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Abstract Background Acupuncture or moxibustion has been proven to be effective for patients with primary dysmenorrhea (PDM). However, the respective advantages and potential central mechanism of acupuncture and moxibustion are worthy of investigating to promote their further application. Methods In this randomized controlled neuroimaging trial, 72 patients with PDM will be randomly assigned to three groups: acupuncture treatment group, moxibustion treatment group, and waiting list group. The acupuncture treatment group and moxibustion treatment group will receive acupuncture or moxibustion, respectively, for a total of 3 sessions over 3 consecutive menstrual cycles, and the waiting list group will not take acupuncture or moxibustion during these 3 menstrual cycles. The COX Menstrual Symptom Scale (CMSS), visual analog scale (VAS), and Pain Catastrophizing Scale (PCS) will be used to evaluate the clinical efficacy. The Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), and 36-Item Short Form Health Survey (SF-36) will be used to assess the mental state and quality of life at baseline and at the end of treatment. Functional magnetic resonance imaging (fMRI) will be performed for detecting the cerebral activity changes at baseline and at the end of the treatment. The clinical data and imaging data will be analyzed among the groups. Correlation analysis will be conducted to investigate the relationship between brain functional changes and symptom improvement. Discussion The application of the randomized controlled neuroimaging trial will provide objective and valid evidence about how acupuncture and moxibustion treatment relieve menstrual pain. The results of this study would be useful to confirm the potential similarities and differences between acupuncture and moxibustion in clinical efficacy and central mechanism for patients with PDM. Trial registration Chinese Clinical Trial Registry ChiCTR2100043732 . Registered on 27 February 2021

Abstract Background Primary dysmenorrhea (PD) is one of the main gynecological complaints in women of child-bearing age, but limited effective treatments are available. Guizhi Fuling Wan (GFW), one of the most widely known traditional Chinese medicine (TCM) formulations, has been commonly used in clinical practice to treat gynecological disorders in China. In recent years, a growing number of studies have shown that GFW is beneficial for patients with PD. However, the quality of evidence is limited, and there are few studies on specific TCM syndromes of GFW for PD. Therefore, we plan to conduct a randomized controlled trial to explore the efficacy and safety of GFW for PD patients with heat-burning blood-stasis syndrome. Methods and analysis The clinical study is a randomized, double-blinded, placebo-controlled trial. Eligible patients will be randomly assigned to the GFW group (treated with GFW) and the control group (treated with a matching placebo) in a 1:1 ratio for three menstrual cycles with a 3-month follow-up. The primary outcome will be the mean change of pain intensity measured by the visual analog scale (VAS). The secondary outcomes will include the Cox Menstrual Symptom Scale (CMSS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS), and the TCM syndrome scale. Adverse events will also be reported. Discussion This randomized trial will be the first rigorous study designed to assess the efficacy and safety of GFW in treating PD with heat-burning blood-stasis syndrome. The finding of this study will provide an objective clinical basis for the use of GFW for PD in the future. Trial registration Chinese Clinical Trial Registry ChiCTR2000034118 . Registered on 24 June 2020

Background: Acupuncture or moxibustion has been proven to be effective for patients with primary dysmenorrhea (PDM). However, the respective advantages and potential central mechanism of acupuncture and moxibustion are worthy of investigating to promote their further application.Methods: In this randomized controlled neuroimaging trial, 72 patients with PDM will be randomly assigned to three groups: acupuncture treatment group, moxibustion treatment group, and waiting list group. The acupuncture treatment group and moxibustion treatment group will receive acupuncture or moxibustion, respectively, for a total of 3 sessions over 3 consecutive menstrual cycles, and the waiting list group will not take acupuncture or moxibustion during these 3 menstrual cycles. The COX Menstrual Symptom Scale (CMSS), visual analog scale (VAS), and Pain Catastrophizing Scale (PCS) will be used to evaluate the clinical efficacy. The Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), and 36-Item Short Form Health Survey (SF-36) will be used to assess the mental state and quality of life at baseline and at the end of treatment. Functional magnetic resonance imaging (fMRI) will be performed for detecting the cerebral activity changes at baseline and at the end of the treatment. The clinical data and imaging data will be analyzed among the groups. Correlation analysis will be conducted to investigate the relationship between brain functional changes and symptom improvement.Discussion: The application of the randomized controlled neuroimaging trial will provide objective and valid evidence about how acupuncture and moxibustion treatment relieve menstrual pain. The results of this study would be useful to confirm the potential similarities and differences between acupuncture and moxibustion in clinical efficacy and central mechanism for patients with PDM.Trial Registration: Chinese Clinical Trial Registry ChiCTR2100043732 . Registered on 27 February 2021. [ABSTRACT FROM AUTHOR]

Abstract Background Primary dysmenorrhea (PD) is the most common complaint in young women and adolescents. Side effects of non-steroidal anti-inflammatory drugs can limit their use. Therefore, non-pharmacological pain relief methods such as auriculotherapy may play an important role in PD management. This study was conducted to compare the effect of auriculotherapy and mefenamic acid on the severity and systemic symptoms of PD. Methods In a randomized clinical trial, 83 students were randomized into two groups. In the auriculotherapy group, electrical stimulation of the ear was conducted once a week for two menstrual cycles. In each cycle close to menstruation, ear seeds were inserted on pressure points to be pressed in times of pain. In the mefenamic acid group, subjects took mefenamic acid capsules upon seeing the initial symptoms of menstruation until the pain reduces. The primary outcomes were mean pain intensity and systemic symptoms associated with it. Pain intensity was measured through the visual analog scale (VAS) and the verbal multidimensional scoring system (VMS). Systemic symptoms were assessed using VMS, as well as the yes/no question form. Results Mean pain intensity with the VAS was significantly lower in the auriculotherapy group than the mefenamic acid group in the first and second cycles of intervention. There was a significant difference in VMS grade between both groups during the second cycle of intervention. In terms of the systemic symptoms in the second cycle of intervention, no subjects had dysmenorrhea grade 3 (common systemic symptoms) in the auriculotherapy group. Whereas in the mefenamic acid group, 16.7% of the subjects still had dysmenorrhea grade 3. There was no significant difference between the two groups in the frequency of systemic symptoms of PD. There was a significant decrease in the frequency of fatigue and diarrhea in both groups. However, there was a significant reduction in the frequency of nausea, headache, and anger in the auriculotherapy group. Conclusion Mean pain intensity with the VAS was lower with the auriculotherapy. Also, 65.9% of auriculotherapy group subjects were in the dysmenorrhea grades 0 and 1. Therefore, auriculotherapy is recommended because of its fewer complications and more effect on PD. Trial registration ClinicalTrials.gov IRCT20181207041873N1. Registered on February 24, 2019. https://en.irct.ir/user/trial/35967/view

Abstract Background Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients. Methods This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups—a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported. Discussion This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea. Trial registration Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019

Background: Primary dysmenorrhea (PD) is one of the main gynecological complaints in women of child-bearing age, but limited effective treatments are available. Guizhi Fuling Wan (GFW), one of the most widely known traditional Chinese medicine (TCM) formulations, has been commonly used in clinical practice to treat gynecological disorders in China. In recent years, a growing number of studies have shown that GFW is beneficial for patients with PD. However, the quality of evidence is limited, and there are few studies on specific TCM syndromes of GFW for PD. Therefore, we plan to conduct a randomized controlled trial to explore the efficacy and safety of GFW for PD patients with heat-burning blood-stasis syndrome. Methods and analysis: The clinical study is a randomized, double-blinded, placebo-controlled trial. Eligible patients will be randomly assigned to the GFW group (treated with GFW) and the control group (treated with a matching placebo) in a 1:1 ratio for three menstrual cycles with a 3-month follow-up. The primary outcome will be the mean change of pain intensity measured by the visual analog scale (VAS). The secondary outcomes will include the Cox Menstrual Symptom Scale (CMSS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS), and the TCM syndrome scale. Adverse events will also be reported. Discussion: This randomized trial will be the first rigorous study designed to assess the efficacy and safety of GFW in treating PD with heat-burning blood-stasis syndrome. The finding of this study will provide an objective clinical basis for the use of GFW for PD in the future. Trial registration: Chinese Clinical Trial Registry ChiCTR2000034118. Registered on 24 June 2020 [ABSTRACT FROM AUTHOR]

Background: Primary dysmenorrhea (PD) is one of the main gynecological complaints in women of child-bearing age, but limited effective treatments are available. Guizhi Fuling Wan (GFW), one of the most widely known traditional Chinese medicine (TCM) formulations, has been commonly used in clinical practice to treat gynecological disorders in China. In recent years, a growing number of studies have shown that GFW is beneficial for patients with PD. However, the quality of evidence is limited, and there are few studies on specific TCM syndromes of GFW for PD. Therefore, we plan to conduct a randomized controlled trial to explore the efficacy and safety of GFW for PD patients with heat-burning blood-stasis syndrome.Methods and Analysis: The clinical study is a randomized, double-blinded, placebo-controlled trial. Eligible patients will be randomly assigned to the GFW group (treated with GFW) and the control group (treated with a matching placebo) in a 1:1 ratio for three menstrual cycles with a 3-month follow-up. The primary outcome will be the mean change of pain intensity measured by the visual analog scale (VAS). The secondary outcomes will include the Cox Menstrual Symptom Scale (CMSS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS), and the TCM syndrome scale. Adverse events will also be reported.Discussion: This randomized trial will be the first rigorous study designed to assess the efficacy and safety of GFW in treating PD with heat-burning blood-stasis syndrome. The finding of this study will provide an objective clinical basis for the use of GFW for PD in the future.Trial Registration: Chinese Clinical Trial Registry ChiCTR2000034118 . Registered on 24 June 2020. [ABSTRACT FROM AUTHOR]

Abstract Background Primary dysmenorrhea (PD) is a leading cause of dysmenorrhea among adolescent girls. Manual acupuncture may be considered as an effective treatment for PD, but high-quality evidence remains limited. This trial aims to evaluate the efficacy and safety of acupuncture for the prevention of PD as compared with sham acupuncture and usual care. Methods/design This is a three-arm, randomized, controlled clinical trial in which the patients, assessors, and statisticians will be blinded. A total of 300 acupuncture-naive patients who were diagnosed as PD will be randomly allocated to the verum acupuncture, sham acupuncture, or usual care groups in a 2:2:1 ratio. Patients in the verum acupuncture group will receive manual acupuncture at specific acupuncture points with penetrating needling, while those in the sham acupuncture group will receive non-penetrating needling at non-acupuncture points. They will be given five sessions over a menstrual cycle for 3 menstrual cycles. Patients in the usual care group will receive health education and informed to receive manual acupuncture for free after waiting for 7 menstrual cycles. The primary outcome will be the change from baseline in the Cox Menstrual Symptom Scale Score (CMSS). The secondary outcomes will be the changes in Massachusetts General Hospital Acupuncture Sensation Scale (MASS), visual analog scale (VAS), Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2), Pittsburgh Sleep Quality Index (PSQI), Beck Anxiety Inventory (BAI), Beck Depression Inventory II (BDI- II), Acupuncture Expectancy Scale (AES), 60-item NEO Personality Inventory-Short Form (NEO-FFI), and acute medication intake. The adverse events will be recorded at every visit. The analyses will be performed base on a full analysis set (FAS) and a per-protocol set (PPS). Discussion This study may provide high-quality evidence regarding the efficacy and safety of manual acupuncture for PD. In addition, the results of this study will help to identify the efficacy of acupuncture due to the specific effects of acupuncture or placebo effects of acupuncture ritual. Trial registration Clinical Trials.gov NCT02783534 . Registered on 26 May 2016

Background: Primary dysmenorrhea (PD) is the most common complaint in young women and adolescents. Side effects of non-steroidal anti-inflammatory drugs can limit their use. Therefore, non-pharmacological pain relief methods such as auriculotherapy may play an important role in PD management. This study was conducted to compare the effect of auriculotherapy and mefenamic acid on the severity and systemic symptoms of PD.Methods: In a randomized clinical trial, 83 students were randomized into two groups. In the auriculotherapy group, electrical stimulation of the ear was conducted once a week for two menstrual cycles. In each cycle close to menstruation, ear seeds were inserted on pressure points to be pressed in times of pain. In the mefenamic acid group, subjects took mefenamic acid capsules upon seeing the initial symptoms of menstruation until the pain reduces. The primary outcomes were mean pain intensity and systemic symptoms associated with it. Pain intensity was measured through the visual analog scale (VAS) and the verbal multidimensional scoring system (VMS). Systemic symptoms were assessed using VMS, as well as the yes/no question form.Results: Mean pain intensity with the VAS was significantly lower in the auriculotherapy group than the mefenamic acid group in the first and second cycles of intervention. There was a significant difference in VMS grade between both groups during the second cycle of intervention. In terms of the systemic symptoms in the second cycle of intervention, no subjects had dysmenorrhea grade 3 (common systemic symptoms) in the auriculotherapy group. Whereas in the mefenamic acid group, 16.7% of the subjects still had dysmenorrhea grade 3. There was no significant difference between the two groups in the frequency of systemic symptoms of PD. There was a significant decrease in the frequency of fatigue and diarrhea in both groups. However, there was a significant reduction in the frequency of nausea, headache, and anger in the auriculotherapy group.Conclusion: Mean pain intensity with the VAS was lower with the auriculotherapy. Also, 65.9% of auriculotherapy group subjects were in the dysmenorrhea grades 0 and 1. Therefore, auriculotherapy is recommended because of its fewer complications and more effect on PD.Trial Registration: ClinicalTrials.gov IRCT20181207041873N1. Registered on February 24, 2019. https://en.irct.ir/user/trial/35967/view. [ABSTRACT FROM AUTHOR]

Abstract Background Unpleasant experience with the previous menstruation can increase the sensitivity to pain which may lead to moderate to severe pain in patients with dysmenorrhea. Eye movement desensitization and reprocessing (EMDR) is a psychological method to alleviate the distress from unpleasant memories and related events and can be used for other conditions such as anxiety, depression, and chronic pain. This protocol was designed to investigate the effect of EMDR therapy on pain intensity in patients with dysmenorrhea. Methods/Design A randomized clinical trial was designed in compliance with the Consolidated Standards of Reporting Trials (CONSORT). Female students who have moderate to severe primary dysmenorrhea (based on a visual analogue scale [VAS] score of at least 4 for two consecutive months) and who live in dormitories at Qazvin University of Medical Sciences in Qazvin, Iran will be invited to participate in the study. The total sample size will be 88 girls, who will be randomly assigned to intervention (N = 44) and control (N = 44) groups. EMDR therapy will be performed for the intervention group, while the control group can use sedative or other pain relife methods as their routin... There will be six treatment sessions, which will be held twice a week. The duration of each session is 30–90 min, according to the convenience of each participant. The data will be collected using the demographic characteristics questionnaire, the VAS, the Subjective Units of Anxiety or Distress Scale (SUD), and the Validity of Cognition Scale (VOC). The data on pain intensity due to primary dysmenorrhea in both groups will be collected at 1 and 2 months before the intervention (to identify eligible participants) and 1 and 2 months after the intervention (follow-ups). Data will be analyzed by using SPSS version 25 software and analysis of variance (ANOVA) with repeated measures with appropriate post hoc tests. A P value of less than 0.05 will be considered significant. Discussion The results are expected to provide the information on the efficacy of EMDR therapy to manage moderate to severe pain in patients with primary dysmenorrhea. Ethics and dissemination The research proposal is approved by the human ethics committee of Qazvin University of Medical Sciences (IR.QUMS.REC.1397.100). The results of this trial will be submitted for publication in a peer-reviewed research journal. Trial registration IRCT20180823040851N1. Registered on 6, October 2018.

Background: Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients.Methods: This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups-a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported.Discussion: This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea.Trial Registration: Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019. [ABSTRACT FROM AUTHOR]

Abstract Background Primary dysmenorrhea (PD), is one of main gynecological complaints in women of child-bearing age. Common medications for PD do not always achieve satisfactory outcome of pain relief. Hence, both health professionals and patients are seeking help from complementary and alternative medicine. The acupoint herbal plaster (AHP), which appears to be a safe and effective way to alleviate menstrual pain, as well as to improve other PD-related symptoms. Despite similar clinical studies for this condition in the past, no high-quality methodology-based clinical trial has been reported to date. The current study aims to assess the efficacy of the AHP compared with the acupoint placebo plaster (APP) and being placed on a waiting-list control group in patients with primary dysmenorrhea. Methods/design This study is a randomized, single-center, placebo-controlled clinical trial. A total of 180 women with PD will be included and randomly allocated to the AHP, APP and waiting-list (WL) groups in a 1:1:1 ratio. Patients in the AHP group will be provided with herbal plasters (Shaofuzhuyu decoction) on various acupoints: Shenque (CV8), Guanyuan (CV4), Qihai (CV5), Ciliao (BL32) and Zigong (EX-CA1). Women in the APP group will receive placebo plasters on the same acupoints, and no intervention will be given to the WL group until completion of the study. The primary outcome will be pain intensity reduction measured by a Visual Analog Scale (VAS), with other outcome measurements including the Cox Menstrual Symptom Scale (CMSS), the 12-Item Short Form Health Survey (SF-12) and the Participant Global Impression of Change (PGIC). All assessments will be performed at baseline, each menstrual cycle during the treatment course and the follow-up course. Any adverse events will be recorded throughout the study. Discussion This is the first study to compare the changes in menstrual pain after three different interventions: the active intervention (AHP), the placebo intervention (APP), and a period of no intervention (WL). This three-arm randomized controlled trial (RCT) aims to investigate the relative contributions of the specific (AHP vs. APP) and non-specific (APP vs. WL) effects to the overall clinical effects of the active AHP on women with PDM. The scientific and rigorous methodology design of this trial should gather good evidence to assess the curative effects and safety of the AHP on PD. Moreover, the results of this study may provide evidence-based references for the treatment of menstrual pain in future. Trial registration Chinese Clinical Trial Registry, ID: ChiCTR-TRC-16008701. Registered on 22 July 2016.

Background: Dysmenorrhea is a common menstrual complaint among adolescent girls and women of reproductive age. The treatment of dysmenorrhea is typically selected from multidisciplinary options, including complementary and alternative medicine such as acupuncture and moxibustion. However, there are few published randomized controlled trials concerning moxibustion treatment for dysmenorrhea. This trial aims to investigate the efficacy and safety of moxibustion for primary dysmenorrhea, and to identify the optimal time of moxibustion treatment for primary dysmenorrhea. Methods/Design: This protocol is for a randomized controlled trial in which the assessor and statistician will be blinded. A total of 222 eligible patients with dysmenorrhea will be randomly assigned to three groups in a 1:1:1 ratio as treatment group A (treated before menstruation onset), treatment group B (treated at the onset of menstruation), or control group C (waiting list group). The participants assigned to the treatment groups will receive suspended moxibustion treatment at Sanyinjiao (SP6) and Guanyuan (CV4), while the waiting list group will not receive moxibustion treatment until the completion of the study. The trial period will consist of three baseline menstrual cycles, three menstrual cycles of treatment, and three menstrual cycles in the follow-up period. The primary outcome will be measured by changes in the Cox Menstrual Symptom Scale and the secondary outcomes will be measured using the Visual Analogue Scale, Cox Retrospective Symptom Scale, diary entries, the Self-rating Depression Scale, and the Self-rating Anxiety Scale. The safety of moxibustion will be assessed at every visit. Discussion: This trial aims to assess the effectiveness and safety of moxibustion for primary dysmenorrhea, as well as to determine whether the optimal time of treatment for primary dysmenorrhea in clinical practice is before or after the onset of menstrual pain. [ABSTRACT FROM AUTHOR]

Background: Primary dysmenorrhea (PD), is one of main gynecological complaints in women of child-bearing age. Common medications for PD do not always achieve satisfactory outcome of pain relief. Hence, both health professionals and patients are seeking help from complementary and alternative medicine. The acupoint herbal plaster (AHP), which appears to be a safe and effective way to alleviate menstrual pain, as well as to improve other PD-related symptoms. Despite similar clinical studies for this condition in the past, no high-quality methodology-based clinical trial has been reported to date. The current study aims to assess the efficacy of the AHP compared with the acupoint placebo plaster (APP) and being placed on a waiting-list control group in patients with primary dysmenorrhea.Methods/design: This study is a randomized, single-center, placebo-controlled clinical trial. A total of 180 women with PD will be included and randomly allocated to the AHP, APP and waiting-list (WL) groups in a 1:1:1 ratio. Patients in the AHP group will be provided with herbal plasters (Shaofuzhuyu decoction) on various acupoints: Shenque (CV8), Guanyuan (CV4), Qihai (CV5), Ciliao (BL32) and Zigong (EX-CA1). Women in the APP group will receive placebo plasters on the same acupoints, and no intervention will be given to the WL group until completion of the study. The primary outcome will be pain intensity reduction measured by a Visual Analog Scale (VAS), with other outcome measurements including the Cox Menstrual Symptom Scale (CMSS), the 12-Item Short Form Health Survey (SF-12) and the Participant Global Impression of Change (PGIC). All assessments will be performed at baseline, each menstrual cycle during the treatment course and the follow-up course. Any adverse events will be recorded throughout the study.Discussion: This is the first study to compare the changes in menstrual pain after three different interventions: the active intervention (AHP), the placebo intervention (APP), and a period of no intervention (WL). This three-arm randomized controlled trial (RCT) aims to investigate the relative contributions of the specific (AHP vs. APP) and non-specific (APP vs. WL) effects to the overall clinical effects of the active AHP on women with PDM. The scientific and rigorous methodology design of this trial should gather good evidence to assess the curative effects and safety of the AHP on PD. Moreover, the results of this study may provide evidence-based references for the treatment of menstrual pain in future.Trial Registration: Chinese Clinical Trial Registry, ID: ChiCTR-TRC-16008701. Registered on 22 July 2016. [ABSTRACT FROM AUTHOR]