Recombinant Zoster Vaccine (Shingrix) and GLP-1 Receptor Agonist for the Preservation of Beta-Cell Function in Adults With Recent-Onset Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial.
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 240
- 试验地点
- 1
研究概览
简要总结
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive destruction of pancreatic beta cells mediated by autoreactive T lymphocytes, resulting in absolute insulin deficiency. Preservation of residual beta-cell function at the time of diagnosis is a critical therapeutic window, as even marginal endogenous insulin secretion - reflected by detectable C-peptide levels - is associated with improved glycemic control, reduced hypoglycemia burden, and decreased long-term vascular complication rates.
This study evaluates the hypothesis that combinatorial immunomodulation - using the AS01B adjuvant system within the Recombinant Zoster Vaccine (RZV; Shingrix, GSK) alongside metabolic and cytoprotective support via a GLP-1 receptor agonist (semaglutide) - can synergistically preserve residual beta-cell function in adults within 100 days of T1D diagnosis. The AS01B adjuvant system activates innate immune pathways that promote regulatory T-cell (Treg) expansion and shift the immunological milieu toward tolerance, while GLP-1 receptor agonism provides direct beta-cell cytoprotection, reduces glucotoxicity, and may suppress autoimmune cytokine signaling.
SHIELD-T1D is a randomized, double-blind, placebo-controlled, parallel-group Phase II clinical trial enrolling 240 adults (18-50 years) diagnosed with T1D within 100 days, with confirmed residual beta-cell function (stimulated C-peptide ≥0.2 nmol/L). Participants are randomized 1:1:1:1 to one of four arms: (1) Shingrix alone, (2) Semaglutide alone, (3) Shingrix + Semaglutide combination, or (4) dual placebo. The primary endpoint is change in 2-hour stimulated C-peptide AUC during a Mixed Meal Tolerance Test (MMTT) from baseline to 12 months.
This phase II randomized, double-blind, placebo-controlled multicenter trial will evaluate the efficacy and safety of the recombinant zoster vaccine (Shingrix) and a glucagon-like peptide-1 (GLP-1) receptor agonist, alone and in combination, for preservation of residual beta-cell function in adults with recent-onset type 1 diabetes. The working hypothesis is that combining AS01 adjuvant-mediated immunomodulation with the metabolic and cytoprotective actions of a GLP-1 receptor agonist will provide dual protection for pancreatic beta cells, slowing autoimmune destruction and improving functional insulin secretion compared with placebo.
详细描述
The immune pathogenesis of T1D involves a failure of central and peripheral immune tolerance, with autoreactive CD4+ and CD8+ T cells targeting beta-cell autoantigens including GAD65, IA-2, and ZnT8. The window between seroconversion and overt hyperglycemia - and particularly the honeymoon phase immediately following diagnosis - represents an optimal period for immune intervention while sufficient beta-cell mass persists.
The Recombinant Zoster Vaccine (RZV; Shingrix) contains the AS01B adjuvant system (MPL + QS-21 in a liposomal formulation), which potently activates plasmacytoid dendritic cells and promotes generation of antigen-specific and bystander Tregs. Preclinical and clinical evidence from autoimmune contexts suggests AS01B may recalibrate the Th1/Treg balance relevant to T1D pathology. Critically, RZV is already FDA-approved with an established safety profile, enabling accelerated clinical translation.
GLP-1 receptor agonists (GLP-1 RAs), including semaglutide, exert pleiotropic beta-cell protective effects beyond glucose lowering: they enhance beta-cell proliferation, reduce endoplasmic reticulum stress, inhibit cytokine-induced apoptosis (IL-1β, TNF-α, IFN-γ), and may modulate macrophage and T-cell activation states. Emerging data suggest GLP-1 RAs reduce insulitis markers in NOD mouse models and improve C-peptide preservation in early T1D.
The combination strategy employed in SHIELD-T1D leverages complementary mechanisms: immune re-education (Shingrix/AS01B) to reduce autoimmune attack while providing metabolic rescue and direct cytoprotection (semaglutide) to maximize survival of existing beta cells.
4.2.2 Study Population and Setting The study will recruit adults aged 18-50 years with recent-onset T1D (diagnosed within 100 days per ADA criteria) from tertiary diabetes referral centers and academic medical centers. Multi-center enrollment across a minimum of three geographically diverse sites is planned to ensure population representativeness and adequate recruitment velocity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Placebo injections will be identical in volume, appearance, and administration route. Randomization codes will be held by an independent unblinded pharmacist. Emergency unblinding procedures are available via a 24-hour DSMB-approved unblinding protocol
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of Type 1 Diabetes (T1D) according to American Diabetes Association (ADA) criteria.
- •Age 18 to 50 years (inclusive) at the time of screening.
- •Randomization within 100 days of the first insulin injection.
- •Confirmed residual beta-cell function, defined as a peak stimulated C-peptide level ≥0.2 nmol/L during a Mixed Meal Tolerance Test (MMTT) performed at screening.
- •Presence of at least one T1D-related autoantibody (GADA, IA-2A, ZnT8A, or ICA).
- •Willingness to comply with intensive insulin therapy and glucose monitoring.
- •Females of childbearing potential must have a negative pregnancy test and agree to use highly effective contraception.
排除标准
- •History of diabetic ketoacidosis (DKA) within 4 weeks of screening.
- •Prior use of any immunotherapy or investigational agents for T1D.
- •Current or prior use of GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT2 inhibitors.
- •History of pancreatitis or medullary thyroid carcinoma.
- •Active or chronic infection (e.g., HIV, Hepatitis B or C, Tuberculosis).
- •Pregnancy or breastfeeding.
- •Significant renal, hepatic, or cardiovascular disease.
- •History of severe allergic reaction to any component of the Recombinant Zoster Vaccine (Shingrix) or semaglutide.
- •Current use of systemic corticosteroids or other immunosuppressive medications.
研究者
Amr kamel khalil Ahmed
Ministry of heath, public health department, saudia arabia
Ministry of Health, Saudi Arabia