechanisms, including through expression of CD39 and CD73 ectonucleotidase molecules,
      which act to hydrolyse pro-inflammatory ATP towards the immune suppressive adenosine
      substrate . Indeed, TREG cells that express CD39 possess increased suppressive function and
      have been associated with resolution of inflammatory bowel disease. Furthermore, suppressive
      function of human TREG cells is mediated in part by CD73. T cells manufactured in the
      TREG/Th2 culture condition have an increase in expression of the TREG-associated effector
      molecules, CD39 and CD73. In addition to the CD39/CD73 ectonucleotidases, TREG cell function
      has also been correlated with expression of CD103, which is an integrin that dictates
      epithelial lymphocyte localization. Indeed, CD103 and IL-2 receptor signaling cooperate to
      maintain immune tolerance in the gut mucosa; furthermore, CD103-expressing TREG cells are
      critical for amelioration of experimental chronic GVHD . T cells manufactured in the TREG/Th2
      culture condition have increased expression of the TREG effector molecule CD103.

      In experimental models, the efficacy of adoptive T cell therapy is dependent upon successful
      engraftment and in vivo T cell persistence. Importantly, the T cell differentiation state
      helps dictate in vivo persistence, with less differentiated cells having increased
      persistence. Murine rapamycin-resistant T cells, which expressed a T central memory (TCM)
      phenotype, had increased in vivo engraftment potential relative to control T cells. In
      addition, human rapamycin-resistant T cells also had increased engraftment in a
      human-into-murine model of xenogeneic graft-versus-host disease. T cells with reduced
      differentiation relative to the T effector memory (TEM) population have increased in vivo
      persistence and mediate increased in vivo effects, including the TCM subset, the naïve T cell
      subset, and more recently, the T stem cell memory (TSCM) subset. This relationship between T
      cell differentiation status and in vivo T cell function is relevant to TREG cells, as: (1)
      TREG cells of TCM phenotype were more effective at reducing experimental GVHD relative to
      TREG cells of TEM phenotype; and (2) TREG cells that expressed the stem cell marker CD150
      were highly effective for the prevention of stem cell graft rejection. T cells manufactured
      in the TREG/Th2 culture condition are enriched for cells having a reduced differentiation
      state consistent with a T stem cell subset, including expression of the CD150 marker.

      It is also important to assess the cytokine secretion profile of the manufactured RAPA-501
      cells. First, it is critical that the cell product is capable of IL-4 secretion, which is the
      driver cytokine for subsequent Th2 differentiation. Second, it is desirable that an
      adoptively transferred T cell population is capable of secreting IL-2, as this capacity
      indicates a progenitor function that permits T cells to expand more readily in vivo without
      the need for exogenous IL-2 . Finally, it is important that the RAPA-501 cell population has
      reduced secretion of the Th1- or Th17-type cytokines IFN-gamma, TNF-alpha, IL-17, and GM-CSF.
      The manufactured RAPA-501 cell product secretes IL-4 and IL-2 with minimal secretion of Th1-
      or Th17-type cytokines.

      Regulatory T cells can also be defined in part by their ability to suppress the proliferation
      or function of effector T cells. Importantly, manufactured TREG/Th2 cells potently suppress
      Th1/Tc1 cell secretion of multiple inflammatory cytokines, including IFN-gamma, GM-CSF, and
      TNF-alpha. To assess the mechanism of suppression, experiments were performed using the
      transwell assay, whereby effector T cells and RAPA-501 cells are separated by a filter that
      prevents cell-to-cell contact but allows cell communication by small soluble mediators such
      as cytokines. RAPA-501 cells acted in a TCR-independent manner to suppress the cytokine
      secretion capacity of effector T cells. Because no co-stimulation was provided to the
      transwell chamber containing RAPA-501 cells, RAPA-501 cells did not require co-stimulation to
      modulate inflammatory cytokine levels, including IL-2, IFN-gamma, GM-CSF, and TNF-alpha. The
      following cytokines and chemokines were reduced by RAPA-501 cells in this transwell assay,
      with relatively equal suppression mediated by CD4+ and CD8+ subsets of RAPA-501 cells: CCL1,
      CCL2, CCL7, CCL11, CCL13, CCL17, CCL20, CCL22, CCL26, CXCL1, CXCL10, CXCL11, CXCL12, IL-6,
      IFN-gamma, GM-CSF, and IL-10. The ability of TREG cells to consume IL-2 is a commonly
      described phenomenon, although previous studies identified the requirement of cell-to-cell
      contact for IL-2 consumption. As such, RAPA-501 cells are uniquely capable of modulating the
      level of multiple inflammatory cytokines in a contact-independent manner. These results
      suggest that RAPA-501 cells represent a suitable candidate for neutralization of multiple
      cytokines and chemokines associated with various diseases, including viral-induced lung
      inflammation. In light of this capacity of the RAPA-501 cell product to suppress T
      cell-mediated inflammation in a TCR-independent manner, RAPA-501 therapy is highly suitable
      for allogeneic, off-the-shelf treatment applications.

      Further experiments were performed to evaluate whether the RAPA-501 cell product might also
      regulate human CNS microglial cells, which are myeloid-derived cells that are analogous to
      the peripheral monocyte population. To evaluate whether the RAPA-501 cell product might
      modulate pro-inflammatory microglial cells in a contact-independent manner, the ability of
      RAPA-501 cells to reduce the inflammatory state of the microglial cell line HMC3 was tested
      in a transwell assay. RAPA-501 cells reduced the HMC3 cell secretion of the pro-inflammatory
      cytokines IL-6 and IFN-gamma and the pro-inflammatory chemokine IP-10 at the relatively low
      ratio of RAPA-501 cells to microglial cells of 1:40. These results demonstrate that the
      RAPA-501 product is capable of inhibiting cytokine and chemokine secretion from
      myeloid-derived populations in a contact- and TCR-independent manner, thereby providing a
      further rationale for allogeneic, off-the-shelf utilization of the RAPA-501 product.

      RAPA-501 cell product for stability of T cell phenotype was also evaluated. That is, it has
      been determined that a limiting factor of TREG cell therapy may be differentiation
      plasticity, for example, whereby TREG cells can be influenced by inflammatory cytokines to
      lose their TREG characteristics and adopt a Th1-type inflammatory state, which may then
      promote disease pathogenesis. To address this possibility, the RAPA-501 cell capacity to
      modulate T cell differentiation transcription factors after an extended culture interval that
      involved T cell co-stimulation, the absence of mTOR inhibitors, and the presence of the
      polarizing inflammatory cytokines IFN-alpha and IL-6 was studied. These experiments
      demonstrated that the RAPA-501 cell product had remarkable differentiation stability
      (continued expression of FOXP3 and GATA3 in CD4+ and CD8+ subsets; lack of up-regulation of
      TBET).

      In summary, RAPA-501 cells express a phenotype consistent with a regulatory T cell
      population, including: stable expression of the TREG and Th2 transcription factors FOXP3 and
      GATA3; expression of the TREG functional molecules CD39, CD73, and CD103; expression of a
      reduced state of T cell differentiation, including expression of the stem cell marker CD150;
      secretion of a Th2 pattern of cytokines with minimal secretion of Th1/Th17-type cytokines;
      functional suppressive capacity against both effector Th1/Tc1 cells and pro-inflammatory
      myeloid cells, including reduced levels of multiple inflammatory cytokines and chemokines;
      and a capacity to inhibit inflammatory effectors in a contact- and TCR-independent manner.
      Collectively, these characteristics of the RAPA-501 product predicts that this therapy
      represents a novel and promising candidate to treat COVID-19-related ARDS.

      This is a first-in-human phase 1/phase 2b study evaluating allogeneic RAPA-501 cell therapy
      in participants with COVID-19-related ARDS. Two phase 1 cohorts will be evaluated, namely, a
      low-dose Cohort 1 (40 x 10^6 cells/infusion) and a high-dose Cohort 2 (160 x 10^6
      cells/infusion); this phase 1 component will utilize dose-limiting-toxicity (DLT) as a
      primary endpoint. Provided that safety is demonstrated in the phase 1 study component, each
      RAPA-501 dose cohort can be evaluated in the randomized phase 2b component. In the phase 2b
      component, for each RAPA-501 dose level determined to be safe, patients will be randomized to
      receive RAPA-501 cells (n=19) or placebo (n=19). After infusion of either RAPA-501 cells or
      placebo, these randomized cohorts will continue on standard-of-care therapy (not
      protocol-driven). The primary endpoint of the phase 2b study is 30-day mortality, with the
      statistical goal of reducing mortality in RAPA-501 recipients relative to the randomized,
      placebo-control cohort.

      Study participants must be hospitalized patients with COVID-19-related ARDS, specifically:
      SARS-CoV-2 infection, as determined by RT-PCR or equivalent test; pulmonary infiltrate on
      radiologic examination; and a diagnosis of ARDS requiring intensive respiratory support
      including non-invasive ventilation such as high-flow nasal cannula or mechanical ventilation.
      The study consists of: (1) a study enrollment step (screening); and (2) after eligibility is
      confirmed, infusion of RAPA-501 cells will be performed. On Cohort 1, infusion of RAPA-501
      cells will be at a dose of 40 x 10^6 cells/infusion; three participants will be initially
      treated, with one week separating participants in this phase 1 component to evaluate for DLT,
      which will be defined as grade 3 or greater toxicity attributable to RAPA-501 cells within
      7-days of infusion. At any point that Cohort 1 therapy is deemed to be safe (either 0/3 or
      1/6 having a DLT), then Cohort 1 RAPA-501 therapy can be evaluated in the randomized phase 2b
      study component to address the primary study objective relating to 30-day mortality. At any
      point that Cohort 1 therapy is deemed to be safe, treatment on Cohort 2 can be initiated,
      which will evaluate the infusion of RAPA-501 cells at a dose of 160 x 10^6 cells/infusion. In
      the same manner as Cohort 1, if Cohort 2 therapy is deemed to be safe, Cohort 2 RAPA-501
      therapy can be evaluated in the randomized phase 2b study component to address the primary
      study objective relating to 30-day mortality. The study will be comprised of three main
      stages: (1) the above-detailed 30-day interval relating to the primary study objectives; (2)
      an extended, total 90-day interval to continue relatively intensive clinical monitoring of
      potential efficacy and safety endpoints; and (3) an extended, total 6-month interval to
      provide long-term clinical follow-up and to continue to monitor for laboratory parameters
      relating to immune and viral endpoints.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Dose-Limiting Toxicity (DLT)
time frame: Through day 7.
description: 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).
measure: Mortality Rate
time frame: 30 days after the first infusion of allogeneic RAPA-501 cells.
description: 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.
measure: Ventilation Support
time frame: 90 days after the infusion of allogeneic RAPA-501 cells.
description: Number of days requiring intensive respiratory support (either high-flow nasal cannula or mechanical ventilation).
measure: Days of Hospitalization
time frame: 90 days after the infusion of allogeneic RAPA-501 cells.
description: Number of days of hospitalization among survivors.
measure: Number of Deaths
time frame: 90 days after the infusion of allogeneic RAPA-501 cells.
description: Number of deaths due to any cause.
measure: Incidence of Infection
time frame: 90 days after the infusion of allogeneic RAPA-501 cells.
description: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection.
measure: GVHD Incidence
time frame: 90 days after the infusion of allogeneic RAPA-501 cells.
description: GVHD incidence and severity.
measure: Viral Load
time frame: Six months after treatment initiation.
description: 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.
measure: Host Immunity
time frame: Six months after treatment initiation.
description: Development of potentially protective host immunity to COVID-19, as determined by serologic studies.
measure: Peripheral Blood Immune Counts
time frame: Six months after treatment initiation.
description: Peripheral blood immune counts, including CD4+ and CD8+ T cells, NK cells, and B cells.
measure: T Cell Expression
time frame: Six months after treatment initiation.
description: T cell expression of co-stimulation molecules (including CD28) and checkpoint receptor molecules (including PD-1).
measure: Peripheral Blood Micro-chimerism
time frame: Six months after treatment initiation.
description: Peripheral blood micro-chimerism, as determined by PCR amplification of donor and host STR loci.
arm group label: Single agent RAPA-501 cells (dose level 1)
arm group type: Experimental
description: Dose level 1 is 40 x 10^6
arm group label: Single agent RAPA-501 cells (dose level 2)
arm group type: Experimental
description: Dose level 2 is 160 x 10^6
arm group label: RAPA-501 cells
arm group type: Active Comparator
description: RAPA-501 cells at either dose level 1 or dose level 2 (whichever has been deemed safe during phase 1)
arm group label: Placebo-control Cohort
arm group type: Placebo Comparator
description: Placebo
intervention type: Biological
intervention name: RAPA-501-Allo off-the-shelf Therapy of COVID-19
description: Allogeneic off-the-shelf RAPA-501 cells
arm group label: RAPA-501 cells
arm group label: Single agent RAPA-501 cells (dose level 1)
arm group label: Single agent RAPA-501 cells (dose level 2)
other name: RAPA-501-Allo cells
intervention type: Other
intervention name: Placebo
description: RAPA-501-Allo cell placebo
arm group label: Placebo-control Cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Daniel Fowler, M.D.
role: Study Director
affiliation: Rapa Therapeutics LLC
facility: 
country: United States
responsible party type: Sponsor
mesh term: COVID-19
sharing ipd: No
submitted: November 10, 2022
returned: December 7, 2022