IMproving Symptomatic Treatment With Pyridostigmine and Amifampridine: a Randomized Double-blinded, Placebo Controlled Crossover Trial in Patients With Myasthenia Gravis (IMPACT-MG)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- A clinically relevant change in Myasthenia Gravis Impairment Index (MGII) compared to placebo.
研究概览
简要总结
A randomized, double-blind, placebo controlled, crossover intervention study evaluating the effect of pyridostigmine (part 1) and amifampridine (part 2) in Myasthenia Gravis (MG).
详细描述
In the first part of the study, patients who are currently using pyridostigmine will be randomly allocated to one of two consecutive treatment periods in which patients either first receive placebo and then their usual dose of pyridostigmine, or vice versa. Each treatment period lasts 5 days with a 2-day wash-out period between each treatment period. Measurements will be performed at every last day of a treatment period (day 5 and day 12).
In the second part of the study the effect of two doses of amifampridine as add-on to pyridostigmine will be studied. Patients will be randomly assigned to either one of three treatment sequences; 1) amifampridine 30 mg - amifampridine 60 mg - placebo or 2) amifampridine 60 mg - placebo - amifampridine 30 mg or 3) placebo - amifampridine 30 mg - amifampridine 60 mg. Again, each treatment period consists of 5 days and will be separated by a 2-day wash-out period. Measurements will be performed at every last day of treatment (day 19, day 26 and day 33).
Patients will have the option to participate in a substudy to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of amifampridine in AChR positive MG patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >18 years
- •AChR positive myasthenia gravis (ocular or generalized)
- •Current use of pyridostigmine
- •MGFA Clinical Classification I-IV
- •Receiving a stable dose of MG treatment (other than pyridostigmine). If applicable:
- •A stable steroid regimen for 1 month
- •Nonsteroidal immunosuppressants: i. Azathioprine, mycophenolate mofetil, cyclosporine or other nonsteroid immunosuppressive agents start > 3 months ago and a stable regimen for 1 month. ii. Rituximab start > 6 months ago, complement inhibitors and Fc receptor inhibitors start > 6 months ago and a stable regimen for 3 months.
- •Additional inclusion criteria for part 2 To be eligible for participation in part 2 of the study patients must score >10 points on the MGII questionnaire at inclusion.
- •We will include a maximum of 5 patients with a MGFA class I (i.e. 20 percent of the total number of included patients) to ensure that this study accurately reflects the clinical population.
排除标准
- •Use of intravenous immunoglobulin or plasma exchange <4 weeks or planned during the trial.
- •Thymectomy < 6 months, or thymectomy (expected) to take place during the trial
- •Use of other acetylcholinesterase inhibitors than pyridostigmine
- •Pregnancy, lactation or intention to become pregnant during the study
- •Treatment with amifampridine is contraindicated. Contraindications include a history of epilepsy, uncontrolled asthma, inherited QT syndrome / a prolonged QT interval (as indicated by ECG), any drug known to cause QT c-prolongation, any drug known to lower the epileptic threshold, a known hypersensitivity reaction to the active substance or to any of the excipients.
- •The patient is unable to fill out the study questionnaires or be interviewed in Dutch, or is unable to undergo the tests needed for the study, or is unable to give informed consent for participation in the study.
- •The investigator can exclude patients for this trial which are deemed not suitable for any reason.
研究组 & 干预措施
Pyridostigmine
The dose of pyridostigmine will be based on the patient's prior experience with pyridostigmine under the assumption that the patient already gained sufficient experience during their disease course to know which dose is effective for them as patients are advised by their treating neurologist to continually adjust their dose based on their symptoms and side effects.
干预措施: Pyridostigmine (Drug)
Placebo (pyridostigmine)
Same as "Experimental", however capsules contain placebo.
干预措施: Placebo (Drug)
Amifampridine (base) with modified release
Patients will receive amifampridine 2 dd 15 mg and amifampridine 2 dd 30 mg as add-on to the pre-study dose of pyridostigmine.
干预措施: Amifampridine (base) with modified release (Drug)
Placebo (amifampridine)
Same as "Experimental", however capsules contain placebo.
干预措施: Placebo (Drug)
结局指标
主要结局
A clinically relevant change in Myasthenia Gravis Impairment Index (MGII) compared to placebo.
时间窗: Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),
次要结局
- Serum half-life (T1/2)(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
- Change on 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) compared to placebo(Assessed on Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),)
- Change on the 15-item revised version of the Myasthenia Gravis Quality of Life questionnaire (MG-QoL15r) compared to placebo(Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),)
- A clinically relevant change (≥2 points change) on the Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to placebo.(Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),)
- A clinically relevant change (≥3 points change) on the Quantitative Myasthenia Gravis (QMG) score compared to placebo.(Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),)
- Number of patients not able to complete first wash-out period due to an increase in myasthenic symptoms.(Assessed on Day 1 (crossover))
- Number of times escape medication is used (including effect on symptoms)(Assessed on Day 1, Day 5 and Day 12 (cross-over),)
- Dose-response between serum concentrations of amifampridine and hand grip strength as measured with hand-held dynamometer.(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
- Utility as assessed by the 5-level EQ-5D (EQ-5D-5L)(Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33)
- Healthcare use as assessed by the adapted iMCQ (iMTA Medical Consumption Questionnaire)(Assessed on Day 1)
- Productivity as assessed by the adapted iPCQ (iMTA Productivity Cost Questionnaire)(Assessed on Day 1)
- Peak Plasma Concentration (Cmax)(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
- Time of maximum concentration (Tmax)(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
- Trough concentration (Ctrough)(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
- Trough concentrations of pyridostigmine and amifampridine(Assessed on Day 1, Day 5, Day 12, Day 19, Day 26 and Day 33 (cross-over),)
- Area under the concentration-time curve (AUC0-8)(Assessed on Day 19, Day 26 and Day 33 (cross-over),)
研究者
Martijn R. Tannemaat, MD PhD
Principal Investigator
Leiden University Medical Center