Randomized, Double-blind, Active & Placebo-controlled, 6-way Crossover Study of Abuse Potential of Oral Gabapentin Enacarbil IR Capsules With and Without Oxycodone in Healthy, Nondependent, Recreational Opioid Users

The purpose of this study is to assess the abuse potential of gabapentin enacarbil immediate release capsules taken alone and in combination with oxycodone in healthy adult, non-dependent, recreational opioid users.

开始日期2022-01-31

申办/合作机构

Arbor Pharmaceuticals, Inc.

NCT06097676

/ Completed临床4期

A Randomized, Double Blind, Active and Placebo Controlled, 5 Way Crossover Study to Determine the Abuse Potential of Orally Administered Gabapentin Enacarbil Immediate Release Capsules in Healthy, Nondependent Recreational Drug Users With Sedative Experience

The purpose of this study is to assess the abuse potential of gabapentin enacarbil in healthy adult, non-dependent, recreational drug users.

开始日期2021-09-28

申办/合作机构

Arbor Pharmaceuticals, Inc.

NCT03082755

/ Recruiting临床4期IIT

Nighttime Agitation and Restless Legs Syndrome in People With Alzheimer's Disease

Nighttime agitation in persons with Alzheimer's disease causes patient suffering, distresses caregivers, and often results in prescriptions for harmful antipsychotics. Effective treatments are lacking because of limited knowledge of the etiology of nighttime agitation. The investigators propose a clinical trial to better elucidate whether a sleep disorder, restless legs syndrome, may be a mechanism for nighttime agitation, and if treatment with gabapentin enacarbil (Horizant®) reduces nighttime agitation, improves sleep, reduces restless legs syndrome behaviors, and reduces antipsychotic medications.

开始日期2017-07-01

申办/合作机构

The University of Texas at Austin

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100 项与加巴喷丁酯相关的临床结果

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100 项与加巴喷丁酯相关的转化医学

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100 项与加巴喷丁酯相关的专利（医药）

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125

项与加巴喷丁酯相关的文献（医药）

2025-01-01·Journal of Clinical Sleep Medicine

Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline

Review

作者: Scharf, Matthew T. ; Falck-Ytter, Yngve ; Koo, Brian B. ; DelRosso, Lourdes M. ; Shelgikar, Anita V. ; Trotti, Lynn Marie ; Winkelman, John W. ; Kazmi, Uzma ; Berkowski, J. Andrew ; Zak, Rochelle S. ; Sharon, Denise ; Walters, Arthur S.

INTRODUCTION:

This guideline establishes clinical practice recommendations for treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in adults and pediatric patients.

METHODS:

The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using the grading of recommendations assessment, development, and evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.

GOOD PRACTICE STATEMENT:

The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RLS.1. In all patients with clinically significant RLS, clinicians should regularly test serum iron studies including ferritin and transferrin saturation (calculated from iron and total iron binding capacity). Testing should ideally be administered in the morning avoiding all iron-containing supplements and foods at least 24 hours prior to blood draw. Analysis of iron studies greatly influences the decision to use oral or intravenous (IV) iron treatment. Consensus guidelines, which have not been empirically tested, suggest that supplementation of iron in adults with RLS should be instituted with oral or IV iron if serum ferritin ≤ 75 ng/mL or transferrin saturation < 20%, and only with IV iron if serum ferritin is between 75 and 100 ng/mL. In children, supplementation of iron should be instituted for serum ferritin < 50 ng/mL with oral or IV formulations. These iron supplementation guidelines are different than for the general population.2. The first step in the management of RLS should be addressing exacerbating factors, such as alcohol, caffeine, antihistaminergic, serotonergic, antidopaminergic medications, and untreated obstructive sleep apnea.3. RLS is common in pregnancy; prescribers should consider the pregnancy-specific safety profile of each treatment being considered.

RECOMMENDATIONS:

The following recommendations are intended as a guide for clinicians in choosing a specific treatment for RLS and PLMD in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. The recommendations listed below are ranked in the order of strength of recommendations and grouped by class of treatments within each PICO (Patient, Intervention, Comparator, Outcome) question. Some recommendations include remarks that provide additional context to guide clinicians with implementation of this recommendation.

ADULTS WITH RLS:

1. In adults with RLS, the AASM recommends the use of gabapentin enacarbil over no gabapentin enacarbil (strong recommendation, moderate certainty of evidence).2. In adults with RLS, the AASM recommends the use of gabapentin over no gabapentin (strong recommendation, moderate certainty of evidence).3. In adults with RLS, the AASM recommends the use of pregabalin over no pregabalin (strong recommendation, moderate certainty of evidence).4. In adults with RLS, the AASM recommends the use of IV ferric carboxymaltose over no IV ferric carboxymaltose in patients with appropriate iron status (see good practice statement for iron parameters) (strong recommendation, moderate certainty of evidence).5. In adults with RLS, the AASM suggests the use of IV low molecular weight iron dextran over no IV low molecular weight iron dextran in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).6. In adults with RLS, the AASM suggests the use of IV ferumoxytol over no IV ferumoxytol in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).7. In adults with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, moderate certainty of evidence).8. In adults with RLS, the AASM suggests the use of dipyridamole over no dipyridamole (conditional recommendation, low certainty of evidence).9. In adults with RLS, the AASM suggests the use of extended-release oxycodone and other opioids over no opioids (conditional recommendation, moderate certainty of evidence).10. In adults with RLS, the AASM suggests the use of bilateral high-frequency peroneal nerve stimulation over no peroneal nerve stimulation (conditional recommendation, moderate certainty of evidence).11. In adults with RLS, the AASM suggests against the standard use of levodopa (conditional recommendation, very low certainty of evidence).Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).12. In adults with RLS, the AASM suggests against the standard use of pramipexole (conditional recommendation, moderate certainty of evidence).Remarks: pramipexole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).13. In adults with RLS, the AASM suggests against the standard use of transdermal rotigotine (conditional recommendation, low certainty of evidence).Remarks: transdermal rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).14. In adults with RLS, the AASM suggests against the standard use of ropinirole (conditional recommendation, moderate certainty of evidence).Remarks: ropinirole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).15. In adults with RLS, the AASM suggests against the use of bupropion for the treatment of RLS (conditional recommendation, moderate certainty of evidence).16. In adults with RLS, the AASM suggests against the use of carbamazepine (conditional recommendation, low certainty of evidence).17. In adults with RLS, the AASM suggests against the use of clonazepam (conditional recommendation, very low certainty of evidence).18. In adults with RLS, the AASM suggests against the use of valerian (conditional recommendation, very low certainty of evidence).19. In adults with RLS, the AASM suggests against the use of valproic acid (conditional recommendation, low certainty of evidence).20. In adults with RLS, the AASM recommends against the use of cabergoline (strong recommendation, moderate certainty of evidence).

SPECIAL ADULT POPULATIONS WITH RLS:

21. In adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin over no gabapentin (conditional recommendation, very low certainty of evidence).22. In adults with RLS and ESRD, the AASM suggests the use of IV iron sucrose over no IV iron sucrose in patients with ferritin < 200 ng/mL and transferrin saturation < 20% (conditional recommendation, moderate certainty of evidence).23. In adults with RLS and ESRD, the AASM suggests the use of vitamin C over no vitamin C (conditional recommendation, low certainty of evidence).24. In adults with RLS and ESRD, the AASM suggests against the standard use of levodopa (conditional recommendation, low certainty of evidence).Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).25. In adults with RLS and ESRD, the AASM suggests against the standard use of rotigotine (conditional recommendation, very low certainty of evidence).Remarks: rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

ADULTS WITH PLMD:

26. In adults with PLMD, the AASM suggests against the use of triazolam (conditional recommendation, very low certainty of evidence).27. In adults with PLMD, the AASM suggests against the use of valproic acid (conditional recommendation, very low certainty of evidence).

CHILDREN WITH RLS:

28. In children with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).

CITATION:

Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152.

2024-07-01·Journal of addiction medicine

Reductions in World Health Organization Risk Drinking Level Are Associated With Reductions in Alcohol Use Disorder Diagnosis and Criteria: Evidence From an Alcohol Pharmacotherapy Trial

Article

作者: Witkiewitz, Katie ; Aldridge, Arnie ; Hallgren, Kevin A ; Tuchman, Felicia R ; O'Malley, Stephanie S ; Richards, Dylan K ; Anton, Raymond F ; Aubin, Henri-Jean ; Mann, Karl ; Kranzler, Henry R

Objectives:

This study aimed to evaluate the validity of World Health Organization (WHO) risk drinking level reductions as meaningful endpoints for clinical practice and research. This study examined whether such reductions were associated with a lower likelihood of a current alcohol use disorder (AUD) diagnosis and fewer AUD criteria.

Methods:

We conducted a secondary data analysis to address these objectives using data from a multisite randomized controlled trial of gabapentin enacarbil extended release in treating moderate to severe AUD among adults (N = 346). Participants received gabapentin enacarbil extended release or placebo for 6 months. The timeline follow-back was used to assess WHO risk drinking level reductions, and the Mini-International Neuropsychiatric Interview was used to assess Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria at baseline (past year) and end of treatment (past month).

Results:

Most participants (80.1%) achieved at least a 1-level reduction in the WHO risk drinking levels from baseline to end of treatment, and nearly half of participants (49.8%) achieved at least a 2-level reduction. At least a 1-level reduction or at least a 2-level reduction in WHO risk drinking level predicted lower odds of an active AUD diagnosis (1-level: odds ratio, 0.74 [95% confidence interval (CI), 0.66–0.84]; 2-level: odds ratio, 0.71 [95% CI, 0.64–0.79]) and fewer AUD criteria (1-level: B, −1.66 [95% CI, −2.35 to −0.98]; 2-level: B, −1.76 [95% CI, −2.31 to −1.21]) at end of treatment.

Conclusions:

World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment.

2024-03-16·Alcohol and alcoholism (Oxford, Oxfordshire)

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder

Article

作者: Garcia, Christian C ; Witkiewitz, Katie ; Aldridge, Arnie ; Mann, Karl ; Hallgren, Kevin A ; Tuchman, Felicia R ; Hoffman, Michaela ; O’Malley, Stephanie S ; Richards, Dylan K ; Kranzler, Henry R ; Aubin, Henri-Jean ; Anton, Raymond F

Abstract:

Aims:

Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems.

Methods:

We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment.

Results:

Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = −0.99, 95% confidence interval (CI) [−1.77, −0.20], P = .014) or at least a 2-level reduction (B = −0.80, 95% CI [−1.47, −0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = −1.01, 95% CI [−1.83, −0.20], P = .015; 2-level: B = −0.90, 95% CI [−1.59, −0.22], P = .010).

Conclusions:

Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

项与加巴喷丁酯相关的新闻（医药）

2024-12-02

·drugs

Guidelines Developed for Treatment of Restless Legs Syndrome

MONDAY, Dec. 2, 2024 -- In a clinical practice guideline issued by the American Academy of Sleep Medicine and published online Sept. 26 in the Journal of Clinical Sleep Medicine , recommendations are presented for the treatment of restless legs syndrome (RLS). John W. Winkelman, M.D., Ph.D., from Massachusetts General Hospital in Boston, and colleagues developed recommendations for treatment of RLS and periodic limb movement disorder in adults and pediatric patients. The researchers developed three good practice statements that were based on expert consensus. They recommend all clinicians should regularly test serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS, ideally in the morning; analysis of these studies influences the decision to use oral or intravenous (IV) iron treatment. The authors also state that addressing exacerbating factors, including alcohol, caffeine, antihistaminergic, serotonergic, and anti-dopaminergic medications, should be the first step in RLS management. They note RLS is common in pregnancy and the pregnancy-specific safety profile of each treatment should be considered. Recommendations for adults with RLS include use of gabapentin enacarbil over no gabapentin enacarbil; use of gabapentin over no gabapentin; use of pregabalin over no pregabalin; and use of IV ferric carboxymaltose over no IV ferric carboxymaltose for those with appropriate iron status (strong recommendations; moderate certainty of evidence). In addition, there is a strong recommendation against use of cabergoline. "Guided by the best evidence in the scientific literature, we've provided recommendations that will improve the ability of clinicians to provide patient-centered care for people who have RLS," Winkelman said in a statement. One author disclosed ties to the pharmaceutical and medical device industries. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

2023-10-30

·药讯社

刚刚！卫健委发布“第三批鼓励仿制药品建议目录（41种）

为落实国务院办公厅《关于改革完善仿制药供应保障及使用政策的意见》有关制定仿制药品目录的部署和要求，2023年，国家卫生健康委、工业和信息化部、国家医保局和国家药品监管局、国家知识产权局等部门组织专家对国内专利即将到期尚未提出注册申请及临床供应短缺（竞争不充分）的药品进行遴选论证，提出了《第三批鼓励仿制药品建议目录》。现予以公示，公示5个工作日。如有异议，请通过以下电话予以反映。电话：（010）68792519 第三批鼓励仿制药品建议目录药物政策与基本药物制度司2023年10月30日附件第三批鼓励仿制药品建议目录序号药品名称英文名称剂型规格1贝美替尼binimetinib片剂15mg2伏环孢素voclosporin胶囊剂7.9mg3伊德利塞idelalisib片剂0.1g片剂0.15g4艾曲泊帕乙醇胺eltrombopag 片剂25mg片剂50mg5拉替拉韦raltegravir干混悬剂0.1g6来法莫林lefamulin注射剂15ml:0.15g片剂0.6g7利非司特lifitegrast滴眼剂0.058芦比替定lurbinectedin注射剂4mg9芦曲泊帕lusutrombopag片剂3mg10哌马色林pimavanserin片剂10mg片剂17mg胶囊剂34mg11瑞卢戈利relugolix片剂0.12g片剂40mg12替拉凡星telavancin粉针剂0.25g粉针剂0.75g13妥卡替尼tucatinib片剂50mg片剂0.15g14福他替尼fostamatinib片剂0.1g片剂0.15g15纳洛醇醚naloxegol片剂12.5mg片剂25mg16帕替司兰patisiran注射剂5ml:10mg17芦卡帕利rucaparib片剂0.25g片剂0.3g18替伏扎尼tivozanib胶囊剂0.89mg胶囊剂1.34mg19阿立哌唑aripiprazole缓释注射剂1.6ml:0.441g缓释注射剂2.4ml:0.675g;缓释注射剂3.2ml:0.96g20阿莫非尼armodafinil片剂50mg片剂0.2g21阿塞那平asenapine舌下片2.5mg舌下片5mg舌下片10mg22奥氮平+沙米啡烷，复方olanzapine + samidorphan, combinations片剂15mg:奥氮平5mg,沙米啡烷10mg片剂20mg:奥氮平10mg,沙米啡烷10mg片剂25mg:奥氮平15mg,沙米啡烷10mg片剂30mg:奥氮平20mg,沙米啡烷10mg23贝派度酸bempedoic acid片剂0.18g24凡他尼布vandetanib片剂0.1g片剂0.3g25非达米星fidaxomicin片剂0.2g26加巴喷汀酯gabapentin enacarbil缓释片0.3g缓释片0.6g27卡波替尼cabozantinib胶囊剂20mg胶囊剂80mg片剂20mg片剂40mg片剂60mg28卡替拉韦cabotegravir缓释注射剂3ml:0.6g29瑞维那新revefenacin吸入溶液剂3ml:0.175mg30利右苯丙胺lisdexamfetamine胶囊剂10mg胶囊剂20mg胶囊剂40mg咀嚼片10mg咀嚼片20mg咀嚼片40mg31瑞卢戈利+雌二醇+炔诺酮，复方relugolix + estradiol + norethindrone, combinations片剂41.5mg:瑞卢戈利40mg,雌二醇1mg,炔诺酮0.5mg32依普利酮eplerenone片剂25mg片剂50mg33硝唑沙奈nitazoxanide片剂0.5g混悬剂5ml:0.1g34氯巴占clobazam片剂20mg膜剂5mg膜剂10mg膜剂20mg混悬剂1ml:2.5mg35Ga-68PSMA-11Gallium-68 PSMA-11注射剂10ml:20mCi36Ga-68dotatateGallium-68 dotatate注射剂10ml:20mCi37F-18多巴Fluorine-18 Fluorodopa注射剂10ml:40.5mCi38F-18氟代雌二醇Fluorine-18 fluoroestradiol注射剂10ml:40.5mCi39F-18 氟化钠Fluorine-18 sodium fluoride注射剂10ml:40.5mCi40F-18氟贝他吡/18F-AV1451Fluorine-18 flortaucipir 注射剂10ml:40.5mCi41I-123间碘苄胍/MIBGlodine I-123 iobenguane注射剂10ml:20mCi

专利到期

2023-03-20

·行舟Drug

日本新药临床研发的桥接策略

点击上方的行舟Drug ▲ 添加关注桥接试验是指在新地区开展的附加试验，通过证明药物在两地区人群生物学特征相似，以允许将先开发地区的临床数据外推到新地区，达到减少重复试验、缩短临床开发周期的目的。1998 年， ICH E5 指南 ( Ethnic Factors in the Acceptability of Foreign Clinical Data) 发布，文件提供了通过桥接试验将海外数据外推用于上市申报的途径。从此，日本对境外试验数据的态度逐步开放。近年来国内学者对欧美的新药研发策略、审评制度开展了研究，但目前对同在亚洲的 ICH 成员国日本的研究较少。由于同属亚洲，中日之间的种族差异应小于与欧美的差异。从以往的成功案例来看，日本监管机构认同亚洲-日本人群比欧美 -日本人群差异更小。尽管如此，目前日本对境外数据态度仍然非常谨慎。本文主要介绍在日本开展桥接临床试验的基本考虑，在日桥接策略的制定，根据药物特点进行的策略调整以及近年来的成功案例分析，为国内药企在日本开展新药研发提供参考。 1 采用桥接策略在日本开展临床研发的基本考虑 1. 1 背景基本一致与其他国家有所不同的是，目前日本要求数据桥接的新老地区在医疗实践等背景方面基本一致。此，桥接对象试验建议选择在背景类似的国家开展( 如果试验药已在多国开展临床试验) ，并且在日桥接试验设计需参考桥接对象试验方案。 1. 2 海外已完成Ⅲ期试验将海外的Ⅲ期试验结果外推至新地区是桥接试验的重要目的之一，所以先发地区应已完成Ⅲ期试验，否则可考虑国际多中心临床试验( multi regionalclinical trials，MＲCT) 。 1. 3 与监管机构充分沟通最后，根据新药特点完成临床研发计划、桥接试验设计、注册申请数据包后，与监管机构沟通并开展试验，试验结束后根据试验结果再次与监管机构沟通，确定是否需要补充试验后提交上市申请。根据已上市成功案例，推荐至少在日本开展临床试验以前、完成桥接试验后进行 2 次与日本监管机构( Pharmaceuticals and Medical Devices Agency，PMDA) 的沟通，并咨询监管机构的意见，确保数据包符合监管机构的要求。 2 在日桥接策略设计2. 1 基础策略设计由于日本对境外数据的保守态度，即使新药没有资料表明有种族差异的风险，往往 PMDA 也会要求在日本开展桥接试验。在日本桥接成立的条件: ①桥接试验与桥接对象试验所在的两国家 /地区的疾病定义、诊断标准、治疗方案基本一致; ②药代动力学( pharmacokinetics，PK) 特征类似; ③用量反应关系类似; ④不良事件谱类似。所以，桥接策略上市的基础数据包为日本人群中的Ⅰ期 + Ⅱ期( 桥接) + 长期试验 + 海外数据。与其他国家不同的是，在日本常需要将单一一个试验称作为“桥接试验”( 通常是 1 个Ⅱ期试验) ，并指定一个设计类似的海外试验为“桥接对象试验”( Ⅱ期或Ⅲ期试验) 。在试验开始前，通常由申办药企撰写两试验桥接成功的标准，并在试验开始前与监管机构沟通。除桥接试验以外，大多数新药还需要在日本开展Ⅰ期试验和长期安全性试验。 2. 2 策略调整在基础策略Ⅰ期 + Ⅱ期( 桥接试验) + 长期试验之上，申办方可根据药物已有的有效性/安全性结果、海外试验开展的数量/样本量、临床急需程度、适应症发病率等特征对基础策略进行调整。常见的策略调整有减免长期试验/Ⅰ期试验/其他试验，也有根据PMDA 的建议增加Ⅱ/Ⅲ期试验或 MＲCT 试验。减免试验情况常由于试验药为临床急需，不适宜开展某项试验，或已有某部分试验结果。而增加试验的情况常由于 PMDA 认为海外试验证据不足，建议在日本增补试验。 3 常见桥接策略及其适用情况3. 1 基础策略( Ⅰ期 + Ⅱ期桥接 + 长期试验) 适用情况 Ⅰ期 + Ⅱ期桥接 + 长期试验是较为常见的在日桥接策略，适用于海外有符合日本监管机构要求的 PK、量效关系、有效性、安全性数据并且无特殊需要关注的其他问题的试验药。试验目的是与桥接对象试验比较，验证两地区的 PK、量效关系、安全性特征是否相似，以及探索在日本人患者中的长期给药安全性。案例－恩替卡韦恩替卡韦在日本提交申请资料时注册分类为新有效成分，申请适应症为抑制乙型肝炎病毒的增殖，本药以此适应症已在 21 个国家/地区上市。由于迫切的临床需要，在美国已通过优先审评上市，在日本同样已纳入优先审评。在日本递交的完整临床试验数据包见图 1。疾病诊疗标准方面: 日本与海外对于乙型肝炎的定义、基本疾病状态、诊断标准、治疗方案等没有差异。 PK 方面: 在单次给药量 0. 1 ～ 1. 0 范围内相同剂量下，在两地的剂量－暴露量关系都为线性。日本健康人中的暴露量大于欧美健康人，但在体重矫正后暴露量基本一致，企业解读暴露量的差异是纳入的健康受试者的体重不同导致的。日本患者中的暴露量略小于欧美患者，经肌酐清除率矫正后暴露量基本一致 ( 比值的 90% 置信区间包含 1) ，认为暴露量的差异源于纳入的患者肾功能差异。暴露反应关系方面: 在所有试验中( 日本人患者和欧美人患者) ，0. 1 mg 组和 0. 5 mg 组疗效都优于 0. 01 mg 组，用量反应 0. 01 mg ＜ 0. 1 mg ≤ 0. 5 mg。在所有阳性药对照试验中 0. 1 mg 和 0. 5 mg 都非劣于阳性药，并且 0. 5 mg 疗效优效于阳性药。暴露反应关系符合桥接试验开始前设定的桥接成功标准。安全性: 不良事件类型及其发生率日本与海外没有重大差异。综合上述结果，机构同意试验药在两地区人群中 PK、暴露反应关系、安全性特征相似，可以将海外临床试验结果外推至日本。 3. 2 减免长期试验/减少长期试验样本量适用情况在试验药不需要开展单独长期试验，或海外已有大量的长期安全性数据时，可以考虑减免或减少在日本的长期试验。如在试验药在临床上不需要长期给药时，可以考虑减免长期试验; 或海外已有大量长期安全性数据，未发现迟发毒性风险，并且试验药为临床急需情况下，可以考虑减少在日本的长期安全性试验样本量或在与监管机构协商的基础上积极开展上市后安全性试验。案例－他达拉非他达拉非在在日本提交申请资料时注册分类为新有效成分，申请适应症为勃起功能障碍，本药以此适应症已在 107 个国家/地区上市。相同适应症已上市一线药物为西地那非、伐地那非，但 5 型磷酸二酯酶( type 5 phosphodiesterase， PDE5) 抑制药类药物具有导致视觉障碍的安全性风险。在海外已经开展长期安全性试验 3 个，患者在需要时服药，连续给药 6 个月至 2 年不等。长期试验中未发现迟发性不良事件，不良事件谱与日本桥接试验、海外安慰剂对照试验一致。并且，不良事件( 如头痛、消化不良、背痛) 最初发现时间都在刚开始给药时，长期给药后发现初次发生的不良事件逐渐减少。他达拉非在日本完成Ⅰ期、Ⅱ期试验后批准上市。机构要求在上市后尽早制定充分完整的调查计划，并开展调查。 3. 3 减免Ⅰ期试验适用情况在试验药不需要/不宜开展单独的Ⅰ 期 PK 试验时，可以考虑减免Ⅰ期试验。如注册分类为新适应症，以其他适应症已经完成了Ⅰ期数据时，可以考虑减免Ⅰ期 PK 试验; 或出于伦理考虑试验药不宜在健康人中开展 PK 试验时，可以考虑在Ⅱ期患者试验中开展 PK 研究。案例－半乳糖苷酶 α 在日本提交申请资料时注册分类为新有效成分，申请适应症为法布里病，本次申请为罕见病用药。考虑到法布里病特征和临床上对本药的需求，不需要在日本开展健康人中的Ⅰ期试验，在Ⅱ期患者中开展疗效试验的同时进行 PK 研究。半乳糖苷酶 α 在日本完成Ⅱ期、长期试验后批准上市。 3. 4 减免其他试验适用情况在试验药出于伦理、患者数量问题，难以开展部分试验，且海外已有参考数据，新地区临床急需时可以考虑减免其他试验。如罕见病用药在海外已经具备参考试验结果时，可以考虑减免相应其他试验。案例－西地那非西地那非本次在日本提交申请资料时注册分类为新适应症、新用量、新剂型，申请适应症为肺动脉高压。西地那非以此适应症肺动脉高压递交申请材料时，已经以治疗勃起功能障碍上市。本次申请为罕见病用药。机构同意由于西地那非已在日本上市，从而减免健康人中的Ⅰ期试验。在海外Ⅲ期试验中，亚洲人患者与欧美患者的量效关系一致，日本人属于亚洲人，机构同意将海外的 Ⅱ、Ⅲ 期临床试验结果外推至日本。本次申请西地那非在日本完成在 6 例患者中的Ⅲ期后，机构批准肺动脉高压为新适应症。 3. 5 增加Ⅱ/Ⅲ期试验适用情况在海外试验结果量效关系不明时， PMDA 可能建议增加Ⅱ/Ⅲ期试验。如在海外试验中未观察明显量效关系趋势时，PMDA 可能建议在日本再次探索最佳临床剂量，并进行疗效确证。案例－恩他卡朋恩他卡朋在日本提交申请资料时注册分类为新有效成分，申请适应症左旋多巴和盐酸左旋多巴联合使用，改善帕金森病病情的内变 ( Wearing － off 现象) 。申请上市时日本没有针对Wearing － off 现象有疗效较好的药物。在日本初次探索剂量反应关系的Ⅱ期试验中，随机交叉单次给予 Wearing － off 患者恩他卡朋 100 mg、 200 mg 或安慰剂。结果观察到试验药与安慰剂比较，给药后左旋多巴 AUC 增加，但未观察到临床效果的改善。并且桥接试验与桥接对象试验的给药剂量有所不同，难以对量效关系一致性进行比较。考虑到以上原因，机构建议增加Ⅱ/Ⅲ试验以患者 ON 时间为主要评价指标，安慰剂对照，平行设计每次给予恩他卡朋 100 mg、200 mg 或安慰剂连续 8 周，每组 90 例，以探索临床用量及验证其有效性及安全性。恩他卡朋在日本完成 I 期、Ⅱ期、Ⅱb 期试验及长期给药试验后批准上市。案例－加巴喷丁酯加巴喷丁酯在日本提交申请资料时注册分类为新有效成分，申请适应症为中高度不宁腿综合征，本药以此适应症尚未在海外上市。由于海外Ⅱ期剂量未探索出明显的量效关系，机构建议在海外试验的 1 200 mg、1 800 mg 基础上增加900 mg 剂量组，以探索临床用量及验证其有效性及安全性。加巴喷丁酯在日本完成Ⅰ期、Ⅱ/Ⅲ期试验及长期给药试验后批准上市。 3. 6 增加 MＲCT 适用情况在一次申报多个剂型/适应症时，可考虑增加 MＲCT 试验以同时批准多个剂型/适应症。如在申报多个剂型时，如剂型改变可能导致疗效/安全性的改变，则需要增加桥接试验或增加 MＲCT; 或在申报多个适应症时，桥接试验未涵盖/海外无Ⅲ期试验结果可外推的适应症可以考虑增加 MＲCT。当桥接试验结果符合桥接成功标准，在日本开展的试验与海外外推的试验结果组成完整的审评资料数据包。案例－枸橼酸托法替尼枸橼酸托法替尼在日本提交申请资料时注册分类为新有效成分，申请适应症为现有治疗方案不理想的关节炎，本药以此适应症尚未在海外上市。在日本的开发计划为桥接和 MＲCT 试验相结合，适应症“临床症状改善”“身体机能改善”采用桥接策略，在日本人患者中确认临床用量后，将海外数据外推至日本。另开展关于“抑制关节破坏”MＲCT 拓展药物使用的范围。机构意见: 在现存治疗效果不佳的关节炎治疗中，本药对于关节痛等症状有效。但难以从结果看出对预防关节构造损伤的效果。另外，身体机能改善应是关节症状减轻的伴随效果，不能列为单独的适应症。枸橼酸托法替尼在日本完成Ⅰ期、Ⅱ期、长期试验及 MＲCT 后，批准适应症为现存治疗效果不佳的关节炎治疗。 4 讨论ICH E5 发布以前，PMDA 几乎不接受境外临床试验数据。自 ICH E5 指导原则提出了桥接策略后， PMDA的态度才逐步开放。但相较于欧美监管机构， PMDA 对于境外数据的态度仍较为谨慎。其态度表现在多个方面: ①即使在新药出现种族差异的风险较小时，PMDA 往往仍要求申办方在日本开展桥接试验。②PMDA 认为桥接试验是一个特定的Ⅱ期试验，而新药在不同人群中的 PK 特征相似应是开展桥接试验的前提条件。大多数情况下，PMDA 要求在日本人群中开展Ⅰ期 PK 试验后，再开展桥接试验。③从已有案例来看，对于海外试验中量效关系不明显的新药，PMDA 常要求在日本人群中重新开展 Ⅱ/Ⅲ 期试验。PMDA 的谨慎态度可能来自于( 且不限于) 以下几个原因: ①日本国内民族单一，国内积累的民族间可比较临床数据较少。②以往在日本开展桥接试验的申办方多为欧美药企，外推至日本的海外试验多为在欧美人群中的数据，由于基因、体型、饮食文化上的差异，可能产生对药物安全性、有效性的较大影响。中国和日本同属于东亚国家，两国人群在基因、体型、饮食差异都远小于与欧美人群的差异。根据以往以桥接策略在日本上市的成功案例，PMDA 也认同东亚人群数据较欧美人群数据更具有参考性的观点。因此，中国人群中的临床数据应是外推至日本支持注册的更佳证据。通过中日之间的数据沟通与交流，有望进一步简化新药在日本的临床研发过程。但至今为止，中国药企与日本监管机构对两国人种间数据桥接的探讨还非常有限。对于中日之间种族差异的研究探索也有许多空白尚待填补。国内药企可以尝试提供新的证据、通过新的方法，与PMDA 沟通来尝试实现在日本更高效的研发策略。文章信息源于公众号临研知识库，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新欢迎订阅+医药大数据|行业动态|政策解读

临床3期

100 项与加巴喷丁酯相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09539	加巴喷丁酯	N03AX12	DB08872

研发状态

批准上市

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适应症	国家/地区	公司	日期
疱疹后神经痛	美国	Azurity Pharmaceuticals, Inc.	2012-06-06
不宁腿综合征	美国	Azurity Pharmaceuticals, Inc.	2011-04-06

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
酒精使用障碍	临床2期	美国	Arbor Pharmaceuticals, Inc.	2015-06-01
偏头痛	临床2期	美国	XenoPort, Inc.	2008-08-01
偏头痛	临床2期	加拿大	XenoPort, Inc.	2008-08-01
糖尿病周围神经病变	临床2期	美国	XenoPort, Inc.	2008-03-01
神经痛	临床2期	美国	XenoPort, Inc.	2008-03-01
糖尿病性神经病变	临床2期	日本	Astellas Pharma, Inc.	2007-07-01
不宁腿综合征1型	临床1期	美国	XenoPort, Inc.	2016-01-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02840240 (CTgov)	N/A	疼痛 \| 麻醉	107	Gabapentin enacarbil (Gabapentin Enacarbil)	製鑰繭遞窪願淵製夢鏇(襯壓製憲鏇壓餘鬱齋艱) = 願積夢鹹鬱築齋蓋夢獵製醖醖齋繭膚繭願鑰觸 (築襯築膚繭鏇夢艱遞範, 襯窪願願積簾蓋繭夢襯 ~ 壓餘鏇選齋簾顧築製鑰) 更多	-	2024-01-09
				Placebo (Placebo)	製鑰繭遞窪願淵製夢鏇(襯壓製憲鏇壓餘鬱齋艱) = 醖壓艱鬱製鏇廠窪網鏇製醖醖齋繭膚繭願鑰觸 (築襯築膚繭鏇夢艱遞範, 簾齋觸簾衊壓製網鹹鑰 ~ 淵觸築積壓餘遞觸衊範) 更多
NCT02642315 (XP-IIT-0034, CTgov)	N/A	不宁腿综合征	10	Horizant	壓夢範鏇膚鹹艱製製製(範衊築壓淵鬱蓋餘鑰餘) = 醖積獵夢製積廠窪鏇繭願廠蓋膚壓鑰構鏇築製 (鬱鑰醖網製繭選顧繭餘, 憲積淵製壓蓋膚壓觸壓 ~ 鬱簾選憲衊築製繭鹽鹽) 更多	-	2022-02-24
NCT03053427 (CTgov)	临床4期	不宁腿综合征	375	Placebo (Placebo)	廠窪醖繭積膚壓顧觸選(簾艱願醖獵鹹糧築憲壓) = 夢鏇窪築鏇齋淵簾衊鬱製鬱鹹簾積蓋壓鏇蓋構 (鑰繭窪餘憲壓餘艱構繭, 鏇鹹製遞築夢鹽築積選 ~ 選積鏇壓襯觸製鑰築鏇) 更多	-	2019-07-10
				Gabapentin enacarbil (Gabapentin Enacarbil)	廠窪醖繭積膚壓顧觸選(簾艱願醖獵鹹糧築憲壓) = 鬱繭襯鹽醖淵觸鑰選夢製鬱鹹簾積蓋壓鏇蓋構 (鑰繭窪餘憲壓餘艱構繭, 壓範夢鹽餘構築壓艱鏇 ~ 遞蓋艱簾積網鑰鑰簾憲) 更多
NCT02252536 (Pubmed) 人工标引	临床2期	酒精使用障碍	346	gabapentin enacarbil	夢製窪廠製壓製壓鹹壓(鑰網鏇鏇壓鑰襯選醖獵) = 襯廠膚顧築憲憲襯憲艱獵蓋壓齋蓋鹹憲窪夢淵 (窪鏇獵蓋廠簾糧淵壓構 )	不佳	2019-01-01
				Placebo	夢製窪廠製壓製壓鹹壓(鑰網鏇鏇壓鑰襯選醖獵) = 獵製製蓋築鏇顧艱築夢獵蓋壓齋蓋鹹憲窪夢淵 (窪鏇獵蓋廠簾糧淵壓構 )
NCT02252536 (CTgov)	临床2期	酒精使用障碍	346	Placebo (Sugar Pill)	構壓鏇夢齋選壓製齋觸(築憲鹹憲餘鹽繭壓醖範) = 築製憲範製鏇鏇衊築膚壓鏇網餘遞襯鹽窪獵淵 (簾夢淵簾膚醖鏇鏇範憲, 壓遞夢範餘願顧鑰糧築 ~ 遞廠遞艱憲構積廠鑰齋) 更多	-	2018-09-21
				gabapentin enacarbil (Gabapentin Enacarbil)	構壓鏇夢齋選壓製齋觸(築憲鹹憲餘鹽繭壓醖範) = 製衊網艱餘蓋顧蓋範鑰壓鏇網餘遞襯鹽窪獵淵 (簾夢淵簾膚醖鏇鏇範憲, 廠夢鬱獵壓夢襯顧餘鹹 ~ 鹽鬱鏇鬱網膚鏇選衊鬱) 更多
AAN2015	N/A	不宁腿综合征	541	Gabapentin Enacarbil 600 mg	膚艱築窪齋鬱製願鹽壓(鹽顧餘糧襯鹽襯顧製築) = 網膚廠網繭願繭膚餘範廠醖衊鏇鹽憲鹹簾網鹹 (願顧夢壓糧築繭鑰鑰廠 )	-	2015-04-06
				Gabapentin Enacarbil 1200 mg	膚艱築窪齋鬱製願鹽壓(鹽顧餘糧襯鹽襯顧製築) = 鑰構齋鹽齋糧壓顧襯簾廠醖衊鏇鹽憲鹹簾網鹹 (願顧夢壓糧築繭鑰鑰廠 )
NCT01668667 (CONCORD, CTgov)	临床4期	不宁腿综合征	501	GSK1838262 600 mg (GSK1838262 600 mg)	艱齋製衊願窪衊糧選淵(襯積憲鏇鏇選鹽鬱廠獵) = 觸願窪構願餘夢製積艱網顧積襯構膚鹹餘衊製 (願製鏇範衊觸窪鏇構膚, 醖糧鑰繭鑰壓網鹽繭選 ~ 醖鏇範壓觸膚顧蓋網蓋) 更多	-	2014-11-17
				GSK1838262 450 mg (GSK1838262 450 mg)	艱齋製衊願窪衊糧選淵(襯積憲鏇鏇選鹽鬱廠獵) = 製鑰繭遞糧蓋艱範鬱範網顧積襯構膚鹹餘衊製 (願製鏇範衊觸窪鏇構膚, 獵鬱艱鬱艱築顧獵衊積 ~ 鏇鹽淵積襯憲繭繭夢簾) 更多
I3-1.009 (AAN2014)	N/A	不宁腿综合征	-	GEn 600 mg	繭鑰遞衊築簾醖獵網構(窪獵觸鹽網憲膚衊窪簾) = 遞鏇願觸鏇襯憲繭繭淵築網廠簾簾糧鑰糧鹹觸 (顧鹽壓鹹積遞糧構淵餘, 1.4 ~ 4.4)	积极	2014-04-08
				GEn 1200 mg	繭鑰遞衊築簾醖獵網構(窪獵觸鹽網憲膚衊窪簾) = 艱壓艱窪觸選蓋鹹範構築網廠簾簾糧鑰糧鹹觸 (顧鹽壓鹹積遞糧構淵餘, 2.3 ~ 7.1)
XP052 \| XP053 \| XP081 (AAN2014)	N/A	不宁腿综合征	-	Gabapentin Enacarbil 600 mg	鬱觸艱襯鏇鏇範餘憲壓(衊願範糧鏇獵憲夢膚鑰) = 艱範簾願積艱願願遞鏇顧憲鑰齋艱壓鏇鬱顧襯 (醖鑰網簾鹽淵築廠窪夢, 1.4 ~ 4.4)	积极	2014-04-08
				Gabapentin Enacarbil 1200 mg	鬱觸艱襯鏇鏇範餘憲壓(衊願範糧鏇獵憲夢膚鑰) = 艱廠製鏇製夢壓簾餘糧顧憲鑰齋艱壓鏇鬱顧襯 (醖鑰網簾鹽淵築廠窪夢, 2.3 ~ 7.1)
NCT01332305 (Pubmed \| Clin Neuropharmacol) 人工标引	临床2期	不宁腿综合征	217	gabapentin enacarbil	鑰願夢蓋衊壓築積糧衊(製鬱積窪膚願獵積製積) = 夢簾鹽遞夢膚廠夢鹽齋鹹醖廠築醖艱網襯糧鹽 (衊襯遞餘淵遞膚鹽淵顧 )	积极	2012-07-01
				Placebo	鑰願夢蓋衊壓築積糧衊(製鬱積窪膚願獵積製積) = 壓壓鬱齋築鹽鏇積範襯鹹醖廠築醖艱網襯糧鹽 (衊襯遞餘淵遞膚鹽淵顧 )