Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter,prospective, randomized,double‐blind clinical trial

There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo‐controlled, double‐blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010‐023746‐67). Patients with transplant glomerulopathy and anti‐HLA donor‐specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m² and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m²) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012‐2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (?4.2 ± 14.4 vs. ?6.6 ± 12.0 mL/min per 1.73 m², P‐value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P‐value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.     

Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing

Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In this study, PURION® (MiMedx, Marietta, GA) processed dehydrated human amnion/chorion tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for the presence of growth factors, interleukins (ILs) and tissue inhibitors of metalloproteinases (TIMPs). Enzyme‐linked immunosorbent assays (ELISA) were performed on samples of dHACM and showed quantifiable levels of the following growth factors: platelet‐derived growth factor‐AA (PDGF‐AA), PDGF‐BB, transforming growth factor α (TGFα), TGFβ1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), placental growth factor (PLGF) and granulocyte colony‐stimulating factor (GCSF). The ELISA assays also confirmed the presence of IL‐4, 6, 8 and 10, and TIMP 1, 2 and 4. Moreover, the relative elution of growth factors into saline from the allograft ranged from 4% to 62%, indicating that there are bound and unbound fractions of these compounds within the allograft. dHACM retained biological activities that cause human dermal fibroblast proliferation and migration of human mesenchymal stem cells (MSCs) in vitro. An in vivo mouse model showed that dHACM when tested in a skin flap model caused mesenchymal progenitor cell recruitment to the site of implantation. The results from both the in vitro and in vivo experiments clearly established that dHACM contains one or more soluble factors capable of stimulating MSC migration and recruitment. In summary, PURION® processed dHACM retains its biological activities related to wound healing, including the potential to positively affect four distinct and pivotal physiological processes intimately involved in wound healing: cell proliferation, inflammation, metalloproteinase activity and recruitment of progenitor cells. This suggests a paracrine mechanism of action for dHACM when used for wound healing applications.     

The effects of zinc supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized,double‐blind,placebo‐controlled trial

This study was performed to determine the effects of zinc supplementation on wound healing and metabolic status in patients with diabetic foot ulcer. The current randomized, double‐blind, placebo‐controlled trial was conducted among 60 patients (aged 40–85 years old) with grade 3 diabetic foot ulcer. Participants were randomly divided into two groups (30 participants in each group) to take either 220 mg zinc sulfate supplements containing 50 mg elemental zinc or placebo daily for 12 weeks. After the 12‐week intervention, compared with the placebo, zinc supplementation was associated with significant reductions in ulcer length (?1.5 ± 0.7 vs. ?0.9 ± 1.2 cm, p = 0.02) and width (?1.4 ± 0.8 vs. ?0.8 ± 1.0 cm, p = 0.02). In addition, changes in fasting plasma glucose (?40.5 ± 71.0 vs. ?3.9 ± 48.5 mg/dl, p = 0.02), serum insulin concentration (?8.0 ± 15.4 vs. +1.1 ± 10.3 µIU/ml, p = 0.009), homeostasis model of assessment‐estimated insulin resistance (?3.9 ± 7.1 vs. +0.8 ± 5.9, p = 0.007), the quantitative insulin sensitivity check index (+0.01 ± 0.03 vs. ?0.002 ± 0.02, p = 0.04) and HbA1c (?0.5 ± 0.8 vs. ?0.1 ± 0.5%, p = 0.01) in the supplemented group were significantly different from the changes in these indicators in the placebo group. Additionally, significant increases in serum HDL‐cholesterol (+4.1 ± 4.3 vs. +1.1 ± 5.1 mg/dl, p = 0.01), plasma total antioxidant capacity (+91.7 ± 213.9 vs. ?111.9 ± 188.7 mmol/L, p < 0.01) and total glutathione (+68.1 ± 140.8 vs. ?35.0 ± 136.1 µmol/L, p = 0.006), and significant decreases in high sensitivity C‐reactive protein (?20.4 ± 24.6 vs. ?6.8 ± 21.3 µg/ml, p = 0.02) and plasma malondialdehyde concentrations (?0.6 ± 0.9 vs. ?0.2 ± 0.7 µmol/L, p = 0.03) were seen following supplementation with zinc compared with the placebo. Zinc supplementation for 12 weeks among diabetic foot ulcer patients had beneficial effects on parameters of ulcer size and metabolic profiles.     

A randomized,prospective, double‐blind,placebo‐controlled trial of the effect of topical diltiazem on posthaemorrhoidectomy pain

Aim Spasm of the internal anal sphincter plays a role in haemorrhoidal disease and may be a source of anal pain after haemorrhoid surgery. In this study, we investigated the effect of topical diltiazem (DTZ) on postoperative pain following Milligan–Morgan haemorrhoidectomy. Method After haemorrhoidectomy, 33 patients were randomly assigned to receive DTZ ointment (2%; n = 16) or a placebo ointment (n = 17). Ointments were applied to the perianal region three times daily for 7 days. A Visual Analogue Scale was used to assess postoperative pain. The primary end‐point was reduction in postoperative pain. Results Patients using the DTZ cream had significantly less pain and greater benefit than those in the placebo group throughout the first postoperative week, and total and daily narcotic analgesic use was higher in the placebo group. There were no differences in morbidity between the two groups. Conclusion Perianal application of DTZ cream after haemorrhoidectomy significantly reduces postoperative pain and is perceived as beneficial, with no increase in associated morbidity.     

Effect of radial shock wave therapy for carpal tunnel syndrome: A prospective randomized,double‐blind,placebo‐controlled trial

Three recent studies demonstrated the positive effect of extracorporeal shock wave therapy (ESWT) for treating carpal tunnel syndrome (CTS). However, none have entirely proved the effects of ESWT on CTS because all studies had a small sample size and lacked a placebo‐controlled design. Moreover, radial ESWT (rESWT) has not been used to treat CTS. We conducted a prospective randomized, controlled, double‐blinded study to assess the effect of rESWT for treating CTS. Thirty‐four enrolled patients (40 wrists) were randomized into intervention and control groups (20 wrists in each). Participants in the intervention group underwent three sessions of rESWT with nightly splinting, whereas those in the control group underwent sham rESWT with nightly splinting. The primary outcome was visual analog scale (VAS), whereas the secondary outcomes included the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), cross‐sectional area (CSA) of the median nerve, sensory nerve conduction velocity of the median nerve, and finger pinch strength. Evaluations were performed before treatment and at 1, 4, 8, and 12 weeks after the third rESWT session. A significantly greater improvement in the VAS, BCTQ scores, and CSA of the median nerve was noted in the intervention group throughout the study as compared to the control group (except for BCTQ severity at week 12 and CSA at weeks 1 and 4) (p < 0.05). This is the first study to assess rESWT in a randomized placebo‐controlled trial and demonstrate that rESWT is a safe and effective method for relieving pain and disability in patients with CTS. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:977–984, 2016.     

A randomized,controlled, double‐blind prospective trial with a Lipido‐Colloid Technology‐Nano‐OligoSaccharide Factor wound dressing in the local management of venous leg ulcers

Venous leg ulcers (VLUs) are the most prevalent chronic wounds in western countries with a heavy socioeconomic impact. Compression therapy is the etiologic treatment of VLU but until now no wound dressing has been shown to be more effective than another. The aim of this study was to assess the efficacy of a new dressing in the management of VLU. Adult patients presenting a noninfected VLU and receiving effective compression therapy were enrolled in this randomized, controlled, double‐blind trial. The VLUs were assessed every 2 weeks for 8 weeks. The primary study outcome was the relative Wound Area Reduction (WAR, in %), and the secondary objectives were absolute WAR, healing rate, and percentage of wounds with >40% surface area reduction. One hundred eighty‐seven patients were randomly allocated to treatment groups. Median WAR was 58.3% in the Lipido‐Colloid Technology‐Nano‐OligoSaccharide Factor (TLC‐NOSF) dressing group (test group) and 31.6% in the TLC dressing group (control group) (difference: ?26.7%; 95% confidence interval: ?38.3 to ?15.1%; p = 0.002). All other efficacy outcomes were also significant in favor of the TLC‐NOSF dressing group. Clinical outcomes for patients treated with the new dressing are superior to those patients treated with the TLC dressing (without NOSF compound), suggesting a strong promotion of the VLU healing process.     

A multicenter,randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers

Venous leg ulcers produce significant clinical and economic burdens on society and often require advanced wound therapy. The purpose of this multicenter, randomized, controlled study is to evaluate the safety and efficacy of one or two applications of dehydrated human amnion/chorion membrane allograft and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. The primary study outcome was the proportion of patients achieving 40% wound closure at 4 weeks. Of the 84 participants enrolled, 53 were randomized to receive allograft and 31 were randomized to the control group of multilayer compression therapy alone. At 4 weeks, 62% in the allograft group and 32% in the control group showed a greater than 40% wound closure (p = 0.005), thus showing a significant difference between the allograft‐treated groups and the multilayer compression therapy alone group at the 4‐week surrogate endpoint. After 4 weeks, wounds treated with allograft had reduced in size a mean of 48.1% compared with 19.0% for controls. Venous leg ulcers treated with allograft had a significant improvement in healing at 4 weeks compared with multilayer compression therapy alone.     

Pre‐operative brachial plexus block compared with an identical block performed at the end of surgery: a prospective,double‐blind,randomised clinical trial

We evaluated whether pre‐emptive analgesia with a pre‐operative ultrasound‐guided infraclavicular brachial plexus block resulted in better postoperative analgesia than an identical block performed postoperatively. Fifty‐two patients undergoing fixation of a fractured radius were included. All patients received general anaesthesia with remifentanil and propofol. Patients were randomly allocated into two groups: a pre‐operative block or a postoperative block with 0.5 ml.kg^?1 ropivacaine 0.75%. After surgery, all patients received regular paracetamol plus opioids for breakthrough pain. Mean (SD) time to first rescue analgesic after emergence from general anaesthesia was 544 (217) min in the pre‐operative block group compared with 343 (316) min in the postoperative block group (p = 0.015). Postoperative pain scores were higher and more patients required rescue analgesia during the first 4 h after surgery in the postoperative block group. There were no significant differences in plasma stress mediators between the groups. Analgesic consumption was lower at day seven in the pre‐operative block group. Pain was described as very strong at block resolution in 27 (63%) patients and 26 (76%) had episodes of mild pain after 6 months. We conclude that a pre‐operative ultrasound‐guided infraclavicular brachial plexus block provides longer and better analgesia in the acute postoperative period compared with an identical postoperative block in patients undergoing surgery for fractured radius.     

The effects of magnesium and vitamin E co‐supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized,double‐blind,placebo‐controlled trial

This study was carried out to determine the effects of magnesium and vitamin E co‐supplementation on wound healing and metabolic status in patients with diabetic foot ulcer (DFU). The current randomized, double‐blind, placebo‐controlled trial was conducted among 57 patients with grade 3 DFU. Participants were randomly divided into two groups to take either 250 mg magnesium oxide plus 400 IU vitamin E (n = 29) or placebo per day (n = 28) for 12 weeks. Compared with the placebo, taking magnesium plus vitamin E supplements reduced ulcer length (β [difference in the mean of outcomes measures between treatment groups] ?0.56 cm; 95% CI, ?0.92, ?0.20; p = 0.003), width (β ?0.35 cm; 95% CI, ?0.64, ?0.05; p = 0.02) and depth (β ?0.18 cm; 95% CI, ?0.33, ?0.02; p = 0.02). In addition, co‐supplementation led to a significant reduction in fasting plasma glucose (β ?13.41 mg/dL; 95% CI, ?20.96, ?5.86; p = 0.001), insulin (β ?1.45 μIU/ml; 95% CI, ?2.37, ?0.52; p = 0.003), insulin resistance (β ?0.60; 95% CI, ?0.99, ?0.20; p = 0.003) and HbA1c (β ?0.32%; 95% CI, ?0.48, ?0.16; p < 0.003), and a significant elevation in insulin sensitivity (β 0.007; 95% CI, 0.003, 0.01; p < 0.001) compared with the placebo. Additionally, compared with the placebo, taking magnesium plus vitamin E supplements decreased triglycerides (β ?10.08 mg/dL; 95% CI, ?19.70, ?0.46; p = 0.04), LDL‐cholesterol (β ?5.88 mg/dL; 95% CI, ?11.42, ?0.34; p = 0.03), high sensitivity C‐reactive protein (hs‐CRP) (β ?3.42 mg/L; 95% CI, ?4.44, ?2.41; p < 0.001) and malondialdehyde (MDA) (β ?0.30 μmol/L; 95% CI, ?0.45, ?0.15; p < 0.001), and increased HDL‐cholesterol (β 2.62 mg/dL; 95% CI, 0.60, 4.63; p = 0.01) and total antioxidant capacity (TAC) levels (β 53.61 mmol/L; 95% CI, 4.65, 102.57; p = 0.03). Overall, magnesium and vitamin E co‐supplementation for 12 weeks to patients with DFU had beneficial effects on ulcer size, glycemic control, triglycerides, LDL‐ and HDL‐cholesterol, hs‐CRP, TAC, and MDA levels.     

IPARZINE‐SKR study: randomized,double‐blind clinical trial of a new topical product versus placebo to prevent pressure ulcers

This study compared the efficacy of a new topical agent (IPARZINE‐4A‐SKR) on preventing category I pressure ulcers (PUs) over a 2‐week period, compared with a placebo. A double‐blind, randomised, multi‐centre, placebo‐controlled clinical trial in two parallel groups was conducted. The primary objective was to compare PU incidence between groups. Hospital and socio‐sanitary centre patients (n = 194) at risk of developing a PU (Braden scale) were randomised into two groups. The intervention group included 99 patients, and the placebo group comprised 95 patients. Patients were comparable in terms of age, sex and PU risk. In both groups, patients had a high risk of developing PUs. The product was applied on the sacrum, trochanters and heels. Six PUs (incidence = 6·1%) were detected in the intervention group versus seven (incidence = 7·4%) in the placebo group. Differences were not statistically significant (z = 0·08; P = 0·94), relative risk = 0·82 (95% confidence interval = 0·29–2·36). The main limitation of the study was the sample size and, therefore, the main difficulty encountered was in determining whether the product is ineffective or simply has not been used with sufficient patients. In conclusion, it is not possible to confirm that there are any differences between the studied and the placebo treatments in the prevention of PUs. The results obtained were similar to those obtained in studies of PU prevention using products based on topical fatty acids.     

Propiverine hydrochloride in Japanese patients with overactive bladder: A randomized,double‐blind,placebo‐controlled trial

Objectives: The aim of this study was to investigate the efficacy and safety of propiverine for overactive bladder (OAB) in Japanese patients. Methods: In this multicentre, randomized, double‐blind study, patients ≥20 years old with symptoms of OAB for ≥12 weeks were allocated to either propiverine (20 mg once daily) or placebo for 12 weeks. Efficacy and quality of life were assessed using a 7‐day bladder diary, the OAB symptom score, and King's Health Questionnaire. Safety was mainly assessed by adverse events and the QTc interval. Results: A total of 567 patients were allocated. Change in number of micturitions/24 h was significantly greater in the propiverine group than in the placebo group (–1.86 vs?1.36, P = 0.001). Compared to placebo, propiverine produced significant improvements in urgency, urgency incontinence, urine volume/micturition, and the OAB symptom score. Significant improvements in urgency, urgency incontinence, and micturition frequency were observed at the first 4 weeks of treatment. All nine domains of King's Health Questionnaire were improved more with propiverine than with placebo. Adverse effects with propiverine were mostly mild, and no patient developed QTc interval prolongation exceeding 500 ms. Conclusion: Propiverine is effective for Japanese OAB patients by improving their symptoms and quality of life with a predictable side‐effect profile.     

Use of an aseptically processed,dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective,randomised, multi‐centre clinical trial in 80 patients

Amnion and chorion allografts have shown great promise in healing diabetic foot ulcers (DFUs). Results from an interim analysis of 40 patients have demonstrated the accelerated healing ability of a novel aseptically processed, dehydrated human amnion and chorion allograft (dHACA). The goal of this study was to report on the full trial results of 80 patients where dHACA was compared with standard of care (SOC) in achieving wound closure in non‐healing DFUs. After a 2‐week screening period, during which patients with DFUs were unsuccessfully treated with SOC, patients were randomised to either SOC alone or SOC with dHACA applied weekly for up to 12 weeks. At 12 weeks, 85% (34/40) of the dHACA‐treated DFUs healed, compared with 33% (13/40) treated with SOC alone. Mean time to heal within 12 weeks was significantly faster for the dHACA‐ treated group compared with SOC, 37 days vs 67 days in the SOC group (P = .000006). Mean number of grafts used per healed wound during the same time period was 4.0, and mean cost of the tissue to heal a DFU was $1771. The authors concluded that aseptically processed dHACA heals DFUs significantly faster than SOC at 12 weeks.     

A prospective,randomised, controlled,multi‐centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft,bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers

A prospective, randomised, controlled, parallel group, multi‐centre clinical trial was conducted at three sites to compare the healing effectiveness of treatment of chronic lower extremity diabetic ulcers with either weekly applications of Apligraf^® (Organogenesis, Inc., Canton, MA), EpiFix^® (MiMedx Group, Inc., Marietta, GA), or standard wound care with collagen‐alginate dressing. The primary study outcome was the percent change in complete wound healing after 4 and 6 weeks of treatment. Secondary outcomes included percent change in wound area per week, velocity of wound closure and a calculation of the amount and cost of Apligraf or EpiFix used. A total of 65 subjects entered the 2‐week run‐in period and 60 were randomised (20 per group). The proportion of patients in the EpiFix group achieving complete wound closure within 4 and 6 weeks was 85% and 95%, significantly higher (all adjusted P‐values ≤ 0·003) than for patients receiving Apligraf (35% and 45%), or standard care (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83·5% compared with 53·1% for wounds treated with Apligraf. Median time to healing was significantly faster (all adjusted P‐values ≤0·001) with EpiFix (13 days) compared to Apligraf (49 days) or standard care (49 days). The mean number of grafts used and the graft cost per patient were lower in the EpiFix group campared to the Apligraf group, at 2·15 grafts at a cost of $1669 versus 6·2 grafts at a cost of $9216, respectively. The results of this study demonstrate the clinical and resource utilisation superiority of EpiFix compared to Apligraf or standard of care, for the treatment of diabetic ulcers of the lower extremities.     

Ciprofloxacin for BK viremia prophylaxis in kidney transplant recipients: Results of a prospective,double‐blind,randomized, placebo‐controlled trial

In kidney transplantation, BK virus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BK viremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double‐blind, placebo‐controlled trial comparing a 3‐month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BK viremia. The primary endpoint of BK viremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P = .03). Higher rates of BK viremia (23.3% vs 11.9%; P = .06) and BK nephropathy (5.8% vs 1.5%; P = .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections (83.3% vs 50%; P = .04). A 3‐month course of ciprofloxacin was ineffective at preventing BK viremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone‐resistant infections. Clinical trial registration number: NCT01789203.     

Amniotic membrane is a potential regenerative option for chronic non‐healing wounds: a report of five cases receiving dehydrated human amnion/chorion membrane allograft

A case series of five patients with a total of six chronic non‐healing wounds (>30 day duration) were non‐randomly selected to evaluate the performance, safety and handling properties of dehydrated human amnion/chorion membrane allograft, an amniotic membrane scaffolding product. The patients had lower extremity wounds that had previously failed standard of care within a university outpatient/inpatient wound healing programme. Five wounds treated with dehydrated amnion/chorion membrane allograft showed a mean 43% area reduction from baseline (51% median) at 3 weeks into treatment and completely healed with a 64‐day median time to closure (SD ±27·6 days). One wound worsened at 3 weeks and was found to have a complete central vein obstruction that was treated with long‐term mild compression but still eventually healed at 6 months. Removing this outlier, the four responding wounds had a 72% mean and 69% median change in area from baseline, at the 3 week point. All five patients received only one application of dehydrated human amnion/chorion membrane allograft, and there were no adverse events. The product was easy to use, administer and handle. In summary, dehydrated human amnion/chorion membrane allograft appears to be a safe, effective and easy to use therapy for chronic non‐healing wounds. This study describes the details of these clinical cases and provides an overview of the current evidence on the use of amniotic tissue in clinical practice.