Claudia Ose

A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder

Introduction Attention-deficit/hyperactivity disorder (ADHD) affects many adults who had ADHD in childhood. Although stimulants and methylphenidate in particular are a common off-label treatment for adult patients with ADHD in European countries, little is known about their long-term efficacy and safety.

Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD

Abstract Objectives. Treatment investigations with methylphenidate in adults with ADHD focus preferentially on the classical psychopathology: inattention, hyperactivity and impulsivity. ADHD-associated emotional symptoms, which are frequently present at least in ADHD subpopulations, were studied rarely. The vast majority of the placebo-controlled trials had observation periods between 4 and 8 weeks. To assess the medium- to long-term effects of extended release methylphenidate (MPH-ER) on emotional symptoms and other psychopathology frequently seen in ADHD patients, we conducted a large-scale, multicenter treatment study. Methods. We performed a randomised, 24-week, double-blind, placebo-controlled study in adults with ADHD. The diagnosis was made on the basis of the DSM-IV criteria, which were confirmed by clinical history and a structured psychopathological interview and the use of rating instruments. 363 patients were randomized to MPH-ER or placebo at a ratio of 2:1. The duration of the titration period was 5 weeks followed by a maintainance phase of 19 weeks. The efficacy measures were the observer rated 10-item Emotional Dysregulation Scale (EDS) derived from the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) and a self-report, six-item Emotional Lability Scale (ELS) extracted from the long version of the Conners Adult ADHD Self Report Scale (CAARS:S:L). In addition we used the SCL-90-R for the assessment of ADHD associated and comorbid psychopathology. Results. MPH-ER was statistically superior to placebo in reducing emotional symptoms as assessed by the EDS and the ELS. Obsessive-compulsive symptoms and those of problems with self-concept declined until the end of the observation period. The decline was more pronounced in MPH-ER treated individuals. The effects remained robust during the entire maintenance period until week 24. Symptoms of anxiety, depression, anger and hostility, phobia, paranoid ideations and psychoticism were not improved. Conclusions. MPH-ER appears to be an efficacious treatment for emotional symptoms with ADHD. Also obsessive-compulsive symptoms and problems with self-concept were affected positively.

Multiscale assessment of treatment efficacy in adults with ADHD: A randomized placebo-controlled, multi-centre study with extended-release methylphenidate

Abstract Objectives. This trial was performed to test the efficacy and safety of an extended-release formulation of methylphenidate (MPH ER). Methods. A total of 162 adults with ADHD according to DSM-IV were treated for 8 weeks with either two daily individually body weight-adjusted doses of MPH ER up to 1 mg/kg per day (N = 84) or placebo (N = 78). The primary efficacy outcome was the Wender–Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 8 weeks after randomization. Secondary efficacy measures were the ADHD Diagnostic Checklist (ADHD-DC), the Conners Adult Attention Deficit Disorder Scale (CAARS-S:L), the Clinical Global Impression (CGI) and the Sheehan Disability Scale (SDS). Results. At week 8 a significantly higher decline of the total WRAADDS score was found in the MPH ER group as compared to the placebo group (P = 0.0003). The rates of responders were 50% in the MPH ER and 18% in the placebo group (P < 0.0001). Furthermore, similar effects were observed for the secondary efficacy variable: ADHD-DC score (P = 0.004), CAARS-S:L score (P = 0.008) and the SDS score (P = 0.017). 50% of the MPH ER group and 24.4% of the placebo group were improved “much” or “very much” according to the CGI rating (P = 0.0001). MPH ER treatment was well tolerated. At week 2 also the mean heart rate was significantly higher in the MPH ER group as compared to the placebo group (P = 0.01). No differences between the study groups were observed regarding mean blood pressure at any visit. Conclusions. This clinical trial demonstrated statistically significant and clinical relevant effects of MPH ER in adults with ADHD for several self- and investigator-rated ADHD psychopathology and also functional efficacy measures.

Randomized comparison of synchronous CABG and carotid endarterectomy vs. isolated CABG in patients with asymptomatic carotid stenosis: the CABACS trial.

Rationale High-grade carotid artery stenosis is present in 6–8% of patients undergoing coronary artery bypass graft surgery. Many cardiovascular surgeons advocate staged or synchronous carotid endarterectomy to reduce the high perioperative and long-term risk of stroke associated with multivessel disease. However, no randomized trial has assessed whether a combined synchronous or staged carotid endarterectomy confers any benefit compared with isolated coronary artery bypass grafting in these patients. Aims The objective of this study is to compare the safety and efficacy of isolated coronary artery bypass grafting vs. synchronous coronary artery bypass grafting and carotid endarterectomy in patients with asymptomatic high-grade carotid artery stenosis. Design Coronary Artery Bypass graft surgery in patients with Asymptomatic Carotid Stenosis (CABACS) is a randomized, controlled, open, multicenter, group sequential trial with two parallel arms and outcome adjudication by blinded observers. Patients with asymptomatic high-grade carotid stenosis scheduled for elective coronary artery bypass grafting will be assigned to either isolated coronary artery bypass grafting or synchronous coronary artery bypass grafting and carotid endarterectomy by 1 : 1 block-stratified randomization with three different stratification factors (age, gender, modified Rankin scale). Study The trial started in December 2010 aiming at recruiting 1160 patients in 25 to 30 German cardiovascular centers. The composite primary efficacy end point is the number of strokes and deaths from any cause (whatever occurs first) within 30 days after operation. A 4·5% absolute difference (4% compared to 8·5%) in the 30-day rate of the above end points can be detected with >80% power. Outcomes The results of this trial are expected to provide a basis for defining an evidence-based standard and will have a wide impact on managing this disease.

Oxygen persufflation as adjunct in liver preservation (OPAL): Study protocol for a randomized controlled trial

BackgroundEarly graft dysfunction due to preservation/reperfusion injury represents a dramatic event after liver transplantation. Enhancement of donor organ criteria, in order to cope with the ever increasing donor shortage, further increases graft susceptibility to ischemic alterations.Major parts of post-preservation injury, however, occur at the time of warm reperfusion but not during ischemic storage; successful reperfusion of ischemic tissue in turn depends on an adequate redox and intracellular signal homeostasis. The latter has been shown experimentally to be favorably influenced by oxygen persufflation within short time spans. Thus viability of marginally preserved liver grafts could still be augmented by transient hypothermic reconditioning even after normal procurement and static cold storage. The present study is aimed to confirm the conceptual expectations, that hypothermic reconditioning by gaseous oxygen persufflation is a useful method to suppress injurious cellular activation cascades and to improve post-ischemic recovery of marginally preserved liver grafts.Methods/DesignOPAL is a prospective single center randomized proof of concept study, including two parallel groups in a total of 116 liver transplant patients. The effect of an in hospital treatment of the isolated liver graft by 2 hours of oxygen persufflation immediately prior to transplantation will be assesses as compared to standard procedure (cold storage without further intervention). The primary endpoint is the peak transaminase serum level (AST) during the first three days after transplantation as a surrogate readout for parenchymal liver injury. Other outcomes comprise patient and graft survival, time of intensive care requirement, hepatic tissue perfusion 1h after revascularisation, early onset of graft dysfunction based on coagulation parameters, as well as the use of a refined scoring-system for initial graft function based on a multi-parameter (AST, ALT, Quick and bilirubin) score. Furthermore, the effect of OPAL on molecular pathways of autophagy and inflammatory cell activation will be evaluated. Final analysis will be based on all participants as randomized (intention to treat).Trial RegistrationCurrent Controlled Trials ISRCTN00167887

Study protocol of Prednisone in episodic Cluster Headache (PredCH): a randomized, double-blind, placebo-controlled parallel group trial to evaluate the efficacy and safety of oral prednisone as an add-on therapy in the prophylactic treatment of episodic cluster headache with verapamil

BackgroundEpisodic cluster headache (ECH) is a primary headache disorder that severely impairs patient’s quality of life. First-line therapy in the initiation of a prophylactic treatment is verapamil. Due to its delayed onset of efficacy and the necessary slow titration of dosage for tolerability reasons prednisone is frequently added by clinicians to the initial prophylactic treatment of a cluster episode. This treatment strategy is thought to effectively reduce the number and intensity of cluster attacks in the beginning of a cluster episode (before verapamil is effective). This study will assess the efficacy and safety of oral prednisone as an add-on therapy to verapamil and compare it to a monotherapy with verapamil in the initial prophylactic treatment of a cluster episode.Methods and designPredCH is a prospective, randomized, double-blind, placebo-controlled trial with parallel study arms. Eligible patients with episodic cluster headache will be randomized to a treatment intervention with prednisone or a placebo arm. The multi-center trial will be conducted in eight German headache clinics that specialize in the treatment of ECH.DiscussionPredCH is designed to assess whether oral prednisone added to first-line agent verapamil helps reduce the number and intensity of cluster attacks in the beginning of a cluster episode as compared to monotherapy with verapamil.Trial registrationGerman Clinical Trials Register DRKS00004716

Safety of Simultaneous Coronary Artery Bypass Grafting and Carotid Endarterectomy Versus Isolated Coronary Artery Bypass Grafting: A Randomized Clinical Trial

Background and Purpose— The optimal operative strategy in patients with severe carotid artery disease undergoing coronary artery bypass grafting (CABG) is unknown. We sought to investigate the safety and efficacy of synchronous combined carotid endarterectomy and CABG as compared with isolated CABG. Methods— Patients with asymptomatic high-grade carotid artery stenosis ≥80% according to ECST (European Carotid Surgery Trial) ultrasound criteria (corresponding to ≥70% NASCET [North American Symptomatic Carotid Endarterectomy Trial]) who required CABG surgery were randomly assigned to synchronous carotid endarterectomy+CABG or isolated CABG. To avoid unbalanced prognostic factor distributions, randomization was stratified by center, age, sex, and modified Rankin Scale. The primary composite end point was the rate of stroke or death at 30 days. Results— From 2010 to 2014, a total of 129 patients were enrolled at 17 centers in Germany and the Czech Republic. Because of withdrawal of funding after insufficient recruitment, enrolment was terminated early. At 30 days, the rate of any stroke or death in the intention-to-treat population was 12/65 (18.5%) in patients receiving synchronous carotid endarterectomy+CABG as compared with 6/62 (9.7%) in patients receiving isolated CABG (absolute risk reduction, 8.8%; 95% confidence interval, −3.2% to 20.8%; PWALD=0.12). Also for all secondary end points at 30 days and 1 year, there was no evidence for a significant treatment-group effect although patients undergoing isolated CABG tended to have better outcomes. Conclusions— Although our results cannot rule out a treatment-group effect because of lack of power, a superiority of the synchronous combined carotid endarterectomy+CABG approach seems unlikely. Five-year follow-up of patients is still ongoing. Clinical Trial Registration— URL: https://www.controlled-trials.com. Unique identifier: ISRCTN13486906.

Botulinum neurotoxin type A in the treatment of classical Trigeminal Neuralgia (BoTN): study protocol for a randomized controlled trial

BackgroundTrigeminal neuralgia is characterized by paroxysmal facial pain attacks. Adequate prophylactic drug therapy is often limited by the lack of efficacy and intolerance due to central nervous system side effects.Subcutaneous injections of botulinum toxin type A are a promising treatment option for patients with unsatisfactory response to drug therapy or neurosurgical intervention. Its effects are expected to last for at least 3 months, so it could be a potential long-term treatment.This is the study protocol of a prospective, placebo-controlled, double blind clinical trial investigating the add-on therapy of subcutaneous administration of botulinum toxin type A injections to standard treatment in therapy-refractory classical trigeminal neuralgia.Methods and designBoTN is a prospective, double blind, placebo-controlled trial with a randomized withdrawal design in which a single blind phase is followed by a double blind phase (see also Methods and design). Eligible patients with classical trigeminal neuralgia who are otherwise refractory to medical and neurosurgical treatment will receive subcutaneous injections of botulinum toxin type A into injection sites of the affected trigeminal branch.In the first phase all patients will receive botulinum toxin type A in a single blinded intervention. Twelve weeks later therapy responders will be allocated to the verum or placebo (saline) arm in a double blind, randomized manner. These injections will be performed at the same sites as the first injections.This trial will be conducted in a tertiary outpatient clinic specialized in the treatment of headache and facial pain. There will be three investigators performing the injections who are experienced in the treatment of headache and facial pain and trained in botulinum toxin type A injections.DiscussionBoTN is designed to assess the efficacy and safety of subcutaneous botulinum toxin type A injections in addition to standard prophylactic treatment in therapy-refractory trigeminal neuralgia.Trial registration numberEU Clinical Trials Register: EudraCT-No: 2014-001959-24 https://www.clinicaltrialsregister.eu/ctr-search/rest/download/trial/2014-001959-24/DEDate of trial registration26 August 2014

A Randomized Trial of Daily Prednisone versus Pulsed Dexamethasone in Treatment-Naïve Adult Patients with Immune Thrombocytopenia: EIS 2002 Study

Oral prednisone is considered the standard first-line therapy of adult immune thrombocytopenia, but its long-term efficacy is limited. We performed a prospective, randomized, multicenter trial comparing daily prednisone (1-2 mg/kg/day for 2-4 weeks with subsequent dose reduction) with six 3-week cycles of pulsed dexamethasone (0.6 mg/kg/day, days 1-4). The primary endpoint was remission duration. Of 26 patients enrolled, 22 were evaluable for response. Nine were treated with prednisone and 13 with dexamethasone. The median follow-up was 46 months. The initial response rate (PLT ≥50 × 109/l) was 100% in both groups. Long-term remissions were significantly more frequent with pulsed dexamethasone than with daily prednisone (12 months posttreatment: 77 vs. 22%; p = 0.027). The side effects were similar, but patients on dexamethasone suffered significantly more often from insomnia, while patients on prednisone tended to have more infectious complications. Although the cumulative cortisol equivalent dose was comparable during the first 4 weeks of therapy, it was significantly higher in the dexamethasone arm than in the prednisone arm during the ensuing treatment period. We conclude that repeated cycles of pulsed dexamethasone are a good alternative to daily prednisone as a first-line treatment of immune thrombocytopenia. The duration and intensity of glucocorticoid therapy are important determinants of treatment outcome.

What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials

Pharmacological intervention with methylphenidate (MPH) is very common and helpful in the treatment of attention-deficit/ hyperactivity disorder (ADHD). It ameliorates inattention, impulsivity and hyperactivity and improves psychosocial functioning. The core symptoms of ADHD are problematic mainly in demanding structured situations such as in the classroom. It was argued that MPH does not only lead to a decrease of hyperactivity in these situations but may also result in a general dampening of motor activity during non-structured leisure time. Unfortunately, only few clinical trials have investigated this practically important issue and thus it is still a matter of debate. It follows that many parents hesitate to accept psychotropic drugs for their children. To elucidate this problem in the current study, not only overall behavioral ratings (half-day blocks) but also day-long actigraphy was applied during an analogue classroom setting, where structured and non-structured situations alternated over time. Fourty-nine children with ADHD were assessed for treatment effects of once-daily extended-release and twice daily immediate-release methylphenidate (MPH) as well as placebo. Both MPH regimes yielded improved behavioral ratings during morning and afternoon, while actigraphy showed reduced motor activity in structured situations, but not during leisure time. Furthermore, the movement information obtained with actigraphy during structured situations could be differentiated from the one gained with overall behavioral ratings. Thus, while behavioral ratings provide a valid estimate of the overall symptomatology, additional information gathered with actigraphy may help to differentiate the impact of medication on hyperactive movement in different situations during the day. This may reflect a more valid picture of a childs real life and improve the quality of clinical trials. Thus, both methods may be regarded as complementary for the assessment of drug effects in children with ADHD and should be a standard of further laboratory school protocols in clinical trials.