References and publications
"The way to gain a good reputation is to endeavor to be what you desire to appear." - Socrates.
At Metronomia, we understand that it takes immense effort and time to build a good reputation and only a few mistakes or minutes to ruin it. That is why we take extreme pride and care in our work. Our references and publications are our testimony!
Helle Lynggaard, James Bell , Christian Lösch , Amel Besseghir , Khadija Rantell, Volker Schoder and Vivian Lanius
Clinical study protocols are the foundation of good clinical studies. Prospective and multidisciplinary collaboration that pays attention to the design of all components of the study protocol can ensure that a clinical study will answer the research questions posed in a reliable manner that is meaningful for decision-makers and patients. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials provides a framework for clinical study planning to ensure alignment between study objectives, design, conduct, and analysis. The estimand or clinical question posed can be regarded as the backbone of the study and the clinical study protocol should reflect estimands accordingly. In practice, stakeholders are still learning how to embrace the estimand framework and how it impacts studies and study documents. In this paper, we anticipate that a protocol structure centred around estimands, or objectives rather than endpoints alone will prevail for all types of studies. To assist sponsors during this paradigm shift, this paper provides discussion and guidance for implementing the estimand framework in protocol templates.
Alexander P J Vlaar, Sanne de Bruin, Matthias Busch, Sjoerd A M E G Timmermans, Ingeborg E van Zeggeren, Rutger Koning, Liora ter Horst, Esther B Bulle, Frank E H P van Baarle, Marcel C G van de Poll, E Marleen Kemper, Iwan C C van der Horst, Marcus J Schultz, Janneke Horn, Frederique Paulus, Lieuwe D Bos, W Joost Wiersinga, Martin Witzenrath, Simon Rueckinger, Korinna Pilz, Matthijs C Brouwer, Ren-Feng Guo, Leo Heunks, Pieter van Paassen, Niels C Riedemann, Diederik van de Beek
Zielen S, Kuna P, Aberer W, Lassmann S, Pfaar O, Klimek L, Wade A, Kluehr K, Raab J, Wessiepe D, Lee D, Kramer MF, Gunawardena K, Higenbottam T, Heath MD, Skinner MA, de Kam PJ.
Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose.
Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31-41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship.
In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature.
PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.
Kebenko M, Goebeler ME, Wolf M, Hasenburg A, Seggewiss-Bernhardt R, Ritter B, Rautenberg B, Atanackovic D, Kratzer A, Rottman JB, Friedrich M, Vieser E, Elm S, Patzak I, Wessiepe D, Stienen S, Fiedler W.
We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded
dose escalation to potentially therapeutic levels.
Zugmaier G, Topp MS, Alekar S, Viardot A, Horst HA, Neumann S, Stelljes M, Bargou RC, Goebeler M, Wessiepe D, Degenhard E, Gökbuget N, Klinger M.
Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC.
Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinicalrelapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.
Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC.
Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
Patients and Methods:
Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15μg/m2/24 hours.
Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.
Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
Reuther M, Spottke EA, Klotsche J, Riedel O, Peter H, Berger K, Athen O, Köhne-Volland R, Dodel RC.
To prospectively assess the health-related quality of life (HrQoL) in Parkinson's disease (PD) during 12 months..
HrQoL was assessed in 145 PD patients using the PD-specific PDQ-39, PDQL and the generic EQ-5D. In addition, clinical rating-scales were used.
All scales showed a pronounced effect of PD. In comparison to an age-matched population the EQ-5D was considerably affected. In comparison to baseline, however, there was no significant change in the generic scale but a significant change in the sum-score of disease-specific HrQoL-scales.
Only disease-specific scales were sensitive to change. Further studies are necessary to evaluate the time-dependent change in HrQoL.
Breuhahn K, Baeuerle PA, Peters M, Prang N, Töx U, Köhne-Volland R, Dries V, Schirmacher P, Leo E.
Epithelial cell adhesion molecule (Ep-CAM) is expressed in a several epithelial tissues and carcinomas, but not on mature hepatocytes. Here, we analysed the expression of Ep-CAM in 230 patients suffering from various liver diseases like chronic hepatitis B and C (HBV and HCV infection), chronic autoimmune hepatitis (AIH), chronic alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hereditary hemochromatosis and dysplastic nodules (DNs) as well as hepatocellular carcinomas (HCCs) and cholangiocellular carcinomas (CCCs) by immunohistochemistry. De novo hepatocellular Ep-CAM expression was found in 75.9% of ALD (22/29), 63.6% of HCV (21/33) and 55.6% of each AIH and HBV cases (5/9 and 15/27, respectively). Lower Ep-CAM expression levels were observed for primary sclerosing liver diseases (PBC and PSC) with 25% (3/12) and 7.7% (1/13) of cases. Moreover, only 14.3% of HCCs (9/63) manifested expression, while all CCCs showed strong Ep-CAM expression (5/5). For DNs and hereditary hemochromatosis, Ep-CAM expression was found in 10 and 50% (3/30 and 2/4), respectively. In HBV and HCV, Ep-CAM expression correlated significantly with inflammatory activity as assessed by histological parameters and to the extent of fibrosis. In addition, for HCV also transaminase levels correlated significantly with Ep-CAM expression. Our results indicate that de novo Ep-CAM expression in hepatocytes is frequent in inflammatory liver diseases and is potentially linked to regenerative activity. CCCs and Ep-CAM positive HCCs may represent an attractive target group for Ep-CAM-directed immunotherapies, yet unwanted toxicity may limit the use of such strategies due to Ep-CAM expression in biliary epithelium and several chronic liver diseases such as HBV-and HCV-hepatitis.
Smala AM, Spottke EA, Machat O, Siebert U, Meyer D, Köhne-Volland R, Reuther M, DuChane J, Oertel WH, Berger KB, Dodel RC.
We evaluated the incremental cost-effectiveness of cabergoline compared with levodopa monotherapy in patients with early Parkinson's disease (PD) in the German healthcare system. The study design was based on cost-effectiveness analysis using a Markov model with a 10-year time horizon. Model input data was based on a clinical trial "Early Treatment of PD with Cabergoline" as well as on cost data of a German hospital/office-based PD network. Direct and indirect medical and nonmedical costs were included. Outcomes were costs, disease stage, cumulative complication incidence, and mortality. An annual discount rate of 5% was applied and the societal perspective was chosen. The target population included patients in Hoehn and Yahr Stages I to III. It was found that the occurrence of motor complications was significantly lower in patients on cabergoline monotherapy. For patients aged >/=60 years of age, cabergoline monotherapy was cost effective when considering costs per decreased UPDRS score. Each point decrease in the UPDRS (I-IV) resulted in costs of euro;1,031. Incremental costs per additional motor complication-free patient were euro;104,400 for patients <60 years of age and euro;57,900 for patients >/=60 years of age. In conclusion, this decision-analytic model calculation for PD was based almost entirely on clinical and observed data with a limited number of assumptions. Although costs were higher in patients on cabergoline, the corresponding cost-effectiveness ratio for cabergoline was at least as favourable as the ratios for many commonly accepted therapies.
Dodel RC, Singer M, Köhne-Volland R, Szucs T, Rathay B, Scholz E, Oertel WH.
This study prospectively assesses the medical costs of Parkinson's disease (PD).
Over a period of 3 months (from July to September 1995), patients with PD documented all items of healthcare provision. These data were then used to calculate medical costs for an individual patient as well as the costs of PD.
Patients and Setting:
We included 20 outpatients with idiopathic PD from the neurological outpatient clinic, Klinikum Grosshadern, Munich, and 20 patients from two office-based neurologists in South-West Germany.
The mean 3-month medical cost of PD in 1995 deutschmarks (DM) was 5210 ($US3390, 2240 Pounds) consisting of DM1410 ($US920, 610 Pounds) for care and nursing, DM1580 ($US1030, 680 Pounds) for drug therapy, DM1320 ($US860, 570 Pounds) for inpatient hospital care, DM40 ($US26, 17 Pounds) for outpatient care and DM860 for other expenses ($US560, 370 Pounds). The expenditure was related to the disease evolution. Patients complaining of one-sided symptoms [Hoehn and Yahr stage I; (HY I)] were less expensive to treat (DM1930, $US1250, 830 Pounds) than patients who were severely incapacitated (HY V) [DM9740, $US6330, 4200 Pounds; HY V]. After 3 to 5 years of levodopa treatment approximately 50% of patients start to experience fluctuations in motor ability and dyskinesias [Unified Parkinson's disease rating scale, part IV (UPDRS IV)]. This onset of motor complications parallels an increase in costs. For patients who experienced motor fluctuations, annual costs were DM6550 ($US4260, 2820 Pounds) compared with DM3030 ($US1960, 1300 Pounds) for patients lacking this problem. Indirect non-medical costs were not calculated due to the limited number of patients. The impact of the disease on work, however, is clearly apparent from the patients' history: 19 out of 34 patients who had already stopped working attributed this to the disease, and only 6 patients were still working at the time of the survey.
PD poses a major financial impact to society which is expected to increase in future years as the age distribution shifts to older age groups. On the basis of a prevalence of PD of 183 per 100,000, we calculated an annual expenditure of DM3.0 billion for the direct medical costs of PD in Germany.
Dodel RC, Singer M, Köhne-Volland R, Selzer R, Scholz W, Rathay B, Oertel WH.
Parkinson's disease (PD) causes significant expense for the national health care system due to its chronic progressive course, the duration of the disease, the high prevalence and the devastating prognosis. In Germany more than DM 320 million are spent for drugs to alleviate parkinsonian symptoms. The aim of this study was to calculate the economic burden of PD by assessing direct medical costs. Forty patients suffering from idiopathic PD were interviewed at an office of neurological specialists and at an outpatient movement disorder clinic about their use of health care resources 3 months prior to the study. The total annual costs reported were DM 14,500, consisting of DM 6500 for drug therapy and DM 8000 for other medical services, including hospital inpatient care (DM 5600), outpatient care (DM 700), medical sundries (DM 1100) and physiotherapy (DM 600). The costs were positively correlated to the extent of the disease (Hoehn and Yahr stage; HY) and the occurrence of motor fluctuations/dyskinesias. We found that both drug-therapy expenses and total medical costs doubled from HYI to HYIV. The rarely employed s.c. therapy with apomorphine additionally increased the costs of drug therapy in HYV. The occurrence of fluctuations/ dyskinesias also increased medical expenses by approximately a factor of two. Indirect burden due to increased days off of work, unemployment and earlier retirement are also significant in Parkinson's disease. This study includes that a treatment which could prevent or retard disease progression as well as a treatment that delays or reduces motor complications would not only ameliorate the situation of patients suffering from PD, but would also lead to significant reductions in cost for the national health care system.
Dodel RC, Pepperl S, Köhne-Volland R, Szucs T, Werhahn KJ, Noachtar S, Oertel WH.
The costs of drug treatment were evaluated for Parkinson's disease, focal dystonias and epilepsy.
Retrospective analysis over a period of 12 months of 785 patients who visited regularly a neurological out-patient department.
Drug treatment caused a mean annual expenditure of DM 3,920.- (US-($) 2590, pounds 1690) for Parkinson's disease (n = 409), DM 3,620.- (US-($) 2390; pounds 1550) for focal dystonias (n = 140) and DM 660.- (US-($) 435, pounds 280) for hemifacial spasm (n = 35) per patient.- In Parkinson's disease costs are dependent on the extent of the disease, the type involved and the presence or absence of motor fluctuations. In Hoehn and Yahr stage I we calculated costs of DM 2,230.- (US-($) 1470; pounds 960), in contrast to DM 11,870.- (US-($) 7830; pounds 5100) in Hoehn and Yahr stage V. The occurrence of fluctuations in motor ability increased annual costs to DM 6,010.- (US-($) 3970, pounds 2580); patients' treatment without motor fluctuations was cheaper (DM 2,700.-; US-($) 1780, pounds 1160).- The annual treatment costs of focal dystonias and facial hemispasm varied due to the location of the involuntary movement and the extent of symptoms: DM 4,900.- (US-($) 3300; pounds 2100) were calculated for the treatment of cervical dystonias, DM 1,480.- (US-($) 930; pounds 600) for the treatment of blepharo-spasm (oromandibular dystonia: DM 1,710.-; US-($) 1200; pounds 800) and DM 600.- (US-($) 470; pounds 300) for the treatment of facial hemispasm.- The drug treatment of epilepsy caused mean costs of DM 1,740.- (US-($) 1160; pounds 750) per year. There were marked differences concerning the different epileptic syndromes and types of seizure.
Costs of drug treatment varied considerably in the three diseases depending on the course, the type and the different forms of the respective disease.
Peikert A, Wilimzig C, Köhne-Volland R.
In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18-65 years with migraine according to the International Headache Society (IHS) criteria (mean attack frequency 3.6 per month) were examined. After a prospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9-12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p < 0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Duration and intensity of the attacks and the drug consumption per attack also tended to decrease compared to placebo but failed to be significant. Adverse events were diarrhea (18.6%) and gastric irritation (4.7%). High-dose oral magnesium appears to be effective in migraine prophylaxis
Wollenberg A, Sidhu MK, Odeyemi I, Dorsch B, Koehne-Volland R, Schaff M, Ehlken B, Berger K.
Rational health care decision-making based on outcomes and economic evidence is essential to provide the best possible care for individual patients with atopic dermatitis (AD).
To describe treatment outcomes and to evaluate resource utilization and associated cost of maintenance use of tacrolimus ointment (MU) vs. standard use of tacrolimus ointment (SU) in adults with AD.
A pan-European, phase III multicentre randomized clinical trial was conducted. Patients with mild to severe AD were randomized to tacrolimus 0.1% ointment (MU) or vehicle (SU) twice per week for 12 months. Disease exacerbations were treated by using open-label tacrolimus 0.1% ointment twice daily. Resource utilization data were collected prospectively alongside the clinical trial. Costs of pooled resource data were determined using German unit cost data. Direct and indirect costs were considered from third party payer, patient and societal perspectives.
All patients with moderate and severe AD were included in a subanalysis, 75 patients in the MU arm (57% moderately affected) and 59 patients in the SU arm (59% moderately affected). In patients with moderate AD, the number of disease exacerbations in the MU arm was 2.4 vs. 5.5 in the SU arm (P<0.001); in patients with severe AD corresponding figures were 2.3 vs. 7.4 (P<0.001), respectively. Mean+/-SD total annual cost per patient was euro1525+/-1081 (MU) vs. euro1729+/-1209 (SU) in patients with moderate AD and euro2045+/-2013 (MU) vs. euro2904+/-1510 (SU) in patients with severe AD.
Maintenance treatment with 0.1% tacrolimus ointment is more effective and leads to cost savings and improved health-related quality of life in comparison with standard use of 0.1% tacrolimus ointment, especially in patients with severe AD.
Spottke AE, Reuter M, Machat O, Bornschein B, von Campenhausen S, Berger K, Koehne-Volland R, Rieke J, Simonow A, Brandstaedter D, Siebert U, Oertel WH, Ulm G, Dodel R.
To prospectively evaluate the health economic burden of patients with Parkinson's disease (PD) in Germany over a 6-month observation period and to identify the predictors of these costs.
Study Design and Methods:
Direct and indirect costs were evaluated in 145 patients with PD (mean age 67.3 +/- 9.6 years). PD patients were recruited from an outpatient department for movement disorders, a specialised PD clinic, two office-based neurologists and general practitioners, all located in Germany, and were enrolled between January and June 2000. Relevant economic data were documented in a patient diary over the 6-month period. Clinical evaluations (Unified Parkinson's Disease Rating Scale [UPDRS]) were performed at baseline and at 3 and 6 months. Costs were derived from various German medical economic resources. Costs were calculated from the perspective of healthcare and transfer payment providers and the individual patient. Indirect costs for lost productivity were also calculated. Costs are presented as means +/- standard deviation (SD). Multivariate regression analyses were performed to identify independent cost predictors. Costs are in year 2000-02 values.
We estimated average per patient direct, indirect and total costs for the 6-month observation period. The costs from the perspective of statutory health insurance (Gesetzliche Krankenkversicherung [GKV]) consisted of direct medical costs 1370 euro +/- 3240 euro, including rehabilitation (420 euro +/- 1630 euro), hospitalisation (710 euro +/-2520 euro), outpatient treatment (40 euro +/- 30 euro), ancillary treatment (190 euro +/- 280 euro) and ambulatory diagnostic procedures (10 euro +/-30 euro). In addition, parkinsonian drug costs were 1520 euro +/-euro1250. Non-medical direct costs calculated from the GKV perspective were estimated to be euro480 +/-euro1710, which included transportation (10 euro+/- 20 euro), special equipment (420 euro +/- 1640 euro), social/home-help services (10 euro +/-110 euro) and sickness benefit (40 euro +/- 540 euro). The total medical (including drug costs) and non-medical direct costs for the GKV were 3380 euro +/- 4230 euro. Univariate predictors for GKV direct costs included occurrence of motor complications and falls, disease severity, nightmares and dementia. However, multivariate analyses only suggested disease severity and health-related quality of life as significant predictors. For nursing insurance, payments of 1330 euro +/- 2890 euro were calculated. For retirement insurance, payments were 650 euro +/- 1510 euro and there were patient (or caregiver) costs of 1490 euro +/- 2730 euro. Total indirect costs amounted to 3180 euro +/-6480 euro.
According to our study, PD puts a high financial burden on society and underscores the need for further economic and medical research to optimise treatment for PD.
Dodel RC, Kirchner A, Koehne-Volland R, Künig G, Ceballos-Baumann A, Naumann M, Brashear A, Richter HP, Szucs TD, Oertel WH.
Pharmacoeconomics. 1997 Dec;12(6):695-706.
Botulinum toxin (BTX) has become a safe and effective therapeutic tool in the treatment of a variety of neurological disorders, especially dystonias. One major disadvantage, however, is the high cost of a single injection of BTX. In this study of 835 patients, we calculated the cost of treatment with BTX serotype A (BTX-A) for different dystonias and hemifacial spasm. The annual expenditure per patient for BTX-A injections in this cohort totalled (mean +/- standard deviation) 1030 Deutschmarks (DM) [1996 values] +/- DM610 [$US570 +/- $US340; 230 +/- 130 pounds sterling (Pound)] for blepharospasm (n = 158), DM1450 +/- DM1520 ($US800 +/- $US830; 310 Pounds +/- 280 Pounds) for craniocervical dystonia (n = 148), and DM1480 +/- DM780 ($US810 +/- $US430; 330 Pounds +/- 180 Pounds) for oromandibular dystonia (n = 16), while the treatment of cervical dystonia consumed DM4590 +/- DM2060 ($US2520 +/- $US1130; 960 Pounds +/- 420 Pounds) [n = 362] per patient. In order to alleviate symptoms in patients with hemifacial spasm (n = 151), DM510 +/- DM270 ($US280 +/- $US150; 110 Pounds +/- 60 Pounds) had to be spent annually. The expenses for surgical therapy for cervical dystonia were DM10,120 +/- DM1900 (n = 54). No major differences concerning expenditure could be found in this study between the 2 available preparations of BTX. However, there appeared to be a lower rate of adverse effects with the Botox formulation, compared with the Dysport formulation, of BTX-A (this difference was statistically significant, i.e. p < 0.001). Although the cost of an individual injection is high, other cost factors also substantially contribute to the societal costs of adult-onset dystonias. Some of these costs may be attenuated with the use of BTX. The subjective and objective relief of these socially devastating and sometimes painful conditions rewards the expenditure associated with the use of BTX-A.
Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC.
¹Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville
²Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell-engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort.
Patients and Methods:
Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs).
Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically.
The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.
Zugmaier G, Topp MS, Alekar S, Viardot A, Horst HA, Neumann S, Stelljes M, Bargou RC, Goebeler M, Wessiepe D, Degenhard E, Gökbuget N, Klinger M.
1Amgen Research (Munich) GmbH, Munich, Germany.
21] Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany  Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg, Würzburg, Germany.
3Amgen Inc., Thousand Oaks, CA, USA.
4Medical Department III, University Ulm, Ulm, Germany.
5Medical Department II, City Hospital and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
6Bone Marrow Transplantation Center, University Münster, Münster, Germany.
7Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg, Würzburg, Germany.
8Metronomia GmbH, Munich, Germany.
9Center of Internal Medicine, J.W. Goethe University, Frankfurt, Germany.
PMID: 25192414, PMCID: PMC4183773, Free PMC Article
Blood Cancer J. 2014 Sep 5;4:244. doi: 10.1038/bcj.2014.64.
No abstract available.
Thaci D, Chambers C, Sidhu M, Dorsch B, Ehlken B, Fuchs S.
Rational healthcare decision-making based on clinical and economic evidence is essential to provide the best possible care for patients with atopic dermatitis (AD).
To evaluate treatment outcomes, resource use and cost associated with twice-weekly tacrolimus 0.03% ointment treatment vs. standard flare-only therapy in children with moderate-to-severe AD.
In a pan-European, Phase III multicentre randomized clinical trial, children with mild-to-severe AD were randomized to 0.03% tacrolimus ointment or vehicle twice weekly for 12 months. Disease flares were treated using open-label tacrolimus 0.03% ointment twice daily. Clinical efficacy data were evaluated in a subgroup of 153 children with moderate-to-severe AD, with resource use data--collected prospectively using caregiver questionnaires--available from 146 children. Pooled costs of resource use were determined using German unit cost data. Direct and indirect costs were considered from third-party payer, patient and caregiver, and societal perspectives.
Twice-weekly tacrolimus ointment reduced the number of flares compared with standard therapy (P < 0.001) and prolonged time to first flare (146 vs. 17 days, P < 0.001). Mean +/- SD annual costs per patient for standard and twice-weekly therapy respectively were 2002 euro +/- 2315 vs. 1571 euro+/- 1122 for severe AD and 1136 euro +/- 1494 vs. 1233 euro +/- 1507 for moderate AD.
In children with AD, twice-weekly treatment with tacrolimus 0.03% ointment reduces the number of flares and prolongs time spent free from flares with no additional cost in children with moderate AD, and may be cost-saving in those with severe AD.
Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, Noppeney R, Hess G, Kallert S, Mackensen A, Rupertus K, Kanz L, Libicher M, Nagorsen D, Zugmaier G, Klinger M, Wolf A, Dorsch B, Quednau BD, Schmidt M, Scheele J, Baeuerle PA, Leo E, Bargou RC.
Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome-negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).
Patients and Methods:
This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m(2)/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate.
Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m(2)/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m(2)/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m(2)/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days).
In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m(2)/day. Single-agent blinatumomab showed antilymphoma activity.
© 2016 by American Society of Clinical Oncology.
Integrating SAE handling into EDC systems reduces workload and increases accuracy and efficiency.
It is widely accepted among clinical trial professionals that EDC solutions deliver many benefits with respect to time, productivity, and costs. This is especially true for the collection and cleaning of standard CRF data such as demographics, concomitant medication, medical history, efficacy, and safety. EDC also covers the areas of patient reported outcomes, central laboratory data, and data from other external sources. However, a very important aspect of clinical trial data management is not adequately addressed in many EDC solutions and eCRFs: namely, the collection, processing, and reporting of Serious Adverse Events (SAE).
In many EDC trials the SAE process is still paper- and fax-based. This process is often carried out in isolation from other data management activities and results in redundant activities such as duplicate documentation for the investigator and drug safety unit.
Holding back progress
There are various reasons for such a lack of integration when collecting, reporting, and processing SAEs and SUSARs (suspected unexpected serious adverse reactions) in eCRFs. First of all, one has to understand the special requirements needed when processing SAEs and SUSARs: different as it is to nonsafety data, data from SAEs and SUSARs have to be processed and reported to regulatory authorities at very short notice, and the required expertise differ greatly from those in the field of clinical data management.
Consequently, most medium and large pharmaceutical or biotech companies have highly specialized in-house drug safety departments, which utilize dedicated database applications for the comprehensive management of SAEs and the reporting of SUSARs. Smaller companies frequently outsource these tasks to CROs, which then provide the appropriate database applications and corresponding processes.
As drug safety reporting is of ever-increasing importance throughout the drug development process, most companies are reluctant to change their existing procedures, which are often reliable but inefficient. They feel it would be better to remain with a flawed but familiar system rather than undergoing the upheaval associated with introducing a new one. Another reason for the lack of integration is the historical use of existing applications, which lack the necessary interfaces to enable the smooth exchange of data with other systems.
Importing or synchronizing SAE data from an EDC system into a drug safety application—preferably in XML format—would require an elaborated and validated functionality, enabling users to handle and track changes, update records, manage queries, and carry out numerous other processes. Many EDC systems do not offer such synchronization options and lack an easy-to-use and flexible import/export functionality. But does this mean we should wait for the "perfect" solution of full SAE reporting capabilities within EDC systems? It would perhaps be wise to consider the interim step of incorporating smart SAE forms into eCRFs. This would allow the use of state-of-the-art EDC functionalities and the seamless transfer of SAE information to drug safety applications.
eCRF SAE forms
It should be noted that, in order to implement an efficient electronic SAE process, it is important to take care of the additional requirements for electronic SAE pages in an EDC system. SAE data pages differ from other eCRF pages in various ways:
- Data entry and updates require immediate attention.
- Most of the data on SAE pages already exist on other pages of the eCRF.
- The query-management process differs and involves the drug safety department.
- The data is frequently incomplete and requires updating.
- Additional reporting requirements are necessary.
However, choosing the right EDC solution, designing smart eCRF pages, and making full use of its capabilities will significantly increase data quality and the efficiency of the SAE process.
An eCRF SAE form and the backend EDC system should:
- Automatically display study information, such as demographics and standard baseline data, which has already been entered into the eCRF.
- Allow the investigator to choose data that has been entered on other forms to be linked to the electronic SAE form. The data only has to be entered once, thus avoiding inconsistencies. This greatly simplifies the documentation of SAEs to specify related medical history and concomitant medication records (see Figure 1).
- Offer specific user rights for drug safety managers to perform data reviews and cleaning within the EDC system, or even enter data into predefined fields (if required).
- Contain fields in which the investigator, CRA or drug safety manager can upload/attach certain information (e.g., hospital/discharge letters).
- Automatically synchronize AE and SAE eCRF forms (see bullet point 1).
- Include an alert system that notifies a predefined group of recipients via email, SMS or automatically generated fax reports.
- Generate on-demand SAE reports in PDF format (full or incremental modified information).
- Offer a standardized and incremental transfer of SAE information to a dedicated drug-safety application, preferably in XML format.
An eCRF SAE form with these features provides a number of benefits by:
- Significantly reducing the collection of redundant data, saving the investigator a lot of time (particularly within studies with a moderate or large number of SAEs) and renders the eCRF SAE form less susceptible to transcription errors.
- Offering more accurate and up-to-date information on the SAE form: changes in the automatically displayed or linked data are available immediately.
- Allowing for more efficient data cleaning, as drug safety managers can utilize the full query management functionality of an EDC system and might achieve a better response to queries. As these queries are processed in the EDC system, they are flagged or listed in specific reports. CRAs can view the queries, assist in answering them, and communicate with investigators.
- Considerably reducing the SAE reconciliation effort required before a database lock, as no redundant information is collected.
- Enabling reporting deadlines to be met with greater ease due to the alert system and electronic data exchange.
- Cutting back the amount of time required for creating follow-up reports by transferring data incrementally from the EDC system to the drug safety application and highlighting the updated information in follow-up reports.
Currently, EDC systems coexist with legacy drug safety applications and paper- or fax-based SAE processes. A state-of-the-art EDC solution should provide features that support electronic SAE handling within the EDC system. Electronic SAE handling has the potential to significantly reduce the workload in drug safety management, especially in studies with a moderate or large number of SAEs. Furthermore, EDC can also improve the quality and accuracy of data in drug safety and SUSAR reporting systems.
With an EDC system that supports the described features, it is possible to establish an efficient electronic SAE management process with only minimum changes to existing processes and systems. Drug safety departments should be able to continue to use their existing systems but observe improvements in the quality and accuracy of data.
The described approach can only be an interim step toward more integrated systems and processes1. However, as interim solutions sometimes tend to last a rather long time in the area of drug development, it would be beneficial to act now and not wait for the "perfect" solution that may come along in the future.
Dieter Meyer *
is head of data management and managing director at Metronomia Clinical Research GmbH, Paul-Gerhardt-Allee 42, 81245 Munich, Germany,
is clinical data manager, EDC, at Metronomia Clinical Research GmbH.
is chief executive officer at Quadratek Data Solutions, Ltd, Hampshire, UK.
*To whom all correspondence should be addressed.
R. Bobo and J. Notte; "Safety Reporting in Clinical Trials," Next Generation Pharmaceutical,
(accessed January 17, 2008).
[Article in German]
Lenk VS1, Dorsch B.
Aktuelle Urol. 2009 Nov;40(6):360-5. doi: 10.1055/s-0029-1124677. Epub 2009 Nov 6.
Background and Purpose:
Urinary tract infection (UTI) is one of the most common bacterial infections in women. Despite the need for therapy alter-natives only the conventional treatment using antibiotics is investigated in the literature. A vaccination, however, can be a useful medical and economic alternative for the treatment of recurrent urinary tract infections.
Materials and Methods:
An open, prospective, not-randomised, multicentric observation study was carried out to determine the costs and effects of a vaccination in 842 patients with recurrent urinary tract infections. The data for efficacy, safety and costs of recurrent urinary tract infections were collected via patient documentation and a standardised documentation of the physicians.
The efficacy was rated as good to very good by 82.7 % of the physicians and 82.1 % of the patients. The values for safety show even better results. They were rated as good to very good by 92.4 % of the physicians and 90.9 % of the patients. The total costs amounted to 433 euro per patient in the six months before vaccination and decreased significantly to 238 euro in the six months after vaccination (p < 0.0001).
The results of this observation study show a clinically relevant reduction of recurrent urinary tract infections with acceptable side effects in the six months after vaccination. As the treatment costs are reduced from a mean of 238 euro to 91 euro per patient. The healthcare insurances can also benefit from the vaccination against recurrent urinary tract infections.
Georg Thieme Verlag Stuttgart * New York.