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

NCT04482699 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: RAPA-501-ALLO-COVID-19
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe COVID-19 Disease

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Dose-Limiting Toxicity (DLT)

  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).

  Through day 7.

• Mortality Rate

  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.

  30 days after the first infusion of allogeneic RAPA-501 cells.

Secondary Outcomes (5)

• Ventilation Support

  90 days after the infusion of allogeneic RAPA-501 cells.

• Days of Hospitalization

  90 days after the infusion of allogeneic RAPA-501 cells.

• Number of Deaths

  90 days after the infusion of allogeneic RAPA-501 cells.

• Incidence of Infection

  90 days after the infusion of allogeneic RAPA-501 cells.

• GVHD Incidence

  90 days after the infusion of allogeneic RAPA-501 cells.

Other Outcomes (5)

• Viral Load

  Six months after treatment initiation.

• Host Immunity

  Six months after treatment initiation.

• Peripheral Blood Immune Counts

  Six months after treatment initiation.

Study Arms (4)

Single agent RAPA-501 cells (dose level 1)

EXPERIMENTAL

Dose level 1 is 40 x 10\^6

Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19

Single agent RAPA-501 cells (dose level 2)

EXPERIMENTAL

Dose level 2 is 160 x 10\^6

Biological: RAPA-501-Allo off-the-shelf Therapy of COVID-19

RAPA-501 cells

ACTIVE COMPARATOR

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

Placebo-control Cohort

PLACEBO COMPARATOR

Placebo

Other: Placebo

Interventions

RAPA-501-Allo off-the-shelf Therapy of COVID-19 BIOLOGICAL

Allogeneic off-the-shelf RAPA-501 cells

Also known as: RAPA-501-Allo cells

RAPA-501 cells; Single agent RAPA-501 cells (dose level 1); Single agent RAPA-501 cells (dose level 2)

Placebo OTHER

RAPA-501-Allo cell placebo

Placebo-control Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants ≥ 18 years of age.
• Participants with SARS-CoV-2 infection, as defined by standard reverse transcriptase polymerase chain reaction (RT-PCR) assay or equivalent test.
• Must have pulmonary infiltrate on radiologic examination.
• 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.
• AST and ALT ≤ 3 x upper limit of normal (ULN).
• 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.

You may not qualify if:

• Active uncontrolled infection with a non-COVID-19 agent.
• Diagnosis of ARDS that is not considered to be high-risk, as defined by PaO2-to-FiO2 ratio of ≥ 150 mm Hg.
• Any irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%.
• End-stage liver disease with ascites unrelated to COVID-19 (Childs Pugh score \> 12).
• 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.
• Known chronic kidney disease of Stage 4 or 5 severity or requiring hemodialysis.
• COVID-19-associated acute kidney injury requiring dialysis.
• HIV, hepatitis B, or hepatitis C seropositive.
• Patients with baseline QTc interval prolongation, as defined by repeated demonstration of a QTc interval \>500 milliseconds.
• Patients on hydroxychloroquine (must discontinue at least 2-days before study entry).
• Pregnant or breastfeeding participants.
• 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.
• Participants with malignancy requiring active therapy (not including non-melanoma skin cancer).
• Recipients of allogeneic hematopoietic cell transplant or solid organ transplant.
• History of WHO Class III or IV pulmonary hypertension.

Sponsors & Collaborators

• Rapa Therapeutics LLC: lead
• Hackensack Meridian Health: collaborator

Study Sites (1)

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

MeSH Terms

Conditions

COVID-19; Pneumonia; Lung Diseases; Respiratory Distress Syndrome; Acute Lung Injury; Lung Injury; Cytokine Release Syndrome; Coronavirus Infections

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Respiratory Tract Diseases; Respiration Disorders; Thoracic Injuries; Wounds and Injuries; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Study Officials

• Daniel Fowler, M.D.

  Rapa Therapeutics LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2020
• First Posted: July 22, 2020
• Study Start: December 30, 2020
• Primary Completion: September 13, 2021
• Study Completion: September 13, 2021
• Last Updated: November 11, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)