Assessing Metabolic Changes in Multiple Sclerosis Using Hyper-polarized Carbon 13 MRI
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- To determine the percent changes in MS lesions, white matter, and whole brain HP 13C pyruvate metabolism measures between the pre-treatment scan and the scan obtained 1.5-months following treatment initiation.
研究概览
简要总结
The main purpose of this study is to assess whether hyperpolarized carbon imaging in relapsing remitting multiple sclerosis (MS) patients can be used to predict response to anti-CD20 disease modifying therapy. Study procedures will include magnetic resonance imaging (MRI) assessments with a hyperpolarized pyruvate sequence, clinical assessment as well as blood markers of disease progression.
This method of imaging utilizes the Warburg effect, where innate immune cells utilize a metabolic shift to glycolysis instead of oxidative phosphorylation. In pre-clinical data, increased hyperpolarized lactate production has been found to be associated with increased microglial/macrophage infiltration in the brain. Although hyperpolarized carbon imaging in humans has been established and used in the field of oncology, this will be one of the first applications of hyperpolarized carbon the study of neuroinflammation in humans. We predict that hyperpolarized carbon imaging may have the potential to monitor and evaluate neuroinflammation in MS, and in particular the innate immune activation state that plays a role in MS progression. This imaging method may provide non-invasive monitoring of disease progression and therapy response for MS patients.
详细描述
This is a prospective investigational study to evaluate the utility of HP 13C pyruvate MRI for assessing metabolism in MS lesions and monitoring response to treatment. A total of 40 relapse-remitting (RRMS) patients naïve to DMT and starting on an anti-CD20 therapy as part of their routine MS clinical care will be recruited. In a preliminary cohort, 8 patients will be imaged once to optimize HP 13C MR parameters for improved spatial and temporal resolution. Using these sequence parameters, we will then image 32 RRMS patients who will undergo a baseline anatomic and HP 13C pyruvate MRI scan prior to receiving treatment. These participants will undergo two more HP 13C pyruvate MRI scans and one standard MRI over the span of approximately one year. Participants will have blood draws for blood-based biomarkers of disease activity and will undergo standard MS clinical assessments.
Multiple Sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system (CNS) among adults, characterized by demyelinating lesions linked to motor and cognitive impairments and permanent disabilities. Presently, MRI is used to assess active/inactive CNS lesions. Although informative for diagnosis, such measures do not correlate well with clinical symptoms or with MS progression. Given the importance of inflammation and oxidative stress in MS1, new non-ionizing imaging methods providing insights on these pathogenic processes would improve patient management and treatment. Hyperpolarization increases the MR signal of 13C probes by >50,000, overcoming the inherently limited sensitivity of endogenous 13C and enables the monitoring of metabolic reactions in the brain in real time in vivo. HP 13C MR was first developed for oncology2,3, and in the last decade, has improved the non-invasive detection of neoplasms through monitoring of increased HP [1-13C]pyruvate to lactate conversion in preclinical models and in the clinic.4-6 A phase I study to assess the safety and tolerability of HP 13C pyruvate injection in healthy volunteers was completed in December 2007, as well as a second safety study in patients over the age of 60 with the majority of subjects tolerating the injection well and the only serious adverse effect being "flushing" with changes in systolic and diastolic blood pressure, thought to be secondary to a baroreflex response. Throughout the study, data on serum biochemistry variables and post-dosing changes were unremarkable, and no notable changes in vital signs, hematology, urinalysis, electrocardiogram (EKG) variables or other safety variables were registered. This has further been validated in men with localized prostate cancer in a UCSF phase I study. In the present study, each subject will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight, which was the administered dose in the prior UCSF phase I study in prostate cancer (NCT01229618). Over 1,000 patients have been safely scanned with HP 13C pyruvate injection before March 2026.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •Subjects must be 18 years or older.
- •Relapsing remitting MS, naïve to DMTs for the past two years minimum
- •Patients must be naive to anti-CD20 therapy with plans to begin the therapy as part of their physician's multiple sclerosis treatment plan. The patients must remain on a form of anti-CD20 therapy for the entirety of their enrollment in the study.
- •Patients enrolled will be screened for at least one MS lesion with a 10mm diameter in one plane.
排除标准
- •Treatment with corticosteroids within 30 days prior to screening.
- •Patients unwilling or unable to undergo MR imaging, including patients with contra-indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular clips.
- •Poorly controlled hypertension, defined as either systolic >160 or diastolic >
- •The addition of anti-hypertensives to control blood pressure is allowed for eligibility determination.
- •Congestive Heart Failure ≥ NYHA Class II.
- •History of clinically significant EKG abnormalities, including QT prolongation or a family history of prolonged QT syndrome.
- •Myocardial infarction within 6 months of study entry.
- •Individuals who are pregnant. Individuals of childbearing potential (defined below) must agree to undergo a urine pregnancy test prior to participating in the study scans. Pregnant individuals are excluded because there is an unknown but potential risk for adverse effects in the unborn child secondary to administration of HP 13C pyruvate to the study participant.
- •A female is considered to not be of childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice), if they meet either of the following two criteria: (1) has reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause); or (2) has undergone surgical sterilization (i.e., hysterectomy and/or bilateral oophorectomy for removal of uterus and/or ovaries).
- •Individuals who are breastfeeding/chestfeeding. Breastfeeding/chestfeeding individuals are excluded because there is an unknown but potential risk for adverse effects in the unborn/nursing child secondary to administration of HP 13C pyruvate to the study participant.
- •Breastfeeding/chestfeeding should be discontinued before administration of HP 13C pyruvate.
- •Known hypersensitivity to HP 13C pyruvate or any of its excipients.
- •History of cancer within five years of enrollment date and/or history of chemotherapy within two years of enrollment date.
- •Any dental braces or permanent or undetachable metals in the jaw or face.
- •Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases that in the PI's judgment may affect the interpretation of study results or patient safety.
- •Individuals with any condition or social circumstance that, in the opinion of the investigator, would impair the participant's ability to comply with study procedures.
- •Glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m² on baseline visit or subsequent study visits, history of kidney disease or history of hypersensitivity to gadolinium contrast agent.
- •Baseline EDSS >6.5
研究组 & 干预措施
HP13C MRI
8 patients will be imaged once to optimize HP 13C MR parameters for improved spatial and temporal resolution. This group will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight. 32 RRMS patients who will undergo anatomic and HP 13C pyruvate MRI scans at timepoints of baseline, 1.5 months, 3 months, 12 months. This group will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight.
干预措施: HP 13C pyruvate injection (Drug)
HP13C MRI
8 patients will be imaged once to optimize HP 13C MR parameters for improved spatial and temporal resolution. This group will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight. 32 RRMS patients who will undergo anatomic and HP 13C pyruvate MRI scans at timepoints of baseline, 1.5 months, 3 months, 12 months. This group will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight.
干预措施: MRI Scanner (Device)
结局指标
主要结局
To determine the percent changes in MS lesions, white matter, and whole brain HP 13C pyruvate metabolism measures between the pre-treatment scan and the scan obtained 1.5-months following treatment initiation.
时间窗: From study initiation to up to 15 months after enrollment of last subject.
Percent changes in lesion HP 13C pyruvate metabolism measures. The following metabolism measures will be assessed at baseline and at 1.5-months following treatment initiation * Peak HP 13C lactate/pyruvate and bicarbonate/pyruvate signal-to-noise ratio * HP 13C lactate/pyruvate and bicarbonate/pyruvate AUC ratio * Metabolic rate constants kPL and kPB in inverse seconds.
次要结局
- To determine the percent changes in MS lesions, white matter, and whole brain HP 13C pyruvate metabolism measures between the pre-treatment scan and the scan obtained 3-months and one year following treatment initiation.(From study initiation to up to 15 months after enrollment of last subject.)
- To determine the repeatability of HP 13C pyruvate metabolism measures in the MS lesions in patients with same-day repeated dose.(From study initiation to 15 months after enrollment of last subject.)
研究者
Ari Green
Professor of Neurology, Chief of the Division of Neuroimmunology and Glial Biology
University of California, San Francisco