van der Sluijs Pleuntje J, Safai Pour Koshar, Berends Cécile L, Kruizinga Matthijs D, Müller Annelieke R, van Eeghen Agnies M, Rodríguez-Girondo Mar, Juachon Maria J, Steenbeek Duco, Cohen Adam F, Zuiker Rob G J A, Santen Gijs W E
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Centre for Human Drug Research, Leiden, the Netherlands.
J Med Genet. 2025 Feb 26;62(3):210-218. doi: 10.1136/jmg-2024-109951.
Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.
This study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).
In the clonazepam group (=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed 'no change' after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.
Our approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in patients.
EUCTR2019-003558-98, ISRCTN11225608.
由于罕见病患病率低、患者表型变异以及期望较高，罕见病的临床试验面临独特挑战。我们对氯硝西泮治疗智力残疾患者（智力残疾的常见病因）的研究突出了这些挑战。先前对Arid1b单倍体不足小鼠的研究表明氯硝西泮对各种认知方面有积极影响。
本研究采用随机、双盲、安慰剂对照、双向交叉研究（RCT），随后采用单病例设计。在交叉研究中，患者接受氯硝西泮（最大0.5毫克，每日两次）或安慰剂治疗22天，有3周的洗脱期。评估包括安全性、耐受性、药代动力学、神经认知任务的药效学、行为和认知功能。在单病例试验的第一阶段确定最佳剂量和个体治疗目标。第二阶段评估治疗效果。该阶段由三个时期组成：安慰剂开放标签期（4周），随后是双盲期（6周），接着是患者接受氯硝西泮的开放标签期（4周）。
在氯硝西泮组（n = 16，15人完成两个时期），7人（44%）报告临床医师总体改善印象有改善，而安慰剂组为2人（13%）。13人（87%）在接受安慰剂后显示“无变化”（氯硝西泮组为2人（13%）），而氯硝西泮组7人（44%）报告病情恶化，通常与副作用有关（n = 6），提示较低剂量可能有益。对RCT应答者进行的三项单病例试验中，有两名患者在双盲期间接受氯硝西泮治疗有所改善，但临床评估认为改善不足。
我们的方法显示了将传统RCT和单病例研究相结合用于智力残疾人群治疗研究的可行性和优势，能够区分真实治疗效果和期望偏差。我们的研究结果表明氯硝西泮对智力残疾患者没有额外的治疗价值。
EUCTR2019 - 003558 - 98，ISRCTN11225608。
