Efficacy and Safety Evaluation of Rapamycin Combined With Methylprednisolone in the Treatment of Hyperthyroidism Exophthalmos: A Randomized, Controlled, Multicenter Clinical Trial.
试验速览
- 阶段
- 早期 1 期
- 入组人数
- 140
- 试验地点
- 1
- 主要终点
- Number of participants with treatment-related adverse events assessed by physical examination, electrocardiogram, and serum biochemical markers.
研究概览
简要总结
This study is a randomized, controlled, multi-center clinical study, the purpose is to evaluate the efficacy and safety of rapamycin combined with methylprednisolone in the treatment of moderate to severe active GO.
GO patients with moderate to severe activity were selected as the research objects, and the screening period was 1 week. Eligible and well-informed subjects were randomly assigned 1:1 to the experimental group (rapamycin + methylprednisolone) or the control group (methylprednisolone group). The control group was given methylprednisolone pulse 500 mg/time once a week for 6 weeks + 250 mg/time once a week for 6 weeks, and the experimental group was given rapamycin 2 mg/day orally for 24 weeks on the basis of methylprednisolone pulse therapy. The follow-up period was from 25th to 36th week.
Before treatment, 1 week after treatment, 6 weeks, 12 weeks, 24 weeks, and 36 weeks, visits were conducted to evaluate the improvement and safety evaluation of patients' GO eye activity, severity, and quality of life. At the end of the 1st week and the 12th week, the blood concentration of rapamycin was measured.
详细描述
Project basis:
Thyroid-associated ophthalmopathy (GO), a vision-threatening autoimmune disease, is the most common extrathyroidal manifestation of Graves disease. At present, GO treatment is still dominated by hormone therapy. From 2010 to 2018, the effective rate of GO hormone shock during moderate to severe activity in our hospital was about 52%. The long-term massive use of hormones can lead to iatrogenic Cushing's syndrome, peptic ulcer, insomnia, delusions, abnormal behavior, pathological fractures, and secondary infections. Therefore, regardless of the disease itself or the treatment method, GO seriously affects the physical and mental health of patients, and optimizing the existing diagnosis and treatment plan has always been a research hotspot in the field. Autoimmunity-induced inflammatory response increased orbital extracellular matrix secretion, and increased fat volume is the cornerstones of the pathogenesis of GO. Previous studies have shown that the PI3K-AKT-mTOR pathway is involved in the synthesis and secretion of extracellular matrix and adipogenesis in orbital fibroblasts. We have demonstrated that RAPA can inhibit orbital collagen and fat deposition in a previous hyperthyroid exophthalmos mouse model. In another small sample (20 patients) study of refractory GD patients, it was also confirmed that methimazole combined with RAPA can effectively reduce thyroid hormone levels, shorten drug withdrawal time, and restore Th17 compared with methimazole alone. /Treg balance. At the same time, there were no adverse reactions in the patients during up to 1 year of follow-up. Therefore, this study intends to carry out large-scale clinical research based on the previous small sample research. A total of 140 patients with GO were enrolled from the endocrinology clinic of our hospital and other hospitals and were randomly divided into two groups. They were treated with methylprednisolone pulse alone and methylprednisolone pulse combined with rapamycin respectively. The clinical and immunological indicators were used to evaluate the effect of RAPA on GO patients. Efficacy and safety, bringing new hope to GO patients.
Research purposes:
To compare the efficacy and safety of rapamycin 2mg/day orally for 24 weeks combined with methylprednisolone pulse therapy and methylprednisolone pulse therapy alone in the treatment of moderate to severe active eye disease.
main target: Rapamycin 2mg/day orally*24 weeks combined with methylprednisolone pulse therapy and methylprednisolone pulse therapy alone in moderate to severe active GO was effective and safe at 24 weeks.
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, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •18-70 years old 2)Clinically diagnosed GO (a. Moderate-severe, b. Active stage)
- •Moderate-severe( CSS Grading Standards for EUGOGO 2021)
- •Active stage (CAS) ≥ 3
排除标准
- •Sight-threatening GO
- •There are obvious abnormalities in laboratory tests: liver damage: ALT and AST ≥ 3 times the upper limit of normal values; kidney damage: serum creatinine ≥ 1.5*ULN; blood routine: hemoglobin < 9g/dl, white blood cell count < 3000/µl or Platelets < 100,000/µl; blood lipids: total cholesterol > 300 mg/dl or triglycerides > 400 mg/dl after lipid-lowering therapy;
- •The patient developed an infection during treatment, requiring intravenous antibiotics, and did not show clinical improvement within 5 days;
- •The subject has a systemic allergic reaction to rapamycin or methylprednisolone;
- •The subject is pregnant during the test;
- •The patient requests to withdraw from the researcher;
- •Investigators believe that they cannot continue to participate in the experiment.
研究组 & 干预措施
The group of Meprednone combined with Rapamycin
The specific dose of methylprednisolone pulse therapy is 500mg / week * 6 + 250mg / week * 6. RAPA has rich experience in the application of renal transplantation, and the recommended maintenance amount for renal transplant patients is 2 mg / day. The efficacy benefits of doses above 2 mg are unclear, and the overall safety of Rapa 2 mg is better than that of patients taking Rapa 5 mg daily. Therefore, based on the clinical experience and clinical research data of RAPA, we would select the dose of Rapamycin as 2mg / day. The experimental group received rapamycin 2 mg/day orally for 24 weeks on the basis of methylprednisolone pulse therapy, and monitor the blood concentration of Rapa at the end of the first week and the end of the 12th week.
干预措施: Rapamycin (Drug)
The group of Meprednone combined with Rapamycin
The specific dose of methylprednisolone pulse therapy is 500mg / week * 6 + 250mg / week * 6. RAPA has rich experience in the application of renal transplantation, and the recommended maintenance amount for renal transplant patients is 2 mg / day. The efficacy benefits of doses above 2 mg are unclear, and the overall safety of Rapa 2 mg is better than that of patients taking Rapa 5 mg daily. Therefore, based on the clinical experience and clinical research data of RAPA, we would select the dose of Rapamycin as 2mg / day. The experimental group received rapamycin 2 mg/day orally for 24 weeks on the basis of methylprednisolone pulse therapy, and monitor the blood concentration of Rapa at the end of the first week and the end of the 12th week.
干预措施: Methylprednisolone (Drug)
The group of Meprednone alone
The specific dose of methylprednisolone pulse therapy is 500mg / week * 6 + 250mg / week * 6. The effect of methylprednisolone pulse therapy on moderate and severe active Tao has been widely verified in clinical work. EUGOGO will take methylprednisolone pulse therapy as the first-line treatment of moderate and severe active Tao in 2020.
干预措施: Methylprednisolone (Drug)
结局指标
主要结局
Number of participants with treatment-related adverse events assessed by physical examination, electrocardiogram, and serum biochemical markers.
时间窗: 24 weeks
To evaluate the number of participants for treatment-related adverse effects of rapamycin 2 mg/day orally for 24 weeks in combination with pulsed methylprednisolone and pulsed methylprednisolone alone in the treatment of moderately to severely active GO.
Number of participants who responded to treatment as assessed by CAS score, eye cleft width, eye movement, etc.
时间窗: 24 weeks
To assess the number of treatment-responsive participants with rapamycin 2 mg/day orally for 24 weeks in combination with pulsed methylprednisolone and pulsed methylprednisolone alone for moderately to severely active GO.
次要结局
- Intraocular pressure(36 weeks)
- Antibody titers(36 weeks)
- Number of participants who responded to treatment as assessed by CAS score, eye cleft width, eye movement, etc.(36 weeks)
- Orbital content volume(36 weeks)
- Number of participants with disease recurrence as assessed by CAS score, eye movement, visual acuity, diplopia, etc.(36 weeks)
- GO-QoL Score(36 weeks)