Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 47
- 试验地点
- 2
- 主要终点
- Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (36 months)
研究概览
简要总结
Rationale: Clemastine fumarate has been identified as potential remyelinating therapy for multiple sclerosis (MS). The (long-term) effects of clemastine need to be confirmed in clinical models for MS. Internuclear ophthalmoparesis (INO) may be used as a clinical model for investigating remyelinating therapies by measuring horizontal eye movements with infrared oculography. Furthermore, infrared oculography combined with a single dose of fampridine may be used to identify individuals with MS that are most likely to benefit from remyelinating therapy.
Objective: To assess the (long-term) efficacy of clemastine fumarate in improving dysconjugacy of eye movements in patients with internuclear ophthalmoparesis and multiple sclerosis. Secondly, to assess whether a response to a single dose of fampridine can predict the effects of clemastine treatment.
Study design: A single-centre double-blind randomized placebo-controlled trial consisting of a 6 months (180 days) treatment period followed by a 30 months follow-up period.
Study population: 80 MS patients, age 18-70 years, with INO.
Intervention: The intervention group will receive 4 mg of clemastine fumarate twice daily (8 mg/day) for 6 months (180 days), the control group will receive an equivalent amount of placebo. At baseline all participants will receive a single 10 mg dose of fampridine.
Main study parameters/endpoints: The primary outcome measure is the change in versional dysconjugacy index (VDI) of area under the curve (AUC) measured by infrared oculography. Secondary outcome measures include changes in other VDI measures (peak velocity per amplitude (PV/Am) and peak velocity (PV)), changes in VDI after single fampridine dose, other oculography parameters (e.g. saccadic latency, anti-saccades), (peripheral) retinal nerve fibre layer (pRNFL) and (macular) ganglion cell inner plexiform layer (mGCIPL) thickness measured by OCT, SDMT, EDSS, high and low contrast visual acuity, subjective visual functioning (NEI-VFQ-25 and NOV-AU questionnaire), quality of life (EQ5D-5L) and fatigue (CIS20R and NFI-MS questionnaire).
Nature and extent of the burden and risks: Participation in the study will consist of a total of 7 study visits. Study visits will include physical/neurological examination, infrared oculography, OCT, visual acuity tests, a cognition test (SDMT), 5 questionnaires and blood samples for safety laboratory tests. Considering both clemastine and fampridine are registered and well-established drugs and have been used in clinical practice, the estimated risk of unexpected adverse reactions is low.
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)
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
- 否
入选标准
- •A clinically definite diagnosis of multiple sclerosis.
- •Diagnosis of internuclear ophthalmoparesis determined by the first infrared oculography at screening with either cut-off of 1.174 of the versional dysconjugacy index area under the curve (VDI-AUC) of 15° saccades or 1.180 of the versional dysconjugacy index peak velocity/saccadic amplitude (VDI-PV/Am) of 15° saccades.
- •Age 18-70 (inclusive)
- •Use of disease modifying therapies is not a contraindication.
- •Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
排除标准
- •MS-related exclusion criteria:
- •Changes in immunomodulatory therapy for multiple sclerosis in the 6 months before inclusion into the study.
- •Clinical relapse of MS or high dosage corticosteroid use within 30 days before inclusion into the study.
- •IMP and medication related exclusion criteria:
- •Contraindications to clemastine use, such as known porphyria or hypersensitivity to clemastine, other antihistamines with a similar chemical structure or any of the excipients.
- •Contraindications to fampridine use, such as hypersensitivity to fampridine or any of the excipients, history of epilepsy, kidney disease (GFR <50 ml/min absolute contraindication; GFR = 50-80 ml/min relative contraindication), use of Organic Cation Transporter 2 (OCT2) inhibitors or history of significant cardiac arrhythmias or conduction block.
- •Concomitant use of Fampridine or any other formulation of 4-aminopyridine (4AP) or diamino4ap that cannot be temporarily suspended prior to each study visit.
- •Changes in the use of medication currently being investigated in remyelination trials within 6 months before screening, including but not limited to domperidone, liothyronine, quetiapine, testosterone and bazedoxifene.
- •Non-incidental use of central nervous system depressants including but not limited to hypnotics, anxiolytics, monoamine-oxidase inhibitors (MAOI'S), tricyclic antidepressants, opioid analgesics and other antihistamines with sedating properties (e.g. promethazine).
- •Other medical history and concomitant disease exclusion criteria:
- •History of significant cardiac conduction block.
- •History of malignancy of any organ system (other than localized squamous or basal cell carcinoma of the skin or adequately treated cervical cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases.
- •Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2; AST, ALT, or alkaline phosphatase > 2 times the upper limit of normal.
- •Any ophthalmological disease which may prevent accurate infrared oculography assessment.
- •Suicidal ideation or behaviour in 6 months prior to baseline.
- •History of drug or alcohol abuse within the past year.
- •Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal or other major diseases that in the PI's judgement may affect interpretation of study results or patient safety.
- •History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study.
- •General exclusion criteria:
- •Pregnancy at the time of inclusion into the study or planning on breastfeeding within the first 7 months after inclusion in the study.
- •Involvement in other study protocol simultaneously without prior approval.
- •Insufficient proficiency in reading Dutch.
- •Unable or unwilling to suspend driving for a duration of 6 months.
研究组 & 干预措施
Clemastine Fumarate
干预措施: Clemastine Fumarate (Drug)
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (36 months)
时间窗: 36 months
The relative change in VDI from baseline will be compared between the treatment and control group at the end of follow-up (36 months).
Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (6 months)
时间窗: 6 months
Our main study parameter is the versional dysconjugacy index (VDI) measured by infrared oculography. The relative change in VDI from baseline will be compared between the treatment and control group at the end of treatment (6 months). The VDI of Area Under the Curve (AUC) will be our primary study parameter. This describes the area under the saccadic trajectory of the horizontal eye position.
次要结局
- Versional Dysconjugacy Index (VDI) - Response to Fampridine(Baseline)
- High and Low Contrast Visual Acuity (HCVA and LCVA)(6 months and 36 months)
- Quality of life (EQ5D-5L)(6 months and 36 months)
- Other Versional Dysconjugacy Index (VDI) measures - Peak Velocity (VDI-pV + VDI-pV/Am)(6 and 36 months)
- Other infrared oculography parameters - Saccadic Latency(6 months and 36 months)
- Other infrared oculography parameters - Proportion of errors in an anti-saccadic task(6 months and 36 months)
- Other infrared oculography parameters - Proportion of correct double-step saccades(6 months and 36 months)
- Subjective visual functioning (NEI-VFQ-25)(6 months and 36 months)
- Fatigue - NFI-MS(6 months and 36 months)
- Expanded Disability Status Scale (EDSS)(6 months and 36 months)
- Other infrared oculography parameters - Error of the final eye position in double-step saccades(6 months and 36 months)
- Symbol Digit Modalities Test (SDMT)(6 months and 36 months)
- Visual complaints (NOV-AU)(6 months and 36 months)
- Fatigue - CIS20R(6 months and 36 months)
研究者
Sam Hof
MD
Amsterdam UMC, location VUmc