Clinical trial NCT04487444: Thymalfasin (Thymosin Alpha 1) to Treat COVID-19 Infection
Official title: A Pilot Trial of Thymalfasin (Ta1) to Treat COVID-19 Infection in Patients With Lymphocytopenia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Covid19
Keywords: thymosin alpha 1
lymphocytopenia
thymalfasin
Lead sponsor: Rhode Island Hospital
Sponsor class: OTHER
First posted: 2020-07-27
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: It is our hypothesis that a course of Ta1 administered to hospitalized individuals with COVID-19 infection and lymphocytopenia will improve the time to recovery (primary objective) and severity of infection (secondary objectives) compared to untreated individuals in the same hospital with comparable lymphocytopenia.

After screening, hospitalized patients with COVID-19 and lymphocytopenia who meet the inclusion criteria will receive Ta1 (1.6 mg) administered subcutaneously (SC) daily for 1 week. Individuals in the control arm will be followed on the identical protocol but will not receive daily Ta1.

Detailed description: Ta1 is a naturally occurring peptide that has been evaluated for its immunomodulatory activities and related therapeutic potential in several conditions and diseases, including infectious disease and cancer. ZADAXIN® brand Ta1 is a synthetic version currently approved for use in 37 countries; in particular it is approved in China for treatment of hepatitis B and to enhance vaccine response. Notably, Ta1 has been used clinically in pilot studies for treatment of severe acute respiratory syndrome (SARS) and other lung infections including acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disorder (COPD), as well as infections after bone marrow transplant. Larger clinical trials have shown significant efficacy for treatment of severe sepsis and hepatitis B, along with certain cancers such as melanoma, hepatocellular, and lung cancer. Ta1 has also demonstrated improvement in response to vaccines in the elderly and in patients immunocompromised by renal disease.

Ta1 restores immune system homeostasis, by acting as multi-tasking protein depending on the host state of inflammation or immune dysfunction (such as infectious disease and cancer). Ta1 is believed to directly enhance the immune systems' recognition of infected cells and tumors cells, while also possibly modulating T cell activity and stimulating both innate and adaptive immunity to clear bacteria, virus, fungi and tumor cells. Ta1 serves a unique function in balancing pro-inflammatory and anti-inflammatory cytokine production through the regulation of distinct Toll-like receptors (TLRs) on different dendritic cell subsets. Data from other coronaviruses such as SARS-CoV and Middle Eastern respiratory syndrome (MERS)-CoV indicate that infection relies on their ability to impair both innate and adaptive immunity. During the 2003 pandemic, Ta1 was used as a prophylactic agent against SARS. Some published reports suggest that timely administration of immune-enhancers such as Ta1 to SARS patients was efficacious to a certain extent in controlling the development of the disease. Another study investigated the clinical manifestations, pharmacotherapy and prognosis of 46 patients with SARS and divided the severe cases (22 cases) into 2 groups according to administration of Ta1 and showed that the incidence rate of pulmonary fibrosis was lower in the group with Ta1 (2 of 14 cases) than the group without (6 out of 8 cases), i.e., 14.3% and 75.0%, respectively.

A recent study presented a retrospective analysis of hospitalized COVID-19 patients in China, in which those treated with Ta1 showed an improvement in lymphocyte subsets as well as a significant reduction in mortality (from 30 to 11%, p = 0.04).

Based on post-marketing treatment experience of more than 600,000 patients, Ta1 has been well tolerated. Ta1 has been administered to elderly subjects (up to 101 years old), children (as young as 13 months), and immunocompromised patients. The most common adverse events (AEs) in previous clinical trials include injection-site pain (such as burning and itching) which was mild and lasted for less than 30 minutes, as well as fever, nausea, and flu-like symptoms which were mild to moderate in severity. Thus, while Ta1 is one of only a few immunomodulatory agents that have been approved for human use, it does not appear to induce most of the side effects and toxicities commonly associated with other biological response modifiers (BRMs) in this class, such as interferon and interleukin (IL)-2.

The primary objective of the study is to determine whether Ta1 administered daily for one week to hospitalized COVID-19 patients with lymphocytopenia will improve time to recovery (free of respiratory failure) compared with a similar population of patients who do not receive Ta1. The secondary objectives are to determine whether hospitalized COVID-19 patients with lymphocytopenia treated with Ta1 will have a milder course of infection in terms of length of hospitalization stay, requirement (and length) for ICU stay, and requirement for supplemental oxygen or mechanical ventilation than patients not treated with Ta1, as well as higher chances of survival.

After screening, hospitalized patients with COVID-19 and lymphocytopenia who meet the inclusion criteria will receive Ta1 (1.6 mg) administered subcutaneously (SC) daily for 1 week. Individuals in the control arm will be followed on the identical protocol but will not receive daily Ta1. After the treatment period, all subjects will be followed and evaluated for efficacy outcomes at Day 14, with follow-up visits at Days 28, 42, and 60 (by phone, if the subject has been discharged from the hospital) to determine any AE/serious adverse event (SAE) and mortality.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* PCR positive for COVID-19 within the last 4 days
* Hospitalized
* SpO2 ≤ 93% on room air or requiring supplemental oxygen at screening (i.e. patients with severe disease)
* Lymphopenia (total lymphocyte count \< 1.5 × 109/L)

Exclusion Criteria:

* Patients on mechanical ventilation
* Patients who are pregnant or breastfeeding
* Patients with multi-organ failure
* Patients with advanced malignancy receiving cytotoxic chemotherapy
* Patients with prior history of solid organ (kidney, liver, heart, lung, pancreas) or bone marrow transplant
* Patients on any other immunomodulatory therapy
* Patients receiving Plaquenil
* Patients who have participated in an investigational drug or device trial in previous 30 days
* Patients with a history of allergy or intolerance to Ta1
* Any other medical or psychiatric condition that, in the opinion of the Investigator, would compromise patient safety or interfere with the objectives of the protocol or completion of the protocol treatment

Primary outcomes:
measure: Time to recovery (free of respiratory failure)
timeFrame: Day 28
Secondary outcomes:
measure: Lymphopenia
timeFrame: Day 14
measure: Survival
timeFrame: Day 28
measure: Hospital length of stay
timeFrame: Day 28
measure: Requirement for high flow oxygen supplementation
timeFrame: Day 28
measure: Duration of high flow oxygen supplementation
timeFrame: Day 28
measure: ICU admission
timeFrame: Day 28
measure: ICU length of stay
timeFrame: Day 28
measure: Mechanical ventilation
timeFrame: Day 28
measure: Duration of mechanical ventilation
timeFrame: Day 28
measure: Change in any existing comorbidities (e.g., worsening congestive heart failure) or occurrence of newly diagnosed disease
timeFrame: Day 28
measure: Incidence of non-COVID-19 infections (other respiratory, urinary tract, cellulitis, etc.)
timeFrame: Day 28
measure: AEs/SAEs
timeFrame: Day 60
measure: Changes to vital signs
timeFrame: Day 28
measure: Changes in laboratory parameters
timeFrame: Day 28
Other outcomes:
Locations:
city: Providence
country: United States
facility: The Miriam Hospital
state: Rhode Island
Study officials:
affiliation: Lifespan
name: Eleftherios Mylonakis, MD PhD FIDSA
role: PRINCIPAL_INVESTIGATOR
References:
citation: Liu Y, Pan Y, Hu Z, Wu M, Wang C, Feng Z, Mao C, Tan Y, Liu Y, Chen L, Li M, Wang G, Yuan Z, Diao B, Wu Y, Chen Y. Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells. Clin Infect Dis. 2020 Nov 19;71(16):2150-2157. doi: 10.1093/cid/ciaa630.
citation: Shehadeh F, Benitez G, Mylona EK, Tran QL, Tsikala-Vafea M, Atalla E, Kaczynski M, Mylonakis E. A Pilot Trial of Thymalfasin (Thymosin-alpha-1) to Treat Hospitalized Patients With Hypoxemia and Lymphocytopenia Due to Coronavirus Disease 2019 Infection. J Infect Dis. 2023 Jan 11;227(2):226-235. doi: 10.1093/infdis/jiac362.