A Phase 2, Randomized, DB-PC, Parallel Group Study for the Treatment of Visual Pathway Deficits In Chronic Optic Neuropathy to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of CNM-Au8 For Remyelination In Multiple Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 73
- 试验地点
- 7
- 主要终点
- Measures of Visual Function
研究概览
简要总结
The objective of this trial is to assess the efficacy and safety of CNM-Au8 as a remyelinating treatment for vision-impairing MS lesions in participants who have chronic vision impairment as a result of Relapsing-Remitting Multiple Sclerosis. The primary endpoint is to assess the efficacy and safety of CNM-Au8 as a remyelinating therapy in patients with stable RMS. The secondary endpoint is Change in Functional Composite Responder Analysis Score from Baseline to Week 24.
详细描述
This is a randomized, double-blind, parallel-group, placebo-controlled study of the efficacy, safety, and pharmacokinetics of CNM-Au8 in stable RRMS patients who have Chronic Optic Neuropathy evidence by low contrast letter acuity deficits at Screening.
Patients will be screened over a 6-week period. Patients who meet the inclusion criteria and none of the exclusionary criteria will be enrolled into the clinical study.
All enrolled patients will have their visual baseline established in both eyes by functional, electrophysiological (at participating research sites), and morphological tests.
For each patient, the eye with the worst Baseline LCLA score will be considered as the affected eye. The other eye will be considered as the fellow eye. If both eyes have the same LCLA score at Baseline, then one eye will be randomly selected by the statistician to assess as the designated affected eye. Efficacy endpoints will be assessed in both the affected and the fellow eyes. Patients will be randomized to one of three groups: placebo, or one of two doses of CNM-Au8. All patients will receive their randomized investigational product (IP) dose daily over at least 24 consecutive weeks during the Fixed Duration Treatment Period. The study will also have a blinded Variable Duration Treatment Period for up to an additional 24-weeks (up to a 48-week maximum blinded duration) until the last-patient enrolled completes his/her Week 24 study visit per the study scheme in Figure 2. When the last enrolled patient completes his or her Week 24 visit, patients enrolled in the Variable Duration Treatment Period will complete the End-of-Study (EOS) visit at their next scheduled study visit.
The primary efficacy outcome measure will be assessed Efficacy will be assessed as an improvement in best-corrected low contrast letter acuity (BC-LCLA). Safety will be assessed up through the frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events (AEs), and changes in safety assessments (e.g., vitals, ECG, C-SSRS).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The drug formulations will be identical in appearance (size, shape, volume, color) and smell. The packaging and labeling will be designed to maintain blinding to the Investigator's team and to patients. There are no visible differences between the active drug, and placebo dosing units
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •At least 18 years of age and up to 55 years of age (inclusive) at Screening.
- •Clinical diagnosis of Relapsing Multiple Sclerosis (meeting McDonald criteria, 2010) who have had RMS no longer than 15 years from diagnosis.
- •Maximum Best Corrected High Contrast Visual Acuity (BC-HCVA) deficit on the Early Treatment Diabetic Retinopathy Study (ETDRS) Chart of 20/200 (6/60 metric) in both eyes.
- •a. BC-HCVA is defined as the last line on the Early Treatment Diabetic Retinopathy Study (ETDRS) Chart that a patient is able to read three (3) or more letters correctly.
- •Best Corrected Low Contrast Letter Acuity (BC-LCLA) (by 2.5% Sloan Chart) must be 20/40 (6/12 metric) (inclusive) or worse in the affected eye and 20/32 (6/9.5 metric) or worse in the fellow eye; and the BC-LCLA must be worse than BC-HCVA for the respective value in both eyes.
- •a. BC-LCLA is defined as the last line on the 2.5% Sloan Chart that a patient is able to read three (3) or more letters correctly.
- •Retinal Nerve Fiber Layer (RNFL) thickness ≥ 70 μm.
- •Stable disease activity based on the investigator's judgment over the previous 6 months.
- •All hematological parameters and biochemical parameters that fall outside the Within Normal Limits range must be assessed as Not Clinically Significant (NCS) and deemed stable or transient in nature.
- •Able to understand and give written informed consent.
排除标准
- •History of AQP4, MOG Ab(+) status, or ≥ 3 segments lesion in the spinal cord.
- •Any diagnosis other than RMS that could explain the patient's signs and symptoms.
- •An acute optic neuritis episode within the prior 6 months.
- •Clinical relapse requiring systemic steroid treatment within the prior 3 months (pre- treatment with systemic steroids during the administration of disease-modifying therapies [DMT] may be allowed after discussion with the Sponsor's Medical Monitor but must not be administered within 30 days of a planned VEP or MRI assessment).
- •Unstable treatment with a disease-modifying therapy (DMT) defined as a treatment change within prior 3-months unless due to intolerability.
- •Current treatment with immunosuppressive or immunomodulatory therapy other than those approved for the treatment of MS.
- •Any treatment with drugs known or suspected of producing retinal or optic nerve toxicity including hydroxychloroquine, chloroquine, clofazimine, vigabatrin, or ethambutol.
- •Any history of ophthalmological cause for retinal damage other than MS (e.g. cataracts, uveitis, macular degeneration, macular exudate, macular edema, glaucoma, severe astigmatism, ocular trauma, neuromyelitis optica, ischemic optic neuropathy, congenital nystagmus, retinal detachment, amblyopia, optic disk drusen).
- •Severe refractive defects: refractive errors (-6 dioptres to +6 dioptres or more in either eye, or axial eye length >26 mm), hypermetropia (> 6 dioptres; cylinder > 3 dioptres); or based on the investigators judgment any other ophthalmic diseases that would confound the study results or assessment of Visual Evoked Potential (VEPs), Best Corrected Visual Acuity (BCVA), Low Contrast Letter Acuity (LCLA), or Optical Coherence Tomography (OCT).
- •History diabetic retinopathy or a previous diagnosis of Diabetes Mellitus or history of prior impaired fasting glucose ≥126 mg/dL (or ≥ 200 mg/dL after oral glucose tolerance test).
- •History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody.
- •History of gold allergy.
- •Patients taking stimulant medications (including: amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate, or modafinil) who have not been on a stable dose greater than or equal to 30 days. Changes to dose will not be allowed during the course of the trial).
- •Patients taking clemastine fumarate, 4-aminopyridine (fampridine), or high dose Biotin (>300 mg/day).
- •Females who have a positive serum pregnancy test result at Screening or Baseline, or who are pregnant, breastfeeding, or planning to conceive during the study or within 180 days after study completion.
- •History or evidence of substance abuse or alcohol abuse within 5 years prior to Screening, including alcoholism; or severe tobacco use (>1 pack/day).
- •Clinical history of toxic neuropathy (e.g., secondary to treatment with ethambutol, isoniazid, linezolid, gentamycin, chloramphenicol, vincristine, or penicillamine).
- •Current enrollment in any other drug or device treatment study within 3 months prior to Baseline. Participation in an observational non-interventional study (i.e., no drug or device therapy) is not an exclusion criterion.
- •Inability to undergo any planned study procedures such as LCLA, VEP, MRI, or OCT; history of severe hypersensitivity to gadolinium-DTPA or reduced renal clearance (GFR must be ≥ 45 mL/min at Screening), claustrophobia; or inability to comply with study requirements based on Investigator judgment.
- •Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (< 150 x 10^9 per liter) or eosinophilia (absolute eosinophil count of ≥ 500 eosinophils per microliter) at Screening.
- •Based on the investigator's judgment, concurrent chronic or acute illness or unstable medical condition that may deteriorate that could confound the results of safety assessments, increase risk to the patient, or lead to difficulty complying with the protocol; including severe disc edema or hemorrhage, any clinically significant cardiac, endocrinological, hematological, hepatic, immunological, metabolic, urological, pulmonary, neurological (any progressive neurological disorder other than RRMS), dermatological, psychiatric (any untreated or unstable psychiatric disease including depression, bipolar and psychosis), renal, severe allergic or anaphylactic reactions, autoimmune, or other major confounding diseases.
- •Any history of previous malignancy, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix, post documented full resections, with clean margins.
- •Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation.
研究组 & 干预措施
15mg CNM-Au8
15mg suspension of clean-surfaced, faceted, gold nanocrystals in 60ml of sodium bicarbonate buffered water
干预措施: CNM-Au8 (Drug)
30mg CNM-Au8
30mg suspension of clean-surfaced, faceted, gold nanocrystals in 60ml of sodium bicarbonate buffered water
干预措施: CNM-Au8 (Drug)
Placebo
The matched placebo to be used in this study will consist of water, sodium bicarbonate, and food coloring to match volume and color of the experimental treatments.
干预措施: Placebo (Drug)
结局指标
主要结局
Measures of Visual Function
时间窗: Baseline to 48 weeks
Change in Best-Corrected Low-Contrast Letter Acuity (BC-LCLA) score: Mean change in BC-LCLA from Baseline to Week 48 in the most affected eye as measured by 2.5% low contrast Sloan letter charts.
次要结局
- Other Measures of Neurological Function(Baseline up to 48 weeks)