Study of Sirolimus in IgG4-related Disease

Combination Therapy of Sirolimus and Glucocorticoids for the Maintenance of Remission in Patients With IgG4-related Disease

gG4-related disease (IgG4-RD) is a newly recognized systemic autoimmune disease that can involve the pan-creatobiliary tract, retroperitoneum/aorta, head and neck region, and salivary glands, et al. Glucocorticoids are the first-line agents for the treatment of IgG4-RD, however, in order to maintain long-term disease stability and avoid disease relapse, glucocorticoids maintenance therapy should last for a long period, which may induce various glucocorticoid-associated adverse reactions. Sirolimus plays dual roles in inhibiting lymphocyte activation and fibroblast proliferation. It is inferred from its mechanism that sirolimus is a good potential treatment option for IgG4-RD. Therefore, we conducted this single-arm clinical trial on patients with IgG4-RD to determine the efficacy and safety of sirolimus.

Study Overview

• Status: Not yet recruiting
• Conditions: IgG4-related Disease
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

IgG4-related disease (IgG4-RD) is a newly recognized systemic autoimmune disease that can involve the pan- creatobiliary tract, retroperitoneum/aorta, head and neck region, and salivary glands, et al. IgG4-RD is characterized by elevated serum IgG4 levels, tumefactive lesions with a dense lymphoplasmacytic infiltration rich in IgG4 positive plasma cells and storiform fibrosis of related organs.

Glucocorticoids are the first-line agents for the treatment of IgG4-RD, however, in order to maintain long-term disease stability and avoid disease relapse, glucocorticoids maintenance therapy should last for a long period, which may induce various glucocorticoid-associated adverse reactions. For some mild IgG4-RD patients without internal organ damage, long-term glucocorticoids therapy may have a low benefit/risk ratio. Further, a substantial proportion of patients cannot tolerate glucocorticoids.

Sirolimus, also known as rapamycin, is a macrolide compound that inhibits its mechanistic target (mTOR), which regulates cell growth and metabolism in response to environmental cues. mTOR is also essential in driving abnormal lineage specification within the immune system in various rheumatic diseases. We discovered that mTOR was highly activated in IgG4RD tissues, and its inhibitor sirolimus appeared as a good treatment candidate.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hui Gao, Doctor; Phone Number: 8613811833264; Email: gh841017@126.com
• Study Contact Backup: Name: Yuying WANG, Master; Phone Number: 8615210976309; Email: wangyuying028@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients diagnosed with IgG4-RD according to the 2011 Comprehensive Diagnostic Criteria for IgG4-RD;
2. Status classified as active disease based on an IgG4-RD Responder Index (RI) ≥2 at screening.

1.Exclusion criteria: 2.Having used glucocorticoids (equivalent to more than 10mg per day of prednisone), immunosuppressant or biologic within 3 months prior to enrollment; 3.Having any contraindication of glucocorticoids or sirolimus, or allergy to sirolimus, or having experienced serious adverse reactions from previous use of any of the above drugs; 4.Combined with other connective disease; 5.History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic or psychiatric) other than IgG4-RD that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion; 6.Active infection, including hepatitis B virus, hepatitis C virus, and tuberculosis; 7.Malignancy within 5 years; 8.Other serious complications or general conditions do not permit; 9.Pregnancy or to be pregnant, or breast feeding; 10.Unable to adhere to follow-up or the patient refuses to provide consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: glucocorticoid and sirolimus combination therapy; Prednisone acetate 0.8mg/Kg/d (maximum dose 60mg/d), reduced by 5mg every 14 days, reduced by 2.5mg every 2 weeks after 30mg/d until discontinuation. At the same time, treatment for prevention or control of osteoporosis was given. Sirolimus: 2mg/day for the first three days and 1mg/day thereafter. The plasma drug concentration was monitored at 14 days, 12 weeks, and 48 weeks of medication to maintain a plasma drug concentration of 4-15 ug/L.

Drug: Sirolimus; Sirolimus The efficacy is evaluated at 12 weeks, and treatment will be adjusted according to the control of disease and adverse effects.For experimental group, if a patient is assessed as treatment failure (TS), the patient should be withdrawn from the study and receive rescue treatment. Whereas, a patient would be transferred to the control group if he/ she cann't stand the side effects of sirolimus but not serious adverse event (SAE).; Other Names: Prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PrRelapse rate	For patients who achieve disease response at 12 weeks, recurrence is defined as increases in the IgG4-RD RI ≥2 and/or the need for the reinstitution of treatment.	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease response rate at 12 weeks	Disease response is defifined as an improvement of the IgG4-RD RI ≥2 compared with baseline.	12 weeks of treatment
Remission rate at 48 weeks	Remission is defined as the achievement of an IgG4-RD RI of 0	48 weeks of treatment
Improvement of patient's global assessment (PGA)	PGA is a validated visual analogue scale that is scored by placing a vertical mark along a 100 mm horizontal line. Zero millimetre indicates no disease activity. A mark of 100 mm indicates the most active disease possible	48 weeks of treatment

Collaborators and Investigators

• Sponsor: Peking University International Hospital
• Investigators: Principal Investigator: Yuying Wang, Peking University International Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2023
• Primary Completion (Anticipated): December 31, 2026
• Study Completion (Anticipated): December 31, 2028

Study Registration Dates

• First Submitted: February 13, 2023
• First Submitted That Met QC Criteria: February 25, 2023
• First Posted (Estimate): February 28, 2023

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 25, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: mTOR; sirolimus; IgG4-related disease
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Immunoglobulin G4-Related Disease; Physiological Effects of Drugs; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Prednisone; Sirolimus
• Other Study ID Numbers: Sirolimus for IgG4-RD

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
• product manufactured in and exported from the U.S.: No