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Author contributions | Study concept and design: M.A.D.S., R.H.P., S.F.G., A.V.A.M., S.P.S., M.B.T., M.M.D.G., A.A.B. and E.B.S.G., M.A.M., E.B.S.G., B.A.B., J.B.C., C.W.L.M.O., T.L.R., P.C.G.L., M.S.A., F.M.L., C.K.V.N., B.S.F.S. and N.U.B. were involved in the acquisition of data. Drafting of the manuscript: M.A.D.S., R.H.P., F.T., J.C.R. and L.P.D. Critical revision of the manuscript: M.A.D.S., R.H.P., S.F.G., L.P.D., R.M.V.M., F.T. and S.P.S. Obtained funding: M.A.D.S., R.H.P., A.A.B. and S.F.G. Study supervision: All authors. All authors read and approved the final manuscript. | PMC10611696 |
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Funding | The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication. | PMC10611696 |
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Data availability | The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary material. | PMC10611696 |
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Competing interests | The authors declare no competing interests. | PMC10611696 |
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References | PMC10611696 |
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Abstract | Editor: Linda WangConflict of interestThe authors declare no conflict of interest.The effectiveness of at-home dental bleaching treatments depends on the time that bleaching products are in contact with the teeth surface and, consequently, on the adequate use of associated custom acetate trays. | PMC10519669 |
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Objective | TOOTH SENSITIVITY | This randomized single-blinded trial aimed to analyze if the daily usage time of these products influences the patient’s compliance behavior when submitted to monitored at-home dental bleaching. Secondary outcomes were color change and tooth sensitivity. | PMC10519669 |
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Methodology | TOOTH SENSITIVITY | Sixty-six volunteers were randomly distributed into three groups (n=22): patients were instructed to use the trays for 2 (G2), 4 (G4), and 8 (G8) hours daily. The daily dental bleaching compliance behavior was measured using a microsensor inserted into the trays. Subjective and objective color evaluation assessments were adopted at baseline (T0), one (T1), two (T2), and three weeks (T3) after the beginning of the bleaching treatment, as well as two weeks after the treatment (T4). Tooth sensitivity was analyzed using the VAS scale, ranging from T1 to T4. | PMC10519669 |
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Results | G2 showed a greater degree of cooperation than G8 and cooperation was inversely proportional to the recommended usage time. Significantly higher color change was observed in the upper arch for G8 when compared to G2 in subjective analysis, from T1 to T4. There were no statistical differences between the groups in objective analysis. | PMC10519669 |
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Conclusion | Shorter recommended usage time of the bleaching product may improve the patient's compliance with at-home dental bleaching treatments. However, increased daily usage time may promote better subjective color change. Bleaching sensitivity was more significant in the first week for a longer time of use. | PMC10519669 |
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Introduction | orthodontic | CAVITY, TOOTH SENSITIVITY | The effectiveness of at-home dental bleaching treatments depends on the time that bleaching products are in contact with the teeth surface and, consequently, on the adequate use of custom acetate trays. The home bleaching treatment was introduced in 1989, recommending the use of a 10% carbamide peroxide for 6 to 8 daily hours.Usage time measurements for removable orthodontic appliances have been performed using an electronic device that is able to identify the temperature of the oral cavity, which can be converted into time of use in the oral cavity.In the literature, there is a lack of studies that evaluate the influence of monitored daily usage times in the compliance of patients during at-home bleaching using randomized clinical trials and in color change and sensitivity. The objective of the present study was to assess the patient’s compliance and the tooth color change and sensitivity during at-home dental bleaching procedures with different usage times. The null hypothesis tested was: [1] daily usage time would not influence patients’ compliance during at-home bleaching; [2] daily usage time would not influence tooth color change during at-home bleaching, and [3] daily usage time would not influence tooth sensitivity during at-home bleaching. | PMC10519669 |
Methodology | PMC10519669 |
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Trial design | TOOTH SENSITIVITY | This study was a prospective, randomized, parallel, single-blind clinical trial, following the guidelines published by the Consolidated Standards of Reporting Trials-CONSORTThe studied factor was the usage time of the trays at three levels: 2 (G2), 4 (G4), and 8 (G8) hours/day. The response variables were the patient’s compliance behavior regarding the usage time of trays, the efficacy of dental bleaching, assessed with visual and spectrophotometric evaluations, and tooth sensitivity. | PMC10519669 |
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Sample size | SECONDARY | The sample size was calculated using a dedicated statistical software package (IBM SPSS Statistics 22.0; IBM Analytics, Armonk, NY, USA). The primary outcome (patient’s compliance behavior) was not used for sample size calculation due to the lack of data about this topic. One of the secondary outcomes was color change: considering a 2.4 standard deviation from a pilot study and the minimum difference to be detected from 3.3, with a 95% confidence level and a maximum acceptable error of 5%, each group required 20 participants. Considering a possible loss of patients, 10% of the total sample was added. The final calculation was 66 participants, once it is a parallel design trial. | PMC10519669 |
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Eligibility criteria | carious lesions, incisors, non-carious cervical lesions, pain, fluorosis, bruxism | ENDODONTICALLY TREATED TEETH, PERIODONTAL DISEASES, ADVERSE REACTION, TOOTH SENSITIVITY | Patients were selected according to the following inclusion criteria: absence of carious lesions; good oral soft tissue health; absence of unsatisfactory and/or fractured restorations; absence of periodontal diseases; absence of non-carious cervical lesions and exposed dentinal tissue in the incisal areas; no history of adverse reaction to peroxides; shade of canines and incisors teeth should be at least A2 (according to Vita Classical Shade Guide, Bad Sackingen, Germany); absence of teeth with spontaneous pain; aged between 18-30 years.The exclusion criteria were: presence of proximal and/or vestibular restorations in the incisor and/or canine teeth; teeth with fixed orthodontic appliances and with resinous residues after bracket debonding; pregnancy; breastfeeding; smoking; routine alcohol use; previous dental bleaching treatments; teeth with fluorosis, enamel stains; endodontically treated teeth; bruxism habits; experiencing tooth sensitivity before this study; unacceptance of the research consent form and/or unavailability/lack of commitment to the research (
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Consort flow-chart of the clinical trial | PMC10519669 |
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Allocation | After selecting the 66 participants, informed consent was obtained from each patient and they were divided into three groups with 22 participants each. Participants’ allocation into these groups was done at an equal rate. The purpose of this allocation was to assign each participant one out of three different usage times, as shown in | PMC10519669 |
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Bleaching procedure | Prophylaxis with pumice stone and water was performed. Alginate impressions (Jeltrate Plus, Dentsply, Petrópolis, RJ, Brazil) of each patient’s upper and lower arches were taken and stone models was fabricated. Ethylene vinyl acetate trays (Bio-Art Equip Odontológicos, Ltda, São Carlos, SP, Brazil) were fabricated using a vacuum-pressing machine (Equip Odontológicos Ltda, São Carlos, SP, Brazil). An electronic microsensor (TheraMon microelectronic system, Sales AgencyGschladt, Hargelsberg, Austria) was attached to the buccal surfaces of the acetate trays in order to monitor the daily usage time. The microsensor was included between the 2 acetate plates, each being 1 mm thick, during the preparation of the trays, in which borders were cut 2 mm beyond the gingival margin, following the gingival contour (scalloped tray), without the presence of reservoirs (
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A- Upper and lower acetate trays with the microsensor attached to the buccal surface; B- Reading station for transferring data to the software | tooth | CAVITY | This microsensor is able to measure the temperature of the oral cavity every 15 minutes with a +/- 0.1º Celsius accuracy.Dental bleaching was performed using 10% carbamide peroxide gel (Opalescense PF, Ultradent Products Inc., South Jordan, UT, USA). Patients were instructed to insert a small drop of bleaching gel on the buccal impression of each tooth on both trays (upper and lower), from the right second premolar to the left second premolar. Patients were instructed to keep the trays on for 2, 4, or 8 hours/day (corresponding to groups G2, G4, and G8, respectively). They were instructed on how and for how long to use the trays by a researcher that was not involved in the implementation and evaluation processes. The dental bleaching technique was performed for 21 consecutive days. Each volunteer’s usage time was obtained and analyzed at the end of the bleaching treatment. | PMC10519669 |
Daily compliance behavior degree | A daily score for the usage time was created: 0 – patient did not used the trays; 1 – patient used the trays for the recommended time; 2 – patient used the trays for less than the recommended time; 3 – patient used the trays for more than the recommended time. The scores were then dichotomized into adequate (Score 1) or inadequate (Scores 0, 2, and 3). All data were registered daily. On all treatment days, each patient was analyzed and categorized according to the scores, so that 21 scores (days) were analyzed per patient. | PMC10519669 |
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Color change | ’ anterior teeth, incisors, tooth | Subjective and objective methods were used to evaluate tooth color. Only the evaluators were unaware of the groups to which the participants had been assigned. Two examiners were trained on shade determination of eight subjects’ anterior teeth in a pilot study. This calibration was performed using Vita shade guide units (A1-D4) and a digital spectrophotometer (Vita Easyshade, Germany) made in the middle third of the upper and lower anterior teeth (incisors and canines), three times. For this, a custom tray was made with an orifice, with a 3.0mm radius window, to standardize the location of the color measuring. The color measurements were performed on the lateral and central incisors and on the canines, in both arches, with 12 teeth being evaluated per patient. The subjective evaluation was initially performed, followed by the objective evaluation. For the subjective evaluation, scores from 1 (B1) to 16 (C4) were assigned.Both measurements were performed at baseline (T0), seven (T1), fourteen (T2), and twenty-one days (T3) of treatment and the mean color change between evaluated teeth (incisors and canines) was calculated. A measurement was performed fourteen days after the completion of the treatment (T4). The color of each tooth was measured using the CIEDE2000 parameters: variables such as L*, a*, b*, h*, and c* coordinates that address not only L* (brightness), a* ( red-green), and b* (yellow-blue) found in the previous formula, but also the saturation (c*), hue angle (h*), matrix rotation term (RT), compensation for neutral colors; lightness compensation (SL), chroma compensation (SC), and hue compensation (SH), allowing a better correlation between the observed colors and bringing this score closer to what can be seen by the human eye. The shade comparison at different periods (T0, T1, T2, T3, and T4) was based on the ΔE00, which was calculated by the following formula: | PMC10519669 |
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Tooth sensitivity | TOOTH SENSITIVITY, TOOTH SENSITIVITY | Tooth sensitivity was analyzed and measured from 0 to 10 in all periods, according to the visual analogue scale (VAS). Volunteers were asked about the intensity of tooth sensitivity caused by the treatment. A value of 0 was set when patients did not have any sensitivity and 10 when severe sensitivity occurred. In case of severe sensitivity, the patient would be excluded from the research and the dental bleaching treatment would be canceled. | PMC10519669 |
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Statistical analysis | ’ compliance behavior, tooth | Statistical analysis was performed using a statistical software package (IBM SPSS Statistics 22.0; IBM Analytics, Armonk, NY, USA). The Kolmogorov-Smirnov test was used to evaluate the normality of the results. The chi-square test was used between the groups to compare the volunteers’ compliance behavior (usage time). The results for tooth color change and sensitivity were submitted to a two-way analysis of variance (ANOVA), followed by a Tukey post-hoc test. Statistical analysis was performed at a 5% significance level. | PMC10519669 |
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Results | The 66 volunteers, aged 18 to 26 years (20±1.9 mean), were analyzed and a total of 462 readings (days of use) were performed for each study group, during the 21 days of treatment. No loss occurred during the follow-up periods. | PMC10519669 |
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Daily compliance behavior degree | Data from daily compliance behavior is shown in
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Distribution of patients’ 0-3 scores (usage time) according to each group | PMC10519669 |
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Dichotomized data regarding the usage time of the dental bleaching product for upper and lower arches for each group (n=462). | PMC10519669 |
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Color change | PMC10519669 |
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Means (SD) of scores obtained by the subjective evaluation on upper and lower arches | Different uppercase letters in column and lowercase in row indicate statistically significant differences (p<0.05). Statistical analysis did not compare the upper arch with the lower arch.
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Means (SD) of color change (ΔE00) obtained by the objective evaluation on upper and lower arches | Different uppercase letters in column and lowercase in row indicate statistically significant differences (p<0.05). Statistical analysis did not compare the upper arch with the lower arch.For all groups, arches, and analysis, a significant and gradual increase in color change was observed (p ≤0.05), stabilizing at T4. | PMC10519669 |
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Tooth sensitivity | PMC10519669 |
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Means (SD) of scores obtained by VAS scale during and after the bleaching treatment | Different uppercase letters in column and lowercase in row indicate statistically significant differences (p <0.05). | PMC10519669 |
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Discussion | Usage-time compliance behavior | SECONDARY, TOOTH SENSITIVITY | This blinded, parallel, randomized clinical trial with similar allocation between treatment groups aimed to evaluate different aspects of bleaching treatment, such as daily compliance behavior, dental color change and tooth sensitivity. The main objective of this study was to assess compliance behavior daily—secondary outcomes are additional dependent variables, hierarchically less important.Based on the results of the present study, the first null hypothesis was rejected, because less usage time promoted more compliance of patients during at-home bleaching. Usage-time compliance behavior variations could possibly compromise the effectiveness of bleaching treatments. The effectiveness of an at-home dental bleaching procedures depends on tray usage time, which is entirely under the responsibility of the patient. Therefore, the clinician must guide the patient on the importance of properly following the recommended usage time in order to obtain effectiveness out of the treatment.A wide variability in usage time within some of the volunteers was observed. Drastic differences were found, with values ranging from 0 hours (Score 0) up to 12 hours and 15 minutes (Score 3), when the actual recommended usage time was 2 hours. This usage time pattern was a characteristic of patients who tried to compensate for little or no use time in a few days, or for those who used the trays while sleeping, for longer than recommended. Schott and LudwigAlthough an 8-hour usage time is associated with use during sleep, a 2-hour usage time is more effective since it can be easily made at any time of the day. This finding is consistent with the medical literature, which suggests that less frequent dosing regimens are associated with better adherence.It was possible to observe, through subjective visual evaluation, higher color change for G8 than G2 at most of the evaluation time. For G2, even with higher patient compliance (score 1), reduced color change was observed, certainly due to the shorter usage time (2 hours). After 2 hours, more than 50% of the active agent is available in bleaching trays with reservoirs, and 19% in the ones without reservoirs.Spectrophotometry is an objective evaluation method capable of expressing minimal color differences in numerical form.Cardoso, et al.In the objective analysis, the difference between the upper arch means of groups G2 and G4 at T4 (0.86) can be correlated with the acceptability and perceptibility values proposed by Paravina, Pérez and GhineaTooth sensitivity may be related not only to bleaching gel concentration, but also to its time of contact with dental structures.However, in T2 and T3 the sensitivity means showed the same level of intensity, with results becoming practically null in T4, observations that are in agreement with other studies. | PMC10519669 |
Conclusions | TOOTH SENSITIVITY | Shorter recommended usage time of acetate trays/dental bleaching products improved patients’ compliance with the at-home dental bleaching treatment. However, increased daily usage time of the bleaching gel promoted better subjective color change. For a longer usage time, tooth sensitivity was more significant in the first week. | PMC10519669 |
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References | PMC10519669 |
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Background | cancer, cancer pain, neuropathic pain, Pain | CANCER, CHRONIC PAIN, CORTEX | Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved. In recent years, transcranial direct-current stimulation (tDCS) of the motor cortex has been shown to be effective to treat chronic pain, essentially neuropathic pain. We propose to test the efficacy of tDCS in patients experiencing cancer pain in the palliative care setting. | PMC9972710 |
Method/design | Depression, Anxiety, Pain, pain | SECONDARY, REFRACTORY CANCER, CORTEX | This article describes the protocol of a bicentre, randomized, parallel-arm, sham-controlled clinical trial evaluating tDCS in the treatment of palliative care patients with refractory cancer pain. Seventy patients between the ages of 18 and 80 years experiencing refractory pain with a pain score of 4/10 on a numerical rating scale (NRS) ranging from 0 to 10 will be enrolled in this trial. The main exclusion criteria are patients unable to fill in the various rating scales and life expectancy less than 3 weeks. Treatment consists of 5 consecutive tDCS sessions targeting the motor cortex (one daily session for 5 days) on the contralateral side to the pain. After randomization (1:1 ratio), 35 patients will receive active stimulation and 35 patients will receive sham stimulation. The primary endpoint is the NRS score and the primary objective is a significant improvement of this score between the baseline score recorded between D-3 and D-1 and the score recorded 4 days after stopping treatment (D8). The secondary objectives are to evaluate whether this improvement is maintained 16 days after stopping treatment (D21) and whether the following scores are improved on D14 and D21: Brief Pain Inventory, Edmonton Symptom Assessment System, Hospital Anxiety and Depression scale, State-Trait Anxiety Inventory and Medication Quantification Scale. | PMC9972710 |
Discussion | cancer, pain | CANCER, POSITIVE | Positive results of this trial would indicate that tDCS can improve pain and quality of life of cancer patients in the palliative care setting. Reduction of analgesic consumption and improvement of activities of daily living should allow many patients to return home with a decreased workload for caregivers. | PMC9972710 |
Keywords | PMC9972710 |
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Background | cancer, cancer pain, chronic pain, Pain | CANCER, REFRACTORY CANCER, CHRONIC PAIN | Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved [In recent years, noninvasive brain stimulation (NIBS) techniques (transcranial magnetic stimulation (rTMS) or transcranial direct-current stimulation (tDCS)) have been successfully used to treat chronic pain [tDCS appears to be more suitable than rTMS for the treatment of palliative care patients, who are often difficult to mobilize, as tDCS can be delivered at the patient’s bedside and possibly even at home, which is not the case with rTMS. tDCS also appears to be rapidly effective (after 5 sessions) in the context of cancer pain, and this effect lasts longer than that of rTMS.The proposed treatment of refractory cancer pain by tDCS in palliative care patients is a new treatment modality that is well adapted to hospitalised patients. Each patient will receive 20 minutes of transcranial direct-current stimulation daily for 5 consecutive days. One arm will receive active stimulation and the control arm will receive sham stimulation. Patients and investigators will be blinded to the type of tDCS. By improving the patient’s activities of daily living, this treatment will enable the patient to return home under good conditions for both the patient and the caregivers. This treatment can also be continued at home. This strategy is consistent with current guidelines in this field, in which the priorities are improvement of quality of life [ | PMC9972710 |
Interventions: tDCS and follow-up intervention | paraesthesia, pain | CHRONIC PAIN, HEAT, CORTEX, PARAESTHESIA | tDCS was tested in healthy subjects from 2000 until 2005, at the time of the first clinical applications in the treatment of chronic pain. tDCS consists of delivering a low-intensity (1 to 2 mA) direct electrical current by means of a pair of electrodes (anode and cathode) applied to the scalp. Electrodes generally have a diameter (round electrode) or a diagonal (rectangular electrodes) ranging from 2 to 3.5 cm. To stimulate a given cortical zone, the anode is placed over of the selected zone, generally identified by means of an EEG headset (10/20 System Positioning). For the treatment of pain, the anode is placed over the primary motor cortex (M1) on the contralateral side to the pain or on the left side in patients with diffuse pain. The cathode is placed over a supposedly neutral cortical zone, usually the contralateral supraorbital cortex with respect to the anode. In this study, the stimulation intensity will be 2 mA using round sponge electrodes 3.5 cm in diameter. As in the case of rTMS, stimulation of M1 is thought to be active by means of the connections between the motor cortex and numerous structures situated away from M1 involved in pain modulation [A tDCS session generally lasts 20 minutes. The patient may experience a feeling of heat or paraesthesia at the site of the electrodes for the first 30 seconds, but subsequently does not experience any sensations, which is why active stimulation will be delivered for the first 30 seconds of the sham procedure [This study will be conducted in patients hospitalised in a unit experienced in palliative care. tDCS will be delivered daily for 5 consecutive days (from Monday to Friday) with the patient either sitting or lying down. | PMC9972710 |
Benefits and risks | pain | ADVERSE EFFECTS, SIDE EFFECTS, REFRACTORY CANCER, BLIND | At the individual level, pain intensity is expected to decrease by the 2nd or 3rd tDCS session, with a more marked improvement after the 5th session. This improvement is expected to last at least 4 days (D8) and up to 16 days (D21) [Side effects are recorded in the electronic observation booklet after each tDCS session (D0, D1, D2, D3, D4) and during the 3 subsequent evaluations (D8, D14 and D21). Side effects [A significant collective benefit could be observed, and tDCS could markedly decrease the length of hospital stay of these patients and their analgesic drug consumption and should therefore have a significant health economics impact. In parallel, the patient’s and caregivers’ quality of life could be significantly improved. In the longer term, continuation of tDCS at home would require a new organization. The development of remote treatment techniques must also be considered [More generally, this protocol raises the issue of clinical research in palliative care patients [In order not to penalize patients in the placebo group, it is planned to lift the blind at D21 and to offer these patients the active treatment outside the protocol. Patients who have been actively treated and whose pain has recurred after D21 will be offered a second treatment outside the protocol.As tDCS is a noninvasive technique with few expected adverse effects, the benefit/risk balance is expected to be highly positive for the patient in this context of refractory cancer pain in the palliative care setting. | PMC9972710 |
Study objective | Anxiety, Pain, cancer pain, pain, chronic pain, Depression, NRS | RESIDUAL, SECONDARY, CHRONIC PAIN, CORTEX | This study is designed to evaluate the analgesic efficacy of 5 consecutive tDCS sessions to the primary motor cortex in patients with cancer pain in the palliative care setting.The primary endpoint is the score of the numerical rating scale (NRS), which measures pain intensity on a scale from 0 to 10 [The secondary objectives will be to evaluate:Immediate impact of each tDCS session on pain intensity.Response rate at the end of treatment.Residual analgesic effect.Effects of TDCS on the other main symptoms likely to impair quality of life.Analgesic consumption on D0 and D8.Secondary endpoints will be:Pain NRS score, MQS (Medication Quantification Scale [Pain NRS scores, recorded before and after each session.Efficacy of treatment, defined by a ≥ 20% reduction of the mean NRS score between D0 and D8 (IMMPACT recommendation in chronic pain [Mean NRS score on D14 and D21 in the 2 arms.Completion of the following questionnaires and scales on D0 and D8:. BPI (Brief Pain Inventory, short form [. ESAS (Edmonton Symptom Assessment System) [. HADS (Hospital Anxiety and Depression Scale) [. STAI-Y (State-Trait Anxiety Inventory (Form Y) [Analgesic consumption assessed by MQS on D0 and D8.Analysis of repeated measurements of quantitative secondary endpoints (NRS, BPI, ESAS, HADS, STAI-Y and MQS) will be based on the mean variations of the endpoint between the baseline assessment (D0) and the D21 assessment. | PMC9972710 |
General study methodology | drowsiness | This is a French bicentre (Clinique Bretéché and CHU/University Hospital Nantes), randomized, comparative, double-blind, sham-controlled trial conducted in two parallel arms: tDCS (35 patients) and sham tDCS (35 patients).Centralized randomization will be performed by software and will be specific to each of the 2 centres. Patients will not be informed about whether they have been allocated to the active tDCS arm or the sham tDCS arm. Physicians performing the tDCS technique and the evaluating physicians will also be blinded to the type of treatment delivered (see “Interventions: tDCS and follow-up intervention”).Doses of analgesic medications (opioids, antiepileptics and antidepressants) must be stable for at least 48 hours (D-3, D0) prior to inclusion in the study. The level of analgesic treatment will be assessed by MQS. Analgesic doses may be able to be decreased from the first day of tDCS depending on its analgesic effect. One of the objectives of tDCS is to decrease the doses of analgesics in order to avoid a state of drowsiness or torpor associated with impaired quality of life. | PMC9972710 |
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Inclusion criteria | cancer pain |
Patients between the ages of 18 to 80 years with cancer pain refractory to medical treatment (mean NRS ≥ 4/10 on 2 consecutive days) in the palliative care setting.Patients agreeing to participate in a research protocol in this palliative care setting. | PMC9972710 |
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Exclusion criteria | cognitive impairment, NRS, pain |
Patients younger than 18 years or older than 80 years.NRS < 4/10 (pain controlled by adapted medical treatment and global management).Patients unable to fill in the various questionnaires, specifically chosen to be simple and easy to fill in.Patients refusing to sign the informed consent form.Patients with cognitive impairment, metal implantation in the brain and mood disordersPatients with a life expectancy less than 3 weeks (duration of study follow-up). | PMC9972710 |
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Recruitment modalities | RECRUITMENT | Patients will be recruited from the Center 1 (Clinique Bretéché rehabilitation and palliative care unit, Nantes), and Center 2 (CHU/University Hospital Nantes palliative care unit). The inclusion of one patient per month corresponds to the recruitment, treatment and follow-up capacities of each of these centres in accordance with the protocol. The study will last 24 months. | PMC9972710 |
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Study plan (Fig. | PMC9972710 |
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Screening visit (D-3) | D-3-D0, NRS, pain | Verification of inclusion and exclusion criteria. Patients will be provided with the information sheet and will be asked to sign the informed consent form. The patient will be provided with NRS forms (3 assessments per day for 48 hours). For organizational reasons, this screening visit will be held on a Friday. NRS scores will be recorded on Saturday and Sunday so that inclusion or exclusion of the patient can be decided on Monday.Study plan: the study will last 24 days (D-3 to D21) including a 3-day inclusion period (D-3-D0), a 5-day treatment period (D0-D4) and a 16-day follow-up period after stopping treatment (D8, D14, D21). Treatment consists of a daily tDCS session on 5 consecutive days. Patients will be randomized to 2 arms (1:1 ratio): active tDCS and sham tDCS. Patients and investigators will be blinded to the results of randomization (double-blind). The primary objective will be a significant reduction of pain evaluated by a numerical rating scale (NRS) from 0 to 10 between the baseline score recorded between D-3 and D0 and the score recorded 4 days after stopping treatment (D8) | PMC9972710 |
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Inclusion visit (visit 1) (D0) | NRS, pain | SECONDARY | Recording of NRS scores for 48 hours (D-3 to D-1) allowing inclusion of the patient. Recording of clinical parameters such as age, sex, weight, height, etc., medical history, previous and concomitant treatments, vital signs. Baseline assessment: NRS, BPI, ESAS, HADS, STAI-Y and MQS (see secondary endpoints). Randomization (by centre, 1:1 ratio). Study personnel (physician and nurses specialized in pain management) will be blinded to the results of randomization. | PMC9972710 |
Treatment with active or sham tDCS (D0-D4) | NRS | Study personnel (physician or trained nurse), but not the patient, will be informed about the results of randomization. tDCS will be delivered daily for 5 consecutive days. The NRS will be scored 3 times a day on these 5 days from Monday to Friday. | PMC9972710 |
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Visit 2 (D8) | NRS | ADVERSE EVENTS | Review of adverse events (AEs), recording of NRS scores and the various other assessment scores (BPI, ESAS, HADS, STAI-Y and MQS) 4 days after stopping treatment. | PMC9972710 |
Patient follow-up | In order to maximize the number of patients evaluable for the primary analysis on the mITT population (modified intention-to-treat [ | PMC9972710 |
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Clinical parameters | Anxiety, Pain, anxiety, cancer pain, pain, depressive, depression, Depression, NRS |
The pain numerical rating scale (NRS) is a pain self-assessment tool. The patient rates his or her pain orally on a scale from 0 to 10, where 0 corresponds to the lower limit defining absence of pain and 10 corresponds to the upper limit defining the worst imaginable pain. The NRS was preferred to a VAS (visual analogue scale) based on the 2009 expert consensus on cancer pain assessment [This scale can be used to include patients considered to experience sufficiently severe pain to justify more or less invasive treatment. For example, pain scored as 3/10 corresponds to moderate pain [The validity and reliability of the NRS for the evaluation of the efficacy of analgesic treatment has been established [The Brief Pain Inventory (BPI) is a self-administered questionnaire constructed and tested in cancer pain [The short form, composed of 9 items, has been validated and shown to be reliable in the assessment of cancer pain [Evaluation of the various symptoms observed in the context of palliative care constitutes an evaluation of the quality-of-life approach in this setting. The Edmonton Symptom Assessment System (ESAS) has been validated and found to be one of the most reliable of the various scales [Since 1983, anxiety and depression are generally evaluated by the HADS (Hospital Anxiety and Depression Scale [The STAI-Y [Scores range from 20 to 80 and are classified in the following way:very high > 65,high: 56 to 65,moderate: 46 to 55,low: 36 to 45,very low ≤35.To date, this scale has not been validated for the evaluation of cancer pain, nor in the context of palliative care. As much as an improvement of a possible depressive state could be explained by the action of the tDCS [The Medication Quantification Scale (MQS) is a scale used to quantitatively evaluate changes in analgesic drug administration [ | PMC9972710 |
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Statistical analysis | NRS | Statistical justification of the sample size: a 2-point improvement of the numerical rating scale is considered to be clinically relevant [As this is the first protocol dedicated to the treatment of painful patients in a palliative care setting with tDCS, we did not find any evidence in the literature that could help us justify the number of needed patients for the evaluation of the other clinical parameters, apart from the NRS.On the basis of these hypotheses:A mean NRS difference of 2 points between the active tDCS arm and the sham tDCS arm,Standard deviation of 2.8,Power of 80%.Alpha risk of 5%,32 patients per arm would be necessary, i.e. a total of 64 patients. In order to ensure sufficient power, an additional 10% of patients will be included in the study, i.e. a total of 70 patients.The study will therefore include 70 patients: 35 in the tDCS arm and 35 in the sham tDCS arm.The variables measured on inclusion will be described for all patients and in each of the two arms by number and percentage for each modality for qualitative variables and by minimum, maximum, mean, standard deviation and quartiles for quantitative variables. The primary efficacy population will be a modified intention-to treat (mITT) population, comprising all randomized patients who have received at least one tDCS session (active or sham) and who were evaluated on D0 (baseline) and on D8. | PMC9972710 |
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Analysis of the primary endpoint | NRS, pain | Analysis of the primary endpoint, the pain NRS, will be performed on the mITT population.The mean NRS score on D8 will be compared between the active tDCS arm and the sham tDCS arm using a mixed linear model in order to take stratification factors into account. | PMC9972710 |
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Analysis of secondary endpoints | NRS, pain | The mean NRS score on D8 will be compared between the active tDCS arm and the sham tDCS arm using a mixed linear model in order to take stratification factors into account. This analysis will also be adjusted for analgesic consumption based on the MQS score.The immediate efficacy of tDCS on pain intensity will be compared between the two arms using a mixed linear model with the pre- and post-tDCS difference of the NRS score as the variable to be explained. This model will take repeated measures per patient into account.The response rate will be compared between the two arms by a mixed logistic model in order to take stratification factors into account.The residual analgesic effect on D14 and D21 will be studied using a mixed linear model in order to take stratification factors into account. This analysis will also be adjusted for analgesic consumption.The course of quality of life assessed by the BPI, ESAS, HADS and STAI-Y between D0 and D7 will be compared between the two arms by a mixed linear model in order to take stratification factors into account.Analgesic consumption, evaluated by the MQS questionnaire, will be compared between the two arms using a mixed linear model.Complementary analysis of the primary efficacy endpoint could be conducted on a per protocol population including all patients of the mITT population not presenting any major protocol violations. These major violations will be defined in the analysis plan before locking the database. | PMC9972710 |
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Randomization | CRF, pain | CRF | Centralized randomization will be performed on D0 after verification of the inclusion criteria. Randomization will be performed under double-blind conditions and will be stratified according to the mean baseline pain intensity (4–6 or 7) over the last 48 hours before inclusion and according to centre.Patients will be randomized to receive either active tDCS or sham tDCS for the 5 treatment days defined by the protocol. The randomization ratio will be 1:1. Randomization will be stratified by centre by means of the Ennov Clinical electronic CRF (Randomization lists will be established by a Nantes university hospital research promotion department statistician.A patient registered in the trial, to whom treatment has been allocated and documented, will be considered to be randomized. A patient cannot be included, evaluated or randomized in the trial more than once. | PMC9972710 |
Acknowledgements | The authors would like to thank Dr. A. Saul for English translation of the manuscript and Mr. A. Legrand (investigation project manager DRCI CHU Nantes), Mr. B. Orofiamma (Atlanstat) for their assistance in methodology and statistics and Dr. M. Royer for the coordination between the two centers (Groupe ELSAN, 58 bis rue de la Boétie 75008 Paris). | PMC9972710 |
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Dissemination of results | The results will be presented at feedback sessions at national and international congresses and may be used to compile guidelines on assessment of the efficacy and safety of tDCS. A research report based on the study results will be submitted to international peer-reviewed journals, in the field of palliative care, oncology and neuromodulation, to be considered for publication. | PMC9972710 |
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Study status | The protocol is for a study that is ongoing, and the investigators are still collecting data. | PMC9972710 |
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Authors’ contributions | CM, AVL, SVT | SVT | JPN, JN, HG, DCD and JPL wrote the manuscript. DCD, AE, AVL, HG are investigators of the Centre 1 (CHU/University Hospital Palliative care Unit), Nantes. AS, ETM, CM, and SVT are investigators of the Centre 2 (Clinique Bretéché, Nantes). All authors have read and approved the manuscript. | PMC9972710 |
Funding | STIMPAL Trial succeeded at 2019 Groupe ELSAN (Clinique Bretéché, 44000 Nantes, France) Call for research proposals, with a grant of 80.000 euros. This study protocol has undergone peer-review by the funding body. | PMC9972710 |
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Availability of data and materials | All data will be anonymized and stored under lock and key, with access granted to the research team only in each of the 2 centers. | PMC9972710 |
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Declarations | PMC9972710 |
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Ethics approval and consent to participate | Domaine de la Santé́) | STIMPLAL design has been approved by Nantes Hospital Ethic’s Committee (GNEDS) Groupe Nantais d’Éthique dans le Domaine de la Santé́), on June, 12th 2019, and by the Comité de Protection des Personnes (CPP) Sud-Méditerranée II à Marseille on November, 6th 2020.All patients admitted to the units will be presented with an information leaflet on the study in French. Consent for inclusion in the study will be obtained from all participants who have the capacity to consent. | PMC9972710 |
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Consent for publication | Not applicable. This manuscript does not contain any individual person’s data. | PMC9972710 |
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Competing interests | None. | PMC9972710 |
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References | PMC9972710 |
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Subject terms | adverse events, blood tests, SAD | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT | OCS-05 (aka BN201) is a peptidomimetic that binds to serum glucocorticoid kinase-2 (SGK2), displaying neuroprotective activity. The objective of this randomized, double-blind 2-part study was to test safety and pharmacokinetics of OCS-05 administered by intravenous (i.v.) infusion in healthy volunteers. Subjects (n = 48) were assigned to receive placebo (n = 12) or OCS-05 (n = 36). , Doses tested were 0.05, 0.2, 0.4, 0.8, 1.6, 2.4 and 3.2 mg/kg in the single ascending dose (SAD) part. In the multiple ascending dose (MAD) part, 2.4 and 3.0 mg/kg doses were administered with 2 h i.v. infusion for 5 consecutive days. Safety assessments included adverse events, blood tests, ECG, Holter monitoring, brain MRI and EEG. No serious adverse events were reported in the OCS-05 group (there was one serious adverse event in the placebo group). Adverse events reported in the MAD part were not clinically significant, and no changes on the ECG, EEG or brain MRI were observed. Single-dose (0.05–3.2 mg/kg) exposure (C | PMC10060579 |
Introduction | neurodegeneration, acute optic neuritis, death, worsening disability, optic nerve demyelination, autoimmune encephalomyelitis, multiple sclerosis, ganglion cell loss), glaucoma, disability | NEURODEGENERATION, AMYOTROPHIC LATERAL SCLEROSIS, OPTIC NERVE, RETINA, NEURODEGENERATIVE DISEASES, AUTOIMMUNE ENCEPHALOMYELITIS, MULTIPLE SCLEROSIS, GLAUCOMA, DISEASES | Development of neuroprotective and remyelinating drugs is a high priority for central nervous system (CNS) diseases, including multiple sclerosis (MS)OCS-05 (previously known as BN201) is a neuroprotective and remyelinating drugCurrently OCS-05 has demonstrated neuroprotective properties by reducing the damage in the optic nerve and retina in in vivo models of acute optic neuritis (AON) such as lysolecithin-induced optic nerve demyelination, and in the experimental autoimmune encephalomyelitis model of MS. Moreover, OCS-05 showed activity in models of neurodegeneration such as the rat glaucoma model (by preventing retinal ganglion cell loss) and the in vitro model of amyotrophic lateral sclerosis (by rescuing motor neuron cells from death after nutritional stress), suggesting that the beneficial effects are mediated by neuroprotection and not immunomodulationOCS-05 is being developed as a neuroprotective treatment for decreasing CNS damage and disability in acute relapses of MS such as AON (i.e., as acute neuroprotection) as well as for the long-term treatment of MS to prevent worsening disability (chronic neuroprotection). The objective of this study was to assess the safety, tolerability, and pharmacokinetics of i.v. OCS-05 in healthy volunteers in order to enable clinical testing in patients with AON, MS, or other neurodegenerative diseases. | PMC10060579 |
Results | PMC10060579 |
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Safety | pneumonia, pain, SAD | PNEUMONIA, UPPER RESPIRATORY INFECTIONS, ADVERSE EVENTS, ADVERSE EVENT, EVENTS | A total of 56 subjects were enrolled in the study (Table Demographics of subjects.In the SAD part, there were a total of 10 TEAEs reported by 9 subjects (22.5%). The majority of subjects reported mild events, considered unrelated to OCS-05 (Table Overall summary of TEAEs – SAD part.During the MAD part, a total of 9 TEAEs were reported by 5 (31.3%) subjects. The majority of subjects reported mild events, considered unrelated to treatment. No significant differences between TEAEs were observed between different OCS-05 doses. Review of the summary statistics revealed little difference between OCS-05 and placebo in the means and mean changes from baseline in 12-lead ECG parameters with similar values observed for placebo, 2.4 mg and 3.0 mg OCS-05. No subjects had 12-lead ECG data that met study stopping criteria. There was 1 serious adverse event (severe pneumonia; unlikely to be related to study medication) following placebo (Table Overall summary of TEAEs–MAD part.Overall, the most common adverse events were pain and upper respiratory infections. No other ECG abnormalities outside the one reported above were detected. Indeed, no abnormalities were observed in blood tests, EEG, or brain MRI. | PMC10060579 |
Pharmacokinetics | SAD | In SAD part, CSummary of derived pharmacokinetic parameters following single dose administration of OCS-05 (i.v. infusion) to healthy male and female subjects.Summary of derived pharmacokinetic parameters following single dose administration of OCS-05 (i.v. infusion) to healthy subjects as means (SD).C(ng/mL)54.3(20.7)222(48.5)474(38.5)828((98.7)2150(231)2750(259)3470(833)T(h)1.50(0.31)2.00(0.42)1.55(0.25)2.00(0.21)1.50(0.45)1.75(0.28)1.75(0.41)AUC(h*ng/mL)113(39.4)500(133.8)1110(108.3)1910(222)4960(625)6160(567)7930(2319)NC(NA)528(141.2)1110(75)1910(241)5150(745)6550(682)8430(2430)AUC(%)NC(NA)1.03(0.54)1.35(0.54)1.59(0.21)1.76(0.39)1.41(0.74)1.56(0.33)k(1/h)NC(NA)0.207(0.12)0.0893(0.02)0.0900(0.01)0.0865(0.02)0.0842(0.04)0.101(0.01)T½(h)NC(NA)3.35(2.96)7.77(2.72)7.71(1.13)8.01(1.43)8.23(4.59)6.84(0.58)Vz(mL)NC(NA)120,000(75,613)298,000(92,232)320,000(57,952)298,000(96,562)280,000(183,194)259,000(75,183)CL(mL/h)NC(NA)24,900(3989.7)26,600(3074)28,800(2519)25,800(4583)23,600(2020)26,300(6505)In the MAD part, CSummary of Derived Pharmacokinetic Parameters Following Multiple Dose Administration of OCS-05 (I.V. Infusion) to Healthy Male and female Subjects.Summary of derived pharmacokinetic parameters following multiple dose administration of OCS-05 (i.v. infusion) to healthy subjects by Day 5 as means (SD).In order to account for a subject who received an incorrect dose (2.85 mg/kg instead of 2.4 mg/kg), due to the administered dose being based on an incorrect weight of 77.1 kg (correct weight 65.0 kg), the PK analysis was also conducted excluding this subject using the supplementary PK set. The analysis of the supplementary PK set gave the same results as those described for the PK set above (data not shown). | PMC10060579 |
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Discussion | axonal degeneration, death, neuronal hypertrophy, SAD | OXIDATIVE STRESS, ASSOCIATED DISEASE | The safety profile of OCS-05 in healthy subjects was favorable at the tested doses in the SAD and MAD parts of this study. With the exception of TEAEs that tended to be higher following placebo during the MAD, there were no other treatment or dose-related trends in safety parameters observed during either part of the study. Pharmacokinetic data for OCS-05 in the SAD and MAD parts of the study demonstrate that the CPreclinical pharmacokinetics studies of i.v. OCS-05 in rats and dogs have shown that a value of blood concentration (CThe doses in this study were chosen based on the human equivalent doses related to animal toxicology studies and based on the NOAEL. As such, we started with a dose × 10 under the NOAEL. The PK data indicate that Cmax is reached within approximately 2 h of single and 5-day multiple-dosing, occurring at or near the end of the 2 h OCS-05 infusion. The AUC%extrap (< 5%) indicates that the large majority of exposure was accounted for during the sampling period (to 24 h post-dose) following both single and multiple dosing. In the study, the t1/2 (geometric mean) ranged from 3.35 to 8.23 h across the 0.2–3.2 mg/kg OCS-05 dose range in Part A and 12.2 and 8.63 h for 2.4 and 3.0 mg/kg OCS-05 in Part B respectively. In both parts of the study, Vz (geometric mean) ranged from 120.0 (120,000 mL/kg) to 320.0 (320,000 mL/kg) L/kg in Part A and Vss (geometric mean) 60.2 (60,200 mL/kg) to 63.6 (63,600 mL/kg) L/kg in Part B, suggesting that OCS-05 is widely distributed to perfused tissues. This study has limitations such as not having collected cerebrospinal fluid samples for measuring OCS-05 concentrations after BBB crossing, not being able to reach the maximum Cmax planned because the AUC reached the stopping rule and not having validated biomarkers of target engagement and pharmacodynamics. Considering the PK profile from this study, the toxicology studies, and that OCS-05 is crossing the BBB by active transportation after IV infusion, we have determined that starting doses for the phase 2 trial being between 2–3 mg/kg (NCT04762017 and EUDRACT: 2020-003147-29). Regarding the mechanism of action of OCS-05 for promoting neuroprotection, we have previously shown that it activates SGK2Downstream effects of SGKs include the E3 ubiquitin ligase Nedd4-2, the FOXO3 and other kinases such as GSK-3B and NRDG1-2. In addition, SGKs regulates ion channels such as Epithelium ion channel (ENaC), CLC2, acid-sensing ion channel 1 (ASIC1), Kv1.3, Kv1.5, Kv4.3, ROMK1, TRVP5, CIC2, SCN5A, KCNE1/KCNQ1, KCNQ4, 4F2/LAT, GluR1 and GluR6, NHE3, as well as glucose transporters SGLT1, GLUT1, aminoacids transporter ASCT2, glutamate transporter EAAT1-5, CreaT, Na–K ATPaseSGK2 induces a broad spectrum of neurotrophic effects on neurons, including induction of neuronal hypertrophy, protection from neuron death and axonal degeneration and promoting axonal regenerationPhosphorylation by SGK induces FOXO3 translocation from the nucleus. FOXO3 contributes to the regulation of various processes such as cell cycle progression, cell size determination, cell death, cell differentiation, resistance to nutrient and oxidative stress, immune response, stress resistance, energetic metabolism and longevityIn summary, the results of this phase 1 study in healthy subjects with i.v. OCS-05 for up to 5 days showed a safe profile and linear pharmacokinetics, supporting testing it as a neuroprotective therapy for AON and MS. OCS-05 is currently being tested in a phase 2 trial in patients with AON of idiopathic origin or due to MS or MOG associated disease (MOGAD) (NCT04762017 and EUDRACT: 2020-003147-29). | PMC10060579 |
Methods | PMC10060579 |
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Ethics statement | The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000, and approved by the Wales Research Ethics Committee and the UK Medicines and Healthcare products Regulatory Agency. The study was registered in EudraCT (number 2017-001202-14) on 06/11/2020. Researchers have disclosed to participants any potential conflict and the sponsor name. If the subject was willing to participate in the study, the informed consent form was signed and personally dated by the subject and the study staff member taking consent. | PMC10060579 |
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Study design | BLIND | This was a randomized, double blind, placebo controlled, 2-part single and multiple ascending dose study. The objectives were to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of OCS-05 in healthy subjects. Inclusion criteria included healthy (as judged by the Investigator; no clinically significant abnormalities) male and female (non-pregnant, non-lactating) subjects between 18 and 55 years of age, with a body weight of ≥ 50.0 kg and ≤ 100 kg and body mass index (BMI) of 18 to 32 kg/m | PMC10060579 |
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Outcomes | ADVERSE EVENT, SECONDARY | The primary endpoint was the presence of Adverse Events (AEs), including and not limited to laboratory safety (biochemistry, hematology, and urinalysis); vital signs (supine systolic/diastolic blood pressure, pulse rate and body temperature); and 12-lead electrocardiogram (ECG: heart rate, PR interval, QRS duration, QT interval, QT interval corrected for heart rate using Bazett’s [QTcB interval] and Fridericia’s [QTcF interval] formulae). The secondary endpoints for this study were pharmacokinetics parameters: maximum concentration (C | PMC10060579 |
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Treatments and doses | SAD | Subjects (n = 48) were randomly 1: 3 assigned to receive placebo (n = 12) or OCS-05 (n = 36). Due to the interlocking design where some subjects received more than one dose level, overall, 14 received placebo and 42 received OCS-05. In the single ascending dose part (SAD), doses administered with 2 h i.v. infusion were 0.05, 0.2, 0.4, 0.8, 1.6, 2.4 and 3.2 mg/kg. In the multiple ascending dose (MAD) part 2.4 and 3.0 mg/kg doses were administered with 2-h i.v. infusion for 5 consecutive days (Table Summary of study design.SD1: Period 1 (0.05 mg/kg)Period 2 (1.6 mg/kg)SD2: Period 1 (0.2 mg/kg)Period 2 (3.2 mg/kg)SD3: Period 1 (0.4 mg/kg)Period 2 (2.4 mg/kg)SD4: Period 1 (0.8 mg/kg)Day -1 to Day -3Dose administered on Day 1 with a washout of at least 14 days between doses in Period 1 and 2MD1: Period 1 (2.4 mg/kg)MD2: Period 1 (3.0 mg/kg)Day -1 to Day 7Doses administered on Days 1—5SD: Study Day. | PMC10060579 |
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Statistical analysis | REGRESSION | Safety population was defined as every subject randomized and treated at least once with either placebo or drug. All statistical analysis were performed using SASAll OCS-05 concentrations and derived PK data were listed and individual and mean (arithmetic and geometric) concentration time data were plotted. Dose proportionality was assessed by performing a regression analysis of the log transformed CFor the Steady State analysis, for each dose level, log transformed trough concentration levels at pre dose each day (Day 2 through to Day 5) were subjected to a mixed-effects analysis of variance (ANOVA), with study day as a fixed effect and subject as a random effect, in order to establish whether and when steady state had been attained for each dose level. Back transformed ratios for the comparisons of each consecutive day (i.e., Day 3/Day 2) were presented along with corresponding 90% CI.For the accumulation analysis, following logarithmic transformation, Cmax and AUC0-tau values were subjected to a mixed effects ANOVA for each dose level, including a fixed effect of study day and random effect of subject. The analysis included only subjects who had available data for both days within a treatment. Point estimates and 90% CI were constructed for the contrasts between Day 5 and Day 1 using the residual mean square error obtained from the ANOVA. The point and interval estimates were then back-transformed to give estimates of the ratios of the geometric LSMeans and corresponding 90% CI and the p-value for the test of the null hypothesis of non-equivalence. In addition, estimated geometric means were produced for each study day. | PMC10060579 |
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Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-32278-0. | PMC10060579 |
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Acknowledgements | We would like to thank Dr Joanne Chang from Oculis SA from her insightfully comments. Editorial assistance with the preparation of the manuscript was provided by Phil Hunt of Southdown Medical Writing Ltd, Worthing, UK, funded by Oculis SA. Anonymized data not published within this article will be made available by request from any qualified investigator. | PMC10060579 |
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Author contributions | P.V.: study design, analysis, and wrote the article. M.M.: study design, analysis and reviewed the article. S.P.: study design, study management and reviewed the article. S.H.: study design, data acquisition, analysis and reviewed the article. A.K.: study design, data acquisition analysis and reviewed the article. | PMC10060579 |
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Funding | This study was funded by Accure Therapeutics, Barcelona, Spain. OCS-05 has been licensed to Oculis SA, Lausanne, Switzerland which is conducting the phase 2 trial. | PMC10060579 |
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Data availability | The study protocol and statistical analysis plan are available in the supplementary material. The datasets generated and/or analysed during the current study are not publicly available due agreement restrictions but are available from the corresponding author on reasonable request. | PMC10060579 |
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Competing interests | MM | FOUNDER | PV holds a patent covering the composition of matter and uses of BN201. PV is a founder, holds stocks in Bionure SL, which has licensed the patent rights to Oculis SL and serves on its scientific advisory board, having been compensated by such activities. MM and SP were employees of Accure Therapeutics (formerly Bionure SL), and SH and AK were employees of Simbec-Orion. | PMC10060579 |
References | PMC10060579 |
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Background | prediabetes, TCM | DISEASE, PREDIABETES | Traditional Chinese medicine (TCM) theories assert that body constitution and meridian energy lay the foundation for disease prevention. TCM-based health concepts have not yet been incorporated into mobile health (mHealth) apps for individuals with prediabetes. | PMC10337399 |
Objective | prediabetes, TCM | PREDIABETES | The aim of this study was to examine the effectiveness of a TCM mHealth app for individuals with prediabetes. | PMC10337399 |
Methods | TCM, prediabetes | MAY, DISEASE, PREDIABETES, -20 | This randomized controlled trial recruited 121 individuals with prediabetes at a teaching hospital in New Taipei City between February 2020 and May 2021. The participants were randomly assigned to the TCM mHealth app group (n=42), ordinary mHealth app group (n=41), or control group (n=38). All participants received the usual care that included 15-20 minutes of health education about the disease, along with healthy diet and exercise encouragement. The ordinary mHealth app included physical activity (PA), diet, and disease education, along with individual records. The TCM mHealth app additionally included | PMC10337399 |
Results | TCM | Compared to the control group, the TCM mHealth app group showed greater improvement in hemoglobin A | PMC10337399 |
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Conclusions | prediabetes | PREDIABETES | Use of either the ordinary or TCM mHealth app improved HRQOL among individuals with prediabetes. Compared to the outcomes of controls not using any app, use of the TCM mHealth app was effective at improving HbA | PMC10337399 |
Trial Registration | ClinicalTrials.gov NCT04096989; https://clinicaltrials.gov/ct2/show/NCT04096989 | PMC10337399 |
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Introduction | Prediabetes, prediabetes, Diabetes, T2DM, prediabetes or diabetes | PREDIABETES, PREDIABETES, DIABETES, DISEASE, TYPE 2 DIABETES MELLITUS | Prediabetes is a subhealth condition characterized by higher than normal blood sugar levels, but not yet at a sufficiently high level to warrant a diagnosis of type 2 diabetes mellitus (T2DM) [The Centers for Disease Control and Prevention Diabetes Prevention Program (DPP) has been shown to effectively delay or prevent the development of T2DM among individuals diagnosed with prediabetes [People’s lifestyles and behaviors have close associations with their sociocultural background [Several measures use different types of classifications for body constitution [Previous studies showed that individuals with prediabetes or diabetes were more deficient in the body constitutions of To the best of our knowledge, no study has been conducted to identify whether TCM-based health concepts could be incorporated into a mobile health (mHealth) app for individuals with prediabetes. The need for incorporating TCM body constitutions is based on two key factors: (1) as a sociocultural appropriate method to contextualize PA and diet, and (2) as possible mediation variables for blood sugar control such as HbA | PMC10337399 |
Methods | PMC10337399 |
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Study Design | prediabetes | ADVERSE EVENTS, MAY, PREDIABETES | This study was an open-label, parallel-group RCT (ClinicalTrials.gov NCT04096989) with a three-group design. We cooperated with the health examination center and outpatient clinics at a teaching hospital in northern Taiwan to recruit individuals diagnosed with prediabetes from February 2020 to May 2021. The inclusion criteria were (1) having been diagnosed with prediabetes (according to an HbAParticipants were randomly assigned to three groups: TCM mHealth app, ordinary mHealth app, or control group. A statistician drew up a computer-generated randomization list. The allocation sequence was kept in an opaque, sealed, and stapled envelope, and a staff member in the outpatient clinic who was not involved in the study held the sealed envelopes. After the participants agreed to participate in the study, the researcher opened the envelope to reveal their group assignment.The informed consent form was signed by all participants before enrollment in the study. The informed consent form stated that the risk of participation in this study was low. If the participants felt physically or mentally unwell due to their participation, they had to contact the researchers and had the right to withdraw at any time. No adverse events were reported during the study period. | PMC10337399 |
Ethics Approval | This study was approved by the institutional review board at Taipei Tzu Chi Hospital (approval no. 08-X-026). | PMC10337399 |
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Intervention | belly breath, prediabetes, Hypertension, T2DM, TCM | DISEASE, HYPERTENSION, PREDIABETES | An expert team that included nursing researchers, TCM doctors, Western medicine doctors, and app developers was formed to guide the development of the intervention app. The team decided that the content embedded in the app would be developed in accordance with the DPP [The mHealth app (both the ordinary and TCM versions) included four modules: health diary, health education, milestone, and chatroom. The “health diary” tracked the participant’s weight, BMI, blood sugar level, dietary diary, and PA over time. “Health education” provided information about specific topics such as learning about prediabetes, Dietary Approaches to Stop Hypertension (DASH) diet, and PA. The TCM mHealth app additionally included health education topics on body constitution, meridian energy, and advice on a body constitution–based diet (such as foods to avoid and foods that are recommended) and PA such as videos, pictures, and descriptive illustrations of types of Qigong (ie, Baduanjin and belly breath). A text message was sent to the participants to remind them to read the topics every week. Milestones were added for the participants to review their goals so that they could make adjustments to reach their monthly goals. For example, if the participants set a goal of an FPG level of 60-99 mg/dL, when this goal was achieved, a window would pop up to show the achievement. The participants could also check bar and line charts over 1 week or 1 month to compare the discrepancy between the actual and desired values as well as actual and ideal behaviors at different time points so that they could adjust their expected goal as needed.In the “chatroom,” personal and group chat rooms were set up using the LINE app (Naver Corp, Gyeonggi Province, South Korea). The researchers sent text messages to the participants in the personal chat room, provided feedback on the results, and encouraged participants to share their experiences in the group chat room. The participants collected virtual gold by completing questionnaires and quizzes and by achieving the set goals. The participants could use the virtual gold to claim actual prizes from the researchers. Gamification elements were added to encourage engagement with the mHealth app. Screenshots and descriptions of the ordinary and TCM mHealth apps are presented in The participants in the TCM and ordinary mHealth app groups received a face-to-face education session on how to use the mHealth app and create a user account. Both mHealth app groups received information about prediabetes and evidence-based methods to decrease the possibility of progression to T2DM (eg, moderate-intensity PA of ≥150 minutes/week, DASH diet, and disease health education). The TCM mHealth app group additionally received body constitution and The researchers monitored logins and log file analysis at least once every week at the mHealth app backend. If the participants did not use the app, complete the diary, or watch health education, additional text messages were sent to the participants. The CONSORT-EHEALTH guidelines [ | PMC10337399 |
Data Collection | Dietary behavior, chronic disease | SECONDARY, CHRONIC DISEASE | Data were collected at baseline (T1), at the end of the 12-week intervention (T2), and 1 month after the intervention (T3). Sociodemographic characteristics (age, gender, marital status, education level, and employment status), clinical characteristics (history of chronic disease and use of TCM), and lifestyle factors (smoking and alcohol drinking) were collected by a structured questionnaire at baseline. Primary outcome measures, including blood sugar control (FPG and HbABody constitution was assessed by the BCQ [Meridian energy was measured using the Meridian Energy Analysis Device (MEAD) ME-PRO 6.1.1 (Medpex Enterprise Ltd, Taichung, Taiwan). The level of meridian energy was assessed using the MEAD values for the 24 acupoints (Ryodoraku points) along the 12 meridians ranging from 0 to 200 µA [HRQOL was measured by the Medical Outcome Survey Short Form (SF-36) Taiwan version. SF-36 is composed of 36 items, which form two summary scales, namely the physical component score (PCS) and the mental component score (MCS). Higher scores on the PCS and MCS indicate a better physical and mental aspect of HRQOL, respectively [The secondary outcomes in this study were BMI, dietary behavior, and PA. Dietary behavior was assessed by the dietary behavior questionnaire, which consisted of 14 items based on a 4-point Likert scale, ranging from 1 (never) to 4 (always). The scores ranged from 14 to 56, with higher scores indicating a better correspondence to the DASH diet [ | PMC10337399 |
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