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Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.
Sperna Weiland, CJ, Smeets, XJNM, Kievit, W, Verdonk, RC, Poen, AC, Bhalla, A, Venneman, NG, Witteman, BJM, da Costa, DW, van Eijck, BC, et al
The lancet. Gastroenterology & hepatology. 2021;(5):350-358
Abstract
BACKGROUND Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING Netherlands Organisation for Health Research and Development and Radboud University Medical Center.
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Metabolomics Analysis of Aspirin's Effects in Human Colon Tissue and Associations with Adenoma Risk.
Barry, EL, Fedirko, V, Uppal, K, Ma, C, Liu, K, Mott, LA, Peacock, JL, Passarelli, MN, Baron, JA, Jones, DP
Cancer prevention research (Philadelphia, Pa.). 2020;(10):863-876
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Abstract
Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.
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Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial.
Atreya, R, Peyrin-Biroulet, L, Klymenko, A, Augustyn, M, Bakulin, I, Slankamenac, D, Miheller, P, Gasbarrini, A, Hébuterne, X, Arnesson, K, et al
The lancet. Gastroenterology & hepatology. 2020;(12):1063-1075
Abstract
BACKGROUND Cobitolimod is a topically administered, DNA-based oligonucleotide that activates Toll-like receptor 9 (TLR9), and previous research has shown clinical efficacy in patients with moderate-to-severe ulcerative colitis. Here we assessed the efficacy and safety of different dose regimens of cobitolimod for induction therapy in patients with moderate-to-severe, left-sided ulcerative colitis. METHODS CONDUCT was a randomised, double-blind, five-arm, placebo-controlled, dose-ranging phase 2b study that recruited patients with moderate-to-severe, left-sided ulcerative colitis, with inadequate response to conventional or biological therapies, from 91 hospitals or outpatient clinics in 12 European countries. Eligible patients had a Mayo score of 6-12 with a centrally read endoscopic subscore (modified to exclude friability from grade 1) of 2 or higher and no individual subscore of less than 1, and confirmation of left-sided disease. Patients were randomised (1:1:1:1:1; block size of ten) via a computer-generated schedule and centralised interactive voice and web response system to receive rectal enemas of cobitolimod at 31 mg, 125 mg, or 250 mg at weeks 0 and 3 (2 × 31 mg, 2 × 125 mg, and 2 × 250 mg groups), cobitolimod at 125 mg at weeks 0, 1, 2, and 3 (4 × 125 mg group), or placebo. Randomisation was stratified by current glucocorticosteroid and previous tumour necrosis factor inhibitor treatment. Patients and all study personnel were masked to treatment allocation. The primary endpoint was the proportion of patients achieving clinical remission (Mayo subscores for rectal bleeding of 0, for stool frequency of 0 or 1 [with ≥1-point decrease from baseline], and for endoscopy of 0 or 1 [excluding friability]) at week 6. The primary analysis (based on intention to treat) and safety analysis were done in all randomly assigned patients who received at least one dose of active study drug or placebo. In this exploratory study, statistical tests were one-sided; p values of less than 0·10 were regarded as statistically significant, with no adjustment for multiplicity. This study is registered with ClinicalTrials.gov, NCT03178669, and is completed; the results here represent the final analysis. FINDINGS 213 patients were randomly assigned between June 30, 2017, and June 26, 2019. Of these, 211 patients received study treatment: 40 in the cobitolimod 2 × 31 mg group, 43 in the 2 × 125 mg group, 42 in the 4 × 125 mg group, 42 in the 2 × 250 mg group, and 44 in the placebo group. A greater proportion of patients were in clinical remission at week 6 in the cobitolimod 2 × 250 mg group than in the placebo group (nine [21%] of 42 patients vs three [7%] of 44; odds ratio [OR] 3·8 [80% CI 1·5-9·5]; one-sided p=0·025). We identified no significant difference in the proportion of patients with clinical remission in the cobitolimod 2 × 31 mg group (five [13%] of 40 patients; OR 2·0 [80% CI 0·7-5·5], p=0·18), 2 × 125 mg group (two [5%] of 43; 0·7 [0·2-2·2], p=0·66), or 4 × 125 mg (four [10%] of 42; 1·4 [0·5-3·9], p=0·33) compared with the placebo group. Treatment-emergent adverse events occurred in 21 (48%) patients in the placebo group, ten (25%) patients in the cobitolimod 2 × 31 mg group, 17 (40%) patients in the 2 × 125 mg group, 15 (36%) patients in the 4 × 125 mg group, and 18 (43%) patients in the 2 × 250 mg group. Severe adverse events occurred in eight (4%) of 211 patients (worsening of ulcerative colitis [seven patients] and abdominal hernia and wound dehiscence [one patient]). Ten patients (two [5%] in the placebo group, two [5%] in the cobitolimod 2 × 31 mg group, two [5%] in the 4 × 125 mg, and four [10%] in the 2 × 250 mg group) had a total of 13 serious adverse events; these were worsening of ulcerative colitis (eight events) and pruritus, rash, abdominal hernia, fascia dehiscence, and deep vein thrombosis (one event each). One patient in the placebo group died from total organ failure after receiving a colectomy for a serious adverse event of disease worsening. INTERPRETATION Two topical administrations of cobitolimod 250 mg were well tolerated and more effective than placebo in inducing clinical remission 6 weeks after the start of treatment. TLR9 activation is a promising novel therapeutic target in ulcerative colitis and warrants further testing, with phase 3 trials of cobitolimod planned. FUNDING InDex Pharmaceuticals.
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The use of 5-aminosalicylate for patients with Crohn's disease in a prospective European inception cohort with 5 years follow-up - an Epi-IBD study.
Burisch, J, Bergemalm, D, Halfvarson, J, Domislovic, V, Krznaric, Z, Goldis, A, Dahlerup, JF, Oksanen, P, Collin, P, de Castro, L, et al
United European gastroenterology journal. 2020;(8):949-960
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BACKGROUND The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice. AIMS The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease. METHODS In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists. RESULTS Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%)). CONCLUSION In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.
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Longitudinal non-adherence predicts treatment escalation in paediatric ulcerative colitis.
Carmody, JK, Plevinsky, J, Peugh, JL, Denson, LA, Hyams, JS, Lobato, D, LeLeiko, NS, Hommel, KA
Alimentary pharmacology & therapeutics. 2019;(8):911-918
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BACKGROUND Medication non-adherence in paediatric ulcerative colitis (UC) has been associated with negative health outcomes including flares in disease activity. However, no studies to date have examined longitudinal adherence to maintenance medication in a prospective controlled trial. AIMS To determine whether objectively measured adherence to standardised mesalazine (mesalamine) therapy over time was related to remission at 52 weeks and the need for treatment escalation in newly diagnosed paediatric patients with UC METHODS PROTECT (NCT01536535) was a prospective, inception cohort, multi-site study of paediatric patients aged 4-17 years with newly diagnosed UC followed for 52 weeks. Patients received standardised mesalazine, with pre-established criteria for escalation to thiopurines or anti-TNFα inhibitors. Patients used pill bottles with electronic caps to monitor mesalazine adherence. We tested whether longitudinal adherence to mesalazine predicted steroid-free remission at week 52 (i.e. quiescent disease on mesalazine alone with no corticosteroids ≥4 weeks prior) and need for treatment escalation (i.e. introduction of immunomodulators, calcineurin-inhibitors or anti-TNFα inhibitors). RESULTS Among 268 patients, average mesalazine adherence trajectories did not predict week 52 steroid-free remission. Declining adherence over time strongly predicted treatment escalation (β = -.037, P = .001). By month 6, adherence rate ≤85.7% was associated with treatment escalation. CONCLUSIONS Non-adherence may have affected therapeutic efficacy of standardised mesalazine, thereby contributing to need for treatment escalation. Routine adherence monitoring for at least 6 months following treatment initiation and addressing adherence difficulties early in the disease course are recommended.
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Efficacy and tolerability of a new ibuprofen 200mg plaster in patients with acute sports-related traumatic blunt soft tissue injury/contusion.
Predel, HG, Giannetti, B, Connolly, MP, Lewis, F, Bhatt, A
Postgraduate medicine. 2018;(1):24-31
Abstract
BACKGROUND Ibuprofen is used for the treatment of non-serious pain. This study assessed the efficacy and safety of a new ibuprofen plaster for the treatment of pain associated with acute sports impact injuries/contusions. METHODS In this randomised, double-blind, multi-centre, placebo controlled, parallel group study, adults (n = 130; 18-58 years of age) diagnosed with acute sports-related blunt soft tissue injury/contusion were randomized to receive either ibuprofen 200 mg plaster or placebo plaster. Plasters were administered once daily for five consecutive days. The primary assessment was area under the visual analogue scale (VAS) of pain on movement (POM) over 0 to three days (VAS AUC0-3d). Other endpoints included algometry AUC from 0 to three days (AUC0-3d) and 0 to five days (AUC0-5d), to evaluate improvement of sensitivity at the injured site, and patient and investigator global assessment of efficacy. Safety was monitored throughout the study. RESULTS The ibuprofen plaster resulted in superior reduction in AUC0-3d compared with placebo; the Least Squares (LS) mean difference was 662.82 mm*h in favour of the ibuprofen 200mg plaster (P = 0.0011). The greater improvement in VAS AUC of POM was also observed after 12 h, 24 h, and five days of therapy. Tenderness also significantly improved with the ibuprofen plaster compared with placebo; LS mean difference in algometry/tenderness AUC0-3d was 1.87 N/cm2*d and AUC0-5d was 1.87 N/cm2*d (P values ≤0.0004). At all study timepoints, a greater percentage of patients and investigators rated the effectiveness of the ibuprofen 200 mg plaster as good/excellent than the placebo plaster. Treatment-emergent adverse events for the ibuprofen plaster were few (≤1.5%) and were mild in severity. CONCLUSIONS The results of this study indicate 200 mg plaster is effective and safe for the treatment of pain due to acute sports-related traumatic blunt soft tissue injury/contusion in adults.
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Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study.
Mizokami, Y, Oda, K, Funao, N, Nishimura, A, Soen, S, Kawai, T, Ashida, K, Sugano, K
Gut. 2018;(6):1042-1051
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Abstract
OBJECTIVE To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use. DESIGN A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study. RESULTS The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified. CONCLUSION The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg). TRIAL REGISTRATION NUMBERS NCT01452750, NCT01456260; Results.
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A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study.
Hoffman, MK, Goudar, SS, Kodkany, BS, Goco, N, Koso-Thomas, M, Miodovnik, M, McClure, EM, Wallace, DD, Hemingway-Foday, JJ, Tshefu, A, et al
BMC pregnancy and childbirth. 2017;(1):135
Abstract
BACKGROUND Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Though complex in its origins, a growing body of evidence suggests that first trimester administration of low dose aspirin (LDA) may substantially reduce the rate of PTB. METHODS Hypothesis: LDA initiated in the first trimester reduces the risk of preterm birth. Study Design Type: Prospective randomized, placebo-controlled, double-blinded multi-national clinical trial conducted in seven low and middle income countries. Trial will be individually randomized with one-to-one ratio (intervention/control) Population: Nulliparous women between the ages of 14 and 40, with a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, no more than two previous first trimester pregnancy losses, and no contraindications to aspirin. INTERVENTION Daily administration of low dose (81 mg) aspirin, initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA, compared to an identical appearing placebo. Compliance and outcomes will be assessed biweekly. OUTCOMES Primary outcome: Incidence of PTB (birth prior to 37 0/7 weeks GA). Secondary outcomes Incidence of preeclampsia/eclampsia, small for gestational age and perinatal mortality. DISCUSSION This study is unique as it will examine the impact of LDA early in pregnancy in low-middle income countries with preterm birth as a primary outcome. The importance of developing low-cost, high impact interventions in low-middle income countries is magnified as they are often unable to bear the financial costs of treating illness. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02409680 Date: March 30, 2015.
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Prospective randomised clinical trial to evaluate the safety and efficacy of nepafenac 0.1% treatment for the prevention of macular oedema associated with cataract surgery in patients with diabetic retinopathy.
Pollack, A, Staurenghi, G, Sager, D, Mukesh, B, Reiser, H, Singh, RP
The British journal of ophthalmology. 2017;(4):423-427
Abstract
BACKGROUND/AIMS: This study evaluated nepafenac ophthalmic suspension 0.1% for prevention of macular oedema (MO) when used 90 days following cataract surgery in patients with diabetic retinopathy (DR). METHODS Randomised, double-masked, vehicle-controlled, parallel group study conducted at 32 centres across the world. Participants were patients with diabetes with non-proliferative diabetic retinopathy scheduled for cataract surgery with (posterior chamber) intraocular lens implantation. Patients were randomised to nepafenac ophthalmic suspension 0.1% or vehicle three times daily, beginning on the day before surgery and continuing through the last study visit (day 90 or early exit). All patients were instilled one drop of tobramycin 0.3% and dexamethasone 0.1% four times daily for 2 weeks after surgery. Primary efficacy end point was the percentage of patients who developed MO (defined as ≥30% increase in central subfield macular thickness from baseline) within 90 days following surgery. The secondary end point was mean change in best-corrected visual acuity (BCVA) from baseline to day 90. RESULTS A total of 175 patients were randomised, with 87 and 88 patients in the nepafenac and vehicle groups, respectively. A significantly greater percentage of eyes in the vehicle group (17.5%; 95% CI 9.9% to 27.6%) developed MO within 90 days following surgery compared with the nepafenac group (5.0%; 95% CI 1.4% to 12.3%, p=0.01). Mean change in BCVA from baseline to day 90 following surgery was greater in the nepafenac group (17.7±14.6 letters) relative to the vehicle group (14.3±13.9 letters), though the difference was not statistically significant (p=0.14). No new safety issues or trends were identified. CONCLUSIONS A 90-day nepafenac treatment regimen prevented MO after cataract surgery in patients with DR and demonstrated no safety issues within this study group. TRIAL REGISTRATION NUMBER NTC00782717 and NCT00939276.
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Moxibustion versus diclofenac sodium gel for the treatment of knee osteoarthritis: a study protocol for a double-blinded, double-placebo, randomised controlled trial.
Zhou, JY, Luo, L, Zhu, LL, Yin, HY, Wu, Q, Peng, JX, Zhang, CS, Lv, P, Tang, Y, Yu, SG
BMJ open. 2017;(4):e012879
Abstract
INTRODUCTION Knee osteoarthritis is a common form of arthritis in elderly patients that is characterised by pain and functional limitation. Moxibustion has been employed to relieve chronic pain as an alternative therapy for knee osteoarthritis. However, the evidence of its efficacy is equivocal due to the low methodological quality in most clinical studies. Therefore, we are performing a double-blinded, double-placebo, randomised controlled trial to evaluate the efficacy of moxibustion in participants with knee osteoarthritis. METHODS AND ANALYSIS This is a multicentre, double-blinded, double-placebo, randomised controlled clinical trial. 144 eligible participants with knee osteoarthritis will be randomly assigned to two different groups in a 1:1 ratio. Participants in the moxibustion group will undergo active moxibustion plus placebo gel, whereas participants in the control group will receive diclofenac sodium gel plus placebo moxibustion. Each participant will receive 12 sessions of active/placebo moxibustion at three acupoints (ST35, ST36 and EX-LE4) as well as 2 months of follow-up. Diclofenac sodium gel or placebo gel at a dose of 4 g per knee will be applied three times per day for 4 weeks. The primary outcome measure will be the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score change at the end of the intervention period from baseline. The secondary outcome measures include changes of other subscales (pain, stiffness and function) of WOMAC, visual analogue scale and patient globalassessment. The safety of moxibustion and diclofenac sodium gel will be assessed at every visit. ETHICS AND DISSEMINATION This trial has been approved by the Sichuan Regional Ethics Review Committee (permission number: 2015KL-014). The results of this study are expected to provide clinical evidence on the efficacy of moxibustion for pain relief and physical function improvement in patients with knee osteoarthritis. The findings will be submitted for publication in peer-reviewed medical journals and presented at relevant academic conferences. TRIAL REGISTRATION NUMBER NCT02769572.