A pilot trial of Thymalfasin (Ta1) to prevent covid-19 infection and morbidities in renal dialysis patients: Preliminary report

Abstract

Purpose

Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are considered particularly susceptible to infection with SARS-CoV2 on the basis of the immunodeficiency associated with advanced age, comorbidity burden, medication use, and need for frequent visits to dialysis clinics. In prior studies, thymalfasin (thymosin alpha 1, Ta1) has been shown to enhance antibody response to influenza vaccine and reduce influenza infection in geriatric populations, including hemodialysis patients, when used as an adjunct to influenza vaccine. Early in the COVID-19 pandemic we speculated that administration of Ta1 to HD patients would result in reduced rate and severity of COVID-19 infection. We also hypothesized that HD patients treated with Ta1 who did become infected with COVID-19 would have a milder course of infection in terms of hospitalization rates, requirement for and length of ICU stays, requirement for mechanical ventilation, and survival. Further, we proposed that patients who avoided COVID-19 infection during the study would have decreased non-COVID-19 infections and hospitalizations compared to controls.

Procedures

The study launched in January 2021 and, as of July 1, 2022, 254 ESRD/ HD patients from five dialysis centers in Kansas City, MO have been screened. Of these, 194 patients have been randomized 1:1 to either Group A (1.6 mg Ta1 given subcutaneously twice weekly for 8 weeks), or Group B (control group not receiving Ta1). After the 8-week treatment period, subjects were followed for an additional 4 months and monitored for safety and efficacy. A data safely monitoring board reviewed all reported adverse effects and commented on study progress.

Results

To date, only 3 deaths have occurred in subjects treated with Ta1 (Group A), compared to 7 in the control (Group B). There have been 12 COVID-19 related serious adverse effects (SAEs; 5 in Group A, and 7 in Group B). The majority of patients have received a COVID-19 vaccine (91 patients in group A, and 76 patients in Group B) at various times throughout the study. Nearing completion of the study, blood samples have been collected and antibody responses to COVID-19 will be analyzed along with safety and efficacy endpoints when all subjects have completed the study.

1. Introduction

Over the past several years it has become increasingly clear that older individuals, particularly those with comorbidities and/or immunosuppression, are at particularly high risk for adverse outcomes from infection by the SARS corona virus 2, COVID-19, especially in those who have not been vaccinated [1]. With this in mind, a pilot clinical trial was begun in early 2021 to investigate the possible efficacy of Thymalfasin (thymosin alpha 1 or Ta1) in reducing the rate or severity of infection by COVID-19 in individuals with end-stage renal disease (ESRD) on hemodialysis (HD).

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 hepatitis B and to enhance vaccine response. Notably, Ta1 has been examined in pilot clinical studies for treatment of severe acute respiratory syndrome (SARS) [2] as well as in other clinical scenarios including acute respiratory distress syndrome (ARDS) [3], chronic obstructive pulmonary disorder (COPD) [4], and after bone marrow transplant for hematologic malignancy [5]. Importantly, a recent retrospective analysis of patients in China with COVID-19 demonstrated reduced mortality in Ta1-treated patients (11% versus 30%, p = 0.04), and improved CD4 and CD8 levels [6]. Further studies with Ta1 in COVID-19 have shown that Ta1 may be beneficial to subgroups of COVID-19 patients at particular risk [7], [8], [9]; the population chosen for the present study may prove to be one of these subgroups. Larger clinical trials have shown significant efficacy for treatment of severe sepsis [10], [11] and hepatitis B [12] along with certain cancers such as melanoma, hepatocellular, and lung cancer [13]. Ta1 has also demonstrated improvement in response to vaccines in the elderly and in patients immunocompromised by renal disease [14], [15], [16], [17], [18], [19], [20]. It has been proposed that the beneficial effects of Ta1 result from activation of toll-like receptor (TLR) 9 in dendritic and other immune system cells, resulting in augmentation of T helper (Th1) function, natural killer (NK) cell activity, and increased antibody responses to T-cell dependent antigens [21], [22], [23]. Importantly, Ta1 also leads to an increase in IL-10 producing regulatory T cells, which create feedback inhibition of cytokine production, hence dampening immune response and preventing a pro-inflammatory cytokine storm [21], [22], [24].

Based upon post-marketing surveillance of the experience of more than 600,000 Ta1 treated patients, Ta1 has proven to be 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 in previous clinical trials include mild injection-site discomfort (burning and itching), as well as fever, nausea, and flu-like symptoms of mild to moderate 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-2.

Patients with ESRD on hemodialysis, in addition to their intrinsic kidney disease and frequent burden of comorbidities [25], also have increased risk of exposure to communicable diseases. This is primarily because such patients frequently visit outpatient clinics two or three times each week for dialysis. The majority of patients are over 60 years old and many are receiving immunosuppressive medications. Accordingly, HD patients have been considered particularly susceptible to COVID-19 infection. Ta1 has been shown to be safely administered to HD patients on a similar schedule to the one used in the current trial, and was efficacious in enhancing (greater than -4 fold) the antibody responses to the influenza vaccine in geriatric & renal dialysis patients [26].

Currently there are 520,000 patients with ESRD in the United States, and 4 million in the world receiving hemodialysis [27]. The primary cause of kidney failure leading to the requirement for HD is diabetes; the second leading cause is hypertension. This patient population has severe challenges, with 51% mortality rate over 5 years [28].

According to recent statistics, more than one in five patients receiving dialysis had evidence of an attenuated immune response to COVID-19 vaccination [28]. Patients undergoing long term dialysis are more than five times more likely to be infected with COVID-19 and nearly four times as likely to die than the general population, with Blacks and Hispanics suffering higher rates of infection and mortality.

2. Study design

It was our hypothesis that a course of Ta1 administered to individuals on HD would reduce the rate of COVID-19 infection, and if infected, would reduce the severity of disease, compared to untreated individuals in the same hemodialysis units with comparable risk. The secondary objectives included an evaluation of the need for hospitalization in those patients who did not become infected with COVID-19. Although no vaccine was available when the study was initiated, we anticipated that such would occur during the projected 18 months of enrollment. We collected serum samples on all subjects every two weeks throughout the on-study period such that if vaccine were to become available, we may be able to detect a difference in antibody titer post-vaccine in those receiving Ta1 vs controls. Furthermore, a rise in COVID-specific antibody in non-vaccinated individuals may be an indication of clinical infection in the absence of other signs of clinical infection.

After screening, renal dialysis patients who met inclusion criteria received Ta1 (1.6 mg) administered subcutaneously twice weekly for eight weeks, during which clinical and laboratory assessments were conducted at 2-week intervals. Individuals in the control arm were followed on the identical protocol, but did not receive twice weekly Ta1. After the treatment period, all subjects were followed for efficacy and safety outcomes (adverse events (AEs), vital signs, and laboratory parameters) for an additional 4 months.

The primary efficacy endpoint is reduction in documented infection with COVID-19. This is defined as clinical suspicion (presence of symptoms of respiratory infection, using a standardized procedure and questionnaire) and laboratory confirmation of COVID-19 infection by polymerase chain reaction (PCR).

The secondary efficacy endpoints are:

• 1.Need for hospitalization
• 2.Hospital length of stay
• 3.ICU admission
• 4.ICU length of stay
• 5.Mechanical ventilation
• 6.Duration of mechanical ventilation
• 7.Recovery time from COVID-19
• 8.Change in any existing comorbidities (e.g., worsening congestive heart failure) or newly diagnosed disease
• 9.Incidence of secondary non-COVID-19 infections (relapses, superinfections and new infections)
• 10.Change in T lymphocyte subsets (CD4, CD8)
• 11.Mortality
• 12.Antibody response to infection and/or vaccination.

The safety endpoints include adverse events (AEs), vital signs, and laboratory parameters.

The study was approved by the Investigational Review Board (WCG-IRB approved study number 1283843; IRB tracking number 20201189). Three data safety meetings were conducted during the trial by the Data Safety Monitoring Board, and no concerns were raised.

As of the date of this publication, the follow-up time period is ongoing and therefore the analysis of efficacy endpoints has yet to be completed.

The study schedule is presented in Fig. 1 .

Fig. 1.

Study Schedule.

3. Study population

Five dialysis sites participated in the study, enrolling a total of 200 subjects and randomizing them to either treatment or control group.

The inclusion criteria were as follows:

• 1.Age 18 years or greater
• 2.Signed informed consent
• 3.Patients with ESRD, receiving hemodialysis 2 or more times each week and expected to continue on dialysis indefinitely.

The exclusion criteria included:

• 1.Patients on short-term hemodialysis, such as those with transient renal dysfunction associated with acute illness who are projected to have return in renal function
• 2.Patients for whom renal transplantation is anticipated within the next six months
• 3.Patients with an anticipated survival of less than 3 months
• 4.Patients with symptoms that might be attributable to COVID-19 infection
• 5.Patients who test positive for SARS-CoV2 at the time of screening
• 6.Patients with active infectious disease requiring antibiotics
• 7.Patients with hospitalization within the previous 3 months for acute myocardial infarction or congestive heart failure
• 8.Patients with advanced malignancy receiving cytotoxic chemotherapy
• 9.Patients with a Karnofsky Performance Scale score of less than 60
• 10.Patients with prior history of solid organ (kidney, liver, heart, lung, pancreas) or bone marrow transplant
• 11.Patients with active autoimmune disease on immunosuppressive medication
• 12.Patients receiving Plaquenil
• 13.Patients who have participated in an investigational drug or device trial in the previous 30 days
• 14.Patients with a history of allergy or intolerance to Ta1
• 15.Patients with 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.

4. Results/discussion

As the follow-up period is still ongoing, the analysis of efficacy endpoints has yet to be conducted. However, the evaluation of deaths provides an intriguing and possible signal of efficacy: there were only 3 deaths in the Ta1 treatment group (from COVID-19, sepsis, and cardiac arrest, respectively), while there were 7 deaths in the control group (from cardiac arrest, heart failure, hyperkalemia, pulmonary edema, unknown cause, and aortic dissection). Interestingly, the 3 subjects who died in the Ta1 treatment group had all been vaccinated against COVID-19 in the preceding 6–12 months; only 3 of those in the control group had been similarly vaccinated. The number of subjects who suffered serious adverse events was essentially the same in the two groups; 27 subjects in the Ta1 group (Table 1 ) and 26 in the control group (Table 2 ).

Table 1.

Serious Adverse Events, Ta1 Treatment Group.

Patient	Details	Body system
001	Sepsis	Immune
	Hypertensive emergency	Circulatory
024	Acute respiratory failure with hypoxia	Respiratory
026	Hypertensive emergency	Circulatory
	Acute respiratory failure with hypoxia	Respiratory
	COVID-negative pneumonia	Respiratory
	Hemoptysis	Circulatory
040	COVID-19 and pleural effusion	Respiratory
042	Cellulitis	Integumentary
043	Ischemic stroke	Circulatory
047	Seizure	Nervous
	Cavitary COVID-negative pneumonia	Respiratory
	Kidney transplant	Renal
051	Acute gout flare-up	Skeletal
057	Pneumonia due to COVID-19	Respiratory
062	Cellulitis from debridement	Integumentary
	Osteomyelitis of toe	Skeletal
063	Multifocal COVID-negative pneumonia	Respiratory
	Renal hemophagocytic cyst	Renal
079	Severe lower left extremity pain	Muscular
085	Suspected COVID-negative pneumonia	Respiratory
	COPD exacerbation	Respiratory
	Chronic diastolic heart failure	Circulatory
	Sepsis	Immune
	Respiratory failure	Respiratory
	Sepsis from COVID-negative pneumonia	Respiratory
	Humerus fracture	Skeletal
090	Worsening of anemia	Circulatory
103	Hypoglycemia	Circulatory
106	Severe sepsis	Immune
	Endocarditis	Circulatory
113	Toe pain with gangrene	Integumentary
	Continued toe pain with gangrene	Integumentary
114	Pulmonary hypertension	Respiratory
	Death (COVID-19)	Respiratory
121	Gangrene and osteomyelitis	Skeletal
	Hypoglycemia	Circulatory
135	COVID-19	Respiratory
	Acute hypoxic respiratory failure	Respiratory
138	COVID-19	Respiratory
145	Venous thromboembolism	Circulatory
	Death (sepsis)	Immune
168	Acute metabolic encephalopathy	Neurologic
	Altered mental status	Neurologic
	Acute metabolic encephalopathy	Neurologic
187	Hyperkalemia	Renal
205	Foot wounds	Integumentary
224	Abdominal pain	Gastrointestinal
248	Femoral fracture after a fall	Integumentary
	Shortness of breath	Respiratory
256	Death (cardiac arrest)	Circulatory

Table 2.

Serious Adverse Events, Control group.

Patient	Details	Body system
002	AV fistula access issues	Circulatory
007	Death (cardiac arrest)	Circulatory
008	Death (hyperkalemia)	Renal
014	Left posterior leg pain	Muscular
22	Kidney transplant	Renal
029	COVID-19	Respiratory
	Systemic inflammatory response syndrome	Immune
	AV graft thrombosis	Circulatory
050	Pulmonary embolism	Respiratory
	COVID-negative pneumonia	Respiratory
	Chronic respiratory failure with hypoxia	Respiratory
052	Pulmonary hypertension	Respiratory
	Severe hyperkalemia	Renal
	Severe hypoglycemia	Circulatory
	Death (aortic dissection)	Circulatory
069	Excess fluid	Circulatory
083	Facial swelling	Circulatory
	Arm and neck swelling	Circulatory
101	COVID-19	Respiratory
102	Death (unknown)	Unknown
104	Death (pulmonary edema)	Respiratory
105	Death (pulmonary edema)	Respiratory
124	COVID-19	Respiratory
125	COVID-19	Respiratory
140	Chest pain associated with DKA	Circulatory
148	COVID-19	Respiratory
160	Death (heart failure)	Circulatory
165	COVID-19	Respiratory
175	Acute hypoxic respiratory failure	Respiratory
178	COVID-19	Respiratory
190	Fatigue, pneumonia	Respiratory
200	Chest pain	Circulatory
206	Inability to access HD graft	Vascular
260	Diarrhea, nausea, and emesis	Digestive

As expected, COVID vaccines became available during the first year of study. Nearly all patients in both arms of the study received either the Pfizer or Moderna vaccine. We have serum stored on all patients at two-week intervals, including a sample before Ta1 treatment and before any evidence of infection. These samples are currently being investigated for COVID-specific antibody (Quest Laboratories) and the data will be included in the final report.

Our study was designed to determine if a course of Ta1 would be safe and effective in protection from COVID infection in a selective population of persons at risk for catastrophic consequences of infection. Although there were SAEs observed in both groups, these were typical of patients with such a high comorbidity burden and there was no apparent difference between the groups. Although there were fewer deaths in the Ta1 treatment group, an analysis of treatment efficacy including rates of COVID infection, clinical course of COVID infection, and development of anti-COVID antibody remain to be determined.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

This is a preliminary report and therefore data are not available yet