Open-label Feasibility Study Research Articles

Parkinson’s Disease: New Insights into Pathophysiology and Rehabilitative Approaches

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, but up till now, its etiology remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. PD prevalence increases steadily with age. Therefore, with the aging population, we will see an increase in social and health impact of this disease. Currently, the drugs available improve physical performances and lengthen life expectancy and autonomy in the activities of daily living by reducing adverse events; it follows that they improve the quality of life of patients. However, these drugs are symptomatic and not curative. When the patient reaches the maximum allowable therapeutic dosage of levodopa, we have to face great difficulties and impotence in disease's management. Recently, the role of rehabilitation in the field of neurodegenerative diseases is becoming more and more important as it results from several studies. In this special issue, we wanted to focus our attention on the “holistic view” of the disease because we believe that only a multidisciplinary approach could help to face it in the best way. PD involves miscellaneous systems (physical, mental, and behavioral structures) affecting also the autonomy in self-care management. Furthermore, in this special issue we wanted to draw the attention to the importance of rehabilitation in PD. An amount of epidemiological evidence stressed the importance of the relationships between genetic and environmental factors. L. Polito et al. summarize evidence on gene-environment interplay in the development of PD focusing on susceptibility factors and causal genetic mutation. To the best of our knowledge, this review is the first attempt to analyze all those genetic factors that modify the impact of environmental exposure. Brilliantly, F. Magrinelli et al. contributed to examining the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD, with particular attention to those clinical features that impair quality of life and functional ability of patients. Starting from anatomic basis of the main circuit involved in PD, subsequently they analyzed the pathophysiology of PD motor symptoms (bradykinesia and tremor rigidity) and signs (postural balance, gait impairment, fatigue, and pain). Currently, pharmacological treatment of motor symptoms of PD depends mainly on the administration of dopaminergic drugs (levodopa and dopamine agonists) and other drugs involved in levodopa metabolism (monoamine oxidase-B inhibitors and catechol-O-methyltransferase inhibitors). Usually, in the late disease stages, PD patients treated by dopaminergic drugs display various complications, such as on-off fluctuations of Parkinsonian symptoms and dyskinesia. Unfortunately, most patients with advanced PD are unsatisfactorily controlled by the usual therapeutic approach. A. Daniele et al. examine other pharmacological targets regardless of the dopaminergic pathway. In particular, they focus on potential beneficial effects of zolpidem, a positive allosteric modulator of GABAA receptors, on the motor symptoms of PD. In fact, some studies have previously suggested that there is a high density of zolpidem binding sites in the globus pallidus and in the substantia nigra, which are the output structures of the basal ganglia. Two experimental works complete this brief special issue. The first is a case control study carried out by M. Tramontano et al. with the aim of investigating the efficacy of a blindfolded balance training in the improvement of gait parameters in people with PD compared to patients who underwent a standard physical therapy program. The second is a prospective open-label feasibility study evaluating the impact of 8-week action observation training (video-therapy) for the treatment of postural instability and balance impairment in PD patients. Although in this latter study A. Santamato et al. did not find positive results, they underline one of the most important shortcomings in PD rehabilitation field. In fact, absence of standard procedures to improve balance and posture in PD subjects makes this area a virgin field to explore. We hope that the contents of this special issue may help clinicians better understand the rationale of current pharmacological and rehabilitation strategies for PD and give viability to further studies that integrate current knowledge with innovations in the field of rehabilitation. Vincenza Frisardi Andrea Santamato Binith Cheeran

Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis.

There are few treatment options for symptomatic knee osteoarthritis (OA). Human amniotic suspension allografts (ASA) have anti-inflammatory and chondroregenerative potential and thus represent a promising treatment strategy. In anticipation of a large, placebo-controlled trial of intra-articular ASA for symptomatic knee OA, an open-label prospective feasibility study was performed. Six patients with Kellgren-Lawrence grades 3 and 4 tibiofemoral knee OA were administered a single intra-articular ASA injection containing cryopreserved particulated human amnion and amniotic fluid cells. Patients were followed for 12 months after treatment. No significant injection reactions were noted. Compared with baseline there were (1) no significant effect of the ASA injection on blood cell counts, lymphocyte subsets, or inflammatory markers and (2) a small, but statistically significant increase in serum IgG and IgE levels. Patient-reported outcomes including International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome, and Single Assessment Numeric Evaluation scores were collected throughout the study and evaluated for up to 12 months. Overall, this study demonstrates the feasibility of a single intra-articular injection of ASA for the treatment of knee OA and provides the foundation for a large placebo-controlled trial of intra-articular ASA for symptomatic knee OA.

A Phase 4, Pilot, Open-Label Study of VIVITROL® (Extended-Release Naltrexone XR-NTX) for Prisoners

This was a Phase 4, pilot, open-label feasibility study of extended-release injectable naltrexone (XR-NTX) administered to pre-release prisoners having a history of pre-incarceration opioid disorder. We evaluated the relationship between XR-NTX adherence and criminal recidivism (re-arrest and re-incarceration) and opioid and cocaine use. Twenty-seven pre-release male and female prisoners who had opioid disorders during the year prior to index incarceration were recruited and received one XR-NTX injection once each month for 7months (1 injection pre-release from prison and 6 injections in the community) and of those 27, 10 (37%) were retained in treatment at 7-months post release. Results indicate those completing 6 compared to those completing <6 injections were less likely to test positive for opioids in the community (0% vs. 62.5%, respectively; p=0.003). Although not statistically significant, individuals who did not complete all 6 injections were more likely to be re-arrested compared to those completing all 6 community injections (31.3% vs. 0%, respectively; p=0.123). Contingent upon further study of a randomized controlled trial, XR-NTX may be a feasible option in the prison setting in view of the lack of potential for diversion. Furthermore, these data suggest that completing the entire course of treatment (6 injections) may reduce opioid use and, to a lesser degree, re-arrest and re-incarceration.

Chronic Low Back Pain: Restoration of Dynamic Stability.

Electrical stimulation for multifidus muscle contraction is a novel approach for treating chronic low back pain (CLBP). A multicenter, open-label feasibility study investigated this modality in patients with continuing CLBP despite medical management and no prior back surgery and no known pathological cause of CLBP. Twenty-six patients with continuing CLBP despite physical therapy and medication were implanted with commercially-available implantable pulse generators and leads positioned adjacent to the medial branch of the dorsal ramus as it crosses the L3 transverse process such that electrical stimulation resulted in contraction of the lumbar multifidus (LM) muscle. Patients self-administered stimulation twice daily for 20 min. Low back pain (VAS), Oswestry Disability Index (ODI) and Quality of Life (EQ-5D) scores were collected at three and five months and compared to baseline. Stimulation was withdrawn between months 4 and 5 to test durability of effect. At three months, 74% of patients met or exceeded the minimally important change (MIC) in VAS and 63% for disability. QoL improved in 84% of patients (N = 19) and none got worse. Five of the 11 patients on disability for CLBP (45%) resumed work by three months. Half the patients reported ≥50% VAS reduction by month 5. Twenty-one lead migration events occurred in 13 patients, of which 7 patients are included in the efficacy cohort. Episodic stimulation to induce LM contraction can reduce CLBP and disability, improve quality of life and enable return to work. A dedicated lead design to reduce risk of migration is required.

Postural and Balance Disorders in Patients with Parkinson's Disease: A Prospective Open-Label Feasibility Study with Two Months of Action Observation Treatment.

Action observation treatment has been proposed as therapeutic option in rehabilitation of patients affected by Parkinson's disease (PD) to improve freezing of gait episodes. The purpose of this prospective open-label feasibility study was to evaluate the impact of 8-week action observation training (video-therapy) for the treatment of postural instability and balance impairment in PD patients. Fifteen PD patients aged under 80 years with scores of 1 to 3 on the Hoehn and Yahr staging and without evidence of freezing of gait were recruited. They underwent 24 sessions of video-therapy training based on carefully watching video clips on motor tasks linked to balance, subsequently performing the same observed movements. No statistically significant differences were observed in the identified outcome measures with the Berg Balance Scale and the Activities-Specific Balance Confidence Scale after two months of follow-up. In the present study, a short course of action observation treatment seems to be not effective in reducing balance impairments and postural instability in patients affected by mild to moderate PD. Further studies with larger samples, longer follow-up period, and standardized protocols of action observation treatment are needed to investigate the effects of this rehabilitation technique in the management of postural and balance disorders of PD patients.

Novel Sodium Hypochlorite Cleanser Shows Clinical Response and Excellent Acceptability in the Treatment of Atopic Dermatitis

The intermittent use of dilute sodium hypochlorite “bleach baths” has shown efficacy as adjunctive therapy for atopic dermatitis (AD). This feasibility study evaluated the clinical response and patient acceptability of treatment with a cleansing body wash containing sodium hypochlorite in children with AD. This was a 12-week open-label feasibility study of 18 children with AD conducted in a pediatric dermatology outpatient clinic between May 2011 and July 2012. Children with moderate to severe AD, defined as an Investigator Global Assessment (IGA) score of at least 3 on a 5-point scale, who were age 6 months and older and had lesional cultures positive for Staphylococcus aureus at baseline were included. Patients were instructed to wash 3 days/week for 12 weeks with the sodium hypochlorite–containing cleansing body wash. During the study period, patient's individualized topical and systemic treatment regimens were continued. Clinical response to treatment was measured using an IGA score and the percentage of body surface area (BSA) affected. Parents were also administered a retrospective questionnaire evaluating acceptability of the product. There was a statistically significant reduction in IGA score at all time points, with an overall mean reduction from baseline to final measurement using the last observation carried forward in all patients of 1.0 (p = 0.001, n = 18). Similarly the mean reduction of BSA affected was 14.8% (p = 0.005, n = 18). Parents reported that the body wash was significantly easier to use than traditional bleach baths (p < 0.001). The significant reductions in clinical disease severity scores with use of this formulation are encouraging.

Developing Patient-Centered Treatment Protocols in Brain Stimulation

This article reports and discusses how quantitative (physiological and behavioral) and qualitative methods are being combined in an open-label pilot feasibility study. The study evaluates safety, tolerability, and acceptability of a protocol to treat depression in HIV-infected individuals, using a 2-week block of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex. Major depressive disorder (MDD) is the second most prevalent psychiatric disorder after substance abuse among HIV-positive adults, and novel antidepressant treatments are needed for this vulnerable population. The authors describe the challenges and contributions derived from different research perspectives and methodological approaches and provide a philosophical framework for combining quantitative and qualitative measurements for a fuller examination of the disorder. Four methodological points are presented: (1) the value of combining quantitative and qualitative approaches; (2) the need for context-specific measures when studying patients with medical and psychiatric comorbidities; (3) the importance of research designs that integrate physiological, behavioral, and qualitative approaches when evaluating novel treatments; and (4) the need to explore the relationships between biomarkers, clinical symptom assessments, patient self-evaluations, and patient experiences when developing new, patient-centered protocols. The authors conclude that the complexity of studying novel treatments in complex and new patient populations requires complex research designs to capture the richness of data that inform translational research.

Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group

Introduction:Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.Methods:This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m–2 plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.Results:Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m–2 plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m–2 plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.Conclusion:Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.

Open-label, Dose-escalation Study of L-glucose as a Bowel Preparation Before Colonoscopy

Purpose: To evaluate the safety, tolerance, and efficacy of three dosing strategies of L-glucose, a non-nutritive enantiomer of D-glucose (Raymer, et al. 2003), as a bowel cleanser prior to colonoscopy. Methods: Men and nonpregnant women over the age of 50 scheduled to undergo routine outpatient colonoscopy were eligible. Exclusion criteria included liver disease, CHF, and creatinine > 1.5 mg/dL. Study enrollment was designed to proceed sequentially in 3 escalating split-dosing cohorts of 24 subjects each (12M, 12F), with the lowest dose enrolling first: 24 g X 24 g, 36 g X 36 g, 48 g X 48 g. Subjects were admitted to one of two Phase I certified study facilities. All subjects drank clear liquids during the entire day before exam. L-glucose was administered as two 8-oz (236 mL) doses, one at 6 pm the evening before colonoscopy and one between 3-4 hours before exam. Bowel cleansing was rated using a global and segmental scoring system. Laboratory parameters were tested at screening, immediately before dosing, 2 hours after the second dose, and on the day following exam. Side effects were recorded by study personnel. Interim analyses of safety and efficacy were used to determine whether to enroll in the highest dosing cohort; if a target success rate of 21/24 Excellent (E) + Good (G) preps was not achieved in the lowest dosing groups, enrollment in the 48 g X 48 g cohort would proceed. Results: 72 subjects (24 in each cohort; 36M, 36F) were enrolled and completed the protocol. The cohorts were similar in age, ethnicity, and BMI. Bowel preparation success (E + G) was achieved in 19/24 (24 g), 21/24 (36 g), and 23/24 (48 g) subjects [see Table]. A dose-response relationship was observed for mean number of bowel movements: 7.6 ± 2.6 (24 g), 10.6 ± 3.9 (36 g), and 11.5 ± 5.5 (48 g). Tolerance to the bowel preparation process was rated “Good” or “Very Good” in 91.7% (24 g), 75.0% (36 g), and 87.5% (48 g). Side effects were reported as mild or moderate in all groups. Vomiting occurred in 2/24 (8.73%) 24 g subjects and 0/48 36 g and 48 g subjects. Taste was rated “Very Pleasant” or “Somewhat Pleasant” in 20/24 (24 g), 19/24 (36 g), and 20/24 (48 g) subjects. No adverse trends were observed in vital signs, routine hematology, serum chemistry, urinalysis, or liver function tests following treatment in each cohort. 70/72 (97.2%) subjects reported a willingness to take the preparation for a future exam.Table: Bowel preparation effectivenessConclusion: In this open-label feasibility study, L-glucose produced superior bowel cleansing in a split-dose of 48 g X 48 g with excellent tolerance and no significant adverse effects. Disclosure: Dr Balaban - Consultant, Fleet Laboratories Dr Thompson - Consultant, Fleet Laboratories. This research was supported by an industry grant from Fleet Laboratories.

The post-infarction nurse practitioner project: A prospective study comparing nurse intervention with conventional care in a non-high-risk myocardial infarction population.

To confirm the feasibility of nurse practitioner interventionin non-high-risk patients with recent myocardial infarction (MI). Observational study. Acute coronary care unit in a teaching hospital. We performed an open-label feasibility study to identify non-high-risk MI patients and evaluate the outcome of a new nurse practitioner intervention programme. The initial pilot phase served to identify the non-high-risk population. In the subsequent confirmation phase, 500 consecutive non-high-risk post-MI patients with preserved LV function without heart failure were included to receive nurse practitioner management. The nurse practitioner intervention started on transfer from the coronary care unit to the cardiology ward and continued thereafter for up to 30 days. Time to first event analysis of death from all causes or repeat myocardial infarction. 500 Patients without signs of heart failure or depressed LV function were identified as nonhigh- risk and eligible for inclusion in the nurse practitioner intervention programme. In the implementation phase, none of the patients died and 0.9% developed a repeat myocardial infarction after 30 days of follow-up. Compared with the pilot phase, patients in the implementation phase spent fewer days in hospital (mean 11.1 versus 6.2 days; p<0.001). It is feasible to identify non-high-risk post-MI patients, who can be managed adequately by a nurse practitioner. Embedding experienced nurse practitioners within critical care pathways may result in significant decreases in length of hospital stay. (Neth Heart J 2009;17:61-7.Neth Heart J 2009;17:61-7.).

Broad-Spectrum Antifungal Prophylaxis in Patients With Cancer at High Risk for Invasive Mold Infections: Point

Invasive fungal infections (IFIs) are a leading cause of infection-related mortality in patients with acute leukemia and prolonged neutropenia and in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). Although invasive candidiasis was the principal IFI predating fluconazole prophylaxis, invasive aspergillosis and other mold infections now cause most deaths from fungal infection in this patient population. The availability of broad-spectrum antifungal agents that can be safely administered over prolonged periods has stimulated interest in using mold-active prophylactic agents early as prophylaxis rather than later as therapy for suspected or documented IFIs. Two recent, prospective, randomized trials have shown a clear benefit of posaconazole prophylaxis in patients with myelodysplastic syndrome and acute mye-logenous leukemia with prolonged neutropenia and in allogeneic HSCT recipients with severe GVHD. In contrast, the peer-reviewed published database on the strategy of preemptive antifungal therapy, in which yeast-active prophylaxis (fluconazole) or no antifungal prophylaxis is used initially and modifications are triggered by a combination of laboratory markers and chest CT scans, is currently limited to an open-label feasibility study. Does sufficient evidence currently exist that the net benefit of the preemptive approach is at least on a par with posaconazole prophylaxis in the specific patient groups that were studied? The authors believe not and that more research is needed before the preemptive strategy can be recommended.

High-dose Bosentan in the Prevention and Treatment of Subarachnoid Hemorrhage-induced Cerebral Vasospasm: An Open-label Feasibility Study

To evaluate the safety of high-dosages of the endothelin ET(A/B )receptor antagonist bosentan in SAH patients at high-vasospasm risk. Ten Fisher group-3 SAH patients, enrolled within 96 h of ictus, received bosentan in a dose-escalation manner (20, 30, 40 mg/kg/day orally every 4 hours on treatment days 1, 2, and 3 respectively, to a maximum dose of 4000 mg/day), followed by maintenance of the maximum tolerated dose until 14 days post-SAH or vasospasm resolution. Further management followed standard protocols: nimodipine in all patients; daily transcranial Doppler (TCD); "triple-H"/endovascular treatment, as indicated. Two of the ten patients never developed any clinical or TCD signs of vasospasm; the other eight patients exhibited some elevation of TCD velocities during the vasospasm watch period. Four of the eight patients remained asymptomatic; of them, one had only mild elevation on peak systolic velocities, thought to represent hyperemia. The other three were further assessed with CT-angiography; this revealed moderate vasospasm (asymptomatic) in only one patient. The remaining four patients developed symptomatic vasospasm requiring endovascular treatment; two developed cerebral infarction; both had started bosentan relatively later than the other subjects. The most common adverse drug effects were flushing and transient liver enzyme elevations, reversible in all. Two patients had ALT/AST elevations >3x normal limit, requiring bosentan-dose reduction or discontinuation (one case each). High-dose bosentan (up to 40 mg/kg/day) appears to be safe in SAH patients at high risk of developing vasospasm. Further studies are required to properly investigate the efficacy of this regimen in the prevention and treatment of SAH-induced vasospasm.

Sublingual Methadone for the Management of Cancer-Related Breakthrough Pain: A Pilot Study

Breakthrough pain is a highly prevalent and difficult to manage cancer pain problem. Current strategies are frequently ineffective, in part because of a mismatch between the sudden onset and brief duration of breakthrough pain and the slower onset and more prolonged duration of oral immediate-release opioids. Novel analgesic interventions are needed to provide a closer match between the temporal profile of the pain and the pharmacodynamics of the pain medication, and novel models of study of breakthrough pain are needed to evaluate them. This is an open-label feasibility study of a model to evaluate sublingual methadone for cancer-related breakthrough pain. The model has three phases: screening, upward titration, and optimal dose evaluation. Seven patients with breakthrough pain because of cancer entered the upward titration phase of the trial, and 61 episodes of breakthrough pain were evaluated with sublingual methadone at escalating doses ranging from 2-18 mg. Toxicity was generally mild and similar to patients' prior breakthrough medication. Four patients entered the optimal dose evaluation phase, and 39 discrete episodes of breakthrough pain were available for evaluation. Significant relief of pain occurred with a median onset of 5 minutes, and no serious adverse events were encountered. This model of assessment of breakthrough pain, whereby each episode of pain is treated as a separate data set and multiple discrete episodes of breakthrough pain are assessed every 5 minutes in each patient, appears to be feasible within the cancer pain population. Preliminary results suggest a very rapid onset of relief of breakthrough pain with sublingual methadone when administered at the optimal dose, consistent with a highly favorable early pharmacodynamic profile of methadone administered via this route. Further study is warranted.

Intermittent leuprolide acetate for the nonsurgical management of women with leiomyomata uteri

Objective: To evaluate the feasibility of intermittent 6-month courses of leuprolide acetate for the long-term control of symptoms attributed to leiomyomata uteri. Design: Prospective open-label feasibility study. Setting: University department of obstetrics and gynecology. Patient(s): Thirty women with abnormal bleeding or discomfort (pain or pressure) due to leiomyomata uteri. Intervention(s): Patients received an initial 6-month course of the GnRH agonist leuprolide acetate, after which they were observed for symptom recurrence. Symptom recurrence was managed by repeated 6-month courses of leuprolide acetate. Main Outcome Measure(s): Relief of symptoms, responses on a quality-of-life questionnaire, serum lipid levels, blood count, and ferritin level. The number of doses of leuprolide acetate required to maintain symptom control was recorded. Serial bone mineral density measurements were made in selected patients. Result(s): Twenty of the 30 women who began therapy with leuprolide acetate continued in the protocol. Each individual 6-month course of leuprolide acetate therapy was followed by a median of 9 additional months of symptom control (range, 2 to >25 months). Women remaining in the protocol experienced a mean decrease of 2.4% in bone mineral density of the lumbar spine; bone mineral density of the hip did not change. Conclusion(s): Intermittent courses of leuprolide acetate can be used in the nonsurgical management of women with symptomatic leiomyomata uteri. Use of antiresorptive add-back therapy and monitoring of bone mineral density can be considered when repeated courses of leuprolide acetate are given.