The HORIZON Recurrent Fracture Trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair

OBJECTIVE: To present the novel design of a trial testing the safety and efficacy of a yearly bisphosponate, zoledronic acid, in preventing new clinical fractures in patients with recent low trauma hip fracture repair. Research design and methods: Randomized, placebo-controlled, triple-blind study. One hundred and fifteen clinical centers worldwide are recruiting approximately 1714 subjects aged 50 years and over (no upper age limit, median age of enrolled subjects to date 79 years) who have undergone surgical repair of a low trauma hip fracture in the preceding 90 days. Patients will be assigned at random to an intervention group (5 mg zoledronic acid intravenously yearly) or a control group (placebo infusion yearly). Both groups receive a loading dose of Vitamin D2 or D3 IM or orally, followed by 800-1200 IU Vitamin D and 1000-1500 mg elemental calcium orally on a daily basis. Concomitant therapy with calcitonin, hormone replacement therapy, selective estrogen receptor modulators, tibolone, and external hip protectors are allowed. MAIN OUTCOME MEASURES: The primary endpoint is subsequent skeletal fractures as adjudicated by a clinical endpoints committee blinded to intervention status. Secondary outcomes include delayed hip fracture healing, changes in bone mineral density, and health resource utilization. Subjects will be recruited over a 3-4 year period and will be followed until 211 primary endpoints are accrued and adjudicated. CONCLUSIONS: This randomized clinical trial is novel among osteoporosis therapies as it (1). targets hip fracture patients, a previously understudied group, and (2). uses only clinically evident fractures as the primary outcome. Ethical and practical considerations in studying this frail population are discussed.     

髋部骨折术后物理措施预防血栓形成的有效性分析

目的探讨髋部骨折围手术期物理措施预防血栓形成的有效性和安全性。方法把96例符合条件的患者分为A和B两组,A组术后应用物理措施预防血栓形成,B组术后应用低分子肝素钙预防血栓形成,通过对比两组深静脉和肺栓塞的发生率及出血性并发症的发生率,比较两组治疗措施的效果。结果 A组48例物理措施预防血栓形成的患者血栓形成的发生率为8.33%,出血性并发症的发生率为2.08%;B组48例应用低分子肝素钙血栓形成的发生率为6.25%,出血性并发症的发生率为4.17%。结论在髋关节骨折术后中单独应用物理措施预防血栓形成的效果并不比单独应用低分子肝素差。     

高龄髋部骨折人工关节置换围术期处理

目的探讨高龄髋部骨折患者人工髋关节置换围术期处理方法。方法回顾性分析2007年2月～2011年4月118例80岁以上高龄髋部骨折患者应用外侧小切口前方入路人工髋关节置换的围术期处理措施。结果全部患者均安全度过手术期,围术期无死亡病例,术后发生各种早期并发症23例（19.49%）。术后1周内107例（90.68%）患侧下肢可完成直腿抬高运动,108例（91.53%）可以利用助行器下地行走活动。结论严格有效的围术期综合处理是高龄髋部骨折患者人工髋关节置换成功的基础和安全保障。     

68例老年髋部骨折术后并发症的防治

目的探讨老年髋部骨折术后并发症的防治。方法对我科2004年1月～2007年1月68例65岁以上老年髋部骨折切开复位内固定术患者术后1周持续监护,就其出现的并发症及治疗进行回顾性分析。结果66例治愈出院,2例死亡,其中1例死亡原因为肺部感染,另1例为顽固性心律失常。病死率为2.9%。结论老年髋部骨折患者术前充分准备及术后并发症的防治是提高手术成功率的关键。     

两种不同方法治疗老年人股骨粗隆间骨折疗效及对髋关节功能影响比较

目的：通过比较不同内固定术在老年人股骨粗隆间骨折的临床疗效,探讨抗旋髓内钉内固定术在老年人股骨粗隆间骨折中的应用价值。方法选择160例老年股骨粗隆间骨折患者为研究对象,根据数字表法随机分为观察组（抗旋髓内钉内固定术）和对照组（动力髋螺钉内固定术）。比较两组患者治疗效果及髋关节功能恢复情况。结果观察组手术时间短于对照组,出血量少于对照组,差异均有统计学意义（t＝4.635、3．643,均P＜0．05）;观察组髋关节功能、疼痛、畸形、运动范围单项评价及总分均显著高于对照组（ t＝4．433、4．364、4．865、3．876、3．645,均P＜0．05）;观察组患者术后髋关节功能优良率为90．0％,显著高于对照组的72．5％（χ2＝5．153,P＜0．05）。结论在老年人股骨粗隆间骨折的治疗中,股骨近端抗旋髓内钉内固定术手术时间短,出血量少,术后髋关节功能恢复好,值得临床推广。     

股骨近端防旋髓内钉、加压滑动鹅头钉和股骨近端锁定加压钢板治疗股骨粗隆间骨折的疗效比较

目的 探讨股骨近端防旋髓内钉(PFNA)、加压滑动鹅头钉(DHS)和股骨近端锁定加压钢板(PFLP)治疗股骨粗隆间骨折的临床疗效。 方法 回顾性分析130例老年股骨粗隆间骨折患者的临床资料,根据手术方式的不同分为三组:PFNA组45例,DHS组50例,PFLP组35例,分别观察手术切口,手术时间,术中出血量,术后并发症发生率,术后髋关节功能恢复情况,术后骨折愈合时间等。 结果 PFNA组在手术切口,手术时间,术中出血量,术后髋关节功能恢复情况方面,与DHS和PFLP组比较差异有统计学意义(P＜0.05),在骨折愈合时间方面比较差异无统计学意义(P＞0.05)。术后随访过程中,PFNA组无一例并发症,DHS组有一例螺钉退钉,PFLP组有一例钢板断裂。 结论 PFNA在治疗老年不稳定性股骨粗隆间骨折患者方面明显优于DHS和PFLP组,在临床治疗中值得广泛推广。     

Reducing the average number of patients needed in a phase II trial through novel design

Abstract

Phase II represents a very important part of the drug development process. It is important that genuinely effective treatments have a high chance of succeeding whilst treatments that will fail at phase III are screened out. Because of the high number of treatments available for testing and limited resources and patients available, it is increasingly of interest to apply novel designs to improve the efficiency of phase II trials. This paper shall argue that phase II presents the most promising area for applying novel designs and will review some recent developments in three classes of novel design: group-sequential designs, multi-arm designs, and enrichment designs. All three types of design considerably improve the efficiency of phase II trials on average and also ensure that patients are more likely to be treated with the best available treatment for them. Although the designs have drawbacks, the considerable advantages mean that these designs will become increasingly important in phase II.     

New horizons for zoledronic acid: results of the HORIZON trials in postmenopausal women with osteoporosis and after hip fracture

Nearly 2 million hip fractures occur each year in the US as a result of osteoporosis. After hip fracture, people are at an increased risk of a further fracture. The HORIZON-PFT (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial), investigated the effect of zoledronic acid on fractures in women with osteoporosis, whereas the HORIZON-RFT (Recurrent Fracture Trial), studied the effect of zoledronic acid after hip fracture. In the HORIZON-PFT, after 3 years the incidence of new vertebral fractures in postmenopausal women, who were not taking any medication for osteoporosis at randomisation, was 10.9% in the placebo group and this was significantly lower in the once-yearly intravenous zoledronic acid group (3.3%). In the second of the HORIZON trials, the RFT, the effect of a single intravenous injection of zoledronic acid within 90 days of fracture on the recurrence of fracture was tested. The primary endpoint was a new clinical fracture, and after a median follow-up of 1.9 years, there were 139 fractures in the placebo group of 1062 and this was significantly reduced to 92 out of 1065 in the zoledronic acid group. Thus, this second HORIZON trial has demonstrated that zoledronic may have a role in preventing recurrent fractures in those who have a recent hip fracture.     

临床药师参与1例反复过敏患者开放性骨折术后感染治疗的药学实践

摘 要1例54岁男性患者，因“左踝骨骨折术后红肿1周”入院，诊断为术后感染。患者在抗感染过程中2次出现药物过敏现象，临床药师通过专业知识协助医师调整治疗方案，减少了患者用药风险，为患者的最终治愈提供帮助。     

The effect of raloxifene therapy on the risk of new clinical vertebral fractures at three and six months: a secondary analysis of the MORE trial

ABSTRACT

Objective: Raloxifene treatment (60?mg/day) significantly decreases the risk of new clinical vertebral fractures by 68% at 1 year compared with placebo. The objective of the present analysis is to evaluate the effects of raloxifene on the incidence of new clinical vertebral fractures at 3 and 6 months after initiation of treatment.

Research design and methods: A double-blind, randomized, placebo-controlled, 4‐year Multiple Outcomes of Raloxifene Evaluation (MORE) trial was conducted in 180 study centers. Postmenopausal women with osteoporosis (N = 7705) were randomized to placebo, or raloxifene at 60 or 120?mg/day.

Main outcome measures: Vertebral radiographs were obtained when patients reported symptoms suggestive of vertebral fracture at or between clinic visits, which were held at 3 and 6 months, and every 6 months thereafter. If a new adjudicated fracture was found, this was considered as a clinical vertebral fracture. The analyses included all randomized patients with a baseline and at least one follow-up radiograph (n = 6828).

Results: One woman treated with raloxifene 60?mg/day (n = 2259) and 10 in the placebo group (n = 2292) had a clinical vertebral fracture in the first 6 months, resulting in a 90% relative risk (RR) reduction [RR 0.10 (95% CI 0.01, 0.63)] and a 0.39% absolute risk reduction (ARR). Similar results were observed with raloxifene 120?mg/day at 6 months. When the raloxifene groups were pooled, a significant (?p = 0.034) decrease in clinical vertebral fracture risk [RR 0.20 (95% CI 0.03, 0.90), ARR 0.17%] was seen as early as 3 months.

Conclusion: The risk of new clinical vertebral fractures was reduced after 3 or 6 months of raloxifene.     

The effect of Frankincense in the treatment of moderate plaque-induced gingivitis: a double blinded randomized clinical trial

Background and the purpose of the study

Extract of Boswellia Serrata species has been used in the Indian traditional medicine in the treatment of various inflammatory diseases. The present study was designed to evaluate anti-inflammatory effects of Frankincense in the treatment of gingivitis, which is a periodontal tissue inflammatory disease.

Methods

This double blind randomized placebo controlled trial was carried out among high school female students with moderate plaque-induced gingivitis. Based on either administration of 0.1 gram of Frankincense extract or 0.2 gram of its powder or placebo and whether the patients undergone scaling and root planning (SRP) or not, they were randomly assigned to 6 groups. The primary efficacy outcome was changes in Gingival Index (Loe & Sillness) and the secondary outcomes were alteration in plaque index (Sillness & Loe), bleeding index (Cowell) and probing pocket depth (WHO probe). All indices were measured in the 0, 7th and 14th days of the study.

Results

Seventy five patients ranged of 15–18 years old were enrolled. At the end of the study, the indices in all groups showed significant decreases in comparison to the first day (p< 0.05), except for the bleeding index in the group without SRP and drug therapy (p=0.111). More precise analysis of data revealed that SRP in association with Frankincense application (either extract or powder) can lead to remarkable decrease in inflammatory indices in comparison to the groups without SRP and drug therapy (p<0.001). In addition, no significant difference was observed between powder or extract therapy (p >0.05) and between patients received either SRP or treatment alone (p=0.169).

Conclusion

Frankincense, a safe and low-cost herbal medicine, may be feasibly applied to improve inflammation based disease of gingival as an adjunct to the conventional mechanical therapy.     

Overview of safety experience with caspofungin in clinical trials conducted over the first 15 years: a brief report

Safety experience is available from 32 completed clinical studies (17 Phase I and 15 Phase II–III) of caspofungin (CAS) conducted between 1995 and 2010 in adult and paediatric patients. Clinical and laboratory adverse events (AEs) were collected from all enrolled subjects and patients. Investigators identified the seriousness, causality and result of all AEs noted during study therapy and for up to 28 days post therapy. Up to 31 December 2010, full safety data are available from 1951 individuals who have received at least one dose of CAS in Phase I–III clinical studies, including 171 paediatric patients, 394 volunteer adult subjects and 1386 adult patients (276 with oropharyngeal/oesophageal candidiasis, 366 with invasive candidiasis, 180 with invasive aspergillosis and 564 with persistent fever and neutropenia). CAS was administered for up to 196 days at daily doses ranging from 5 mg to 210 mg. Overall, 41.8% of CAS recipients had an AE that was classified as drug-related. The most frequently reported drug-related AEs were fever (9.3%), chills (5.2%), increased alanine aminotransferase (6.5%), increased aspartate aminotransferase (6.0%) and increased alkaline phosphatase (5.2%). Serious AEs were reported in 27.3% of CAS recipients overall but were attributed to CAS in only 0.8%, and discontinuation of CAS due to a drug-related AE was infrequent (2.7%). Dose-related CAS toxicity was not observed. In conclusion, CAS has demonstrated a favourable safety profile in 1951 adult and paediatric patients enrolled in clinical trials.     

Availability of post-trial access in clinical trials: a review of clinical trial protocols submitted to the research ethics board of the University of the Philippines Manila

Objectives: Ethics guidelines such as the Declaration of Helsinki and the CIOMS International Ethical Guidelines for Health-related Research Involving Humans require the sponsors, in cooperation with relevant stakeholders, to provide post-trial access (PTA) to intervention and knowledge, especially in clinical trials held in resource-poor regions. To date, we have very limited knowledge in terms of whether PTA is provided at all, and in what form. To partially address this current limitation, this study wished to explore whether, for which type of drugs and in what form PTA is provided in the Philippines.

Methods: We looked at all the clinical trial protocols submitted to the University of the Philippines Manila from 2012 to 2017. A total of 193 clinical trial protocols were included in the study. To identify whether, for which drug type and in what form PTA is provided, we gathered the following information: start and end date of the trial, name of study drug, tested indication of the study drug, region the sponsor is from, type/category of the study drug, type of funding agency, provisions for PTA (yes or no) and the explanation for the provisions. PTA provisions were further described according to the form in which PTA was provided and the types of drugs that were given PTA.

Results: Of the 193 protocols, 51.81% indicated PTA, though PTA in the form identified in guidelines can be partially accounted for in only 29.5% (57). The most common form of PTA is the provision or sharing of information (40). None of the protocols provided PTA in the form of access to intervention after the trials, with the possible exemption of 10 protocols that declared future evaluation of the sponsor for PTA depending on patient need, and another seven that might offer the option to transfer to an open-label extension study after the trial.

Conclusion: More work is needed if PTA, as stipulated in ethics guidelines, is to be reflected in reality.     

The efficacy of Prrrikweg? gel in the treatment of insect bites: a double-blind, placebo-controlled clinical trial

Objective: This study was conducted to examine the efficacy of Prrrikweg^® gel, a homeopathic after-bite gel, in relleving the effects of mosquito bites, in particular itching and erythema. Design: A double-blind, randomized, placebo-controlled clinical trial. Setting: London School of Hygiene and Tropical Medicine. Subjects: 100 healthy volunteers. Methods: All subjects were bitten under laboratory conditions by Aedes aegypti mosquitoes at one spot on the ventral aspect of the left forearm and another on a corresponding position on the right forearm. One spot was treated with the homeopathic after-bite gel and the other with a placebo gel. Main outcome measures: Itching was assessed on a 5-point discrete rating scale at 0, 0.5, 1, 26.5, and 48 h post-bite to compare the itch-relieving efficacy of the two treatments. Erythema development was assessed by photographing the bite sites, measuring length and width of the erythema with at baseline (T₀) to the mean erythema surface at 0.5, 1, 26.5, and 48 h post-bite (T_mean) for the two treatments. Results: Testing erythema development by comparing the ratio T₀/T_{mean, after-bite gel} and the ratio T₀/T_{mean, placebo gel} gave a two-tailed p=0.098 (95% Cl,–0.031–0.361) in favour of the after-bite gel. There was not a statistically significant difference between the itch relief provided by the two treatments (two-tailed p=0.424; 95% Cl,–0.541–0.191). The correlation between itching and erythema was significant (r=0.46; p<0.001). Conclusions: There are strong indications that the homeopathic after-bite gel reduces erythema development following mosquito bites. The homeopathic mother tinctures of Echinacea angustifolia DC., Ledum palustre L, Urtica urens L. as well as the Hamamelis extract in this gel, whether alone or in combination, are the biologically active ingredients. The homeopathic after-bite gel was not demonstrated to relieve itching, however, based on the correlation between erythema and itching, an effect on itching is not inconceivable.     

Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial*

ABSTRACT

Objective: This trial was conducted to compare the efficacy and tolerability of a fixed dose of escitalopram 10?mg/day with sertraline optimally dosed within its recommended dose range (50–200?mg/day) for the treatment of major depressive disorder.

Methods: In this multicenter trial, depressed patients (DSM?IV defined; baseline Montgomery–Asberg Depression Rating Scale [MADRS] ≥ 22) aged 18–80 years were randomly assigned to 8 weeks of double-blind treatment with escitalopram (10?mg/day) or sertraline (50–200?mg/day) following a 1?week single-blind placebo lead-in period. There was no placebo comparison arm. Sertraline was initiated at 50?mg/day, and could be increased by 50?mg/day at weekly intervals based on clinical need and tolerability at the lower dose level. The blind was maintained with matching double-blind placebo capsules for the escitalopram group. Change from baseline to endpoint in MADRS total score (last observation carried forward) was the primary efficacy measure.

Results: A total of 212 patients received double-blind medication. At week 8, the mean sertraline dosage was 144?mg/day (median = 150?mg/day). Mean changes from baseline to endpoint in MADRS scores were –19.1 and –18.4 for the escitalopram and sertraline groups, respectively. At endpoint, 75% and 70% of escitalopram- and sertraline-treated patients, respectively, were responders (≥ 50% improvement from baseline in mean MADRS scores). Both treatments were generally well tolerated; only 2% and 4% of patients prematurely discontinued escitalopram and sertraline treatment, respectively, due to adverse events.

Conclusion: No differences in efficacy were observed for fixed-dose escitalopram 10?mg/day and sertraline flexibly dosed from 50–200?mg/day. At these doses, both escitalopram and sertraline were generally well tolerated.     

益气活血法对全髋关节置换术后下肢深静脉血栓形成的临床干预

目的探讨益气活血法对全髋关节置换术后下肢深静脉血栓形成的影响。方法回顾分析益气活血法在全髋关节置换术36例中的应用效果并加以分析。结果 36例患者全髋关节置换术后未发生下肢深静脉血栓。未发生肺部感染与尿路感染。术后住院时间为15～42d。结论益气活血法在围手术期的应用是预防全髋关节置换术后并发下肢深静脉血栓形成的有效方法 。     

Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of phase III studies

ABSTRACT

Objective: The marketed doses of ibandronate, 150?mg once-monthly oral and 3?mg quarterly intravenous (IV) injection, produce greater increases in lumbar spine bone mineral density than treatment with the 2.5?mg oral daily dose. This meta-analysis assessed whether these doses also reduce fracture risk relative to placebo.

Study design and methods: Individual patient data from the intent-to-treat populations of the BONE, IV fracture prevention, MOBILE, and DIVA studies were grouped into three dose levels based on annual cumulative exposure (ACE), defined as the annual dose (mg) × bioavailability (0.6%, oral; 100%, IV) or placebo. Six key non-vertebral fractures (NVFs) (clavicle, humerus, wrist, pelvis, hip, and leg), all NVFs, and all clinical fractures were examined.

Results: This meta-analysis included 8710 patients. Cox proportional-hazards models estimated the adjusted relative risk (RR) for fracture with ibandronate versus placebo, and time to fracture was compared using log-rank tests. The high-dose group (ACE?≥?10.8?mg) showed significant reductions in the adjusted RR of key NVFs (34.4%, p?=?0.032), all NVFs (29.9%, p?=?0.041), and clinical fractures (28.8%, p?=?0.010) relative to placebo. The high-dose group also had significantly longer time to fracture versus placebo for key NVFs (p?=?0.031), all NVFs (p?=?0.025), and clinical fractures (p?=?0.002). Study limitations included: not all studies were placebo-controlled; a limited number of baseline characteristics were available for multivariate analyses.

Conclusion: Ibandronate at dose levels of ACE?≥?10.8?mg, which includes the marketed 150?mg once-monthly oral and 3?mg quarterly IV injection regimens, may provide significant non-vertebral and clinical fracture efficacy.     

The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre,randomized, double-blind,placebo-controlled phase I clinical trial

ContextCapsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma.ObjectiveTo observe the clinical safety and tolerability of CALAS.Materials and methodsSubjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects.ResultsSixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%).Discussion and conclusionsCALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.