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Warm-needling acupuncture and medicinal cake-separated moxibustion for hyperlipidemia: study protocol… Liu, Mailan; Zhang, Qian; Jiang, Shan; Liu, Mi; Zhang, Guoshan; Yue, Zenghui; Chen, Qin; Zhou, Jie; Zou, Yifan; Li, Dan; Ma, Mingzhu; Dai, Guobin; Zhong, Huan; Wang, Zhihong; Chang, Xiaorong Jul 10, 2017

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STUDY PROTOCOL Open AccessWarm-needling acupuncture and medicinalcake-separated moxibustion forhyperlipidemia: study protocol for arandomized controlled trialMailan Liu1†, Qian Zhang2†, Shan Jiang3†, Mi Liu1, Guoshan Zhang1, Zenghui Yue1, Qin Chen4, Jie Zhou4,Yifan Zou1, Dan Li1, Mingzhu Ma1, Guobin Dai1, Huan Zhong1, Zhihong Wang5* and Xiaorong Chang1*AbstractBackground: Acupuncture and moxibustion has been widely applied to hyperlipidemia treatment in clinical practicein China, serving as an alternative treatment to statins. Warm-needling acupuncture and medicinal cake-separatedmoxibustion have been separately reported with potential therapeutic effects on hyperlipidemia treatment in severalstudies but with limitations in study methodology. Combining these two modalities may provide a more advantageousstrategy in treating hyperlipidemia. Therefore, a strict evaluation through well-designed randomized controlled trials(RCT) is necessary to determine their efficacy and safety on hyperlipidemia.Methods: The study a multicenter, open-label, randomized, stratified, active-controlled, noninferiority trial with twoparallel groups. Subjects with hyperlipidemia will be stratified into different groups by risk levels of heart diseases. Theythen will be instructed to the Therapeutic Lifestyle Change (TLC) diet. Those who have not reached the target lipidlevel will be randomly assigned to the treatments of either acupuncture and moxibustion or simvastatin with a 1:1allocation. One hundred and thirty subjects are aimed to be recruited. The duration of intervention for this study will be12 weeks, followed by another 4 weeks for post-treatment assessment. The primary outcome is percentage changefrom baseline to the end of the study in low-density lipoprotein cholesterol (LDL-C). Other indicators in lipid change,safety and adherence will also be assessed secondarily. The repeated measures, linear mixed-effects model will beapplied to the analysis.Discussion: Acupuncture and moxibustion could be a potentially effective treatment alternative for hyperlipidemia. Astudy with careful design is developed to evaluate the efficacy and safety of combined acupuncture and moxibustion, byintegrating the traditional Chinese Medicine (TCM) regimens with the standardized Western medicine appraisal approach.Trial registration: ClinicalTrials.gov, NCT02269046. Registered on 26 September 2014.Keywords: Hyperlipidemia, Acupuncture, Moxibustion, Warm-needling acupuncture, Medicinal cake-separatedmoxibustion, Traditional Chinese medicine, Randomized controlled trial* Correspondence: wzh6172555@126.com; xiaorong_chang@126.com†Equal contributors5Changchun University of Chinese Medicine, 1035 Boshuo Rd., JingyueEconomic Development District, Changchun 130117, Jilin Province, China1Acupuncture and Tuina School, Hunan University of Chinese Medicine, 300Xueshi Rd., Yuelu, 410208 Changsha, Hunan, ChinaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Liu et al. Trials  (2017) 18:310 DOI 10.1186/s13063-017-2029-xBackgroundBackground and rationaleHyperlipidemia refers to a condition caused by abnormalmetabolism where low-density lipoprotein-cholesterol(LDL-C), serum total cholesterol (TC), triglycerides (TG),and/or high-density lipoprotein (HDL-C) are above rec-ommended levels. This condition is associated with thedeterioration in lifestyle and dietary habits and representsan important risk factor for cardiovascular morbidity andmortality. Hyperlipidemia is a risk factor for atheroscler-osis, cardiovascular disease, stroke, and other diseases.Large randomized controlled trials in hyperlipidemiatreatment have provided evidence that reducing LDLcholesterol concentration with statins is efficient in bothsecondary and primary cardiovascular disease (CVD) pre-vention [1, 2]. As a result, individuals at moderate or highCVD risk are often considered as candidates for lipid-lowering therapy with statins. However, statin therapy canincur significant cost to the society. In addition, statintherapy is often associated with low treatment complianceand high rates of side effects [3, 4].Acupuncture and moxibustion has been widely appliedto hyperlipidemia treatment in clinical practice of China.Thus, an increasing number of studies have exploredwhether acupuncture and moxibustion could serve as analternative treatment for subjects with hyperlipidemia.As shown in a meta-analysis, acupuncture solely, com-pared to statins, has demonstrated a more significant ef-fect on decreasing TG and increasing HDL-C, but nosuperiority in lowering the LDL-C and TC [5]. Mean-while, moxibustion, which is often administered withacupuncture in Traditional Chinese Medicine (TCM)practice, also plays an essential role in lipid-lowering bywarming meridians and facilitating lipid conversion inthe TCM theory. The recent studies have furtherrevealed the biological pathway in lipid-lowering ofmoxibustion [6–8]. This modality, especially the warm-needling acupuncture (acupuncture with a moxa stick),can enhance microcirculation, adjust the lipid metabol-ism, and thus lower the blood viscosity [6–8].Medicinal cake-separated moxibustion, an importantkind of moxibustion, applies the acupoints, moxibustion,and traditional Chinese herb in an integrative way. It hasgained increasing popularity in the practice of hyperlipid-emia treatment and thus been further assessed on its po-tential impact. Some findings have shown, from aperspective of gene transcription and protein expression,that the medicinal cake-separated moxibustion could pre-vent the formation of atheromatous plaque by adjustingToll-Like Receptor (TLR) signaling pathways as well asperoxisome proliferator-activated receptors (PPARs), inorder to delay atherosclerosis (AS) formation and stabilizeatheromatous plaque [9, 10]. Chang et al. indicated thatboth the medicinal cake-separated moxibustion and directmoxibustion have a certain protective action on endothe-lial cells of the aorta in the rabbit of hyperlipidemia [9].Yue et al. found that herb-partition moxibustion delaysthe formation of atherosclerosis through the inhibition ofTLR4 expression [10]. This has provided a new strategyfor the research on AS pathogenesis and prevention. Inaddition, based on clinical observation and systematic re-view of TCM literature, the selection of meridians andacupoints potentially having effect on hyperlipidemiatreatment, has been studied and identified, which includesten meridians (five Yin and five Yang meridians), and fiveacupoints (Stomach (ST), Spleen (SP), Ren (RN), Bladder(BL) and Pericardian (PC)) [11]. Based on these findings,several clinical studies on assessing medicinal cake-separated moxibustion have been undertaken, testingdifferent acupoint prescriptions, medicinal-cake ingredi-ents, treatment duration, etc., in attempt to identify aneffective and standardized regimen [6, 12–16]. Most ofthese studies have shown possible therapeutic effects ofthe medicinal cake-separated moxibustion on hyperlipid-emia, superior to the placebo or noninferior to statins.In general, acupuncture and moxibustion is shown tobe possibly effective in treating hyperlipidemia, withlower cost and fewer serious adverse events [17, 18].However, due to the lack of robust study design and as-sessment methodology in existing clinical studies, thefindings should be interpreted with caution. Accordingto previous attempts on identifying an optimal regimenof acupuncture and moxibustion for treating hyperlipid-emia, the warm needling acupuncture along with medi-cinal cake-separated moxibustion seems to be a modalitythat successfully combines the advantages of both acu-puncture and moxibustion. This is worth further explor-ing to warrant its therapeutic effects [12, 15, 16]. So far,very few studies on this combined intervention are avail-able. Hence, there is a need for a well-designed random-ized control trial to validate the efficacy and safety ofwarm-needling acupuncture along with medicinal cake-separated moxibustion, by comparing it with statins.Hypotheses and objectivesHypotheses Warm needling acupuncture and medicinal cake-separated moxibustion (short as “acupuncture andmoxibustion” in the following text) is noninferior toactive control, in subjects with hypercholesterolemia,on° percent change of LDL-C° absolute change of LDL-C° percent change of HDL-C° percent change of TC° percent change of TG° rate of subject achieving LDL-C goalLiu et al. Trials  (2017) 18:310 Page 2 of 17 Acupuncture and moxibustion is superior to activecontrol, in subjects with hypercholesterolemia, onsafety and tolerability° AdherencePrimary objectivesTo evaluate the effect of 12 weeks of acupuncture andmoxibustion compared with active control, on percent-age change from baseline in low-density lipoproteincholesterol (LDL-C) among those with hyperlipidemia.Secondary objectives To assess the effects of 12 weeks of acupuncture andmoxibustion, compared to active control, in subjectswith hypercholesterolemia, on° the absolute change in LDL-C,° the percent change in high-density lipoproteincholesterol (HDL-C),° the percent change in total cholesterol (TC)° the percent change in triglyceride(TG)° the rate of subjects achieving LDL-C goal. To evaluate the safety and tolerability of acupunctureand moxibustion, given for 12 weeks, in subjects withhypercholesterolemia To evaluate the adherence of acupuncture andmoxibustionTrial designThis is a multicenter, open-label, randomized, stratified,active-controlled, noninferiority trial with two parallelgroups. Randomization will be performed with a 1:1 allo-cation. Subjects with LDL-C values above the recom-mended level who meet the inclusion/exclusion criteriawill be stratified based on their risk levels of heart disease[19, 20]. Then, they were instructed to follow the NCEPAdult Treatment Panel (ATP) [20] Therapeutic LifestyleChange (TLC) diet first. After TLC is completed, subjectswho have not reached the target lipid level will be ran-domly assigned to the treatments of either acupunctureand moxibustion or simvastatin. The duration of treat-ment for this study will be 12 weeks, followed by another4 weeks for post-treatment assessment.MethodsThe SPIRIT figure for schedule of enrolment (Fig. 1),interventions, and assessments of this study, and theSPIRIT Checklist are included as Additional file 1 of thisprotocol.Study settingThe study will include four sites in Hunan, China. Theyare First Affiliated Hospital of Hunan University of ChineseMedicine, Changsha Chinese Medicine Hospital, YueyangChinese Medicine Hospital, and Chenzhou Chinese Medi-cine Hospital. Other sites may be added for participationin the study. Sites that do not enroll any subjects within 3months of site initiation will be closed. Each site mustfollow this study protocol; otherwise, it will be closed. TheSteering Committee will audit and review the interventionperformed in each site, to ensure that they are followingthis protocol.Inclusion criteriaTo be included to the study, patients must:1. Provide informed consent2. Be male or female ≥18 to ≤75 years of age3. Have a fasting triglyceride level ≤400 mg/dL(4.5 mmol/L) by central laboratory at screening4. Have a fasting LDL-C as determined by centrallaboratory on admission and meeting the followingLDL-C values based on risk factor (see Table 2 inAppendix 1) status [19, 20]: 0–1 Risk Factor Group: LDL-C ≥160 mg/dl 2+ Risk Factor Group: LDL-C ≥130 mg/dl CHD or CHD risk equivalents (see Table 3 inAppendix 1): LDL-C ≥100 mg/dlExclusion criteriaSubjects are excluded from the study if they are diag-nosed with one or more of the following conditions: Coronary heart disease (CHD) or CHD riskequivalent who are not receiving statin therapy withLDL-C at screening of ≤99 mg/dL Heart failure of New York Heart Failure Association(NYHA) class II, III or IV or last known leftventricular ejection fraction <30% Cardiac arrhythmia within 3 months prior torandomization that is not controlled by medication Myocardial infarction, unstable angina, percutaneouscoronary intervention (PCI), coronary artery bypassgraft (CABG) or stroke Planned cardiac surgery or revascularization Type 1 diabetes; Newly diagnosed type 2 diabetes (within 6 monthsof randomization or new screening fasting plasmaglucose ≥126 mg/dL (7.0 mmol/L) or HbA1c ≥6.5%),or poorly controlled type 2 diabetes (HbA1c >8.5%) Persistent systolic blood pressure (SBP) >160 mmHg or diastolic BP (DBP) >100 mmHg Thyroid stimulating hormone (TSH) < lower limit ofnormal (LLN) or TSH >1.5 × upper limit of normal(ULN), estimated glomerular filtration rate (eGFR)<30 ml/min/1.73 m2, aspartate aminotransferase(AST) or alanine aminotransferase (ALT) >2 × ULN,creatine kinase (CK) >3 × ULN (all at initialLiu et al. Trials  (2017) 18:310 Page 3 of 17screening or at the end of lipid stabilizationperiod(s) by the central laboratory) Known major active infection, or major hematologic,renal, metabolic, gastrointestinal or endocrinedysfunction Deep vein thrombosis or pulmonary embolismwithin 3 months prior to randomizationSubjects are also excluded if they have taken any ofthe following medications for more than 2 weeks in thelast 3 months prior to LDL-C screening: systemic cyclo-sporine, systemic steroids, isotretinoin (e.g., Accutane).Some anticoagulation treatments are also excluded (anti-platelet agents are permitted). Female subjects cannot bepregnant or be breastfeeding and premenopausal womenmust have to be willing to use at least one highly effect-ive method of birth control during treatment and for anadditional 15 weeks after the end of treatment.RecruitmentEach investigating site was chosen based on documenta-tion for patient availability. Sites will utilize two mainsources for identifying and recruiting potential subjectsas described below: Incoming hyperlipidemia patients: the four sites inthis study are famous for hyperlipidemia treatmentin Hunan, China, thus the incoming patients aimingfor hyperlipidemia treatments are the primarysource for recruitment Advertisements: the participation opportunity to thisstudy will be advertised widely in local newspapersand other publications that target hyperlipidemiatreatments, in order to recruit enough participantsin the recruiting periodInterventionsAll eligible subjects will be instructed to follow theNCEP Adult Treatment Panel (ATP) lifestyle-modification diet first [20]. This approach is designatedtherapeutic lifestyle changes (TLC). After TLC is com-pleted, subjects who have not reached the target lipidlevel will be randomly assigned to the treatments of ei-ther acupuncture and moxibustion or simvastatin.Fig. 1 SPIRIT Figure for schedule of enrolment, interventions, and assessments of the AMHRCTstudyLiu et al. Trials  (2017) 18:310 Page 4 of 17Therapeutic Lifestyle Change (TLC)Subjects who meet the inclusion/exclusion criteria willinitiate TLC. ATP III recommends a multifaceted life-style approach to reduce risk for CHD. Its essential fea-tures are: Reduced intakes of saturated fats (<7% of total calories)and cholesterol (<200 mg per day) (see Table 4 inAppendix 1 for overall composition of the TLC Diet) Therapeutic options for enhancing LDL loweringsuch as plant stanols/sterols (2 g/day) and increasedviscous (soluble) fiber (10–25 g/day) Weight reduction Increased physical activityTLC adherence report form is made and sent to sub-jects to monitor their lifestyle change process. Re-assessment will be conducted after the TLC period.Acupuncture and moxibustion versus simvastatinAccording to the re-assessment of fasting lipid after TLC,a decision will be made on whether the lipid level hasarrived at the target level (see Table 5 in Appendix 1) andwhether subjects should continue with the intervention.For those who have not reached the target lipid level, theywill be randomized in equal proportions between “acu-puncture” and “simvastatin.”Acupuncture and moxibustion Rationale for treatment:Warm-needling acupuncture and medicinal cake-separated moxibustion will be applied in the studywhich is guided by the approach of TraditionalChinese Medicine (TCM). The cake-separatedmoxibustion treatment belongs to the category ofindirect moxibustion which applies moxibustion,herb and acupoints together. In this treatment, adrug-cake mixture is allocated upon selectedacupoints, and then the lit moxa cone is placed ontothe cake. In this case, the moxa-effect enhanced bythe active components of the drug cake is allowed topenetrate through the skin and the acupoints.Based on the TCM theory that the heart is in chargeof the blood circulation and blood vessels, somespecific acupoints related to heart meridian andheart are selected, such as the Shu acupoint (RN14)and the Mu acupoint (BL15) of the heart meridian.BL18, BL20 and BL23 are used to tonify the spleenQi, strengthen the liver Qi and also maintain thekidney Qi, as well as facilitate the conversion oflipids in the liver. ST40 and ST25, which belong tothe stomach meridian and help the transformationfunction of spleen, can protect and work againsthyperlipidemia by assisting the removal of phlegmfrom the body.Additionally, five Chinese herbal medicines areselected, including Salviae Miltiorrhizae Radix (Danshen), Crataegi Fructus (Shan zha), Curcumae Radix(Yu jin), Rhei Radix et Rhizoma (Da huang), andAlismatis Rhizoma (Ze xie). They are able to activatethe blood circulation, remove blood stasis and pain,clear away heart fire, remove irritability, nourish theblood and calm down the mind.In clinical practice, several studies with small samplesizes have assessed a variety of acupointprescriptions, medicinal cake ingredients, treatmentduration, etc. [12, 16]. Among these studies, Li et al.applied warm needling acupuncture on acupointssuch as Fenglong (ST40, bilateral), Zusanli (ST36,bilateral), etc., once a day for 35 days, over a periodof 12 weeks, showing a significant decrease inLDL-C, noninferior to statins [12]. Li et al. appliedmedicinal cake-separated moxibustion on twogroups of acupoints, alternating over a period of 40days with each group receiving 20 times of interven-tion [16]. This study demonstrated a remarkable de-crease in LDL-C and TC, superior to the effect of aplacebo. Meanwhile, Chang et al. have also exam-ined effects of medicinal cake-separated moxibustionwith different dosage upon blood fat and hemorheol-ogy in patients with hyperlipemia, showing thatthree moxa cones and five moxa cones both havetherapeutic effect [17]. With these studies, so far weknow, warm-needling acupuncture and cake-separated moxibustion are both effective for hyper-lipidemia, respectively. Together with our previousclinical experiences on treating hyperlipidemia, weselected the studies mentioned above as pilot studiesof this trial in determining the procedure course ofthe intervention. Needling/moxibustion details (demonstrated in Table 1) Treatment regimen:Interventions of warm-needling acupuncture andmedicinal cake-separated moxibustion will be splitinto two groups. Group 1 (warm-needling acupunctureand medicinal cake-separated moxibustion) and group2 (medicinal cake-separated moxibustion only) willalternate by week over the administration period(shown in Fig. 2), in order to avoid fatigue andnonresponse of acupoints due to constant stimulation Practitioners: registered acupuncturists who havecompleted post-secondary education on acupuncture,practiced acupuncture for more than 3 years, andpassed the national qualification exam for Chinesemedicine doctorsSimvastatin Dosage: simvastatin (10 mg/day)Liu et al. Trials  (2017) 18:310 Page 5 of 17 AdministrationAll simvastatin tablets will be stored in the centralpharmacy and assigned to each investigator site by aqualified staff. The drug will be administered orallyto subjects at the investigator site by a physician ora nurse in accordance with instructions in themedication guides Schedule: 7 days per week for 12 weeks Dosage adjustment:there will be no dose adjustments in this study. If, inthe opinion of the investigator, a subject is unable totolerate a specific dose of simvastatin and requiresdosage adjustment, that subject will discontinuesimvastatin but will continue to return for all otherstudy procedures and measurements until the end ofthe studyDiscontinuity of interventionSubjects in the study are able to withdraw from thestudy at any time, either partially or entirely.When a subject fully consents to withdrawal from thestudy, the subject will no longer receive the investiga-tional treatment and will have the right to discontinueany further involvement in the study, including any for-mat of follow-up. Below is a list of reasons for discon-tinuing intervention: Withdrawal of full consent from subject Subject requests the ending of investigationalintervention Administrative decision by the principal investigator Unanimous decision by the principal investigator/physician Pregnancy in a female subject Adverse event (e.g., serious adverse event related tothe intervention)Concomitant medicationThe following treatments are not permitted during thestudy: Prescribed lipid-regulating medications other thanacupuncture and moxibustion or simvastatin, such asfibrates and derivatives, bile-acid sequestering resins Red yeast rice, niacin >200 mg per day, omega-3fatty acid (e.g., DHA and EPA) >1000 mg per day.Any other drug that significantly affects lipid metab-olism (e.g.,, systemic cyclosporine, systemic steroids(administered intravenously (IV), intramuscularly(IM), or per os (PO)), vitamin A derivatives and ret-inol derivatives for the treatment of dermatologicconditions (e.g.,, Accutane)). Vitamin A as part of amultivitamin preparation is permitted. Prescribed amphetamines, or amphetaminederivatives, and weight-loss medicationsBesides, simvastatin or foods that are known potentinhibitors of CYP3A (itraconazole, ketoconazole, andother antifungal azoles, the macrolide antibioticsTable 1 Needling and acupuncture detailsWarm needling acupuncture (needle + moxa stick)Acupoints Fenglong (ST40, bilateral), Zusanli (ST36, bilateral),Sanyinjiao (SP6, bilateral)Depths ofinsertionFenglong (ST40) for 1.0 to 2.0 cun, Zusanli (ST36)and Sanyinjiao (SP6) for 1.0 to 1.5 cun (“cun” is atraditional Chinese measure using the width of aperson’s thumb at the knuckle, whereas the widthof the 2 forefingers denotes 1.5 cun and thewidth of 4 fingers (except the thumb) side-by-sideis 3 cuns. Therefore, 1 cun may vary from personto person)NeedlestimulationManual manipulationResponseselicitedDe qi sensationNeedle retentiontime30 minNeedlespecificationsSterile single-use acupuncture needles of 25–40 mmin length and 0.30 mm in diameter; manufacturedby Suzhou Medical Supplies Co., Ltd., Suzhou, ChinaMoxibustionspecificationsSmall moxa stick, made of mugwort, with 1.5 cmlength; manufactured by Suzhou Medical SuppliesCo., Ltd., Suzhou, ChinaManipulation (1) locate and sterilize the acupoints; (2) insert theneedles and stimulate to elicit response; (3) attacha small moxa stick to the needle tail and light themoxa stick; and (4) retain needles with moxa sticksfor 30 minMedicinal cake-separated moxibustion (medicinal cake +moxa cone)Acupoints Juque (RN14), Tianshu (ST25, bilateral), Pishu(BL20, bilateral), Xinshu (BL15, bilateral), Ganshu(BL18, bilateral), Shenshu (BL23, bilateral)Cake ingredients Dan Shen (Radix Salviae Miltiorrhizae), Shan Zha(Fructus Crataegi), Yu Jin (Radix Curcumae), DaHuang (Radix et Rhizoma Rhei) and Ze Xie(Rhizoma Alismatis)Cake preparationmethodAll cake ingredients in the same quantities werecollected, ground into powder, mixed well withvinegar, and made into round, thin cakes of 1.5 cmin diameter, 3 mm in thickness and 3 g in weight;manufactured by Suzhou Medical Supplies Co., Ltd.,Suzhou, ChinaMoxibustionspecificationsMoxa cone, made of mugwort, with 1 cm indiameter; manufactured by Suzhou MedicalSupplies Co., Ltd., Suzhou, ChinaRetention time 3 cones in total for 30 minManipulation (1) locate the acupoints; (2) place the herbal cakeon to the acupoints; (3) place a moxa cone ontothe herbal cake and light the moxa cone; (4)renew the moxa cone once it is fully consumed,with 3 moxa cones in total per acupoint; and (5)retain herbal cakes with moxa cones for 30 minLiu et al. Trials  (2017) 18:310 Page 6 of 17erythromycin, clarithromycin, and the ketolide antibiotictelithromycin, HIV protease inhibitors, the antidepres-sant nefazodone and grapefruit juice in large quantities(more than 1 quart daily)) should not be used during thestudy, because of their potential impacts on the metabol-ism of certain statins.Outcome measurementsPrimary outcomeThe primary outcome is the percentage change frombaseline to the end of the study (after the 12-week inter-vention and after another 4-week follow-up) in LDL-C.The calculated LDL-C concentration will be determinedat screening (entry to the study), day 1 (after TLC iscompleted and eligibility is determined), week 6, andweek 12. LDL-C will be measured by preparative ultra-centrifugation by the central laboratory. The LDL-Cconcentration calculated at screening will be reportedonly for the eligibility decision. The baseline lipid mea-surements for the purpose of analysis will be the day-1lipid measurement after TLC (lipid stabilization). Thiswill be collected after a ≥9-h fast and before receivingintervention.Secondary outcomesThe secondary outcomes consist of three aspects: efficacy,safety and adherence. The efficacy outcomes include, fromthe baseline to the end of the study (after 12-week inter-vention and after another 4-week follow-up), the absolutechange in LDL-C, the percentage change in HDL-C, thepercentage change in total cholesterol (TC), the per-centage change in TG, and the rate of subjects achievingLDL-C goal (see Table 5 in Appendix 1) [21]. The safetyoutcomes will be assessed by the physical examination,vital signs (including sitting blood pressure (BP) and heartrate (HR), electrocardiogram (ECG) and subject incidenceof adverse events, after 12-week intervention and after an-other 4-week follow-up. The adherence outcome will beexamined by the adherence rate, calculated as:Adherence Rate ¼ Number of treatments conducted=Number of treatments planned:Study proceduresThe study consists of four periods: Screening, TLC,Intervention, and Follow-up period. For the purpose ofthis study, a week is defined as seven calendar days. Amonth is defined as 28 days.ScreeningScreening is conducted among subjects who meet theinclusion criteria to determine the eligibility of subjectsto enter the study. In order to determine the eligibilityfor the study, they will enter the screening process bysigning and dating the Informed Consent Form for thisstudy.The following data will be obtained and proceduresperformed during initial screening: Written informed consent Medical history Vital signs (see Appendix 2) Review for adverse events (serious adverse events(SAEs) and study-related AEs are collected duringscreening) Concomitant therapy Physical examinationFig. 2 Treatment regimen flowchart. This figure demonstrates the treatment regimen and flowchart for intervention of warm needling andmedicinal cake-separated moxibustionLiu et al. Trials  (2017) 18:310 Page 7 of 17 12-lead ECG in triplicate using centralized ECGservices equipment Blood draw for fasting lipids, chemistry and serumpregnancy (women of childbearing potential only)by central laboratory (Appendix 2)TLC periodSubjects who complete the screening successfully andwho meet the inclusion/exclusion criteria will initiatetherapeutic lifestyle change (TLC). The TLC adherencereport form is made and sent to subjects to monitortheir lifestyle change process. Re-assessment will be con-ducted after the TLC period.Intervention periodIntervention day-1 visit According to the re-assessmentof fasting lipids after the TLC, a decision will be made onwhether the lipid level has arrived at the target level andwhether subjects should continue with the intervention.For those who have not reached the target lipid level, theywill undertake randomization and receive first administra-tion of the intervention and the date for that is consideredto be day 1. For those who have reached the target lipidlevel after the TLC, they will be followed up for another 6weeks and re-assessed for relative indexes in week 6.Week 6 visit (±3 days) Re-assessment on the study in-dicators of subjects will be conducted, including efficacy,safety, and adherence.Week 12 end of study visit (±3 days) Re-assessmenton the study indicators of subjects will be conducted, in-cluding efficacy, safety, and adherence.Follow-up periodA 4-week follow-up after treatment will be done in orderto measure and monitor AEs and the effects of treat-ments at week 16. The study indicators of subjects willinclude efficacy and safety.Trial flowchart(Please refer to the supplementary document: Fig. 3.Trial flowchart)Sample sizeA significance level of 0.95 and a power of 0.80 will beallocated for the calculation of sample size. In accord-ance with a previous study [17], we could employ aneffect size of 0.343 on absolute value change of LDL-Cvalue, and a standard deviation of 0.7. In this case we es-timate that the sample size for the acupuncture groupand active control group should be approximately 65, re-spectively. The total sample size needed is 130.In case of missing observation and patients lost, we as-sume that 90% of subjects will remain in the study.Thus, the sample size for two groups should be roughly70 for each group.Stratified and blocked randomizationAccording to the re-assessment of fasting lipid after theTLC, a decision will be made on whether the lipid levelhas arrived at the target level and whether subjectsshould continue with the intervention. Subjects willreceive the intervention at the site at which they arerecruited. Within each site, subjects will be stratified byrisk groups (0–1 risk group, 2+ Risk Factor Group, andCHD or CHD risk equivalents group), as target lipidlevels differ according to different risk groups. Subjectswho have not reached the target lipid level after TLC,will be randomized to two arms at a ratio of 1:1 (acu-puncture and moxibustion versus simvastatin). Therandomization will be blocked (size = 4) to ensure thatequal numbers of subjects are allocated to each arm. Acomputer-generated, blocked randomization sequencewill be used to randomize subjects in the study. Assign-ment to the two treatment arms will be generated by theprincipal biostatistician using R (version 3.1.1; R Founda-tion for Statistical Computing, Austria. ISBN 3-900051-07-0) before the start of the study. The sequence will beheld in a secure location in the hospital by the principalbiostatistician; the researchers will be blinded to thenumber of cases in each randomization block and indi-vidual subject allocation will be conducted remotely viatelephone based on the randomization sequence. Once asubject is eligible to receive the intervention, the princi-pal biostatistician will be informed and will let physi-cians know each subject’s allocation by phone.BlindingDue to the nature of the acupuncture and moxibustioninterventions, neither participants nor care providerscan be blinded to allocation and treatment stages, butare strongly inculcated not to disclose the allocationstatus of the participant at the follow-up assessments.The outcome assessment will be conducted by outcomeassessors blind to the treatment allocation. In the stageof data analyses, an employee outside the research teamwill feed data into the computer in separate datasheetsso that the data analysts can analyze the data withouthaving access to information about the allocation.To maintain the overall quality and legitimacy of theclinical trial, code breaks should occur only in excep-tional circumstances when knowledge of the actual treat-ment is absolutely essential for further management ofthe patient. Investigators, including the outcome as-sessors and data analysts blind to treatment allocation,Liu et al. Trials  (2017) 18:310 Page 8 of 17are encouraged to discuss with the medical advisor phy-sicians if they believe that unblinding is necessary.The investigator is encouraged to maintain the blindas far as possible. The actual allocation must not bedisclosed to the patient and/or other study personnel.There should not be any written or verbal disclosureof the code in any of the corresponding patient docu-ments. The investigator must report all code breaks(with reason) as they occur on the correspondingCase Report Form page. Unblinding should not ne-cessarily be a reason for study drug discontinuation.Data collection methodsThe method of outcome data collection has been listedin previous parts. In order to ensure the data quality,each site’s personnel involved in this study will betrained to master the data collection requirements; thedata to be collected and the procedures to be conductedat each visit will be reviewed in detail.Participant retentionIn order to promote participant retention, once a patientis enrolled or randomized, the study sites will make everyreasonable effort to follow the patient for the entire studyperiod. In detail, study investigators and staff will: Maintain participants’ interests by materials andphone calls Provide periodic communications via materials andtalks to inform the participants of ouracknowledgement for their support Be as flexible as possible with the study schedule inresolving time conflicts with participants’ work and lifeParticipant withdrawalParticipants will possibly withdraw from the study dueto any reason at any time. The study investigators mayalso withdraw participants from the study with thepurpose of protecting them and/or if they are unwillingto follow the study procedures. Once a withdrawalFig. 3 Trial flowchart. This figure provides an overview of participant flow in this trialLiu et al. Trials  (2017) 18:310 Page 9 of 17happens, it should be recorded by the steering commit-tee and the data management team.Data managementData forms and data entryIn this study, all data will be entered electronically. Ori-ginal data along with the data collection form will be ar-chived at the participating sites. Once a form has beenfilled out, the participating site staff will copy the form andsend it to data management team for electronic re-entry.Participant files will be stored by participation number.The storage location should be secured and accessible.The files will be kept in storage for 5 years after the study.Data transmission and editingData transmission refers to the transmission of datafrom the original data form to computers used by thedata management team. Data entry staff will carefullycheck whether the transmission is correct at the time ofdata entry. Data editing, either modification on singlerecord or on multiple records, will be documented,along with the reason of the editing.Data discrepancy reports and solutionsErrors may be detected by data analysts, including miss-ing data error, or other specific errors in the data. Theanalyst should summarize the error and report to thedata manager. The data manager who receives the datadiscrepancy reports will forward the specific problem tothe data management staff in the participating site, re-trieve the original data forms, and check whether thereis an inconsistency.There are several solutions for data discrepancy. If thedata in the database is inconsistent with the original form,a primary choice is to correct the record in the database.Other alternative choices include missing data imputationtechniques, data correction by checking other sources,and modifying the original data. The discrepancy reportsand solutions should be documented for future reference.Data back-upThe primary database will be backed up once per month. Atthe same time, the data analysis files will also be backed up.Statistical methodsDataset analysisFor the primary endpoint of percentage change in LDL-C from baseline, the efficacy of acupuncture and moxi-bustion will be evaluated at week 12 by comparing thetreatment effect to that of the active control group. Atype I error of 0.05 will be allocated to the test.There are three main analysis sets: Full analysis set (FAS): includes all randomizedsubjects who have received at least 1 investigationaltreatment Completer Analysis Set (CAS), includes subjects inthe FAS who completed their scheduled interventionand have a nonmissing LDL-C value at week 12 Effect Durability Analysis Set (EDAS), includessubjects in the FAS who completed their scheduledintervention and have non-missing LDL-C values atweek 6 and week 12Statistical analysis planThe primary analysis set for the primary endpoint is theFAS. It is to use the repeated measures, linear mixed-effects model, including terms for treatment group,stratification factor, baseline LDL-C, scheduled visit andthe interaction of treatment with scheduled visit. Miss-ing values will not be imputed when the repeated mea-sures, linear mixed-effects model is used.We will use the chi-squared test for binary outcomes,and the t test for continuous outcomes. For subgroupanalyses, we will use regression methods with appropri-ate interaction terms (respective subgroup treatmentgroup). Multivariable analyses will be based on logisticregression for binary outcomes and linear regression forcontinuous outcomes. We will examine the residual toassess model assumptions and goodness-of-fit. For timedendpoints, such as mortality, we will use the Kaplan-Meier survival analysis followed by the multivariableCox proportional hazards model for adjusting for base-line variables. We will calculate Relative Risk (RR) andRR Reductions (RRR) with corresponding 95% con-fidence intervals to compare dichotomous variables, anddifference in means will be used for additional analysisof continuous variables. P values will be reported to fourdecimal places with P values < 0.05 reported as P < 0.05.Up-to-date versions of R (R Foundation) will be used toconduct analyses. For all tests, we will use two-sided Pvalues with alpha no greater than 0.05 level of signifi-cance. We will use the Bonferroni method to appropri-ately adjust the overall level of significance for multipleprimary outcomes, and secondary outcomes.In investigation of the robustness of the analysis re-sults, the primary analysis will be repeated using theCAS. In addition, parametric analysis of covariance(ANCOVA) and appropriate nonparametric methodswill be used on the FAS, in which missing data will beimputed using the last-observation-carried-forward(LOCF) approach. The primary analysis will also be re-peated for subgroups of interest.Interim analysesAn interim-analysis is performed on the primary end-point when 50% of patients have been randomized andLiu et al. Trials  (2017) 18:310 Page 10 of 17have completed the interventions. The interim-analysisis performed by an independent statistician, blinded forthe treatment allocation. The statistician will report tothe independent data monitoring committee. The datamonitoring committee will have unblinded access to alldata and will discuss the results of the interim-analysiswith the steering committee in a joint meeting. Thesteering committee decides on the continuation of thetrial and will report to the central ethics committee.Consistency analysisTo evaluate the consistency of the treatment effect ofacupuncture and moxibustion, the following analyseswill be performed: Consistency of treatment effects (acupuncture andmoxibustion versus simvastatin) of week 6 and week12: the 95% CI of the difference of the treatmenteffect at week 6 and the treatment effect at week 12will be provided from the repeated measure mixed-effect model. The estimations will be from the FASand the EDAS LDL change from week 6 to week 12:the treatment effect of percentage change from week6 to week 12 will be estimated by using anANCOVA model. The estimation of 95% CI will bebased on the EDASAnalysis of other secondary efficacy endpoints will besimilar to the primary analysis of the primary endpoint.All tests will be based on a significance level of 0.05,without adjustment for multiple endpoints.Safety summaries and adherence analysisSafety summaries will include the subject incidence of AEs,summaries of laboratory parameters, vital signs, and ECGs.Data monitoringA Data Monitoring Committee (DMC) has been estab-lished. The DMC is independent of the study organizers.During the period of recruitment to the study, interimanalyses will be supplied, in strict confidence, to the DMC,together with any other analyses that the committee mayrequest. This may include analyses of data from othercomparable trials. In the light of these interim analyses,the DMC will advise the trial steering committee when: The active intervention has been proved, beyondreasonable doubt, to be different from the control(standard management) for all or some types ofparticipants, and The evidence on the outcomes is sufficient to guidea decision from the health care providersThe Trial Steering Committee can then decidewhether or not to modify intake to the trial. Unless thishappens, however, the Steering Committee will remainignorant of the interim results.Adverse eventsAn adverse event is defined as “any untoward medicaloccurrence in a clinical trial subject” [22]. An adverseevent may or may not have a causal relationship withthe treatment in the study. All adverse events observedby the investigator or study practitioner (e.g., physi-cians), or reported by the subjects, are to be recorded inthe medical record of the subject. If a pre-existing med-ical condition of the subject worsens, this is consideredone type of adverse event. For example, if a patients’ dia-betes, migraine headaches or gout worsens in time (e.g.,increased in severity, frequency of duration) with theadministration of the treatment, this indicates that theadministration of the treatment may be associated witha significant worse outcome in the subject.All adverse events observed by the investigator orstudy practitioner (e.g., physicians) or reported by thesubject after randomization through the end of studywill be reported by the investigator to the applicableelectronic Case Report Form (eCRF) (e.g., Adverse EventSummary eCRF).Adverse event attributesBelow are the attributes the investigator must assign toeach adverse event: Adverse event diagnosis or syndrome(s), if known(if not known, signs or symptoms), Dates of onset and resolution, Severity (and/or toxicity per protocol) Assessment of relatedness to investigationtreatment, and Action takenAdverse event assessmentBelow is a list of questions the investigators must assess.Each question is answered with either a “yes” or “no”: Is there a reasonable possibility that the event mayhave been caused by the study intervention? Is there a reasonable possibility that the event maybe related to screening procedures? Is there a reasonable possibility that the event mayhave been caused by a study activity/procedure?Adverse events and laboratory testsLaboratory tests results will be reviewed thoroughly bythe investigator to determine whether the change inLiu et al. Trials  (2017) 18:310 Page 11 of 17abnormal values from the baseline values is clinically sig-nificant (based on clinician’s own judgment). Afterreviewing the changes, the investigator will determinewhether an adverse event will be reported. Abnormal laboratory findings that are not clinicallysignificantly different from baseline values will notbe recorded as adverse events Laboratory findings that are clinically significant,that require treatments or adjustments from thecurrent treatment will be recorded as adverse events Clinically sequelae should also be recorded as theadverse event, where applicableAdverse events and participant withdrawalThe investigator will use his/her clinical judgment todetermine whether a subject should be removed from thestudy due to adverse events. The subject or their legal rep-resentatives also have the full right to withdraw from thetreatment due to an adverse event or concerns for an ad-verse events. However, the investigator will encourage thesubjects to undergo at least an end of the study assessment.Serious adverse eventsDefinitionA serious adverse event is defined as an adverse eventthat meets at least one of the following criteria: Fatal Life-threatening (places the subject at immediaterisk of death) Requires in-patient hospitalization or prolongationof existing hospitalization, (the criterion of “requireshospitalization” for an adverse event, indicates anevent necessitated an admission to a health carefacility, e.g., overnight stay in hospital) Results in persistent or significant disability/incapacity Congenital anomaly/birth defect Other medically important serious eventA serious adverse event can still be recorded if an in-vestigator considers an event to be clinically significant.In this case, the event will be classified as “other medic-ally important serious event” and comprehensive docu-mentation of the events’ severity will be recorded on thesubject’s medical record. Some examples of this include:allergic bronchospasm, convulsions, blood dyscrasia, orevents that necessitate an emergency room visit, out-patient surgery, or urgent intervention.Reporting procedures for serious adverse eventsAll observed or reported serious adverse events afterrandomization through 4 weeks after the last investigationaltreatment will be recorded on the subjects’ medical recordsby the investigator and submitted to the principal investiga-tor within one working day of discovery of the adverseevent. These include: new information reported on a previ-ously known serious adverse event, serious adverse eventpossibly related to the treatment, and full withdraw by thesubject from the study due to serious adverse event.In the case of a serious, unexpected, and relatedadverse event, the subject may be unblinded by the in-vestigator prior to submission of the adverse event tothe regulatory authority. Investigators will receive infor-mation on how to report adverse serious events to au-thorities in accordance to local requirements and GoodClinical Practice prior to the clinical trial. All serious ad-verse events will be reported to appropriate IndependentEthics Committee (IEC).Pregnancy reportingIf a pregnancy occurs during the time when the femalesubject is undertaking the study intervention, the preg-nancy should be reported to the research team. Preg-nancy after undertaking the study intervention for anadditional 4 weeks should also be reported.Study disseminationConfidentialityAll study-related information will be stored securely atthe study site. All participant information will be storedin locked file cabinets in areas with limited access. Alllaboratory specimens, reports, data collection, process,and administrative forms will be identified by a codedID (identification) number only to maintain participantconfidentiality. All records that contain names or otherpersonal identifiers, such as locator forms and InformedConsent Forms, will be stored separately from studyrecords identified by code number. All local databaseswill be secured with password-protected access systems.Forms, lists, logbooks, appointment books, and anyother listings that link participant ID numbers to otheridentifying information will be stored in a separate,locked file in an area with limited access. Participants’study information will not be released outside of thestudy without the written permission of the participant.Access to dataThe Data Management Coordinating Center will overseethe intrastudy data sharing process. All data sets will bepassword-protected. The principal investigator will havedirect access to the data sets. With her permission, thestatistician will utilize the data sets for analyses. Re-quests from outside for further research cooperation willbe discussed by the Steering Committee. The researchLiu et al. Trials  (2017) 18:310 Page 12 of 17protocol will be published. There is no plan for grantingpublic access to the full participant-level data sets.Publication policyAll publications should be conducted and monitored bythe principal investigator and the Steering Committee.That means that each paper or abstract must be written,reviewed, released, and published with the authorizationof the PI and the Steering Committee. The timing ofpresentation of the endpoint data and the meetings atwhich they may be presented will also be determined byPI and the Steering Committee.In order to achieve the study objectives and main-tain scientific integrity, data should be analyzed col-lectively; a participating site is not permitted topublish its data and analysis results independently. Ifthere are some invitations from workshops, symposia,and volumes in related area, individuals who work onsuch requests should report to the PI and SteeringCommittee with a detailed proposal, and state clearlywhat to present and how to present.Authorship eligibilityMany topics will be suggested based on the study data-base, and each topic might be possible to be developedinto a peer-reviewed article. The PI and the SteeringCommittee will work together to decide the authorshipof each article, on basis of contributions to the manu-scripts; the investigator who contributes most will beconsidered as the first author. Disputes regardingauthorship will be resolved by the PI with careful con-siderations. If professional writers are needed, the PI andthe Steering Committee will determine whether to in-clude them in authorship.DiscussionThe current conventional treatment on hyperlipid-emia, statins, not only can entail significant cost topatients and society, but also is associated with lowtreatment compliance and high rates of side effects[3, 4]. Effective treatment alternatives on hyperli-pidemia have been explored to address the shortcom-ings of statins; and acupuncture and moxibustion areconsidered as potentially effective regimens based onclinical practices and clinical research [9–11, 17, 18, 23].However, acupuncture and moxibustion, separately,have not been proved to be as effective as statin fromprevious studies, despite the existence of their clinicaleffects [9–11, 17, 18, 23]. Additionally, as approachesof complementary and alternative medicine (CAM),their introduction to the mainstream medical commu-nity is often limited due to lack of robust evidenceand differences in the philosophy adopted. Therefore,the RCT described in this paper has been developedto validate the efficacy and safety of combined acu-puncture and moxibustion on hyperlipidemia via awell-designed evaluation.There are several strengths in design of this study.First, the intervention adopted in this study is devel-oped not only based on profound TCM theory butalso supported by comprehensive scientific research.The theory guiding the acupoints selection and trad-itional Chinese herb composition has been studied,identified and well-demonstrated in this study whichis discussed in the “Treatment rationale” section.Meanwhile, several studies from the perspectives oflaboratory animal medicine and clinical medicine havebeen conducted [9–11, 17, 18, 23] which serve as thekey foundation of intervention development in thisstudy. Specifically, the biological mechanism was ex-plored on how cake-separated moxibustion can havean impact upon hyperlipidemia; and the acupointselection and regimen implementation from ampleTCM theory were validated in multiple clinicalstudies.Second, the TLC will be included prior to both in-terventions of acupuncture and moxibustion and sta-tins, which enables this study to reflect the actualpractice in clinical settings to the greatest extent. Ac-cording to the guideline of hyperlipidemia treatment[20], TLC is recommended as the first step beforeany other treatment. By adhering to the commonlyadopted clinical guideline during study procedure, onthe one hand, we can take good care of the “non-maleficence” and “justice” principles in study ethics,because the opportunity of receiving appropriatemedication will not be compromised for patients at-tending this study; on the other hand, this can en-hance the generalizability of this study due tofollowing the clinical operations in real life.Third, the stratification on risk levels for heart dis-ease [19, 20] will be applied to this study, whichmakes possible that the effect of interventions of thisstudy can be differentiated and specified according todifferent risk groups. Patients with hyperlipidemiamay enter the study with different initial lipid levels,due to different time points of initiating medicationintervention for groups with different risk levels.Meanwhile, the goal lipid level for each patient mayalso differ accordingly. It is impractical and erroneousto set exactly the same criteria in determining theclinical effect for all the patients. In recognition onthis, patients will be stratified by their risk levels dur-ing the study, and then the effects of acupunctureand moxibustion versus simvastatin can be observedand examined within different risk levels, instead ofLiu et al. Trials  (2017) 18:310 Page 13 of 17within a large group with extensive variance. Thisstratification reflects that patient’s risk levels for heartdiseases are considered important impacting factorson the outcomes in this study; it enables exploringthis impact upon the effects of interventions, whichcan further guide the appropriate intervention by tar-geting on the right populations. In addition, differenttreatment goals will be adopted for different riskgroups according to the standard clinical guideline;this ensures the study will be implemented in accord-ance with the daily clinical practices to the most ex-tent, thus, the external validity can be mostlywarranted.However, certain limitations still exist in this study.One is the absence of a placebo control group due tothe limited study budgets. Because of this lack ofcomparison, it may not be able to determine whetherthe outcome observed is due to the therapeutic effectof acupuncture and moxibustion or its placebo effect,if acupuncture and moxibustion is proved to be infer-ior to simvastatin. Nevertheless, judgment from clin-ical experiences and relevant findings from previousstudies can help in identifying and justifying the effectwith clinical significance.Another limitation is the absence of blinding in pa-tients and health care providers due to the operationcharacteristics of acupuncture and moxibustion. Withpatients knowing their intervention assignments afterrandomization, there may be a potentially higher pos-sibility of cross-over between and drop-off from thesetwo arms; thus, the potential selection bias mayoccur. But detailed explanation can be given to pa-tients on these two arms of interventions in order toinform potential effects and safety in both arms. Thiswill help limiting the drop-off and cross-over rates.Moreover, with the intervention assignment revealed,the effect identified from the acupuncture and moxi-bustion group may not fully result from its thera-peutic aspect but a psychological aspect. But theoutcome measures examined in this study are all ob-jective – based on the fasting lipid level; and in theanalysis process intervention assignment is fully blind-ing to data assessors. Therefore, the information biasdue to lack of blinding could be controlled to a con-siderable extent.ConclusionIn conclusion, efforts have been devoted, in thisstudy, to developing a well-designed assessmentapproach to evaluate the efficacy and safety ofcombined acupuncture and moxibustion on treatinghyperlipidemia, by integrating the TCM regimens withthe standardized Western medicine appraisal approach. Itis expected this assessment will introduce a potentiallyeffective alternative treatment of hyperlipidemia by bor-rowing the wisdom from the time-tested practiceapproach, TCM.Trial status Primary registry and trial identifying number:ClinicalTrials.gov NCT02269046 Date of registration in primary registry: 16 October2014 Primary sponsor: The First Affiliated Hospital ofHunan University of Traditional Chinese Medicine Contact for public queries: Dr. Mailan Liu. Email:445007305@qq.com Contact for scientific queries: Dr. Xiaorong Chang.Email: xrchang1956@163.com Public title: Acupuncture and Moxibustion forHyperlipidemia Scientific title: Acupuncture and Moxibustion forHyperlipidemia (AMH-RCT): Study Protocol for aRandomized Controlled Trial Countries of recruitment: China Health condition(s) or problem(s) studied:hyperlipidemia Intervention(s): acupuncture and moxibustion,simvastatin Study type: interventional Date of first enrollment: December 2014 Target sample size: 130 Recruitment status: recruitingAppendix 1Table 2 Major risk factors for CHD other than LDL [13]Cigarette smokingHypertension (BP ≥140/90 mmHg or on antihypertensive medication)Low HDL cholesterol (<40 mg/dL)Family history of premature CHD (CHD in male first degree relative<55 years; CHD in female first degree relative <65 years)Age (men ≥45 years; women ≥55 years)Table 3 CHD and CHD equivalents• Other clinical forms of atherosclerotic disease (peripheral arterialdisease, abdominal aortic aneurysm, and symptomatic carotidartery disease)• Diabetes• Multiple risk factors that confer a 10-year risk for CHD >20%Liu et al. Trials  (2017) 18:310 Page 14 of 17Appendix 2 Measurement of Lipid level and VitalSignsMeasurement of Vital SignsBlood pressure (BP) and heart rate (HR) should bemeasured at each visit. BP should continue to bemeasured in the same arm as in the parent studyunless a concomitant condition favors the use of adifferent arm. The appropriate size cuff should beused.The diastolic blood pressure (DBP) will be recordedas the pressure noted when sound disappears(Korotkoff Phase V). BP and HR measurementsshould be determined after the subject has beenseated for at least 5 minutes. The subject’s pulseshould be measured for 30 seconds and the numbershould be multiplied by 2 to obtain heart rate.Lipid MeasurementsThe baseline lipid measurements for the purpose ofanalysis will be the central laboratory screening andday 1 lipid measurement collected after a ≥ 9 hourfast and before receiving intervention. At each timepoints, calculated LDL-C concentration will be de-termined. In addition, at screening, day 1, week 6,and week 12 LDL-C will be measured by prepara-tive ultracentrifugation by the central laboratory.Only the screening calculated LDL-C concentrationwill be reported to the site for the eligibility deci-sion. For subjects who are rescreened, data fromthe first screening period will not be used for theanalysis. Investigators, subjects, and the study teamwill be blinded to post-randomization central la-boratory lipid panel values for the duration of thestudy until unblinding of the database. In addition,investigators and staff involved with this trial andall medical staff involved in the subject’s medicalcare should refrain from obtaining lipid panels be-tween randomization and at least 4 weeks after thesubject ends the study at week 12 (to avoidpotential unblinding). If a lipid panel is drawn, allreasonable steps must be undertaken to avoidinforming the subject and study personnel of theresults.Laboratory AssessmentsAll screening and on-study laboratory samples will beprocessed and sent to the central laboratory.The central laboratory will provide a study manualthat outlines handling, labeling, and shipping proce-dures for all blood samples. The date and time ofsample collection will be recorded in the sourcedocuments at the site.Table below outlines the specific analytic for serumchemistry, hematology, urinalysis, and other testing tobe conducted.Table 5 Three Categories of Risk that Modify LDL-C GoalsRisk Category LDL Goal (mg/dL)CHD and CHD risk equivalents <100Multiple (2+) risk factors <1300 to 1 risk factor <160Table 4 Nutrient Composition of the TLC DietNutrient Recommended IntakeSaturated fata Less than 7% of total caloriesPolyunsaturated fat Up to 10% of total caloriesMonounsaturated fat Up to 20% of total caloriesTotal fat 25-35% of total caloriesCarbohydrateb 50-60% of total caloriesFiber 20-30 g/dayProtein Approximately 15% of total caloriesCholesterol Less than 200 mg/dayTotal calories (energy)c Balance energy intake and expenditureto maintain desirable body weight/preventweight gainaTrans fatty acids are another LDL-raising fat that should be kept at alow intakebCarbohydrate should be derived predominantly from foods rich in complexcarbohydrates including grains, especially whole grains, fruits, and vegetablescDaily energy expenditure should include at least moderate physical activity(contributing approximately 200 Kcal per day)Chemistry Coagulation Urinalysis Hematology Other LabsSodiumPotassiumChlorideBicarbonateTotalproteinAlbuminCalciumMagnesiumPhosphorusGlucose(Fasting)BUN orUreaCreatinineUric acidTotalbilirubinDirectbilirubinCKALPLDHAST (SGOT)ALT (SGPT)PT/INR SpecificgravitypHBloodProteinGlucoseBilirubinWBCRBCEpithelialcellsBacteriaCastsCrystalsHemoglobinHematocritMCVMCHMCHCRDWPlateletsWBCDifferential• Neutrophils• Bands• Eosinophils• Basophils• Lymphocytes• MonocytesFasting lipids• Total cholesterol• HDL-C• LDL-C• Triglycerides• VLDL-CApoA1ApoBhsCRPLp(a)Anti-AMG 145antibodiesPK• AMG 145• PCSK9HbA1cFSH (if needed perexclusion 4.2.17)TSHeGFR (calculated)Fasting Vitamin ELiu et al. Trials  (2017) 18:310 Page 15 of 17Additional fileAdditional file 1: SPIRIT 2013 Checklist. (DOC 121 kb)AbbreviationsAE: Adverse event; AHA: American Heart Association; ALP: Alkalinephosphatase; ALT: Alanine aminotransferase; AMH: Acupuncture andMoxibustion for Hyperlipidemia; ANCOVA: Analysis of covariance;ApoA1: Apolipoprotein A-1; ApoB: Apolipoprotein B; AST: Aspartateaminotransferase; BL: Bladder meridian; BP: Blood pressure; CABG: Coronaryartery bypass graft; CAS: Complete analysis set; CHD: Coronary heart disease;CI: Confidence interval; CK: Creatine kinase; CVD: Cardiovascular disease;DBP: Diastolic blood pressure; DHA: Docosahexaenoic acid; DMC: Datamonitoring committee; ECG: Electrocardiogram; EDAS: Effect durabilityanalysis set; eGFR: Estimated glomerular filtration rate; EPA: Eicosapentaenoicacid; FAS: Full analysis set; HDL-C: High density lipoprotein cholesterol;HR: Heart Rate; hsCRP: High sensitivity C-reactive protein; IEC/IRB: Independent Ethics Committee/Institutional Review Board; LDH: Lactatedehydrogenase; LDL-C: Low-density lipoprotein cholesterol; LLN: Lower limitof normal; LOCF: Last observation carried forward; Lp(a): Lipoprotein(a); NCEPATP III: National Cholesterol Education Program Adult Treatment Panel III;NYHA: New York Heart Failure Association; PC: Pericardian meridian;PCI: Percutaneous coronary intervention; PPAR: Peroxisome Proliferator-Activated Receptor; RBC: Red blood cells; RCT: Randomized Controlled Trial;RN: Ren meridian; RR: Relative Risk; RRR: RR reductions; SAE: Serious adverseevent; SBP: Systolic blood pressure; SP: Spleen meridian; ST: Stomachmeridian; TC: Total cholesterol; TCM: Traditional Chinese Medicine;TG: Triglycerides; TLC: Therapeutic Lifestyle Change; TLR: Toll-like receptor;TLR4: Toll-like receptor 4; TSH: Thyroid Stimulating Hormone; ULN: Upperlimit of normal; VLDL-C: Very low-density lipoprotein cholesterol; WBC: Whiteblood cellAcknowledgementsWe thank our colleagues from Hunan University of Chinese Medicine, China,Rural Coordination Center of BC, Vancouver, Canada, University of BritishColumbia, Vancouver, Canada, The Third Clinical College of Zhejiang ChineseMedical University, China, and Changchun University of Chinese Medicine,China, who provided insight and expertise that greatly assisted the research.FundingThe funding sources are disclosed in the supplementary document: FundingDisclosure. There are three sponsors for this study; all of them are externalfunding sources. The 1st funding source is the State Administration of TraditionalChinese Medicine of China, with the Grant Number of 2015CB554502. The 2ndfunding source is the National 973 Projects of Chines, coming from the Ministryof Science and Technology of China, with the Grant Number of 2014CB543102.The 3rd source is the Third Clinical College of Zhejiang Chinese MedicineUniversity, with the Grant Number of ZTK2014A03. All the three foundingsources have no role in the design of the study and collection, analysis, andinterpretation of data and in writing the manuscript.Availability of data and materialsNot applicable at this stage.Authors’ contributionsAll authors have made substantial intellectual contributions to this protocol.ML and XC have led on the systematic literature review and the researchquestion. ML and QZ led on developing the interventions. ML, QZ, and SJled on the study design. QZ and SJ led on the statistical analysis scheme.ML, GZ, and XC provided improvements on interventions. ZY, JZ and GDdeveloped the data management scheme. ZW and QC developed theadverse events management scheme. XC, GZ, and JZ provided the principlesof study dissemination. ML, QZ, and SJ drafted the manuscript together, andtheir contributions are equal. YZ, DL, MM, and HZ revised the manuscriptcritically. All authors have contributed to the drafting process. All authorshave read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationThe consent form for publication will be provided to patients if they participatein this study. Results and articles will be published after the patients/participantsthey sign the consent form for publication which shows that they agree to thepublication of identifiable data. The form has been approved by the EthicsCommittee of Hunan University of Chinese Medicine. Please refer to thesupplementary document: Consent Form.Ethics approval and consent to participateResearch ethics approvalThe protocol has been reviewed and approved by the Independent EthicsCommittee (IEC) of 1st Affiliated Hospital, Hunan University of Chinese Medicinefor approval (Ethics Approval Reference Number: HN-LL-KY-2014-005-01). Theother three hospitals located in nearby cities participating in this research areaffiliated to 1st Affiliated Hospital of Hunan University of Chinese Medicine. Anyclinical research activities in the three hospitals are led by 1st Affiliated Hospitaland should be approved by the IEC of 1st Affiliated Hospital.The investigator will make safety and progress reports to the IEC within 3 monthsof study termination. These reports will include the total number of participantsenrolled and summaries of data monitoring committee review of safety.Protocol modificationsAny modifications to the protocol which may impact the conduct of the study,potential benefit of the patient or may affect patient safety, including changesof study objectives, study design, patient population, sample sizes, studyprocedures, or significant administrative aspects will require a formalamendment to the protocol. Such amendment will be initiated by the steeringcommittee and approved by IEC of Hunan University of Chinese Medicine.Administrative changes of the protocol are minor corrections and/orclarifications that have no effect on the way the study is to be conducted.These administrative changes will be agreed upon by principal investigator,and will be documented in a memorandum. The IEC of Hunan University ofChinese Medicine may be notified of administrative changes.Participation ConsentPhysicians responsible for interventions will introduce the information of thetrial to potential participants. If the patient shows interests in participating,the physician must provide a consent form for patients and obtain theirconsents for participation and publication. Written informed consent mustbe obtained before protocol specific procedures are undertaken. The risksand benefits of participating in the study will be verbally explained to eachpotential subject before entering into the study. If acupuncture orsimvastatin is administered during a study visit, administration must be aftercompletion of vital signs, ECG, and blood draw procedures, as applicable.The original consent form in Chinese with an English Translated version willbe submitted as supplementary documents.Supplementary documentsEthics approval has been obtained from Hunan University of ChineseMedicine. Please refer to the supplementary document: Ethics Approval.Consent to participate is included in consent form, please refer to thesupplementary document: Consent Form.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Acupuncture and Tuina School, Hunan University of Chinese Medicine, 300Xueshi Rd., Yuelu, 410208 Changsha, Hunan, China. 2Rural CoordinationCenter of BC, Vancouver, BC, Canada. 3University of British Columbia,Vancouver, BC, Canada. 4The Third Clinical College of Zhejiang ChineseMedical University, Hangzhou, China. 5Changchun University of ChineseMedicine, 1035 Boshuo Rd., Jingyue Economic Development District,Changchun 130117, Jilin Province, China.Received: 2 November 2016 Accepted: 26 May 2017References1. Reiner Z. Statins in the primary prevention of cardiovascular disease. NatRev Cardiol. 2013;10:453–64.2. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary preventionof cardiovascular disease, The Cochrane Library. 2013.Liu et al. Trials  (2017) 18:310 Page 16 of 173. Farnier M, Davignon J. Current and future treatment of hyperlipidemia: therole of statins. Am J Cardiol. 1998;82:3J–10J.4. Feingold K. Statin therapy in hyperlipidemia: balancing the risk and benefits.2014.5. 张宝珍, 张凯, 刘玉珍. 针灸丰隆治疗高脂血症临床随机对照试验 Meta分析.中国中医药信息杂志 2014;21:11-15.6. 马明云. 温和灸影响高脂血症患者微循环的临床研究: 南京: 南京中医药大学; 2013.7. 许辛寅. 艾灸足三里丰隆对高脂血症模型大鼠干预及临床验证研究:广州: 广州中医药大学; 2012.8. 蒋月琴. 温针灸足三里对高脂血症血脂指标的影响分析.医学理论与实践 2016;29:3226-3228.9. Xiaorong C, Jie Y, Zenghui Y, et al. Effects of medicinal cake-separatedmoxibustion on plasma 6-keto-PGF1alpha and TXB2 contents in the rabbitof hyperlipemia. J Tradit Chin Med. 2005;25:145–7.10. Yue Z-H, He X-Q, Chang X-R, et al. The effect of herb-partition moxibustionon Toll-like receptor 4 in rabbit aorta during atherosclerosis. J AcupunctMeridian Stud. 2012;5:72–9.11. Liu M, Hu WH, Xie S, et al. Characteristics of acupoint and meridianselection in acupuncture for hyperlipidemia (Chinese). Chin AcupunctMoxibustion. 2015;35:512–6.12. 李光华. 针灸治疗高脂血症的效果分析. 中西医结合心血管病电子杂志.2016;20.13. 陈仲杰. 高脂血症 “温灸和之” 有效性及不同灸治时程对调脂效应的影响: 万方数据资源系统; 2012.14. 刘未艾, 常小荣, 刘密, et al. 不同灸量隔药饼灸对高脂血症患者血脂及血液流变学的影响. 辽宁中医杂志 2013;9:1787–1790.15. 常小荣, 严洁, 易受乡, et al. 隔药饼灸治疗血脂异常的临床研究.中华中医药学刊 2010:8–10.16. 李爱军. 隔药饼灸治疗高脂血症的临床研究. 广西中医药 2007;30:12–13.17. Liu W, Chang X, Liu M, et al. Effects of herbal-cake-separated-moxibustionsized cones at different dosages on blood fat and hemorheology inpatients with hyperlipemia. Liaoning Chin Med J. 2013;40:1787–90.18. Liu M, Chen X, Lu X, et al. Systematic review of acupuncture treatment effectson patients with hyperlipidemia. J Hunan Univ Chin Med. 2014;12:015.19. Smith SC, Grundy SM. 2013 ACC/AHA guideline recommends fixed-dosestrategies instead of targeted goals to lower blood cholesterol. J Am CollCardiol. 2014;64:601–12.20. Program RotNCE. Detection, evaluation, and treatment of high bloodcholesterol in adults (Adult Treatment Panel III). In: National Institutes ofHealth; 2001.21. NCEPNE Panel. Third report of the National Cholesterol Education Program(NCEP) expert panel on detection, evaluation, and treatment of high bloodcholesterol in adults (Adult Treatment Panel III) final report. Circulation.2002;106:3143.22. Cox EE, Ghali WA, Hébert P, et al. Patient safety: a fundamental aspect ofclinical trials through a review of a study on Canadian adverse events. EliteTeam of Editorial Members . 2014;170:103.23. Chang X, Zhou G, Yan J, et al. Effects of cake-separated moxibustion onHDL-C LDL-C of patients with hyperlipidemia (Chinese). Chin J Basic MedTradit Chin Med. 1999;5:53–5.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Liu et al. Trials  (2017) 18:310 Page 17 of 17


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