Treatment of Low Dose IL-2 and Ganciclovir in Cytomegalovirus Infection

The Efficiency and Safety of Low Dose IL-2 and Ganciclovir in Treatment of Cytomegalovirus Infection: an Open Label, Prospective and Control Trial

Cytomegalovirus (CMV) infections is a severe infection in patients of rheumatic disease treated with corticosteroid and immunosuppressive agents. Ganciclovir is the main therapy in CMV infection, accompanied with diverse side effects, including neutropenia, anemia, disorder of renal function and so on, which are also common symptoms of rheumatic diseases. Additionally, prolonged antiviral treatment may delay recovery of virus, specific immune responses, resulting in an increasing of late-onset CMV disease.

IL-2 is a pleotropic cytokine which can promote the proliferation and function of CD8+ T cells and NK cells through the combination with IL-2 receptor. Recently, several studies have revealed that low dose IL-2 is an effective and safe therapy for autoimmune disease. In systemic lupus erythematous patients, additionally, patients treated with low-dose IL-2 had lower incidence of infection with increased percentages of natural killer (NK) cells.

In this prospective clinical trial, we propose to assess the effective and safety of low-dose IL-2 combined with ganciclovir in the treatment of CMV infection. Meanwhile, we will assess the immune response of after IL-2 treatment.

Study Overview

• Status: Unknown
• Conditions: Cytomegalovirus Infections
• Intervention / Treatment: Drug: Low-dose IL-2 and ganciclovir

Detailed Description

In rheumatic diseases, CMV infection are more frequent in patients after corticosteroid pulse treatment and long-term treatment of corticosteroid and immunosuppressor.

If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously, The CMV-DNA levels will be monitored until it turned out to be negative. In this period, we will simultaneously monitor the immune response in regard to CMV infection, including innate immune response, such as IFN-γ, TNF-α, natural killer cells, and adaptive immune response, such as CMV specific CD8+ T cells, T helper cells and so on.

We will follow these patients for at least 3 months after drug withdrawal. If patient belonging to any of these two groups develops a viral infection, then the patient will receive treatment with ganciclovir.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of Rheumatic disease by the Criteria ;
2. Patients have current CMV infection, CMV-DNA are positive.
3. Apply corticosteroid less than 1.0mg/kg/d.

Exclusion Criteria:

1. CMV-DNA is negative.
2. Other infection, such as bacteremia, hepatitis B and C viruses, HIV, syphilis, bacteremia, Epstein-Barr virus and so on.
3. Known allergies, hypersensitivity, or intolerance to IL-2 or its excipients.
4. Severe comorbidities: including 1) Heart failure (≥ grade III NYHA); 2) Renal insufficiency (creatinine clearance ≤30 ml/min); 3) Hepatic insufficiency (serum ALT or AST >3 times the ULN, or total bilirubin >ULN for the central laboratory conducting the test); 4) Other disease including hematopathy, gastrointestinal disease, endocrinopathy, pulmonary, neuropathy.
5. Malignancy.
6. Had uncontrolled psychiatric or emotional disorder.
7. Pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment of low-dose IL-2 and ganciclovir; If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group and low-dose IL-2 is defined as 1 million IU per day subcutaneously.	Drug: Low-dose IL-2 and ganciclovir; If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously.
Placebo Comparator: Treatment of ganciclovir; If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in ganciclovir treatment group.	Drug: Low-dose IL-2 and ganciclovir; If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of NK cells cytotoxicity after treatment	NK cells cytotoxicity will be detected by flow cytometry	Days 7 after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The total dose for anti-viral drugs.	The total dose of ganciclovir	Day for drug withdrawal.
The change of cytokine after low-dose IL-2 treatment.	Detect by flow cytometry and ELISA.	Day after anti-viral treatment and 3 months.
The change of NK cell subsets.	Detect by flow cytometry.	Day after anti-viral treatment and 3 months.
The change of level of CMV immunoglobulin M (IgM)	Detect by EILSA.	Day for drug withdrawal and 3 months.
The change of level of CMV immunoglobulin G (IgG)	Detect by EILSA.	Day for drug withdrawal and 3 months.
The day for CMV infection patients convert into negative.	CMV-DNA will be detected by PCR	Days when CMV-DNA are less than 10^3 copies.

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Investigators: Principal Investigator: Zhanguo Li, PhD MD, Peking University People's Hospital

Publications and helpful links

General Publications

• He J, Zhang R, Shao M, Zhao X, Miao M, Chen J, Liu J, Zhang X, Zhang X, Jin Y, Wang Y, Zhang S, Zhu L, Jacob A, Jia R, You X, Li X, Li C, Zhou Y, Yang Y, Ye H, Liu Y, Su Y, Shen N, Alexander J, Guo J, Ambrus J, Lin X, Yu D, Sun X, Li Z. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2020 Jan;79(1):141-149. doi: 10.1136/annrheumdis-2019-215396. Epub 2019 Sep 19.

Helpful Links

• clinicaltrials.gov

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2020
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): March 30, 2021

Study Registration Dates

• First Submitted: January 9, 2020
• First Submitted That Met QC Criteria: January 9, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 9, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Ganciclovir; Ganciclovir triphosphate
• Other Study ID Numbers: TLDIGCI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No