Prospective, double-blind, randomized, placebo-controlled phase III study evaluating efficacy and safety of octagam 10% in patients with dermatomyositis ("ProDERM Study")
INTRODUCTION Dermatomyositis (DM) is an inflammatory myopathy characterized by distinct skin manifestations and muscle weakness. Intravenous immunoglobulin (IVIg) has been used off-label as adjuvant therapy in DM, but is not indicated for DM, due to lack of proven efficacy in a large randomized controlled trial. The objective of the ProDERM (Progress in DERMatomyositis) study was to evaluate the efficacy, safety and long-term tolerability of IVIg (Octagam 10%) in patients with DM in a randomized, placebo-controlled, double-blind, Phase III study. METHODS Adult patients with active DM who were continuing standard therapy at a stable dose were eligible for this study. Patients were randomized 1:1 to receive either 2 g/kg of IVIg or placebo, administered every 4 weeks until week 16 (First Period). Patients were switched to the alternate treatment if they showed clinical deterioration in the First Period. After response assessment at week 16, all patients on placebo and those without deterioration on IVIg entered the open-label Extension Period, receiving 2 g/kg IVIg every 4 weeks for 24 weeks. RESULTS The primary efficacy endpoint was the proportion of responders in the IVIg vs placebo arm at week 16, where response was defined per 2016 ACR/EULAR Myositis Response Criteria of at least minimal improvement [Total Improvement Score (TIS) ≥20] and without deterioration at 2 consecutive visits up to week 16. TIS consists of composite response criteria, combining weighted improvement in 6 core set measures (CSMs), Global Disease Activity (Physician and Patient), manual muscle testing-8 (MMT-8), Health Assessment Questionnaire, extra-muscular disease activity, and muscle enzymes. Secondary endpoints included the mean change in individual CSMs, time to improvement in TIS, time to confirmed deterioration in the First Period, and the overall proportion of patients with deteriorations. Adverse events, including infusion reactions and thromboembolic events, were recorded. CONCLUSIONS The ProDERM study was the first to assess the long-term efficacy and safety of IVIg (Octagam 10%) in a placebo-controlled, blinded, randomized trial in DM. The study aimed to inform on the use of IVIg in the treatment of DM, and results are expected in Q3 2020. CLINICALTRIALSGOV IDENTIFIER NCT02728752.
Effects of Therapy with Fibrin Glue combined with Mesenchymal Stem Cells (MSCs) on Bone Regeneration: A Systematic Review
Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized cell lines. Fibrin sealant or fibrin glue is a natural polymer involved in the coagulation process. Fibrin glue provides a temporary structure that favors angiogenesis, extracellular matrix deposition and cell-matrix interactions. Additionally, fibrin glue maintains the local and paracrine functions of MSCs, providing tissue regeneration through less invasive clinical procedures. Thus, the objective of this systematic review was to assess the potential of fibrin glue combined with MSCs in bone or cartilage regeneration. The bibliographic search was performed in the PubMed/MEDLINE, LILACS and Embase databases, using the descriptors ("fibrin sealant" OR "fibrin glue") AND "stem cells" AND "bone regeneration", considering articles published until 2021. In this case, 12 preclinical and five clinical studies were selected to compose this review, according to the eligibility criteria. In preclinical studies, fibrin glue loaded with MSCs, alone or associated with bone substitute, significantly favored bone defects regeneration compared to scaffold without cells. Similarly, fibrin glue loaded with MSCs presented considerable potential to regenerate joint cartilage injuries and multiple bone fractures, with significant improvement in clinical parameters and absence of postoperative complications. Therefore, there is clear evidence in the literature that fibrin glue loaded with MSCs, alone or combined with bone substitute, is a promising strategy for treating lesions in bone or cartilaginous tissue.
Intravenous tranexamic acid reduce postoperative drainage and pain after open elbow arthrolysis: A randomized controlled trial
Journal of shoulder and elbow surgery. 2021
BACKGROUND Open elbow arthrolysis (OEA), which has become an established treatment for post-traumatic elbow stiffness (PTES), requires complete release of contracture tissue and wide excision of ectopic bone, which results in extensive bleeding. The aim of the present study is to evaluate the efficacy of intravenous tranexamic acid (TXA) on postoperative drainage, calculated blood loss and early clinical outcomes in patients undergoing OEA. METHODS A double-blind, randomized, placebo-controlled trial including 96 patients undergoing OEA was undertaken. Patients received intravenously either 100 mL saline (placebo group, n = 48), or 100 mL saline plus 1 g TXA (TXA group, n = 48) before skin incision. The primary outcome was the drainage volume on postoperative day (POD) 1 to 3. Secondary outcomes included the calculated blood loss, elbow pain score measured by Visual Analog Scale (VAS), elbow function valued by Mayo Elbow Performance Score (MEPS), and rate of complications after OEA. RESULTS Mean total postoperative drainage volume (TXA group: 182 mL vs. placebo group: 214 mL, p = 0.003) and mean calculated total blood loss (TXA group: 582 mL vs. placebo group: 657 mL, p = 0.004) were significantly lower in the TXA group. No transfusions were necessary in either group. Mean VAS pain scores in elbow motion showed marked differences between both groups on POD 1 (TXA: 5 vs. placebo: 6, p = 0.003) and POD 2 (TXA: 4 vs. placebo: 5, p = 0.023), but not in other postoperative time points. No differences were detected in complications, such as pin-related infection, hematoma, new or exacerbation of ulnar nerve symptoms, and recurrent heterotopic ossification. At the 6-month follow-up, no statistical differences were found between the two groups with respect to the elbow functions including range of motion, VAS score and MEPS. CONCLUSION Intravenous administration of TXA significantly decreased the postoperative drainage volume and the total estimated blood loss, and alleviated the elbow pain with motion during early postoperative days in patients undergoing OEA. LEVEL OF EVIDENCE Level I; Randomized Controlled Trial; Treatment Study.
A novel approach for knee osteoarthritis using high molecular weight hyaluronic acid conjugated to plasma fibrinogen - interim findings of a double-blind clinical study
OBJECTIVE Osteoarthritis (OA) is a widespread degenerative joint disease leading to progressive loss of function and pain. Available treatments do not provide long-term relief or improvement. This study aimed to assess the safety and efficacy of a novel intra articular supplement, made of high molecular-weight hyaluronic acid (HA) uniquely conjugated to either purified (RegenoGel) or autologous plasma-derived fibrinogen (RegenoGel-OSP), as a long-term treatment for knee OA. METHODS Sixty-seven consecutive participants (mean age 67.26 ± 7 years) with symptomatic OA were randomly assigned to receive intraarticular injections of either RegenoGel, RegenoGel-OSP or saline solution (placebo). The active treatment groups received a second, repeat injection of the corresponding treatment at the 3-month evaluation, at which time, the placebo group was divided into two subgroups, one receiving RegenoGel and the other receiving RegenoGel-OSP. The OA symptoms were assessed by VAS, WOMAC, and IKDC questionnaires at baseline and at 1, 3, 4, and 6 months following the first injection. OA-related quality of life was evaluated by the SF-12 survey. RESULTS Our preliminary data suggests that both fibrin-HA formulations have positive effects on OA symptoms for all assessed parameters with the most prominent trend for reduction in OA-associated pain. Pooled data analysis of RegenoGel and RegenoGel-OSP shows significantly improved VAS scores compared to placebo at three months after the first injection, and sustained for another three months after the second injection. Both RegenoGel, RegenoGel-OSP had an excellent safety profile. CONCLUSIONS Interim analysis results indicate that RegenoGel and RegenoGel-OSP are safe and are potentially effective for at least six months in alleviating pain and symptoms of knee OA.
A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures
Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 hours following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P=0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
Autologous Interleukin 1 Receptor Antagonist Blood-Derived Products for Knee Osteoarthritis: A Systematic Review
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2019;35(7):2211-2221
PURPOSE To systematically review the available clinical data regarding the use of autologous IL-1 receptor antagonist blood products (AILBPs) and their validity as an alternative intra-articular (IA) therapy for symptomatic knee osteoarthritis (OA). METHODS The PubMed, MEDLINE, Embase, and Cochrane Library databases were searched from inception to June 2018. All randomized controlled trials (RCTs) and noncomparative studies that evaluated the clinical efficacy of AILBPs (i.e., autologous protein solution and autologous conditioned serum) for knee OA were included. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index. The secondary outcomes measured were the Knee Injury and Osteoarthritis Outcome Score, visual analog scale score, Short Form 36 (SF-36) score, radiographic scores, and adverse events, which were qualitatively analyzed. RESULTS We included 8 studies, comprising 3 RCTs (Level II) and 5 noncomparative studies (Level IV), with a total of 592 patients (mean age, 56.4 years; 49.7% male patients). The RCTs represented high methodologic quality, whereas the noncomparative studies represented moderate to good quality. With AILBPs, 2 of 4 studies (50%) showed improvements in the Knee Injury and Osteoarthritis Outcome Score symptom and sport subscales, 5 of 7 studies (71%) achieved improvements in the Western Ontario and McMaster Universities Osteoarthritis Index score, and 4 of 5 studies (80%) attained improvements in the visual analog scale pain score from baseline to final follow-up. Most adverse events associated with AILBPs were mild to moderate in severity and were primarily localized to the injection site. CONCLUSIONS Limited evidence substantiates that AILBPs are a safe and tolerable IA injection therapy that may improve pain parameters and functionality for mild to moderate knee OA patients and may be an effective adjunct for those unresponsive to traditional IA therapies. LEVEL OF EVIDENCE Level IV, systematic review of Level II through IV studies.
The Safety of Blood Flow Restriction Training as a Therapeutic Intervention for Patients With Musculoskeletal Disorders: A Systematic Review
The American journal of sports medicine. 2019;:363546519882652
BACKGROUND The effectiveness of blood flow restriction training (BFRT) as compared with other forms of training, such as resistance training, has been evaluated in the literature in clinical and nonclinical populations. However, the safety of this intervention has been summarized only in healthy populations and not in clinical populations with musculoskeletal disorders. PURPOSE To evaluate the safety and adverse events associated with BFRT in patients with musculoskeletal disorders. STUDY DESIGN Systematic review. METHODS A literature search was conducted with 3 online databases (MEDLINE, CINAHL, and Embase). Eligibility criteria for selecting studies were as follows: (1) BFRT was used as a clinical intervention, (2) study participants had a disorder of the musculoskeletal system, (3) authors addressed adverse events, (4) studies were published in English, and (5) the intervention was performed with human participants. RESULTS Nineteen studies met eligibility criteria, with a pooled sample size of 322. Diagnoses included various knee-related disorders, inclusion body myositis, polymyositis or dermatomyositis, thoracic outlet syndrome, Achilles tendon rupture, and bony fractures. Nine studies reported no adverse events, while 3 reported rare adverse events, including an upper extremity deep vein thrombosis and rhabdomyolysis. Three case studies reported common adverse events, including acute muscle pain and acute muscle fatigue. In the randomized controlled trials, individuals exposed to BFRT were not more likely to have an adverse event than individuals exposed to exercise alone. Of the 19 studies, the adverse events were as follows: overall, 14 of 322; rare overall, 3 of 322; rare BFRT, 3 of 168; rare control, 0 of 154; any adverse BFRT, 10 of 168; any adverse control, 4 of 154. A majority of studies were excluded because they did not address safety. CONCLUSION BFRT appears to be a safe strengthening approach for knee-related musculoskeletal disorders, but further research is needed to make definitive conclusions and to evaluate the safety in other musculoskeletal conditions. Improved definitions of adverse events related to BFRT are needed to include clear criteria for differentiating among common, uncommon, and rare adverse events. Finally, further research is needed to effectively screen who might be at risk for rare adverse events.
Tranexamic acid reduces blood loss after primary shoulder arthroplasty: a double-blind, placebo-controlled, prospective, randomized controlled trial
JSES open access. 2018;2(1):23-27
Background: Tranexamic acid (TXA) is an antifibrinolytic that has been shown to decrease blood loss and transfusion rates after hip and knee arthroplasty, with only limited evidence to support its use in shoulder arthroplasty. This study was conducted to determine whether intravenous (IV) TXA is more effective than placebo in reducing blood loss after primary total shoulder arthroplasty (TSA). Methods: In this prospective, double-blind, placebo-controlled, randomized clinical trial, patients undergoing primary anatomic and reverse TSA were randomized to receive 1 g of intravenous TXA or a placebo of an equivalent volume of intravenous normal saline administered 10 minutes before the incision. The primary outcome measurement was calculated postoperative blood loss. Secondary outcomes included transfusion rates, weight of hemoglobin loss, hospital length of stay, and thromboembolic events. Results: The study enrolled 110 patients, 2 of whom were excluded because they did not have a postoperative hemoglobin measurement, and the remaining 108 patients (52 for TXA, 56 for placebo) were analyzed. There were no significant differences between TXA and placebo groups in preoperative characteristics. For the primary outcome, the TXA group had significantly lower postoperative blood loss of 1100.9 +/- 367.4 mL compared with 1274.5 +/- 460.0 mL for the placebo group (P = .03). For secondary outcomes, TXA had lower weight of hemoglobin loss compared with placebo (152.2 +/- 57.3 g vs. 178.0 +/- 65.8 g; P = .03). No patients in the TXA or placebo groups required a transfusion. Conclusions: Intravenous TXA reduced blood loss after primary TSA compared with placebo.
Tranexamic acid administration for anatomic and reverse total shoulder arthroplasty: a systematic review and meta-analysis
JSES open access. 2018;2(1):28-33
Background: Tranexamic acid (TXA) has been shown to reduce perioperative blood loss and risk of blood transfusion. Evidence establishing its efficacy in total shoulder arthroplasty (TSA) is limited. The current study evaluated the effect of TXA on perioperative blood loss and transfusion risk after TSA. Methods: A systematic review and meta-analysis of TXA administration for TSA was performed, and 6 studies with a total of 680 patients were found. Data on change in hemoglobin, drain output, total blood loss, and transfusion were extracted. Meta-analysis was performed with stratification into reverse and anatomic TSA subgroups. Results: TXA administration was associated with decreased change in hemoglobin (-0.63 g/dL; 95% CI, -0.87 to -0.39 g/dL; P < .00001), drain output (-112.05 mL; 95% CI, -182.29 to -41.81 mL; P < .0001), and total blood loss (-231.87 mL; 95% CI, -334.23 to -129.48 mL; P < .00001) after reverse TSA. There was a trend toward reduction in transfusion rate after reverse TSA (-4%; 95% CI, -8% to 0%; P = .06). TXA administration was associated with reduced drain output after anatomic TSA (-123.07 mL; 95% CI, -163.93 to -82.20 mL; P < 0.00001). TXA administration was not associated with decreased transfusion rate after anatomic TSA. Data to evaluate the effect of TXA on change in hemoglobin and total blood loss after anatomic TSA were insufficient. Conclusions: Routine administration of TXA reduces perioperative blood loss and may reduce the risk of transfusion after reverse TSA. Future studies are needed to further characterize its effect on the risk of transfusion after reverse TSA and efficacy in anatomic TSA.
Efficacy and safety of topical tranexamic acid in knee arthroplasty
Medicina Clinica. 2018;151((11):):431-434
INTRODUCTION AND OBJECTIVE Tranexamic acid (TXA) is commonly used to control postoperative blood loss in total knee arthroplasty. In order to avoid adverse effects associated with intravenous administration, topical use has been proposed as an alternative. Our aim was to evaluate the efficacy and safety of topical TXA in total knee arthroplasty. MATERIAL AND METHODS A total of 90 patients scheduled for unilateral total knee arthroplasty were included in a prospective randomised study. All surgeries were performed under spinal anaesthesia, tourniquet and the same postoperative protocol. Patients were allocated to one of the 3 groups according to the application of TXA: group A (n=30) 1g of topical TXA; group B (n=30) 1g of TXA intravenous and in group C or the control group (n=30) no drug was administrated. Parameters related to blood loss and drain outputs were compared between the 3 groups. RESULTS The results revealed that post-operative decrease in haemoglobin level was significantly lower in group A (1.95g/dL) than group B (2.25g/dL) and group C (2.96g/dL), P<.01. Total postoperative blood loss was lower in group A (195mL) than group B (466mL) and group C (718mL), P<.01. There was no significant difference in complications and allogenic blood transfusion rate between the 3 groups. CONCLUSIONS According to the results, topical application of 1g TXA significantly reduced blood loss in patients undergoing total knee arthroplasty more than intravenous or no administration of TXA.