Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 7
- 主要终点
- T-reg number
研究概览
简要总结
In the last years research has pointed out potential mechanisms of pathogenesis in ALS including lack of degradation of abnormally accumulated proteins inside motor neurons, and an unbalanced function of the immune system leading to the prevalence of a neurotoxic function over neuroprotection. These two mechanisms contribute to ALS progression hence representing important therapeutic targets to modify disease expression.
With a phase II clinical trial the investigators aim to study the biological response in ALS treated with Rapamycin, to obtain predictive information for a larger study.
Eight Italian Centres will enroll 63 patients; treatment will be double blinded to patients and physicians, and will last 18 weeks.Follow up will be carried out for 36 months (total duration: 54 weeks).
详细描述
This is a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial for people with ALS.
The aim is to study the biological and clinical effect of Rapamycin (in two different doses) in addition to Riluzole on ALS patients through comparison with patients treated with Riluzole and placebo.
Rapamycin has been shown to enhance proteins degradation, and this has been associated with beneficial effects in models of neurodegeneration. Its immunomodulatory effects are also well established, notably the ability to suppress inflammatory neurotoxic responses mediated by T cells. As ALS is characterized by heterogeneous pathology and protein accumulation, some patients may respond to therapies that accelerate the clearance of abnormally accumulated proteic aggregates, while suppressing neurotoxic immune elements.
Subjects will be enrolled in 3 groups of 21 subjects; treatment will be double blinded to patients and physicians, and will last 18 weeks. Active treatment will include oral Rapamycin at different doses: Rapamycin 1mg/m2/day or Rapamycin 2mg/m2/day. Rapamycin will be administered at fast, in the morning, once a day. Rapamycin levels will be measured (HPLC) to avoid toxicity (>15 ng/ml), but treating neurologists will have no access to blood laboratory data. Dosages will be adjusted accordingly and sham adjustments will be done in the placebo Group too. Post-treatment follow up will be 36 weeks. Globally the study will lasts 24 months. To monitor adverse events, examination and routine laboratory work (cell count, lipids and protein profile, kidney and liver function, C reactive protein) will be performed before taking Rapamycin/placebo. Non-routine laboratory studies include quantification and characterization of Tregs, lymphocytes phenotype, mTOR (mammilian target of rapamycin) downstream pathway activation in peripheral blood mononuclear cells (PBMC), inflammasome components in PBMC and proinflammatory cytokine production in monocytes, peripheral biomarkers. Cerebrospinal fluid (CSF) will be taken at baseline and at week 18 to measure neurofilaments and to dose Rapamycin to understand whether sufficient levels of Rapamycin can be found in the central nervous system (CNS).
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
- Double (Participant, Investigator)
盲法说明
treatment double blinded to patients and physicians
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Prior use of Sirolimus
- •Prior allergy/sensitivity to Sirolimus or macrolides
- •Any medical disorder that would make immunosuppression contraindicated, including but not limited to, acute infections requiring antibiotics, patients with known diagnosis of HIV, tuberculosis, hepatitis B or C infection or history of malignancy
- •Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease
- •White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%
- •Patient who underwent non invasive ventilation, tracheotomy and /or gastrostomy
- •Women who are pregnant or breastfeeding
- •Participation in pharmacological studies within the last 30 days before screening
- •Patients with known superoxide dismutase 1 (SOD1) mutation or with familial ALS and a family member carrying SOD1 mutation.
研究组 & 干预措施
placebo
Patients assigned to this arm will take Riluzole as usual + placebo tablets
干预措施: Placebo Oral Tablet (Drug)
Rapamycin 1 mg/m2
Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day
干预措施: Rapamycin (Drug)
Rapamycin 1 mg/m2
Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day
干预措施: Placebo Oral Tablet (Drug)
Rapamycin 2 mg/m2
Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 2 mg/m2/day
干预措施: Rapamycin (Drug)
结局指标
主要结局
T-reg number
时间窗: comparison between baseline and treatment end (week 18)
Proportion of patients exhibiting a positive response (considered as increase in Treg of at least 30%), comparing baseline and treatment end between Rapamycin and placebo arm
次要结局
- Number of serious adverse events (SAEs) and AEs in placebo and treatment arms(At week 18 and 54)
- Rapamycin efficacy in inhibiting Mtor pathway(At week 8-18-30-54)
- Changes in CSF neurofilaments(Baseline and week 18)
- Changes in blood biomarkers(Baseline, week 8-18-30-54)
- Rapamycin-induced changes in inflammatory status(Baseline and week 8-18-30-54)
- Changes in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised(Up to week 54)
- Changes in Forced vital capacity (FVC)(Up to week 54)
- Changes in activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations(At baseline and at week 8-18-30-54)
- Tracheostomy-free survival rate(Up to week 54)
- Change in quality of life(From baseline to week 8, 18, 30 and week 54)
- Rapamycin capacity to pass through blood brain barrier(At week 18)
研究者
JESSICA MANDRIOLI
MD, PI
Azienda Ospedaliero-Universitaria di Modena