Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Phase Ib study of durvalumab (MEDI4736) in combination with carbon-ion radiotherapy and weekly cisplatin for patients with locally advanced cervical cancer (DECISION study): study protocol for a prospective open-label single-arm study.

INTRODUCTION: Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects. OBJECTIVE: We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer. METHODS AND ANALYSIS: This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Efficacy and Safety of Propranolol Gel for Infantile Hemangioma: A Randomized, Double-Blind Study.

We aimed to evaluate the efficacy and safety of propranolol gel at various concentrations with infantile hemangiomas after proliferative phases. We designed a single-center, randomized, double-blind, dose-dependent trial with placebo control and randomized patients to receive propranolol gel at 0, 1, or 5%, twice daily for 24 weeks. The primary efficacy endpoint was the percentage change in redness of the tumors. Safety endpoints were skin characteristics changes and systemic symptoms. We made two comparisons to evaluate the superiority of 1 and 5% propranolol gels against placebo for primary endpoint analysis and used the t-test to compare parents' satisfaction with these treatments. Initially, 19 patients were enrolled, but 8 were excluded from the analysis. We were underpowered to answer the question of efficacy. In the per-protocol set, we found similar results for the redness percentage change among the patients on placebo, 1 and 5% gel. However, the difference in redness before and after treatment suggested a slight decreasing trend of lesion's redness as the propranolol concentration increased. The difference in parents' satisfaction between the placebo and 5% propranolol gel groups was significant (p = 0.08). We observed no serious adverse events. We did not find an obvious dose-dependent effect for the propranolol gel treatment against infantile hemangiomas after the proliferative phase. However, external applications twice daily were less burdensome for parents and led to good compliances. It had a favorable safety profile in Japanese pediatric patients with infantile hemangiomas.

A phase III, multicenter, single-arm study to assess the utility of indocyanine green fluorescent lymphography in the treatment of secondary lymphedema.

OBJECTIVE: Indocyanine green (ICG) fluorescent lymphography might be useful for assessing patients undergoing lymphatic surgery for secondary lymphedema. The present clinical trial aimed to confirm whether ICG fluorescent lymphography would be useful in evaluating lymphedema, identifying lymphatic vessels suitable for anastomosis, and confirming patency of lymphaticovenular anastomosis in patients with secondary lymphedema. METHODS: The present phase III, multicenter, single-arm, open-label, clinical trial (HAMAMATSU-ICG study) investigated the accuracy of lymphedema diagnosis via ICG fluorescent lymphography compared with lymphoscintigraphy, rate of identification of lymphatic vessels at the incision site, and efficacy for confirming patency of lymphaticovenular anastomosis. The external diameter of the identified lymphatic vessels and the distance from the skin surface to the lymphatic vessels using preoperative ICG fluorescent lymphography were measured intraoperatively under surgical microscopy. RESULTS: When the clinical decision for surgery at each research site was made, the standard diagnosis of lymphedema was considered correct. For the 26 upper extremities, a central judgment committee who was unaware of the clinical presentation confirmed the imaging diagnosis was accurate for 100.0% of cases, whether the assessments had been performed via lymphoscintigraphy or ICG lymphography. In contrast, for the 88 lower extremities, the accuracy of the diagnosis compared with the diagnosis by the central judgment committee was 70.5% and 88.2% for lymphoscintigraphy and ICG lymphography, respectively. The external diameter of the identified lymphatic vessels was significantly greater in the lower extremities than in the upper extremities (0.54 ± 0.21 mm vs 0.42 ± 0.14 mm; P < .0001). Also, the distance from the skin surface to the lymphatic vessels was significantly longer in the lower extremities than in the upper extremities (5.8 ± 3.5 mm vs 4.4 ± 2.6 mm; P = .01). For 263 skin incisions, with the site placement determined using ICG fluorescent lymphography, the rate of identification of lymphatics vessels suitable for anastomosis was 97.7% (95% confidence interval, 95.1%-99.2%). A total of 267 lymphaticovenular anastomoses were performed. ICG fluorescent lymphography was judged as "useful" for confirming patency after the anastomosis in 95.1% of the cases. CONCLUSIONS: ICG fluorescent lymphography could be useful for improving the treatment of patients with secondary lymphedema from the outpatient setting to surgery.

Efficacy and safety of nelfinavir in asymptomatic and mild COVID-19 patients: a structured summary of a study protocol for a multicenter, randomized controlled trial.

OBJECTIVES: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. TRIAL DESIGN: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. PARTICIPANTS: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator INTERVENTION AND COMPARATOR: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). MAIN OUTCOMES: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. RANDOMIZATION: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). BLINDING (MASKING): Only the assessors of the primary outcome will be blinded (blinded outcome assessment). NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman's equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. TRIAL STATUS: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. METHODS AND ANALYSIS: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). ETHICS AND DISSEMINATION: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. TRIAL REGISTRATION NUMBER: UMIN000018752.