2 Minute Medicine Rewind July 29, 2024

Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

1. Six-year follow-up data reveal that ME/CFS patients treated with cyclophosphamide reported greater and more lasting improvements than those treated with rituximab or placebo.

Evidence Rating Level: 2 (Good) 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with unknown etiology, no validated biomarker, and no approved effective treatment. In the past, some ME/CFS patients with cancer have reported that their cancer drug treatment, which included the cytotoxic drug cyclophosphamide or rituximab, unexpectedly had beneficial effects on their ME/CFS symptoms. These observations suggest that ME/CFS may be associated with an autoimmune pathomechanism involving B cells/plasma cells and antibodies. To explore the long-term course of disease symptoms and possible late side effects of treatment, this study provided six-year follow-up data for patients with ME/CFS enrolled in the two clinical trials RituxME and CycloME. The RituxME follow-up study was conducted between 01.05.2021 to 01.09.2021, six years after inclusion, and the CycloME follow-up study was conducted between 25.10.2022 to 31.01.2023, six to seven years after inclusion. The RituxME randomized, double-blind and placebo-controlled phase III trial included 151 patients: 77 in the rituximab and 74 in the placebo group; however, patients were informed of their intervention group allocation after 24 months. The CycloME open-label trial included 40 patients who had knowledge of their active treatment the entire time. Both trials had similar inclusion time-period, inclusion criteria, except that patients with mild ME/CFS were not included in CycloME, and patients with disease duration > 15 years were not included in RituxME. For the six-year follow-up study, patient-reported outcome measures (PROMs) were used to compare values at baseline, at 18 months, and at six-year follow-up from the CycloME and the RituxME trials. In total this study included 112/148 (75.7%) of eligible participants from the RituxME trial, 58 in the rituximab group (mean age at baseline ±SD = 38.2 ±12.2 years, female N (%) = 48 (83%)) and 54 in the placebo group (mean age at baseline ±SD = 36.2 ±11.3 years, female N (%) = 48 (89%)), and 34/36 (94.4%) from the CycloME trial (mean age at baseline ±SD = 41.4 ±10.4 years, female N (%) = 26 (76%). Mean short Form 36 Physical Function (SF-36 PF) scores at baseline, 18 months, and at six years were 32.9, 42.4, and 45.5 in the RituxME rituximab group, 32.3, 45.5, and 43.1 in the RituxME placebo group, and 35.4, 54.4, 56.7 in the CycloME trial. At six-year follow-up, the percentage of patients with SF-36 PF > 70 was higher for patients treated with cyclophosphamide (44.1%) compared to those treated with rituximab (27.6%) or placebo (20.4%). The percentage of patients with SF-36 PF > 90 (within normal range) was also higher for patients treated with cyclophosphamide (17.6%) compared to those treated with rituximab (8.6%) or placebo (7.4%). Furthermore, a lower percentage of patients treated with cyclophosphamide (5.9%) had worsening symptoms at six years, indicated by a reduction in SF-36 PF of 20 points lower from baseline), compared to those treated with rituximab (10.3%) or placebo (14.8%). No serious unexpected adverse reactions were observed. Overall, study results support the hypothesis that ME/CFS may be associated with an autoimmune pathomechanism which may be targetable by immunomodulatory drugs. Despite encouraging results in the CycloME trial, cyclophosphamide should not be used for ME/CFS patients outside of clinical trials until future research is available as it carries toxicity concerns.

ZY5301 Tablet vs Placebo for Treatment of Chronic Pelvic Pain After Pelvic Inflammatory Disease A Phase 2 Randomized Clinical Trial

1. Patients with pelvic inflammatory disease randomized to receive 2 weeks of ZY5301 tablet treatment had significantly reduced remission of chronic pelvic pain in women, with acceptable tolerability.

2. A ZY5301 dose of 600 mg/d was recommended for the phase 3 trial.

Evidence Rating Level: 1 (Excellent)

Chronic pelvic pain (CPP) is a common sequela of pelvic inflammatory disease (PID) and its management is challenging due to a lack of available established treatments. Jincaopian (ZY5301) is a part preparation extracted from Ajuga decumbens Thunb. (jingucao), a medicinal plant native to China commonly used to treat chronic pelvic inflammation and hysteromyoma. ZY5301 is rich in bioactive components involved in anti-inflammatory activities. Phase 1 of this clinical trial evaluated the safety of ZY5301 administration and recommended a maximum daily dose of 1200mg for the phase 2 clinical trial. This multicenter, placebo-controlled, double-blind, dose-parallel, phase 2 randomized clinical trial evaluated the efficacy and safety of ZY5301 for CPP treatment in women with PID. Women aged 18-55 with PID were recruited and 180 eligible participants were randomized 1:1:1 to receive ZY5301 300mg/d, ZY5301600 mg/d, or placebo orally 3 times a day for 12 weeks. Visual analog scale (VAS) scores were the main measure used to evaluate the efficacy outcome. Safety was evaluated by the occurrence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs). Due to patients lost to follow-up (1.7%), a total of 177 were analyzed with 60 patients in the ZY5301 300 mg/d group (mean [SD] age, 37.4 [8.1] years), 58 in the ZY5301 600 mg/d group (mean [SD] age, 37.1 [7.9] years), and 59 in the placebo group (mean [SD] age, 38.9 [7.3] years). After 12 weeks of treatment, the mean (SD) change in VAS score from the baseline was −2.1 (1.7) points, −3.5 (1.5) points, and −3.8 (1.7) points in the placebo, ZY5301 300 mg/d, and ZY5301 600 mg/d groups, respectively (P < .001), with a significant difference between the active treatment groups and the placebo group (P < .001), but not between 300 mg/d and 600 mg/d groups. The pain remission rates at week 12 were 43.3% and 53.5% in the ZY5301 300 mg/d and ZY5301 600 mg/d groups, respectively, a significant difference compared with the placebo group (11.9%; P < .001). Although the ZY5301 600 mg/d group had better efficacy than the ZY5301 300 mg/d group, the difference was not significant. Both ZY5301 300 mg/d and 600 mg/d had a good safety profile as there were no significant differences in TEAEs and TRAEs between the ZY5301 groups and the placebo group, and no adverse reactions specific to ZY5301 tablets were observed. Overall, the results of this phase 2 clinical trial found that 12 weeks of ZY5301 tablet treatment led to a significant remission of CPP in women with PID, with acceptable tolerability. Pain remission rate at week 12 was chosen as the primary efficacy end point, and ZY5301 600 mg/d was recommended as the therapeutic dosage for the phase 3 clinical trial.

Overground Gait Training With a Wearable Robot in Children With Cerebral Palsy A Randomized Clinical Trial

1. Overground Robot-assisted gait training (RAGT), using a new torque-assisted wearable exoskeletal robot significantly improved gross motor function and gait pattern in children with cerebral palsy (CP).

2. RAGT may complement standard rehabilitation by providing adequate assistance and therapeutic support to children with CP.

Evidence Rating Level: 1 (Excellent)

As children with cerebral palsy (CP) experience gait impairments that significantly impact daily activities and social integration, a key therapeutic goal in children with cerebral palsy (CP) is to enhance their walking ability. The technologically advanced robot-assisted gait training (RAGT) may contribute to effective rehabilitation; however, evidence on their effectiveness in children with CP is weak and inconsistent. Specifically, there is a lack of multicenter large-scale randomized clinical trials examining the effects of overground wearable exoskeleton RAGT in children with CP. Torque-assisted wearable RAGT device is a recently developed robotic suit that allows training on various terrains and can assist joint motion based on assist-as-needed control; however, few have been tailored for children. This prospective, single-blinded randomized clinical trial thus investigated the effects of overground RAGT using an untethered, torque-assisted, wearable exoskeletal robot in children with CP from 5 pediatric rehabilitation centers in Korea. 90 children with CP aged 6 to 15 years and 98 to 150 cm tall were randomly assigned 1:1 to the intervention or control group. The experimental group underwent 30 minutes of RAGT, whereas the control group underwent 30 minutes of conventional physical therapy (PT) 3 days per week for 6 weeks. Functional and kinematic assessments were performed for all patients at baseline, at the end of the 6-week intervention, and after the 4-week follow-up to investigate effect maintenance. In total, 78 participants completed the intervention, with 37 participants in the RAGT group (mean [SD] age, 9.57 [2.38] years; 18 [48.6%] female), and 41 participants in the control group (mean [SD] age, 9.32 [2.37] years; 15 [36.6%] female). Post-intervention assessments found that compared to the control group, the RAGT group showed significantly improved gross motor function as measured by the GMFM-88 total (mean difference, 2.64; 95% CI, 0.50-4.78), dimension E (mean difference, 2.70; 95% CI, 0.08-5.33), and GMFM-66 (mean difference, 2.52; 95% CI, 0.42-4.63) scores. Changes in Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI-CAT) responsibility domain scores were also greater in the RAGT group compared with the control group (mean difference, 2.52; 95% CI, 0.42-4.63), indicating independence in daily living. As immediate increases in the GMFM-88 total, dimension E, and GMFM-66 scores in the RAGT group were 2.7%, 2.3%, and 1.2%, respectively, minimal clinically important difference (MCID) thresholds were achieved after the intervention, indicating clinically significant improvements. Furthermore, compared to the control at the 4-week follow-up, the RAGT group showed significantly greater improvements in balance control (mean difference, 1.48; 95% CI, 0.03-2.94) and Gait Deviation Index (mean difference, 6.48; 95% CI, 2.77- 10.19). Overall, study results suggest that this new torque-assisted wearable exoskeletal robot can provide adequate assistance and therapeutic support that can complement standard rehabilitation for children with CP.

Personal protective effect of wearing surgical face masks in public spaces on self-reported respiratory symptoms in adults: pragmatic randomised superiority trial

1. Wearing surgical face masks was superior to not wearing surgical face masks in reducing the risk of respiratory symptoms over 14 days among Norwegian adults.

Evidence Rating Level: 2 (Good)

During the COVID-19 pandemic, wearing face masks was a widely implemented public health measure to limit the spread of the virus; however, its effectiveness in lowering the risk of respiratory infections is mixed. This pragmatic parallel two-arm individually randomized superiority trial thus evaluated the personal protective effect of wearing versus not wearing surgical face masks in public spaces over 14 days on self-reported symptoms consistent with a respiratory infection. This study was conducted in Norway between 10 February 2023 and 27 April 2023, after the most acute phase of the COVID-19 pandemic, but during the normal influenza season in the Nordic countries. 4647 adults > 18 years of age were randomised 1:1 to the intervention arm and control arm. Participants in the intervention arm were assigned to wear a surgical face mask in public spaces (eg, shopping centres, streets, public transport) over a 14-day period. Participants in the control arm were assigned to not wear a surgical face mask in public places. Among the participants randomized, 4575 participants were included in the intention-to-treat analysis, with 2313 (50.6%) in the intervention arm (mean age ±SD = 51 ±15.2) years, female N (%) =1423 (61.5%)) and 2262 (49.4%) in the control arm (mean age ±SD = 51 ±16.3 years, female N (%) = 1365 (60.3%)). Number of participants that self-reported respiratory symptoms consistent with respiratory infection were 163 (8.9%) in the intervention arm and 239 (12.2%) in the control arm. Compared to not wearing a mask, wearing a mask reduced the odds and absolute risk of self-reported symptoms (marginal odds ratio (OR) 0.71, 95% CI 0.58 to 0.87; P = 0.001; absolute risk difference −3.2%, 95% CI −5.2% to −1.3%; P < 0.001). No statistically significant effect was found on self-reported or registered COVID-19 infection. Overall, study results suggest that wearing face masks may be effective in reducing the incidence of self-reported respiratory symptoms consistent with respiratory tract infections.

Use of fluoroquinolones and the risk of aortic and mitral regurgitation: A nationwide case-crossover study

1. Patient data from a Taiwanese national database demonstrated that those who took fluoroquinolones had a greater risk of aortic and mitral regurgitation.

2. When excluding patients treated for pneumonia however, patients who took fluoroquinolones had a greater risk of mitral but not aortic regurgitation.

Evidence Rating Level: 2 (Good)

Fluoroquinolones (FQs) are broad-spectrum antibiotics used to treat a variety of infections. There is conflicting evidence for whether FQs increase the risk of aortic and mitral regurgitation. This nationwide case-crossover study thus examined the association between FQs and the risk of aortic and mitral regurgitation. Study data was retrieved from the Longitudinal Health Insurance Database 2000 (LHID2000), a subset of the National Health Insurance Research Database (NHIRD) that has been validated to be representative of the general Taiwan population. Patients over 20 years old diagnosed with aortic regurgitation (AR) or mitral regurgitation (MR) between January 1, 2000, and December 31, 2012 were included. A unidirectional case-crossover design was used without selecting controls from an external population. Antibiotics of primary interest were oral form drugs of fluoroquinolones (FQs). A total of 26,650 patients were included in the study and separated into subcohorts of patients with MR alone (n = 20,884, mean age ±SD = 49.9 ±17.6 years, male N (%) = 7,381 (35.4%)), AR alone (n = 3,940, mean age ±SD = 70.9 ± 12.9 years, male N (%) = 1,955 (49.6%)), or combined AR and MR (n = 1,866, mean age ±SD = 65.9 ± 13.9 years, male N (%) = 784 (42.0%)). Before exclusion of pneumonia diagnosed within 2 months before the index date, patients who took FQs had a significantly greater risk of AR or MR (adjusted odds ratio [aOR] 1.51, 95% confidence interval [CI] 1.30–1.77), any AR (combined AR and MR) (aOR 1.50, 95% CI 1.10–2.04), and any MR (combined AR and MR) (aOR 1.37, 95% CI 1.16–1.62). After the exclusion of pneumonia, FQs exposure was no longer significantly associated with a larger risk of any AR (P = 0.101); however, it remained significantly associated with a greater risk of MR (aOR 1.38, 95% CI 1.17–1.62) and any MR (aOR 1.25, 95% CI 1.05–1.48). Overall, study findings provide evidence that there may be an association between the use of FQs and valvular conditions. Although further information is needed to validate these findings, this may be used to inform the prescribing of physicians for patients who have a history of, or are at risk of valvular heart conditions.

Image: PD

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