Multiple Treatment Research Articles

Plain language summary of the MonumenTAL-1 study of talquetamab in people with relapsed or refractory multiple myeloma.

This plain language summary describes the results of a phase 1 research study (or clinical trial) called MonumenTAL-1 published in the New England Journal of Medicine in December 2022. A phase 1 study is an early clinical trial where researchers evaluate how safe a medicine is at different doses in a small number of people. In the MonumenTAL-1 study, researchers looked at a new medicine under development called talquetamab, for people living with multiple myeloma (a type of blood cancer) who did not respond (refractory), stopped responding (relapsed), or who had difficulty dealing with their previous treatments. The phase 1 MonumenTAL-1 study was performed in 2 parts. Safety was the main focus of Part 1 in which side effects, and how serious they were, were assessed. The results of Part 1 were used to identify doses of talquetamab that were well tolerated, without a need to stop treatment or reduce the doses, for further study in Part 2. Part 2 of the study examined how well talquetamab worked to decrease signs of the cancer and what side effects, and their severity, people experienced at the doses identified in Part 1. In Part 1 of the study, researchers identified 2 doses of talquetamab for further study: 405 micrograms for every kilogram of body weight (μg/kg) given weekly and 800μg/kg every other week. All participants experienced at least one side effect of treatment at these 2 doses. Less than half of participants (43% at 405μg/kg weekly dose and 34% at the 800μg/kg every other week dose) experienced serious side effects which are those side effects that led to hospitalization, death, or permanent or life-threatening damage). The most common side effects at both doses were a condition known as cytokine release syndrome (CRS); changes in blood cell levels (where different types of cells in the blood were measured); changes in skin such as itching, dry skin, eczema, ulcers or shedding; changes in nails such as discoloration or ridging (lines or dents); and changes in sense of taste such as food tasting sour or metallic. CRS is caused by the overactivation of the immune system (the body's natural defense system) and can result in fever, feeling sick (nausea), being tired (fatigue), low blood pressure, low blood oxygen levels and body aches. Most cases of CRS, as well as most other side effects, were mild or moderate. Most common serious events were CRS, fever and bone pain. Most people had fewer signs of the cancer after taking talquetamab, and the response was similar between the 2 doses. The median duration of response at the 2 identified doses was 8-10months. Most of the side effects people experienced when taking talquetamab were mild or moderate. Most people who took talquetamab responded to the treatment even though they hadn't responded or stopped responding to previous multiple myeloma treatments or stopped taking those treatments because they were unable to tolerate them. These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.

Spontaneous Skin Infection Secondary to Mycobacterium abscessus Var Massiliense in An Immunocompetent Patient

M. abscessus var. abscessus and M. abscessus var. massiliense are fast growing non-tuberculous mycobacteria that cause skin and soft tissue infections. We present a 32-year-old female that initiated her current condition two years ago prior her medical assessment due to an event of cellulitis in the front part of her legs and later on being in contact with contaminated water. Two weeks later after the exposure she developed a dermatosis in the same region characterized by disabling pain, intermittent fever and edema without achieving improvement after being treated with multiple topic treatments. For these reasons, extension studies were carried out to get to the diagnosis of infection related to Mycobacterium abscessus var. massiliense, this gave the opportunity to give a successful therapeutic approach. Finally, after being treated for a month, an adequate evolution was obtained.

The semiconstrained DRUJ prosthesis: blessing or curse?

There are numerous operative procedures to treat osteoarthritic changes or a significant instability of the distal radioulnar joint (DRUJ). The key problem of most methods is the destabilization of the forearm leading to secondary painful impingement between the radius and ulna, as well as a significant limitation of forearm rotation. The Aptis-Prosthesis designed by Scheker represents a complete substitute for the DRUJ. It is mostly used after the failure of various treatment options to solve the primary problems (arthritis, instability). We have used this type of prosthesis mostly after multiple operative treatments for more than 25years. In the following retrospective study, we analyzed the data of patients that received an Aptis-prosthesis between 2016 and 2021. We have implanted this prosthesis in 13 cases (11 female, 2 male). Routinely, we document the clinical outcome concerning range of motion (ROM), grip strength, and pain according to numeric rate scaling (NRS) after more than 12months (month 12-24). In addition, complications, osseous changes, and the rate of loosening of the prosthesis were registered. Furthermore, DASH-Score and patients ' satisfaction were evaluated. Also-as with other implants-follow-up x-rays were performed. Removal or significant revision of any of the prostheses was not needed. The ROM was 68.1° ± 19.7° for pronation and 72.3° ± 20.9° for supination, grip strength amounted to 27.7kg ± 11.0kg equaling 83% of the contralateral side. NRS was 0 at rest and 1.2 (0-2) under weight-bearing. A lysis margin of the radial tap was noted in the radiological examination in 2 patients but without any signs of loosening. The DASH-Score added up to 31.8 ± 13.8 (13-55). All patients were satisfied or very satisfied having this implant. The semiconstrained Aptis-prosthesis is a safe and efficient treatment option after failed DRUJ surgeries. It is striking that of the 20 implanted prostheses no significant revision or explantations were necessary over a period of 25years.

Transcranial histotripsy parameter study in primary and metastatic murine brain tumor models

Objective This study investigated the effect of various histotripsy dosages on tumor cell kill and associated bleeding in two murine brain tumor models (glioma [Gl261] and lung metastasis [LL/2-Luc2]). Methods and materials GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10–20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4–6 h post-treatment. Results All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×108) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10–20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups. Conclusions Our results suggest that a lower number of histotripsy pulses at fewer focal locations can achieve substantial tumor kill while minimizing hemorrhage.

Practice patterns in the management of pediatric iliofemoral arterial thrombosis

BackgroundAcute arterial thrombosis can be life- and limb-threatening. Most pediatric patients with iliofemoral arterial thrombosis are treated successfully with medical therapy; however, expert consensus is limited, and many recommendations are based on the extrapolation of adult data. We aim to understand treatment patterns and long-term outcomes after pediatric acute iliofemoral arterial thrombosis, from which management recommendations can be informed. MethodsA single-institution retrospective study of pediatric patients diagnosed with iliofemoral arterial thrombosis from 2009 to 2018 was performed. Multiple parameters of management and follow-up were evaluated. Children anticoagulated for ≤28 days versus >28 days were compared. Data analysis used Fisher exact and Mann-Whitney U tests. ResultsTwo hundred thirty-six children were included. Median age at diagnosis was 65 days (interquartile range 17–163), with 207 diagnosed as infants, 15 diagnosed between 1 to 2 years, and 14 diagnosed between 2 to 16 years. The median treatment duration was 28 days (interquartile range 13–42); patients treated for >28 days had a longer time for thrombus resolution, and more follow-up ultrasounds were performed. Limb length discrepancy did not differ between the groups (1.0% vs 6.3%, P = .06), and no patients were documented to have developed peripheral arterial disease over a median 6.5-year follow-up. Multiple treatment strategies were employed, the most common being heparin bridged to enoxaparin (25.0%) and enoxaparin monotherapy (21.6%). Eight patients (3.4%) underwent surgical intervention. ConclusionPediatric iliofemoral arterial thrombosis is primarily a disease of infants treated adequately with heparin or enoxaparin, infrequently requires surgical intervention, and is rarely associated with long-term complications. When guided by thrombus resolution on ultrasound, a four-week or shorter course of anticoagulation does not increase the need for surgical intervention or long-term complications.

Multiple laccase-mediator system treatments for carbonaceous matter degradation in double refractory gold ore

Double refractory gold ore contains a higher level of gold than general ore but has been ignored in industry due to economic reasons. To improve gold recovery from double refractory gold ore (DRGO), the sulfides must be oxidized to release gold grains and the carbonaceous matter must be degraded to minimize “preg-robbing” during cyanidation. Recently, the degradation of carbonaceous matter in DRGO by enzymatic reactions has gained extensive interest owing to its environmental friendliness. Reportedly, laccase using 1-hydroxybenzotriazole hydrate (HBT) as an electron mediator can improve gold extraction from DRGO. In the present study, multiple-divided additions of the laccase-mediator system (LMS) are performed to maintain the enzyme activity, thus resulting in an improvement of gold extraction to 86.1%, compared with performing single addition with the same final dose, which yields a gold extraction of only 67.0%. However, multiple-divided additions of a higher dose of LMS decrease the gold extraction. The total dose of laccase is optimized to 11.87 U/100 mL of 5.0 g pretreated DRGO with a C content of 5.2%. These interesting results are comprehensively interpreted by combining different characterization methods for natural carbonaceous matter, including thermogravimetry-differential thermal analysis, Raman spectroscopy, and three-dimensional fluorescence spectrometry. This LMS proposed represents a novel approach worthy of further attention, especially in understanding carbon science in hydrometallurgy.

The Role of Salvage Radical Prostatectomy in Patients with Radiation-Resistant Prostate Cancer.

There are multiple treatment strategies for patients with localized prostate adenocarcinoma. In intermediate- and high-risk patients, external beam radiation therapy demonstrates effective long-term cancer control rates comparable to radical prostatectomy. In patients who opt for initial radiotherapy but have a local recurrence of their cancer, there is no unanimity on the optimal salvage approach. The lack of randomized trials comparing surgery to other local salvage therapy or observation makes it difficult to ascertain the ideal management. A narrative review of existing prospective and retrospective data related to salvage radical prostatectomy after radiation therapy was undertaken. Based on retrospective and prospective data, post-radiation salvage radical prostatectomy confers oncologic benefits, with overall survival ranging from 84 to 95% at 5 years and from 52 to 77% at 10 years. Functional morbidity after salvage prostatectomy remains high, with rates of post-surgical incontinence and erectile dysfunction ranging from 21 to 93% and 28 to 100%, respectively. Factors associated with poor outcomes after post-radiation salvage prostatectomy include preoperative PSA, the Gleason score, post-prostatectomy staging, and nodal involvement. Salvage radical prostatectomy represents an effective treatment option for patients with biochemical recurrence after radiotherapy, although careful patient selection is important to optimize oncologic and functional outcomes.

Healthcare professionals’ views on shared decision-making in plastic surgery in the Netherlands

In shared decision-making (SDM), patients and healthcare professionals (HCPs) reach a joint clinical decision based on the best available evidence and the patient's preferences. SDM seems particularly valuable in plastic surgery, as often multiple treatment options are available. This cross-sectional online survey study aimed to assess HCPs' views and knowledge about SDM, identify facilitators and barriers of SDM, and determine specific requirements for SDM within plastic surgery. Participants were HCPs working in plastic surgery in the Netherlands. Participant characteristics, SDM knowledge, perceived facilitators and barriers, and requirements were assessed using a custom-made online survey. Two researchers thematically analyzed qualitative data. We received 124 responses (with a response rate of 23%). Most respondents were attending plastic surgeons (79%), and 60% had more than 10 years of experience. Almost all respondents considered SDM important (91%), and most (78%) indicated that they applied SDM during consultations. However, only 15% of the HCPs showed a comprehensive understanding of the principle of SDM. Sufficient time, available sources of information (on treatment options and SDM), and decision support tools were identified as important requirements for SDM. Despite the positive attitudes toward SDM, there is a clear need for SDM training of HCPs, uniform sources of information and guidelines, and improved awareness and availability of decision support tools. National plastic surgery societies can play a crucial role in improving SDM-related knowledge, the availability of information and decision support tools, and the implementation of SDM in the field of plastic surgery.

An Improved Dunnett’s Procedure for Comparing Multiple Treatments with a Control in the Presence of Missing Observations

Dunnett’s procedure has been frequently used for multiple comparisons of group means of several treatments with a control, in drug development and other areas. However, in practice, researchers usually face missing observations when performing Dunnett’s procedure. This paper presents an improved Dunnett’s procedure that can construct unique ensemble confidence intervals for comparing group means of several treatments with a control, in the presence of missing observations, using a derived multivariate t distribution under the framework of Rubin’s rule. This procedure fills the current research gap that Rubin’s repeated-imputation inferences cannot adjust for multiplicity and, thereby, cannot give a unified confidence interval to control the family-wise error rate (FWER) when dealing with this problem. Simulation results show that the constructed pooled confidence intervals archive nominal joint coverage and the interval estimations preserve comparable precision to Rubin’s repeated-imputation inference as the missing rate increases. The proposed procedure with propensity-score imputation method is shown to produce more accurate interval estimations and control the FWER well.

Adherence, per-protocol effects, and the estimands framework.

In the statistical literature, treatment effects in clinical trials are frequently described as either ITT or per-protocol effects. The estimand given for the per-protocol effect is the effect in adherers, where adherers are typically defined as adhering to the intervention as specified in the trial protocol. This dichotomy of treatment effects is unhelpful when there are in reality multiple treatment effects that can be of clinical interest and relevance. The terms "per-protocol" and "adherence" are confusing to non-statisticians. Protocols always allow for discontinuation of randomized treatment so participants discontinuing have actually followed the protocol. When rescue or additional medication is available, the effect in adherers could mean the effect regardless of use of these medications or the effect in a counterfactual world where the participant did not take the medication. Adherence can mean continuing to be prescribed a treatment or some arbitrary level of compliance with a medication that has been prescribed. The ICH E9 (R1) estimands framework provides an improved alternative for the description of treatment effects in clinical trials. Identification of important intercurrent events and the strategy used to handle these events is key to determining the treatment effect. When designing a trial, estimands should be properly defined according to this framework. It is time the statistical literature abandoned describing treatment effects as the effect in adherers or the per-protocol effect.

Drug interactions and drug-food interactions in patients receiving diabetes mellitus treatment

Drug interaction is the change of a drug's effects by the preceding and/or concurrent administration of a different substance (precipitant drug). Drug interactions may either intensify or weaken the effects that one or both medications are supposed to have. Any drug's therapeutic, preventative, or diagnostic capabilities may change as a result. A major contributing factor to the prevalence and occurrence of adverse medication responses and adverse drug events might be drug interactions. Patients receiving drug combinations or polypharmacy or suffering from co-morbid diseases like diabetes, hypertension, peptic ulcer, fungal infections, and neurodegenerative disorders have a much higher rate of occurrence and incidence of drug interactions. As these patients receive prolonged and multiple treatments, the risk of drug interactions rises. Conclusion: Drug interactions are more likely to occur in diabetes patients who are also getting a mix of medications for diabetic complications. As a result, the frequency of drug interactions is fast increasing. Because of its increasing incidence and the corresponding rise in morbidity and mortality, diabetes mellitus has been regarded as a major public health concern globally. The major goal of this review study is to highlight the different medication interactions that may occur between drugs and foods, as well as to record any unfavorable side effects of other treatments used in conjunction with antidiabetic drugs in diabetic patients.

A Multiple Synergic Treatment for Non-Healing Ulcer Management in a Patient with Klippel–Trenaunay Syndrome

A Multiple Synergic Treatment for Non-Healing Ulcer Management in a Patient with Klippel–Trenaunay Syndrome

Tumor Vascular Destruction and cGAS-STING Activation Induced by Single Drug-Loaded Nano-Micelles for Multiple Synergistic Therapies of Cancer.

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS-STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic-co-glycolic) acid co-polymer (PLGA-PEG), obtaining PLGA-PEG/DMXAA (PPD) nanoparticles to induce the tumor-specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD-mediated therapies could trigger potent systemic anti-tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS-STING pathway. Together with anti-PD-L1, PPD-mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug-loaded nano-micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.

Limb-Girdle Muscular Dystrophies Classification and Therapies.

Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. This review article presents 39 genes associated with LGMDs. Some forms are inherited in a dominant fashion, while for others this occurs recessively. The classification of LGMDs has evolved through time. Lately, to be considered an LGMD, the mutation has to cause a predominant proximal muscle weakness and must be found in two or more unrelated families. This article also presents therapies for LGMDs, examining both available treatments and those in development. For now, only symptomatic treatments are available for patients. The goal is now to solve the problem at the root of LGMDs instead of treating each symptom individually. In the last decade, multiple other potential treatments were developed and studied, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing.

Triploid Pacific oysters exhibit stress response dysregulation and elevated mortality following heatwaves.

Polyploidy has been suggested to negatively impact environmental stress tolerance, resulting in increased susceptibility to extreme climate events. In this study, we compared the genomic and physiological response of diploid (2n) and triploid (3n) Pacific oysters (Crassostrea gigas) to conditions present during an atmospheric heatwave that impacted the Pacific Northwestern region of the United States in the summer of 2021. Climate stressors were applied either singly (single stressor; elevated seawater temperature, 30°C) or in succession (multiple stressor; elevated seawater temperature followed by aerial emersion at 44°C), replicating conditions present within the intertidal over a tidal cycle during the event. Oyster mortality rate was elevated within stress treatments with respect to the control and was significantly higher in triploids than diploids following multiple stress exposure (36.4% vs. 14.8%). Triploids within the multiple stressor treatment exhibited signs of energetic limitation, including metabolic depression, a significant reduction in ctenidium Na+ /K+ ATPase activity, and the dysregulated expression of genes associated with stress response, innate immunity, glucose metabolism, and mitochondrial function. Functional enrichment analysis of ploidy-specific gene sets identified that biological processes associated with metabolism, stress tolerance, and immune function were overrepresented within triploids across stress treatments. Our results suggest that triploidy impacts the transcriptional regulation of key processes that underly the stress response of Pacific oysters, resulting in downstream shifts in physiological tolerance limits that may increase susceptibility to extreme climate events that present multiple environmental stressors. The impact of chromosome set manipulation on the climate resilience of marine organisms has important implications for domestic food security within future climate scenarios, especially as triploidy induction becomes an increasingly popular tool to elicit reproductive control across a wide range of species used within marine aquaculture.

Topical Clascoterone: A Potential Treatment for a Hidradenitis Suppurativa Subgroup

This commentary is a follow-up to the article “Use of topical clascoterone for the treatment of hidradenitis suppurativa [1]”. In this article, we described the successful treatment of a 23-year-old female with Hurley stage 1 Hidradenitis Suppurativa (HS) with topical clascoterone 1% cream [1]. With a waxing and waning course, HS is a chronic and debilitating inflammatory skin disease that often requires multiple treatments [2]. Inadequately treated painful nodules and abscesses in intertriginous areas can subsequently develop into fistulae, draining sinus tracts, and scars [2,3]. Thus, while many clinical trials are focused on the population of patients with moderate to severe disease, treatment of HS early in the disease course is of paramount importance, to improve both the characteristic HS lesions and the quality of life of affected patients [2].

Management of Enterocutaneous Fistula with VAC therapy. Case report and literature review

Enterocutaneous fistulas are a rare complication of the usual abdominal-intestinal surgical practice that represent a challenge for the surgeon in his treatment that is generally stagnant due to the progressive deterioration of the condition of the patient suffering from the fistula. There are multiple treatment modalities and accepted schemes. In recent years, VAC therapy has gained ground in this pathology,We presenting the case of a 60-year-old man who presented enterocutaneous fistula after ileostomy closure as a postoperative complication, which is managed with therapy. VAC.

Two-stage response adaptive randomization designs for multi-arm trials with binary outcome

ABSTRACT In recent years, adaptive randomization methods have gained significant popularity in clinical research and trial design due to their ability to provide both efficiency and flexibility in adjusting the statistical procedures of ongoing clinical trials. For a study to compare multiple treatments, a multi-arm two-stage design could be utilized to select the best treatment from the first stage and further compare that treatment with control in the second stage. The traditional design used equal randomization in both stages. To better utilize the interim results from the first stage, we propose to develop response adaptive randomization two-stage designs for a multi-arm clinical trial with binary outcome. Two allocation methods are considered: (1) an optimal allocation based on a sequential design; (2) the play-the-winner rule. Optimal multi-arm two-stage designs are obtained under three criteria: minimizing the expected number of failures, minimizing the average expected sample size, and minimizing the expected sample size under the null hypothesis. Simulation studies show that the proposed adaptive design based on the play-the-winner rule has good performance. A phase II trial for patients with pancreas adenocarcinoma and a germline BRCA / PALB2 mutation was used to illustrate the application of the proposed response adaptive randomization designs.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data

IntroductionPeople with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach...

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20mg/0.4ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses≥30mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20mg/0.4ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20mg dose was developed and is available for use in clinical practice.