Open-label Multicenter Clinical Trial Research Articles

Reconstructing avascular necrotic femoral head through a bioactive β-TCP system: From design to application

A variety of techniques have been used for treating avascular necrosis of the femoral head (ANFH), but have frequently failed. In this study, we proposed a β-TCP system for the treatment of ANFH by boosting revascularization and bone regeneration. The angio-conductive properties and concurrent osteogenesis of the highly interconnected porous β-TCP scaffold were revealed and quantified through an in vivo model that simulated the ischemic environment of ANFH. Mechanical test and finite element analysis showed that the mechanical loss caused by tissue necrosis and surgery was immediately partially compensated after implantation, and the strength of the operated femoral head was adaptively increased and eventually returned to normal bone, along with continuous material degradation and bone regeneration. For translational application, we further conducted a multi-center open-label clinical trial to assess the efficacy of the β-TCP system in treating ANFH. Two hundred fourteen patients with 246 hips were enrolled for evaluation, and 82.1% of the operated hips survived at a 42.79-month median follow-up. The imaging results, hip function, and pain scores were dramatically improved compared to preoperative levels. ARCO stage Ⅱ disease outperformed stage Ⅲ in terms of clinical effectiveness. Thus, bio-adaptive reconstruction using the β-TCP system is a promising hip-preserving strategy for the treatment of ANFH.

A phase 2 study of neoadjuvant lenvatinib in locally advanced invasive thyroid cancer.

TPS6105 Background: Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor that has demonstrated meaningful benefit in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). In SELECT, lenvatinib significantly prolonged progression-free survival (PFS) and was associated with an overall response rate (ORR) of 65% in patients with RAI-refractory DTC, with the greatest degree of tumor shrinkage occurring in the first 2 cycles. The robust activity of lenvatinib in DTC suggests that neoadjuvant treatment in patients presenting with bulky neck disease may make surgery more feasible, allows for optimal surgical outcomes and less aggressive surgical management. Neoadjuvant lenvatinib to improve surgical outcomes in locally advanced DTC has not been studied to date. This phase 2 study will examine the efficacy and safety of lenvatinib prior to thyroidectomy, with the goal of achieving more favorable surgical outcomes. Methods: This is a Simon two-stage Phase 2 open-label multicenter clinical trial for adult patients who meet the following criteria: have been diagnosed with locally advanced or persistent/recurrent thyroid and/or cervical nodal DTC, deemed at risk for R2 resection (surgical margins with macroscopic tumor) (as evident by vocal cord paralysis by laryngoscopic exam, imaging documenting extrathyroidal/extranodal extension, or major vessels involvement), have measurable disease per RECIST v1.1, have an ECOG performance status ≤ 1, and no contraindication to surgery. A total of 28 patients will be enrolled from three centers (Massachusetts General Hospital/Massachusetts Eye & Ear Infirmary (MGH/MEEI), Memorial Sloan-Kettering Cancer Center (MSKCC), and MD Anderson Cancer Center (MDACC)). Participants will receive up to 6 cycles of lenvatinib prior to surgery depending on response. Participants will undergo restaging at the end of cycle 2, 4, and 6. Participants with sufficient response to treatment who projected to achieve an R0 or R1 resection will stop lenvatinib and proceed to surgery within 7-10 days from the last dose. Participants who do not have a sufficient response who are tolerating treatment, will receive an additional 2-4 cycles of lenvatinib, followed by surgery. The primary objective is the R0 (surgical margins free from tumor)/R1 (surgical margins free from macroscopic tumor) resection rate. Secondary outcome measures include R0/R1 resection rates in each of 5 pre-specified anatomic target interfaces (perithyroid muscles, cartilage, esophagus, recurrent laryngeal nerve, major vessels), evaluation of the change in surgical morbidity complexity MGH/MEEI-MSKCC-MDACC (MMM) score and the Invasive Thyroid Class, ORR prior to surgery per RECIST v1.1, and the safety of lenvatinib in this patient population. The study is currently accruing with 11 patients enrolled at time of submission. Clinical trial information: NCT04321954 .

AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

Intranasal ketamine for procedural sedation in children: An open-label multicenter clinical trial

IntroductionThere are limited options for pain and distress management in children undergoing minor procedures, without the burden of an intravenous line insertion. Prior to this study, we conducted a dose-escalation study and identified 6 mg/kg as a potentially optimal initial dose of intranasal ketamine. ObjectiveTo assess the efficacy and safety of intranasal ketamine at a dose of 6 mg/kg for procedural sedation to repair lacerations with sutures in children in the emergency department. MethodsWe conducted a single-arm, open-label multicenter clinical trial for intranasal ketamine for laceration repair with sutures in children aged 1 to 12 years. A convenience sample of 30 patients received 6 mg/kg of intranasal ketamine for their procedural sedation. The primary outcome was the proportion (95% CI) of patients who achieved an effective procedural sedation. ResultsWe recruited 30 patients from April 2018 to December 2019 in two pediatric emergency departments in Canada. Lacerations repaired were mostly facial in 21(70%) patients and longer than 2 cm in 20 (67%) patients. Sedation was effective in 18/30 (60% [95% CI 45, 80]) children and was suboptimal in 5 (17%) patients but procedure was completed in them with minimal difficulties. Sedation was poor in the remaining 7 (23%) patients, with 3 (10%) of them required additional sedative agents. No serious adverse events were reported. ConclusionsUsing a single dose of 6 mg/kg of intranasal Ketamine for laceration repair led to successful sedation in 60% of patients according to our a priori definition. An additional 17% of patients were considered suboptimal, but their procedure was still completed with minimal difficulty.Clinical trial registration: ClinicalTrials.gov (NCT03053947).

Eye Dynamics and Engineering Network Consortium: Baseline Characteristics of a Randomized Trial in Healthy Adults

To improve understanding of intraocular pressure (IOP) and its variance, this project identifies systemic and ocular characteristics of healthy eyes of adult volunteers including IOP variation, ocular biometrics, and aqueous humor dynamics (AHDs). These data serve as baseline controls for further studies from the Eye Dynamics and Engineering Network (EDEN) Consortium. Multicenter open-label clinical trial in healthy adults randomized to 1 week treatment with 2 approved glaucoma drugs in a crossover design. Among 135 healthy participants, 122 participants (aged 55.2 ± 8.8 years; 92 females, 30 males) completed the protocol. Participants from the University of Michigan, Mayo Clinic, and University of Nebraska Medical Center underwent measurements of ocular biometrics, AHD, and IOP using 4 tonometers. Intraocular pressure data during 3 study visits without glaucoma medications were used in the analysis. The PhenX Toolkit survey acquired standardized data on medical history, surgical history, medications, smoking and alcohol exposures, and physical measures. The variability of IOP measurements within eyes was assessed as visit-to-visit IOP variation, within-visit IOP variation, and within-visit positional IOP variation. The concordance (or correlation) between eyes was also assessed. Average positional change of > 4.7 mmHg was detected with a range of 0.5-11.0 mmHg. Pearson correlation of IOP between eyes within a visit was 0.87 (95% confidence interval [CI], 0.82-0.91) for Goldmann applanation tonometry, 0.91 (95% CI, 0.88-0.94) for Icare rebound tonometry, and 0.91 (95% CI, 0.88-0.94) for pneumatonometry. There was a 4% to 12% asymmetric fluctuation of 3 mmHg or more between eyes between visits using rebound tonometry, 9% with Goldmann applanation tonometry, and 3% to 4% by pneumotonometry. The coefficient of variation between visits for the same eye ranged from 11.2% to 12.9% for pneumatonometry, from 13.6% to 17.4% for rebound tonometry, and 15.8% to 16.2% for Goldmann applanation tonometry. The current study from the EDEN Consortium describes measurement methods and data analyses with emphasis on IOP variability. Future papers will focus on changes in ocular biometrics and AHD with timolol or latanoprost treatment. Proprietary or commercial disclosure may be found after the references.

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Dabigatran following acute transient ischemic attack and minor stroke II (DATAS II).

Rationale Patients with transient ischemic attack or minor stroke are at high risk of early recurrent cerebrovascular events. Anticoagulation with heparin or warfarin acutely after ischemic stroke is at least as efficacious as aspirin for preventing recurrent events but is associated with an increased risk of clinical worsening due to hemorrhagic transformation. Aim and hypothesis We aim to demonstrate the safety of early anticoagulation with dabigatran, an oral direct thrombin inhibitor, in acute cerebrovascular syndrome patients. The primary hypothesis is that symptomatic hemorrhagic transformation rates in dabigatran and aspirin-treated patients will be similar. Sample size estimates At least 136 participants in two groups required to demonstrate an absolute between-group difference in the rate of hemorrhagic transformation of 5.6% with 80% power, assuming alpha = 5%. Methods and design A randomized, multicenter open-label clinical trial (NCT02295826). Three-hundred participants with a transient ischemic attack/ischemic stroke (National Institutes of Health Stroke Scale ≤ 9) will undergo magnetic resonance imaging within 72 h of symptom onset and will be randomized to aspirin 81 mg daily or dabigatran 150 mg twice daily for 30 days. Participants undergo repeat magnetic resonance imaging at 30 days and clinical assessment to 90 days. Study outcomes The primary outcome is the symptomatic hemorrhagic transformation rate. Secondary outcomes include recurrent stroke and new ischemic lesions on repeat magnetic resonance imaging. Discussion This study will determine the safety of early anticoagulation with dabigatran in patients with acute transient ischemic attack/ischemic stroke and will inform the design of a phase III randomized trial aimed at demonstrating reduced recurrent early ischemic events after acute transient ischemic attack/stroke.

Rhodiola rosea in Subjects with Prolonged or Chronic Fatigue Symptoms: Results of an Open-Label Clinical Trial

Background:Rhodiola rosea roots and rhizomes are a herbal medicine for temporary relief of stress symptoms such as fatigue and sensed weakness. A daily dosage of 400 mg is recommended. Methods: A dry ethanolic extract of R. rosea (WS® 1375) was studied in 100 subjects with prolonged or chronic fatigue symptoms. In an uncontrolled, open-label multicenter clinical trial, the subjects were administered 2 × 200 mg WS® 1375 over 8 weeks. Outcome measures were scales and tests related to fatigue. They were evaluated in an exploratory data analysis to generate hypotheses regarding efficacy. The pilot character of the trial is marked by its broad focus on subjects suffering from fatigue in general and by its comparatively long duration. Results: The greatest change was observed after 1 week of treatment. The fatigue symptoms continued to decline further, with statistically significant improvement at week 8. The safety assessments of WS® 1375 during the trial proved to be favorable, with most adverse events being of mild intensity and not related to the study drug. Conclusions: The results indicate that 2 × 200 mg WS® 1375 may be an effective treatment in subjects suffering from prolonged or chronic fatigue. The safety and tolerability of WS® 1375 also presented a favorable profile.

A phase II therapeutic, open label, multi-center clinical trial of NPC-1C, a chimeric monoclonal antibody(mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results.

500 Background: NEO-102 is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Its mechanism of action is through antibody dependent cellular cytotoxicity (ADCC). An earlier, phase I study, established the maximum tolerated dose at 3.0 mg/kg IV every 2 weeks with encouraging early signs of clinical activity. We report initial results of the subsequent phase II study. Methods: This is a single arm, open label multi-center clinical trial of NEO-102 in adults with mCRC pts who failed at least two lines of standard chemotherapy (C). An immunohistochemistry (IHC) based companion diagnostic assay was used to select eligible pts whose tumors express the target in > 20% of tumor cells. NEO-102 at 3.0 mg/kg IV was administered q 2 weeks until disease progression. The primary endpoint was OS. A minimum of 43 pts were needed assuming that treatment with NEO-102 will improve OS by 40% (7.0 months) using a one-sided significance level of 10% and 80% power for this study compared to historical control of 5 months. Additional objectives were to evaluate response rate as measured by RECIST criteria and analyze patient PBMCs for ADCC and immune cytokine profiling. Results: A total of 47 pts enrolled were evaluable. 26 pts were male and 35 pts were white. Twenty-four out of 47 pts (51%) remain alive as of September 2015 with an ongoing median OS of 7.0 months (Range 2-22 months). Of these heavily pre-treated pts, 42 were evaluable for response, 13 (31%) demonstrated stable disease by RECIST. Seven pts had more than 4 doses of treatment, maximum 13 doses. Grade 3 adverse events were anemia 1/47 (2%), hyperbilirubinemia 1/47 (2%), diarrhea 1/47 (2%), fatigue 1/47 (2%), headache 1/47 (2%), nausea 1/47 (2%) and vomiting 1/47 (2%). No grade 4 toxicities were reported. Conclusions: In the monotherapy phase 2 study of NEO 102 in patients with refractory mCRC preliminary results demonstrate excellent tolerability and encouraging OS. Updated OS and Progression Free Survival data will be presented at the ASCO 2016 GI Cancers symposium. Additional combination trials with NEO-102 and C are underway. Clinical trial information: NCT01040000.

Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation

Despite improving experience and techniques, ischemic and bleeding complications after transcatheter aortic valve implantation (TAVI) remain prevalent and impair survival. Current guidelines recommend the temporary addition of clopidogrel in the initial period after TAVI to prevent thromboembolic events. However, explorative studies suggest that this is associated with a higher rate of major bleeding without a decrease in thromboembolic complications. The POPular TAVI trial is a prospective randomized, controlled, open-label multicenter clinical trial to test the hypothesis that monotherapy with aspirin or oral anticoagulation (OAC) after TAVI is safer than the addition of clopidogrel for 3 months, without compromising clinical benefit. This trial encompasses 2 cohorts: cohort A, patients are randomized 1:1 to aspirin vs aspirin + clopidogrel, and cohort B, patients on OAC therapy are randomized 1:1 to OAC vs OAC + clopidogrel. Primary outcome is freedom from non-procedure-related bleeding at 1 year. Secondary net-clinical benefit outcome is freedom from the composite of cardiovascular death, non-procedural-related bleeding, myocardial infarction, or stroke at 1 year. The primary outcome is analyzed for superiority, whereas the secondary outcome is analyzed for noninferiority. Recruitment began in February 2014, and the trial will continue until a total of 1,000 patients (684 expected in cohort A and 316 in cohort B) are included and followed up for 1 year. The POPular TAVI trial (NCT02247128) is the first large randomized controlled trial to test if monotherapy with aspirin or OAC vs additional clopidogrel after TAVI reduces bleeding with a favorable net-clinical benefit.

Transcatheter arterial embolization of hypervascular tumors with HepaSphere: prospective multicenter open label clinical trial of microspheres in Japan

To evaluate the feasibility and safety of transcatheter arterial embolization (TAE) with the use of HepaSphere microspheres for hypervascular tumors. This was a prospective multicenter open label clinical trial involving six institutions in Japan. TAE was performed with the HepaSphere microspheres for hypervascular tumors in various locations. The endpoint of the study was the feasibility and safety of the procedure. The feasibility and safety were evaluated according to technical success and adverse events, respectively. Adverse events that were related to TAE were evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0. Twenty-four patients were enrolled. The technical success rate was 100% (24/24). Twenty-two (92%) patients developed a total of 50 symptomatic adverse events, including 30 grade 1 events, 17 grade 2 events, and 3 grade 3 events. The most frequent adverse event was fever with an incidence of 63%, followed by abdominal pain (25%). TAE for hypervascular tumors with the HepaSphere microspheres was feasible and rarely caused major adverse events. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111534).

Neoadjuvant capecitabine chemotherapy in women with newly diagnosed locally advanced breast cancer in a resource-poor setting (Nigeria): Efficacy and safety in a phase II feasibility study.

e11554 Background: The majority of clinical trials of neoadjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open label multicenter clinical trial designed to evaluate the efficacy, safety and tolerability of neoadjuvant capecitabine in locally advanced breast cancer. Methods: Planned treatment consisted of 24 weeks of capecitabine at a dose of 1000mg/m2 twice daily (2000mg/m2 total per day). Each cycle consisted of a 14-day period of therapy followed by a 7-day pause, and patients were evaluated after 3 cycles and taken off study if no response was documented. Responding patients were treated for no more than 8 cycles. The primary endpoints were partial, complete clinical response and pathologic complete response. Results: A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first 3 cycles of therapy, partial clinical responses were seen in 5 of 16 patients (31%; 95% CI 11% - 59%). Of the remaining 11 patients, 8 had no response or stable disease, and 3 had progressive disease. Seven pateints proceeded with further therapy, two of them with stable disease but exactly in the border line of 25% increase. By physical examination, only 2 of the 6 patients had a documented complete clinical response, while by ultrasonomammography, partial responses were observed in 5 patients. Thus, overall response rate at the end of 8 cycles were 31.1% both by clinical examination and by ultrasonomammography. Clinical response by physical examination and radiologic response by ultrasonomammography were highly concordant (the spearman correlation between the two ratios was 0.70). The most common adverse effect was Grade 1 Hand and Foot Syndrome in 75% of patients. Conclusions: Despite several limitations, we successfully carried out this phase II feasibility study of neoadjuvant capecitabine for locally advanced breast cancer in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

Combination of Amlodipine plus Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensive Patients

Antihypertensive therapy is effective in reducing the risk of major adverse cardiovascular events. However, blood pressure (BP) control rate remains poor and the optimal combination therapy against hypertension is not established in China. The objective of this study was to evaluate the long-term efficacy and safety of two antihypertensive regimens, amlodipine plus telmisartan and amlodipine plus amiloride/hydrochlorothiazide, in patients with essential hypertension and at least one cardiovascular risk factor. In a multicenter open-label clinical trial, eligible patients were randomized to receive treatment with amlodipine 2.5-5 mg plus amiloride/hydrochlorothiazide 1.25-2.5 mg/12.5-25 mg (Group A) or amlodipine 2.5-5 mg plus telmisartan 40-80 mg (Group T). If a target BP was not reached, other antihypertensive agents would be added. The target BP was <130/80 mmHg for patients with diabetes mellitus or chronic kidney disease and <140/90 mmHg for others. Efficacy variables were changes from baseline in systolic BP and diastolic BP at the endpoint of 96 weeks. Safety evaluations included monitoring of any adverse events (AEs). Of 13,542 patients randomized, 13,080 (96.6%) completed the study: 6529 in Group A and 6551 in Group T. At endpoint, the BP levels were reduced by 27.4/14.3 mmHg in Group A and 27.1/14.5 mmHg in Group T. The BP control rates were similar for the two therapeutic regimens (87.5% vs 86.1%). Less than 4% of patients in each group discontinued their drugs during follow-up. Peripheral edema was one of the most common AEs, and occurred in only 24 patients in Group A and 19 in Group T. Long-term combination therapy with amlodipine plus telmisartan or amlodipine plus amiloride/hydrochlorothiazide was not only well tolerated but also efficacious in reducing BP levels with acceptable control rates in the majority of hypertensive patients. ClinicalTrials.gov number NCT01011660.

New Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines for Advanced Non–Small Cell Lung Cancer: Comparison With Original RECIST and Impact on Assessment of Tumor Response to Targeted Therapy

The purpose of this article is to compare the recently published revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) to the original guidelines (RECIST 1.0) for advanced non-small cell lung cancer (NSCLC) after erlotinib therapy and to evaluate the impact of the new CT tumor measurement guideline on response assessment. Forty-three chemotherapy-naive patients with advanced NSCLC treated with erlotinib in a single-arm phase 2 multicenter open-label clinical trial were retrospectively studied. CT tumor measurement records using RECIST 1.0 that were generated as part of the prospective clinical trial were reviewed. A second set of CT tumor measurements was generated from the records to meet RECIST 1.1 guidelines. The number of target lesions, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0. The number of target lesions according to RECIST 1.1 decreased in 22 patients (51%) and did not change in 21 patients (49%) compared with the number according to RECIST 1.0 (p < 0.0001, paired Student's t test). Almost perfect agreement was observed between best responses using RECIST 1.1 and RECIST 1.0 (weighted kappa = 0.905). Two patients with stable disease according to RECIST 1.0 had progressive disease according to RECIST 1.1 criteria because of new lesions found on PET/CT. There was no significant difference in time to progression between RECIST 1.1 and RECIST 1.0 (p = 1.000, sign test). RECIST 1.1 provided almost perfect agreement in response assessment after erlotinib therapy compared with RECIST 1.0. Assessment with PET/CT was a major factor that influenced the difference in best response assessment between RECIST 1.1 and RECIST 1.0.

Evaluation of Open-Label Topiramate as Primary or Adjunctive Therapy in Infantile Spasms

A multicenter open-label clinical trial was conducted to evaluate the clinical usefulness of topiramate (TPM) as primary or adjunctive therapy for infantile spasms in the postmarketing period in China. Thirty-four centers participated in the trial. Patients included in the study had 1 or more seizures per day before treatment. One hundred twenty (22.1%) very young patients with an age younger than 6 month and 64.2% of patients were younger than 1 year at start of treatment. All patients received a starting dose of 0.5 to 1 mg kg d TPM twice daily. The dosage was increased by 0.5 to 1 mg kg d every 5 to 7 days up to 3 to 5 mg kg d. The resulting range of the total TPM dosage was 25 to 200 mg d (3.57-20 mg kg d), with a median value of 73.9 mg d. Seizure outcomes were measured by intention-to-treat analysis. Patients were seen by a neurologist, and their data were evaluated at the day of inclusion and after 4, 8, 12, 16, and 20 weeks (from visit 1 to visit 5) of treatment. Five hundred forty-four patients entered the study. After 20 weeks of TPM treatment, 239 patients (43.9%) were seizure-free. A higher proportion of patients in the monotherapy group than in the add-on therapy group showed a seizure rate reduction. An increase in seizure frequency was observed in 8 patients (1.5%) during the 20-week treatment period. Nineteen patients were withdrawn before completing the study, and in 46 cases, some data of the structured data files and questionnaires were missing. No efficacy of TPM treatment was recorded in these cases. Adverse effects occurred in 211 patients (38.8%). Most frequent side effects were anorexia and somnolence. Topiramate proved to be an effective and safe monotherapy and add-on therapy in patients with infantile spasms younger than 1 year.

Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial

This multicenter clinical trial was performed to evaluate the efficacy and safety of mizoribine for the treatment of Sjögren's syndrome. Fifty-nine patients with a definite diagnosis of Sjögren's syndrome received 150;Smg of mizoribine daily for 16 weeks. The salivary secretion volume was determined at baseline, at weeks 8 and 16 after the start of the study treatment by the Saxon test, and clinical manifestations were assessed by the investigator and the patients using a 10-cm visual analog scale (VAS). Adverse drug reactions were reported in 18 patients, of whom 6 patients had to discontinue the study due to such adverse reactions; however, no serious adverse drug reactions definitely related to the study drug were noted. The salivary secretion volume, the rate of change in salivary secretion, the patients' own assessments of dry mouth and dry eyes, the investigators' assessment of oral sicca symptoms, and the investigators' overall assessment improved following the treatment regimen with statistical significance at week 16 after the start of treatment in comparison to the baseline values. These results suggested that mizoribine may be effective in producing a subjective and objective amelioration of the glandular symptoms in patients with Sjögren's syndrome, without observing any serious adverse effects related to this drug.

Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial

This multicenter clinical trial was performed to evaluate the efficacy and safety of mizoribine for the treatment of Sjögren's syndrome. Fifty-nine patients with a definite diagnosis of Sjögren's syndrome received 150^Smg of mizoribine daily for 16 weeks. The salivary secretion volume was determined at baseline, at weeks 8 and 16 after the start of the study treatment by the Saxon test, and clinical manifestations were assessed by the investigator and the patients using a 10-cm visual analog scale (VAS). Adverse drug reactions were reported in 18 patients, of whom 6 patients had to discontinue the study due to such adverse reactions; however, no serious adverse drug reactions definitely related to the study drug were noted. The salivary secretion volume, the rate of change in salivary secretion, the patients’ own assessments of dry mouth and dry eyes, the investigators’ assessment of oral sicca symptoms, and the investigators’ overall assessment improved following the treatment regimen with statistical significance at week 16 after the start of treatment in comparison to the baseline values. These results suggested that mizoribine may be effective in producing a subjective and objective amelioration of the glandular symptoms in patients with Sjögren's syndrome, without observing any serious adverse effects related to this drug.

Early vs Standard Intervention with an Extended Epoetin alfa (EPO) Dose Regimen of 120,000 Units (U) Every 3 Weeks (Q3W) in Chemotherapy (CT)-Induced Anemia: Results for Elderly vs. Younger Patients in a Randomized Clinical Trial.

A recently completed randomized open-label multicenter clinical trial in cancer pts with CT-induced anemia showed that an extended dose regimen of EPO 120,000 U administered subcutaneously Q3W effectively maintained hemoglobin (Hb) levels within the range of 11–13 g/dL whether initiated early (Hb of ≥11 and ≤12 g/dL) or at a standard threshold (Hb<11 g/dL)1. As elderly pts are particularly sensitive to the effects of anemia related to CT, we postulated whether this group had outcomes (Hb response, transfusion use, and safety) similar to younger patients following treatment with Q3W EPO. 136 pts with non-myeloid malignancy, CT planned for ≥9 wks, and baseline (BL) Hb ≥11 and ≤12 g/dL were randomized either to early intervention with immediate EPO or to standard intervention with EPO when Hb decreased to <11 g/dL. Drug was held for Hb>13 g/dL and dose reduced for Hb>12 g/dL or increase >1.5 g/dL in any 3-wk period (current labeling recommends Hb not to exceed 12 g/dL). If, at any dosing visit after the 1st EPO dose, Hb decreased to <10.0 g/dL, pts were switched to EPO 40,000 U weekly. The primary efficacy endpoint was Percent Values in Range (PVR; the proportion of weekly Hb levels that were ≥11 and ≤13 g/dL). Reported here is a retrospective subset analysis comparing key efficacy and safety results for elderly (≥65 yrs) vs. younger (<65 yrs) pts enrolled in the prospective study. 62 elderly pts (mITT population; 29 early, 33 standard) and 73 younger pts (mITT; 39 early, 34 standard) were randomized to a treatment group and had ≥1 Hb value. Mean BL Hb was 11.5 g/dL in each of the 4 subgroups. The most common tumor sites were colorectal [elderly early intervention group (n=7, 24%)] and breast [elderly standard intervention group (n=11, 32%)], younger early (n=13, 33%), and younger standard intervention (n=18, 53%). Key efficacy and safety results are shown in the table. Clinically relevant thrombotic vascular events (CRTVEs) included a deep vein thrombosis (DVT) in the elderly early group; 1 DVT and 1 pulmonary embolism (PE) in the elderly standard group; 1 pulmonary artery thrombosis, 2 DVTs, 1 PE, 1 thrombosis NOS, and 1 jugular vein thrombosis among 5 pts in the younger early group; and 2 DVTs, 2 PEs, and 1 thrombosis NOS among 4 pts in the younger standard group. The 4 deaths were attributed to the following causes: acute respiratory failure/progression of COPD (eldery early pt), worsening metastatic gastric cancer/hemorrhage brain metastasis (younger early pt), and lower GI bleed and cardiopulmonary arrest, each in 1 younger standard pt. EPO 120,000 U Q3W initiated early or at a standard threshold resulted in similar efficacy and safety outcomes in elderly vs. younger subsets of cancer pts with CT-induced anemia. 1ASCO 2007 Annual Mtg, Abstract 19564.≥65 Yrs<65 YrsEarly, n=29Standard, n=33Early, n=39Standard, n=34Mean Age ± SD (yrs)71.8±5.773.7±4.852.1±9.748.7±11.1Mean PVR (95% CI)59.8(49.1,70.5)56.8(45.6,68.0)60.0(50.3,69.7)63.1(54.0,72.2)PRBC Transfusion After 4 Wks of EPO, n(%)2(6.9)3(12.0) [of 25 treated pts]4(10.3)1(3.8) [of 26 treated pts]Dose Reduction, n(%)12(41)6(18)17(44)7(21)Dose Withhold, n(%)10(34)4(12)16(41)7(21)CRTVE Pts, n(%)1(3)2(6)5(13)4(12)Death, n(%)1(3)01(3)2(6)PVR, percent values in range; CRTVE, clinically relevant thrombotic vascular event.

High doses of pergolide improve clinical global impression in advanced Parkinson's disease—A preliminary open label study

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate to severe Parkinson's disease (PD) in an open-label multicenter clinical trial. The primary objective was to assess the amount of reduction in levodopa, the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of 12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a maximum of 12 mg/day in combination with a simultaneous decrease of levodopa doses in 100 mg steps. Levodopa was reduced from 500 mg/day (median) to 250 mg/day. Mean UPDRS part III improved significantly ( p = 0.01). Clinical global impression improved significantly after 24 weeks ( p < 0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal pain, and peripheral edema. Twenty-two patients finished the complete study according to protocol. A possible relationship to the study medication was assumed for two serious adverse events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced stages of PD if given in appropriate regimens.