Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Shielding requirements of a SPECT insert for installation in a PET/MRI system

The objective of this work is to evaluate the shielding requirements of a SPECT insert for installation in the Siemens Biograph mMR in order to perform simultaneous SPECT/MR imaging of the human brain. We intend to use the radionuclides 99mTc, 123I and 111In. The main photopeaks of these radionuclides have the following energies: 140.5, 159.0, 171.3 and 245.4 keV. There is also about ~3% of emission probability of high energy gamma photons for 123I in the range of 248-784 keV. The main constraints to the design of the gamma shielding are the presence of high energy photons, the weight, the MR compatibility and the PET LSO crystals intrinsic activity. We used GATE to simulate a SPECT acquisition, defining an MRI system with LSO crystals, a partial SPECT ring and a NEMA phantom. We also defined a lead (Pb) base plate (BP) to simulate the support system and three Pb shielding volumes with variable thickness: front and end (FE), back (B), and lateral (L) shield. These volumes reduce interference from out-of-field activity, LSO intrinsic activity and edge effects, respectively. We performed 4 sets of simulations, with variable FE, variable B, variable L and variable BP thickness, respectively, with a NEMA phantom filled with 185 MBq of 123I or 111In. For all simulations, we compared the different energy spectra and count-distribution plots. Results show that a Pb shielding configuration with a thickness of 6 mm-F, 2 mm-E, 3 mm-B, and 5 mm-L is appropriate for the insert. For 123I there is still a high contribution from high energy photons, as the amount of shielding is limited by weight, however this contribution is likely to be overestimated in the simulations as compared to practice. The effect of the LSO intrinsic activity is negligible at the energies of interest

Design optimization and evaluation of a human brain SPECT-MRI insert based on high-resolution detectors and slit-slat collimators

Multi-modality scanners have become increasingly popular in recent years. While PET/CT, SPECT/CT and PET/MRI systems are now commercially available, SPECT/MRI systems are still in a development phase. The aim of this work was to design a SPECT insert for a conventional MRI scanner in order to perform simultaneous SPECT/MRI studies. The SPECT system will consist of a stationary ring of detectors equipped with multi-pinhole or slit-slat collimators. The detector ring will contain multiple small scintillation detectors with Si-based optical readout units. We have investigated a series of design options using analytical calculations of resolution and sensitivity as well as simulations based on various digital phantoms. Our results show that the highest sensitivity is achieved with a multi-pinhole collimator with 2x2 pinholes per detector. However, due to artifacts appearing as a result of cross-talk related to the parallax effect, a better solution could be the 2-slit slit-slat system, with only 5% lower sensitivity. With a target resolution of 10 mm FWHM, the mean sensitivity over a central ROI for this system was 6.30·10-4

Variance prediction in SPECT reconstruction based on the Fisher information using a novel angular blurring algorithm for computation of the system matrix

In this paper we propose a Gaussian decomposition approach to compute the SPECT imaging system matrix. The flexibility of our method allows the implementation of a wide range of imaging systems. With the system matrix, we predict the variance in reconstructed images using the Fisher information matrix and local block circulant approximation. We present results of noise prediction for 3 multi-pinhole systems and 3 multi-slit slit-slat systems, each of them being designed to be inserted in an MRI system. Results show that for a particular phantom 2x2 multi-pinhole and 2 slits slit-slat systems achieve lowest variance. 2013 IEEE

Novel collimation for simultaneous SPECT/MRI

The aim of this work is to develop an optimal collimator design for a stationary, compact SPECT insert for an MRI system, intended to perform simultaneous brain SPECT/MRI in humans. The SPECT insert will consist of a single ring of 25 SiPM-based detectors, insensitive to magnetic fields (5 by 10cm, 0.8mm intrinsic resolution). Compactness is needed due to limited space inside the MRI bore. Here we introduce the concept of an interior slit in the slat component of a slit-slat collimator, providing the possibility of having longer slats extending beyond the slit collimator. We also explore the use of mini-slit arrays to obtain improved angular sampling of the object - we call this an MSS collimator.We compared various multi-pinhole and multi-slit slit-slat configurations, using analytical calculations of sensitivity for a target resolution of 10mm FWHM and simulations with digital phantoms. All slit-slat configurations provided higher sensitivity when compared to the corresponding pinhole designs. The highest sensitivity was obtained for the 2-slit configuration (3.8x10-4). Simulations with a uniform phantom showed reduced sampling artefacts for both the MSS and the corresponding multi-pinhole configuration, in comparison to the other geometries. With a Derenzo phantom, better reconstructed uniformity was observed for the same configurations, with slightly better resolution for the pinhole configuration. With a Defrise phantom, better axial resolution was observed for the slit-slat as compared to the pinhole collimators, and also a more uniform axial coverage. The proposed MSS design demonstrates good reconstructed uniformity and sensitivity, and less sampling artefacts when compared to other collimator configurations, and is therefore the design of choice for the SPECT/MRI insert

Development of a Practical Calibration Procedure for a Clinical SPECT/MRI System Using a Single INSERT Prototype Detector and Multimini Slit-Slat Collimator

In the context of the INSERT project, we have been developing a clinical single photon emission computed tomography (SPECT) insert for a magnetic resonance imaging (MRI) system, in order to perform simultaneous SPECT/MRI of the human brain. This system will consist of 20 CsI:Tl scintillation detectors, 5-cm wide and 10-cm long, with a 72-channel silicon photomultiplier (SiPM) readout per detector, and a multimini slit-slat (MSS) collimator set up in a stationary partial ring. Additionally the system has a custom-built transmit/receive MR coil to ensure compatibility with the SPECT system. Due to the novel design of the system/collimator, existing geometric calibration methods are not suitable. Therefore we propose a novel and practical calibration procedure that consists of a set of specific independent measurements to determine the geometric parameters of the collimator. This procedure was developed utilizing a prototype system that consists of a reduced-size single detector with a 36-channel SiPM-based readout and a single MSS collimator module. Validation was performed by reconstructing different imaging phantoms, using a rotating stage to simulate a tomographic acquisition. Regarding uniformity, the coefficient of variation (COV) for the cylinder phantom reconstructed with correct calibration parameters is 6.7%, whereas the COV using incorrect parameters is 9.4%. The quality of the phantom reconstructions provide evidence of the applicability of the proposed method to the calibration of the prototype system. This procedure can be easily adapted for the final INSERT system

Development of a Practical Calibration Procedure for a Clinical SPECT/MRI System Using a Single INSERT Prototype Detector and Multimini Slit-Slat Collimator

In the context of the INSERT project, we have been developing a clinical single photon emission computed tomography (SPECT) insert for a magnetic resonance imaging (MRI) system, in order to perform simultaneous SPECT/MRI of the human brain. This system will consist of 20 CsI:Tl scintillation detectors, 5-cm wide and 10-cm long, with a 72-channel silicon photomultiplier (SiPM) readout per detector, and a multimini slit-slat (MSS) collimator set up in a stationary partial ring. Additionally the system has a custom-built transmit/receive MR coil to ensure compatibility with the SPECT system. Due to the novel design of the system/collimator, existing geometric calibration methods are not suitable. Therefore we propose a novel and practical calibration procedure that consists of a set of specific independent measurements to determine the geometric parameters of the collimator. This procedure was developed utilizing a prototype system that consists of a reduced-size single detector with a 36-channel SiPM-based readout and a single MSS collimator module. Validation was performed by reconstructing different imaging phantoms, using a rotating stage to simulate a tomographic acquisition. Regarding uniformity, the coefficient of variation (COV) for the cylinder phantom reconstructed with correct calibration parameters is 6.7%, whereas the COV using incorrect parameters is 9.4%. The quality of the phantom reconstructions provide evidence of the applicability of the proposed method to the calibration of the prototype system. This procedure can be easily adapted for the final INSERT system

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals