BACKGROUND: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China.
METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit.
RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses.
CONCLUSIONS: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA.
BACKGROUND: ClinicalTrials.gov identifier, NCT04419233.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase.
METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician\'s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively.
RESULTS: Although donepezil\'s superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937).
CONCLUSIONS: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

The present study aims to estimate the frequency of COVID 19 infections in vaccinated health personnel at a Los CObos Medical Center in Bogotá, Colombia. The percentage of people positive to the PCR test and their clinical characteristics were analyzed.
We performed a cross-sectional study. The primary study variable was the COVID vaccination registry. We analyzed sex, age, signs, and symptoms. Multivariable logistic regression was applied to assess changes over time and to identify variables associated with vaccination in target groups.
A cohort of 999 people working at Los Cobos Medical Center and followed from March to August 2021. The average age of this cohort was 37.0 years (devest = 10.5 years), 67.7 % were women. Two hundred eleven physicians, 287 nurses, 305 assistants, and 196 clerks follows. In addition, 8.4 % to be PCR positive after vaccination. The average age was 36.0 (devest = 23.4 years), 59 women and 25 men. Of these, 15 were administrative, 14 were doctors, 29 nurses, and 26 nursing assistants. The vaccination status found that 21.4 % do not vaccinates, 7.1 % were partially vaccinated, and 71.4 % with a complete schedule. When questioned about symptoms in these patients, 4.0 % were symptomatic, and 5.9 % were asymptomatic.
A recent epidemiological study involving 12,364 health workers with a mean age of 38 years quantifies the protection in six months from the vaccine. The presence of antibodies was associated with 83 % protection against active SARS-CoV-2 infection (PCR positivity during the study period), which confirms the existence of protective Immunity at levels comparable to those obtained by the approved vaccines; our study found effectiveness of 92.6 %. Higher than that found in this study, possibly explained by the characteristics of the individuals included.

Background: The infliximab biosimilar CT-P13 was approved in Thailand in 2015. Methods: This open-label, multicenter, post-marketing surveillance study evaluated the safety (events of special interest [ESIs]; primary end point) and effectiveness of 46 weeks of CT-P13 treatment according to routine practice in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA), with 1 year follow-up post-treatment. Results: 30 patients were enrolled (16 RA, 8 AS and 6 PsA). Infections were the most frequently reported study drug-related ESIs (2 RA and 2 AS). One patient with RA and one with PsA experienced infusion-related reactions. No cases of tuberculosis, malignancy (as expected, given 1 year follow-up), or drug-induced liver disease were reported. Disease activity improved across indications. Conclusion: CT-P13 was well tolerated and effective across indications.
Infliximab is one biological medicine used to treat inflammatory diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). CT-P13 is a near-identical copy, called a biosimilar, of the original (‘reference’) version of infliximab. CT-P13 is the first biosimilar to receive regulatory approval for treatment of the same three diseases from the European Medicines Agency (EMA) and US Food and Drug Administration. Biosimilarity means that CT-P13 does not differ from the original version of infliximab in clinically important ways, such as how safe it is and how well it works. CT-P13 and reference infliximab provided similar symptom relief during previous clinical trials, and both drugs caused similar side effects. It is important to monitor the safety and performance of CT-P13 when given during routine clinical practice, and in different ethnic populations, such as through the study reported here. Following regulatory approval in Thailand, 30 patients prescribed CT-P13 during routine clinical practice participated in this study. The study included 16 patients with RA, eight with AS and six with PsA. The patients took CT-P13 for 46 weeks and were monitored for a further year. Side effects of CT-P13 were as expected based on previous experience and did not raise any safety concerns. Based on the known safety profile of CT-P13, the study looked at some side effects in particular: infections were the most common of these side effects, experienced by 16 patients overall (seven patients with RA, five patients with AS and four patients with PsA). CT-P13 improved symptoms for all of the diseases. The study suggests that CT-P13 can be given safely and reduces symptoms in Thai patients with AS, RA or PsA. Thai Clinical Trials Registry: TCTR20170817005 (www.thaiclinicaltrials.org/show/TCTR20170817005).

BACKGROUND: The use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) for acute musculoskeletal pain should be at the lowest effective dosage and for the shortest duration to minimize potential adverse effects. This study evaluated treatment satisfaction, effectiveness, and tolerability of a low-dose diclofenac epolamine 12.5-mg soft capsule formulation (DHEP 12.5-mg capsules) using patient-reported outcome measures in a real-life setting over a short period (3 days) in subjects with mild-to-moderate acute musculoskeletal pain.
METHODS: A prospective, open-label, phase IV clinical study in adult outpatients at hospital clinic departments/general practitioner\'s clinics at eight sites in Italy. The primary efficacy variable was the degree of satisfaction with treatment at 72 ± 7 h after initiation of treatment, assessed using the Overall Satisfaction Question of the Pain Treatment Satisfaction Scale (PTSS) and described by classic descriptive statistics. Secondary objectives were to evaluate the analgesic effect after the first administration and over time; the time to and satisfaction with the onset of pain relief, amount of and duration of pain relief; pain intensity differences over time; and safety and tolerability. The investigator\'s satisfaction with the treatment was also assessed. Subjects initially took 1-2 capsules of the study treatment and then one or two soft capsules every 4-6 h according to their needs. Not more than six soft capsules were to be taken in any 24-h period.
RESULTS: A total of 182 subjects (mean age, 56.2 years; 54.4% female) took ≥ 1 dose of DHEP capsule and were included in the full analysis set. The most common musculoskeletal conditions were arthralgia (39.0%) and low back pain (23.1%). All subjects completed the study, and 165/182 (90.7%, 95% CI 0.86, 0.95) were satisfied or very satisfied with the treatment at 72 ± 7 h after the first dose (primary efficacy variable). Similar percentages were recorded for treatment satisfaction concerning other efficacy parameters. The onset of the analgesic effect was rapid, with complete pain relief reached after a mean of 49.45 min. Investigators rated their overall treatment satisfaction as 92.9%. Treatment was well tolerated.
CONCLUSIONS: The low-dose (12.5 or 25 mg) oral diclofenac epolamine soft capsules formulation exerted rapid, effective, and safe analgesic activity in patients with mild-to-moderate musculoskeletal pain, with subjects\' overall satisfaction with treatment more than 90%.
BACKGROUND: EudraCT Number: 2018-004886-15 (Study 18I-Fsg08). Registered 04/09/2018.

Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML.
Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc).
Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia\'s formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively.
Fractionated GO dosing regimen (3 mg/m2/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO\'s known safety profile, and ADA presence appears unassociated with potential safety issues.
Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).

Background: Fibromyalgia is a chronic neurological condition characterized by widespread pain. The effectiveness of current pharmacological treatments is limited. However, several medications have been approved for phase IV trials in order to evaluate them. Aim: To identify and provide details of drugs that have been tested in completed phase IV clinical trials for fibromyalgia management in adults, including the primary endpoints and treatment outcomes. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Method: Publicly available and relevant phase IV trials registered at ClinicalTrials.gov were analyzed. The uses of the trialed drugs for fibromyalgia were reviewed. Results: As of 8 August 2022, a total of 1,263 phase IV clinical trials were identified, of which 121 were related to fibromyalgia. From these, 10 clinical trials met the inclusion criteria for the current study. The drugs used in phase IV trials are milnacipran, duloxetine, pregabalin, a combination of tramadol and acetaminophen, and armodafinil. The effectiveness of the current pharmacological treatments is apparently limited. Conclusion: Due to its complexity and association with other functional pain syndromes, treatment options for fibromyalgia only are limited and they are designed to alleviate the symptoms rather than to alter the pathological pathway of the condition itself. Pain management specialists have numerous pharmacologic options available for the management of fibromyalgia.

BACKGROUND: Achieving prolonged therapy with parenteral proteasome inhibitors (PIs) in clinical practice can be challenging.
OBJECTIVE: To increase the duration of PI-based therapy, improve outcomes, and maintain QoL.
METHODS: Prospective study (NCT03173092) evaluating iCT from parenteral bortezomib-based induction to all-oral IRd. IRd was received for up to 39 cycles or until progression/toxicity (Manda CLML 2020). Interim data (N=101) were previously reported (Rifkin ASH 2021). We report results from the fully accrued study cohort (enrollment completed, May 2021; N=141).
METHODS: US community sites.
METHODS: Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients with ≥stable disease after 3 cycles of bortezomib-based induction.
METHODS: Primary endpoint: 2-year progression-free survival (PFS) rate. Other endpoints included: key secondary, overall response rate (ORR; partial response [PR]+very good PR [VPGR]+complete response [CR]) and duration of treatment (DOT); secondary, overall survival (OS), safety, and QoL.
RESULTS: At Feb-28-2022, 140 patients (median age, 72.5 years [range, 48-90]; 79% ≥65 years; 42% ≥75 years) had received IRd; 94% had ≥1 comorbidity at IRd initiation. Median follow-up was 20.0 months. 2-year PFS was 69% (95% confidence interval [CI]: 59-77%). ORR was 62% (CR, 8%; VGPR, 24%; PR, 30%) after bortezomib-based induction, increasing to 78% (CR, 33%; VGPR, 27%; PR, 18%) after iCT. At data cut-off, 28 patients (20%) were ongoing on IRd, median DOT with IRd was 10.0 months, and median duration of all PI-based treatment was 12.7 months. 2-year OS was 85% (95% CI: 76-90%). 66% of patients had grade ≥3 treatment-emergent adverse events (TEAEs) (treatment-related, 36%), 44% had serious TEAEs (treatment-related, 14%), and 6 on-study deaths had occurred. Most common TEAEs (any-grade/grade ≥3) were diarrhea (48%/9%), peripheral neuropathies not elsewhere classified (39%/4%), and fatigue (34%/4%). Modification/discontinuation of ixazomib, lenalidomide, or dexamethasone due to TEAEs occurred in 59%/15% of patients. Patient-reported QoL (EORTC QLQ-C30 Global Health Status/QoL score) and treatment satisfaction (TSQM-9 Global Satisfaction, Effectiveness, and Convenience scores) were maintained on IRd.
CONCLUSIONS: Improved responses and promising PFS and OS were seen following iCT to IRd in these mostly elderly, community-treated patients with NDMM and comorbidities, with no adverse impact on QoL/treatment satisfaction. Safety results were consistent with previous reports.

BACKGROUND: Increasing the duration of proteasome inhibitor-based treatment could improve outcomes in NDMM patients.
OBJECTIVE: To evaluate the comparative effectiveness of in-class transition (iCT) to IRd following V-based induction vs continued V-based therapy.
METHODS: A secondary analysis of patients from US MM-6, (NCT03173092; Manda CLML 2020; phase IV, single-arm study) which is evaluating iCT from parenteral V to all-oral IRd (\'IRd\' cohort), and a comparator (\'V-based\') cohort of patients from INSIGHT MM (Costello Future Onc 2019; prospective, observational study) who continued to receive V-based therapy.
METHODS: Routine community clinical practice in the US.
METHODS: Non-transplant-eligible NDMM patients with ≥stable disease after 3 cycles of V-based induction and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 from US MM-6 (IRd cohort, n=100) and INSIGHT MM (V-based cohort, n=111).
METHODS: First-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. Kaplan-Meier methodology was used for time-to-event outcomes. To reduce imbalances between cohorts, inverse probability of treatment weighting (IPTW) was used.
RESULTS: Results are presented as IRd vs V-based cohorts. After IPTW, median age was 75.0 vs 74.8 years; 56.7 vs 51.3% of patients were male, 37.4 vs 29.1% had ECOG PS of 2, and 48.8 vs 41.4% were International Staging System stage III at diagnosis. Initial induction therapy was VRd/V-cyclophosphamide (C)-d/VRCd in 79.5/17.7/2.8 vs 77.3/19.5/3.1% of patients. ORRs were 73.2 (95% confidence interval [CI]: 65.0-81.3) vs 57.5% (95% CI: 47.9-67.1; p<0.0001). Median DOT was 10.8 (95% CI: 6.5-24.4) vs 5.3 months (95% CI: 4.3-7.0; p<0.0001; median follow-up, 20.3 vs 15.8 months). Median PFS and OS were not estimable in either cohort. 24-month PFS rates were 85.7 (95% CI: 68.1-94.0) vs 76.5% (95% CI: 62.6-85.8). 24-month OS rates were 94.0 (95% CI: 77.7-98.5) vs 84.9% (95% CI: 70.6-92.6). Overall, 17.6% discontinued IRd and 24.4% discontinued V due to an adverse event.
CONCLUSIONS: In NDMM patients treated at US community oncology clinics, those who transitioned to IRd following 3 cycles of V-based induction had significantly higher ORR and longer DOT than those who continued to receive V-based therapy.

Exploratory experiments are widely characterized as experiments that do not test hypotheses. Experiments that do test hypotheses are characterized as confirmatory experiments. Philosophers have pointed out that research programmes can be both confirmatory and exploratory. However, these definitions preclude single experiments being characterized as both exploratory and confirmatory; how can an experiment test and not test a hypothesis? Given the intuition that some experiments are exploratory, some are confirmatory, and some are both, a recharacterization of the relationship between exploratory and confirmatory experimentation is needed. I discuss \'phase IV\' trials to show what this recharacterization could look like. Phase IV trials can be exploratory and confirmatory insofar as they concurrently test hypotheses and explore for unforeseen phenomena. Even if it is uncontroversial that a single experiment can have multiple aims, the recharacterization of the relationship between exploratory and confirmatory experimentation is still required for these aims to be held together coherently. I offer an alternative characterization of the relationship between exploratory and confirmatory experimentation where the former remains a distinct kind of experimentation but is not characterized as non-hypothesis-testing.