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Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.
Brandenburg, VM, Sinha, S, Torregrosa, JV, Garg, R, Miller, S, Canals, AZ, Bahr, D, Joubert, PH, Salcedo, C, Carroll, KJ, et al
Journal of nephrology. 2019;(5):811-821
Abstract
BACKGROUND Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification. METHODS In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations. RESULTS Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related. CONCLUSIONS SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.
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Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers.
Rothenberg, ME, Tagen, M, Chang, JH, Boyce-Rustay, J, Friesenhahn, M, Hackos, DH, Hains, A, Sutherlin, D, Ward, M, Cho, W
Clinical drug investigation. 2019;(9):873-887
Abstract
BACKGROUND AND OBJECTIVE Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. METHODS This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. RESULTS Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. CONCLUSION GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.
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Efficacy of Plantago major, chlorhexidine 0.12% and sodium bicarbonate 5% solution in the treatment of oral mucositis in cancer patients with solid tumour: A feasibility randomised triple-blind phase III clinical trial.
Cabrera-Jaime, S, Martínez, C, Ferro-García, T, Giner-Boya, P, Icart-Isern, T, Estrada-Masllorens, JM, Fernández-Ortega, P
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2018;:40-47
Abstract
PURPOSE Oral mucositis is one of the most common adverse effects of chemotherapy and radiotherapy. The aim of this study was to compare the efficacy of Plantago major extract versus chlorhexidine 0.12% versus sodium bicarbonate 5% in the symptomatic treatment of chemotherapy-induced oral mucositis in solid tumour cancer patients. METHOD Multicentre randomised controlled trial estimated sample of 45 solid tumour patients with grade II-III mucositis. The participants were randomised to one of three treatments, consisting of sodium bicarbonate 5% aqueous solution together with: an additional dose of sodium bicarbonate 5% aqueous solution, Plantago major extract, or chlorhexidine 0.12%. The primary outcomes were severity of mucositis, pain intensity, oral intake capacity and quality of life. The independent variable was treatment group, and confounders included sociodemographic data, neutrophil count, chemotherapy drug and dose received. RESULTS Of the 50 patients enrolled, 68% (n = 34) achieved grade 0 mucositis (none), with those using the double sodium bicarbonate rinse healing in five days on average (95% CI 3.9, 6.5) versus seven days (95% CI 5.3, 9,0) for the chlorhexidine group and seven days (95% CI 5.3, 8.5) for the Plantago major group. The pain experienced by the participants lessened over the 14 days of treatment, but differences in pain intensity between the three groups did not show statistical significance (p = 0.762). CONCLUSIONS Healing time was shorter with the double sodium bicarbonate solution compared to the other two rinses, but the differences were not significant. Our results suggest it may be time to reconsider the use of Plantago major extract in the management of oral mucositis.
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Efficacy and safety of a fixed-dose combination of nimesulide/pantoprazole compared to naproxen/esomeprazole for pain relief in patients with osteoarticular diseases and dyspeptic symptoms.
Scheinberg, M, Pott Júnior, H, Macêdo, EA, Bocchi de Oliveira, MF, Ecclissato, C, Amazonas, RB
Drug design, development and therapy. 2018;:2775-2783
Abstract
PURPOSE This study investigated the safety and efficacy of fixed-dose combination tablets of naproxen/esomeprazole magnesium and nimesulide/pantoprazole to determine if both regimens are equally suited to relieve pain in patients with osteoarticular diseases and dyspeptic symptoms. METHODS Patients were randomly assigned to receive either nimesulide/pantoprazole (100 mg/20 mg) twice daily or naproxen/esomeprazole magnesium (500 mg/20 mg) twice daily for 14 days. The primary endpoint was defined as the mean change in modified Western Ontario and McMaster Universities Osteoarthritis Index pain subscale. Secondary endpoints were mean visual analog scale score of dyspeptic symptoms (nausea, abdominal discomfort/pain, epigastric burning, postprandial fullness), mean visual analog scale score of individual dyspeptic symptoms, and individual score of dyspeptic symptoms according to patient diary. This study is registered at ClinicalTrials.gov: NCT01670552. RESULTS A total of 490 patients were enrolled and randomized, and 399 completed treatment (naproxen/esomeprazole, n=201; nimesulide/pantoprazole, n=198). The difference in mean change in the modified Western Ontario and McMaster Universities Osteoarthritis Index pain score after 7 days of treatment between the two treatment groups was 2.33 mm (95% CI, -1.22 to 5.89 mm). After 14 days of therapy, the difference was 0.45 mm (95% CI, -3.29 to 4.19 mm). The most common adverse events in the pooled group were abdominal discomfort, abdominal distention, dyspepsia, and nausea, but none of these was deemed to be clinically meaningful. CONCLUSION The present study demonstrated noninferiority of a 14-day regimen with a fixed-dose combination of nimesulide/pantoprazole compared to naproxen/esomeprazole for the treatment of osteoarticular pain.
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Evolution of pain at 3 months by oral resveratrol in knee osteoarthritis (ARTHROL): protocol for a multicentre randomised double-blind placebo-controlled trial.
Nguyen, C, Boutron, I, Baron, G, Coudeyre, E, Berenbaum, F, Poiraudeau, S, Rannou, F
BMJ open. 2017;(9):e017652
Abstract
INTRODUCTION Osteoarthritis (OA) pathophysiology is driven in part by joint inflammation. Resveratrol has in vitro anti-inflammatory properties. We aim to assess the efficacy of oral resveratrol for knee pain at 3 months in people with knee OA. METHODS AND ANALYSIS We will conduct a randomised double-blind placebo-controlled trial. Overall, 164 individuals with knee OA fulfilling 1986 American College of Rheumatology criteria will be recruited in three tertiary care centres in France and randomised to receive oral resveratrol, 40 mg (two caplets) two times per day for 1 week, then 20 mg (one caplet) two times per day or a matching placebo for a total of 6 months. Randomisation will be centralised and stratified by centre. The allocation ratio of assignments will be 1:1. The primary outcome will be the mean change from baseline in knee pain on a self-administered 11-point pain Numeric Rating Scale at 3 months. Secondary outcomes will be the mean change in knee pain at 6 months, the function subscore of the Western Ontario and McMaster Universities Arthritis Index score, patient global assessment, proportion of responders according to the Osteoarthritis Research Society International-Outcome Measures in Rheumatology criteria at 3 and 6 months, and self-reported number of intra-articular injections of corticosteroids or hyaluronic acid and consumption of analgesics and non-steroidal anti-inflammatory drugs since the last contact. Other interventions will be allowed and self-reported. Adherence will be monitored by capsule counts and a booklet and adverse events recorded at 3 and 6 months. Statisticians, treating physicians and participants will be blinded to the allocated treatment. ETHICS AND DISSEMINATION The oral resveratrol in knee osteoarthritis (ARTHROL) trial has been authorised by the AgenceNationale de Sécurité du Médicament et des Produits de Santé and ethics were approved by the Comité deProtection des Personnes Île-de-France III. The findings of the study will be published in a peer-reviewed journal and disseminated at conferences. The design of ARTHROL will warrant the translation of its findings into clinical practice. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT02905799. Pre-results. First received: 14 September 2016. Last updated: 16 September 2016. Status: not yet recruiting.
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Oxidative Stress as a Physiological Pain Response in Full-Term Newborns.
Perrone, S, Bellieni, CV, Negro, S, Longini, M, Santacroce, A, Tataranno, ML, Bazzini, F, Belvisi, E, Picardi, A, Proietti, F, et al
Oxidative medicine and cellular longevity. 2017;:3759287
Abstract
This research paper aims to investigate if oxidative stress biomarkers increase after a painful procedure in term newborns and if nonpharmacological approaches, or sex, influence pain degree, and the subsequent OS. 83 healthy term newborns were enrolled to receive 10% oral glucose or sensorial saturation (SS) for analgesia during heel prick (HP). The ABC scale was used to score the pain. Advanced oxidation protein products (AOPP) and total hydroperoxides (TH) as biomarkers of OS were measured at the beginning (early-sample) and at the end (late-sample) of HP. The early-sample/late-sample ratio for AOPP and TH was used to evaluate the increase in OS biomarkers after HP. Higher levels of both AOPP and TH ratio were observed in high degree pain (4-6) compared with low degree pain score (0-3) (AOPP: p = 0.049; TH: p = 0.001). Newborns receiving SS showed a significantly lower pain score (p = 0.000) and AOPP ratio levels (p = 0.021) than those without. Males showed higher TH levels at the end of HP (p = 0.005) compared to females. The current study demonstrates that a relationship between pain degree and OS exists in healthy full-term newborns. The amount of OS is gender related, being higher in males. SS reduces pain score together with pain-related OS in the newborns.
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A naturally-inspired, curcumin-based lecithin formulation (Meriva® formulated as the finished product Algocur®) alleviates the osteo-muscular pain conditions in rugby players.
Di Pierro, F, Zacconi, P, Bertuccioli, A, Togni, S, Eggenhoffner, R, Giacomelli, L, Scaltrini, S
European review for medical and pharmacological sciences. 2017;(21):4935-4940
Abstract
OBJECTIVE Curcumin is one of the most investigated phytochemical products because of its low toxicity and its broad spectrum of bioactivity, including anti-inflammatory and analgesic properties. A new delivery form of curcumin, resorting to phosphatidylcholine (Meriva®, formulated as the finished product Algocur®) has been developed to increase its bioavailability. In this study, we tested the efficacy and safety of a Meriva®-based product in rugby players suffering by different osteo-muscular pain conditions PATIENTS AND METHODS In this pilot study, 50 male rugby players with osteo-muscular pain due to traumatic injuries, physical overload or acute episode of chronic pain were recruited and treated with conventional analgesic drugs (n = 25) or Meriva®-based product (n = 25) for a maximum of 10 days. The pain perception and the functio laesa were evaluated at baseline and after 1, 3, 6, 10 and 20 days from the initiation of the treatment protocol. Treatment tolerability, compliance, and adverse events were also reported. RESULTS During the study, the analgesic effect decreased in both treated group compared to baseline, starting from the third day of treatment. Similarly, the impaired physical function evaluated after 3, 6, 10 and 20 days improved in Meriva®-based product treated group and in subjects treated with conventional analgesic drugs, compared to the baseline condition. The percentage of excellent adherence to treatment or tolerability was higher in the Meriva®-based product treated group. Only 1 (4%) subject treated with Meriva®-based product experienced adverse events whereas 4 (16%) subjects treated with conventional analgesic drugs reported gastric pain as an adverse event. CONCLUSIONS Despite the small sample size and the group heterogeneity, this study suggests that the naturally-derived, curcumin-based delivery form, Meriva® (formulated as the finished product Algocur®), could represent a promising safe, analgesic remedy in painful osteo-muscular conditions associated with intense, high impact, physical activities.
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Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.
Hoppe, C, Jacob, E, Styles, L, Kuypers, F, Larkin, S, Vichinsky, E
British journal of haematology. 2017;(4):620-629
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Abstract
Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.
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Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial.
Basch, E, Pugh, SL, Dueck, AC, Mitchell, SA, Berk, L, Fogh, S, Rogak, LJ, Gatewood, M, Reeve, BB, Mendoza, TR, et al
International journal of radiation oncology, biology, physics. 2017;(2):409-418
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Abstract
PURPOSE To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). METHODS AND MATERIALS Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. RESULTS Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling "too sick." CONCLUSIONS Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies.
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An open-label six-month extension study to investigate the safety and efficacy of an extract of Artemisia annua for managing pain, stiffness and functional limitation associated with osteoarthritis of the hip and knee.
Hunt, S, Stebbings, S, McNamara, D
The New Zealand medical journal. 2016;(1444):97-102
Abstract
AIMS: This six-month single-centre open-label extension study, conducted at the University of Otago, Dunedin, follows from a previously published 12-week pilot double-blind randomised placebo-controlled study of dietary supplement, Arthrem® (ART) in patients with osteoarthritis (OA) of the hip or knee. The pilot double-blind study showed that treatment with ART 150 mg twice-daily was associated with clinically relevant pain reduction. The extension study aims were to assess longer-term safety and efficacy during six months' treatment following the pilot trial. METHOD Patients who completed the pilot double-blind study had the option to continue on open-label treatment with ART for a further six months. Safety was assessed by adverse event monitoring and laboratory tests at three and six months. Efficacy was assessed at three and six months using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®). RESULTS Thirty-four patients entered the optional extension and 28 completed six months' treatment. ART was well tolerated when taken for up to nine months. Improvements in WOMAC® efficacy parameters reported in the double-blind phase of the study were maintained over six months. CONCLUSION ART appears to be a safe and effective alternative for managing the symptoms of OA over an extended period.