Recombinant human C1 esterase inhibitor treatment for hereditary angioedema attacks in children.

BACKGROUND: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1-INH (rhC1-INH) for HAE attacks in children. METHODS: This open-label, phase 2 study included children aged 2-13 years with C1-INH-HAE. Eligible HAE attacks were treated intravenously with rhC1-INH 50 IU/kg body weight (maximum, 4200 IU). The primary end-point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end-point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). RESULTS: Twenty children (aged 5-14 years; 73 HAE attacks) were treated with rhC1-INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1-INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0-65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0-126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment-related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. CONCLUSIONS: Recombinant human C1-INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults.

Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. METHODS: We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. FINDINGS: Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of -4·4 attacks (p<0·0001) and -2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. INTERPRETATION: Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. FUNDING: Pharming Technologies.

Efficacy and safety of diclofenac diethylamine 1.16% gel in acute neck pain: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP. METHODS: In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM), pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after 48 h). Adverse events (AEs) were recorded throughout the study. RESULTS: The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm) vs. placebo (56.9 mm) (p < 0.0001), representing a clinically relevant decrease from baseline (75% vs. 23%, respectively). All POM scores were significantly lower with DDEA gel vs. placebo from 1 h, as were PAR and NDI scores from first assessment (24 h) onwards (all p < 0.0001). Response to treatment was significantly higher with DDEA gel (94.4%) vs. placebo (8.3%) (p < 0.0001). There were no AEs with DDEA gel. CONCLUSIONS: DDEA 1.16% gel, which is available over-the-counter, was effective and well tolerated in the treatment of acute neck pain. The tools used to assess efficacy suggest that it quickly reduced neck pain and improved neck function. However, questions remain regarding the comparability and validity of such tools. Further studies will help ascertain whether DDEA 1.16% gel offers an alternative treatment option in this common, often debilitating condition. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01335724.

Efficacy and Safety of an Etofenamate Medicated Plaster for Acute Ankle Sprain: A Randomized Controlled Trial.

BACKGROUND: The favorable benefit-risk profile of topical nonsteroidal anti-inflammatory drugs (NSAIDs) makes them a preferred treatment for pain relief in soft tissue injuries. PURPOSE: To assess the efficacy and safety of a novel etofenamate 70-mg medicated plaster in patients with acute uncomplicated ankle sprain. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with grade 1 or 2 ankle sprain of recent onset were randomized to etofenamate or placebo plasters (1:1) applied twice daily for 7 days. Clinical assessments, including ankle pain on movement (POM) in mm on a 100-mm visual analog scale (VAS), were made at predefined intervals during the treatment period. RESULTS: In total, 156 male or female adult patients (mean age, 35.3 ± 11.8 years) were enrolled. The fall in VAS values for POM from baseline to 72 hours was markedly in favor of the etofenamate plaster, with respective reductions of 52.7% and 24.0% for active and placebo plasters (least squares mean treatment difference, 22.1 mm; P value for analysis of covariance < .0001). Similar clinically relevant differences between etofenamate and placebo were seen for POM at the 48-, 96-, and 168-hour visits (P < .0001). These differences between etofenamate and placebo plasters were reflected in area under the curve for POM, pain at rest, and ankle swelling measured at various time points during the 7 days. Time taken to achieve a meaningful (30%) and optimal (50%) reduction of POM was significantly shorter in the etofenamate group. The responder rate (proportion of patients with at least 50% pain reduction at 72 hours) was 52.5% for the etofenamate plaster and 7.7% for the placebo. A significantly greater proportion of patients randomized to etofenamate rated their progress and/or the treatment as "good" or "very good." The medicated plasters adhered well over the 12-hour dosing period and were very well-tolerated. CONCLUSION: With respect to the investigated indication, uncomplicated ankle sprain, the etofenamate plaster has therapeutic efficacy that is similar to that for the best available topical NSAID formulations. REGISTRATION: 2016-000252-99 (EudraCT number).

Hereditary Angioedema Attack in Utero and Treatment of the Mother and Fetus.

Hereditary angioedema (HAE), an inherited deficiency of functional C1 esterase inhibitor (C1-INH), is characterized by unpredictable recurrent episodes of painful and often disabling swelling in subcutaneous and/or submucosal tissues. We report the case of a 23-year-old woman with type I HAE who had abdominal, facial, and peripheral attacks throughout her first pregnancy. A facial HAE attack occurred at week 38 of her pregnancy, and symptoms improved after self-administration of 50 U/kg of recombinant human C1-INH (total dose, 3500 U), but soon after she had an unusual abdominal sensation. Ultrasonography detected fetal lower lip swelling (∼3 times the normal size) and limb swelling. Physical examination of the mother found cervical dilatation, indicating the final stages of labor. Two hours after treatment of her HAE attack, she spontaneously delivered a healthy male infant. Photographs taken within 2 minutes of delivery revealed resolution of the infant's facial edema, and the limb edema was resolved within 30 minutes. By 10 minutes postdelivery, the mother's facial attack had almost completely resolved. Ten months after birth, genetic analysis confirmed that the infant had type I HAE. This is the first documented case of an HAE attack in utero. Treatment of the mother with recombinant human C1-INH was effective for the maternal and fetal attacks, with resolution within approximately 2 to 2.5 hours for both patients.

Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

A dysregulated immune response with hyperinflammation is observed in patients with severe coronavirus disease 2019 (COVID-19). The aim of the present study was to assess the safety and potential benefits of human recombinant C1 esterase inhibitor (conestat alfa), a complement, contact activation and kallikrein-kinin system regulator, in severe COVID-19. Patients with evidence of progressive disease after 24 h including an oxygen saturation <93% at rest in ambient air were included at the University Hospital Basel, Switzerland in April 2020. Conestat alfa was administered by intravenous injections of 8400 IU followed by 3 additional doses of 4200 IU in 12-h intervals. Five patients (age range, 53-85 years; one woman) with severe COVID-19 pneumonia (11-39% lung involvement on computed tomography scan of the chest) were treated a median of 1 day (range 1-7 days) after admission. Treatment was well-tolerated. Immediate defervescence occurred, and inflammatory markers and oxygen supplementation decreased or stabilized in 4 patients (e.g., median C-reactive protein 203 (range 31-235) mg/L before vs. 32 (12-72) mg/L on day 5). Only one patient required mechanical ventilation. All patients recovered. C1INH concentrations were elevated before conestat alfa treatment. Levels of complement activation products declined after treatment. Viral loads in nasopharyngeal swabs declined in 4 patients. In this uncontrolled case series, targeting multiple inflammatory cascades by conestat alfa was safe and associated with clinical improvements in the majority of severe COVID-19 patients. Controlled clinical trials are needed to assess its safety and efficacy in preventing disease progression.

Efficacy of two dosing schemes of a liquid containing ivy leaves dry extract EA 575 versus placebo in the treatment of acute bronchitis in adults.

INTRODUCTION: The results of a clinical trial published in 2016 showed the efficacy of ivy leaves dry extract EA 575 versus placebo in the treatment of patients suffering from acute cough. A clinical trial with a very similar design was conducted to not only show the reproducibility of former results but also to investigate an alternative dosing scheme. METHODS: This randomised, placebo-controlled, multicentre, double-blind clinical trial was conducted to assess the efficacy and safety of a liquid containing EA 575 in the treatment of acute bronchitis. A total of 209 patients were treated with a liquid containing EA 575 as an active investigational medicinal product (verum) either two (7.5 mL) or three (5 mL) times a day or placebo in the respective dosing scheme for 1 week, with a total observational period of 2 weeks. The primary efficacy outcome was a change in Bronchitis Severity Score (BSS) of the pooled placebo and pooled verum groups between visits 1 and 5. Additional secondary parameters were assessed, including, for example, change in cough severity as assessed by a visual analogue scale (VAS) and the Verbal Category Descriptive (VCD) score. RESULTS: Superiority of verum over placebo was during and at the end of treatment, as measured by BSS. No significant differences between the dosing schemes were observed. VCD scores and VAS measurements also showed the superiority of verum over placebo. CONCLUSION: The existing data on the clinical efficacy of EA 575 were confirmed. Furthermore, a new dosing scheme was shown to be noninferior to the currently used scheme while maintaining the safety and tolerability of the well-established cough liquid containing EA 575.

Efficacy and tolerability of a new ibuprofen 200mg plaster in patients with acute sports-related traumatic blunt soft tissue injury/contusion.

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.

Efficacy and safety assessment of acute sports-related traumatic soft tissue injuries using a new ibuprofen medicated plaster: results from a randomized controlled clinical trial.

OBJECTIVE: To investigate the efficacy and safety of a recently developed ibuprofen medicated plaster in the treatment of acute sports impact injuries/contusions. METHODS: In this double-blind, multi-center, placebo-controlled, parallel group, phase 3 study (EudraCT Number: 2012-003257-2) patients (n = 132; ages 18 to 60 years) diagnosed with acute sports-related traumatic blunt soft tissue injury/contusion to the upper or lower limbs were randomized to receive either ibuprofen 200 mg plaster (n = 64) or placebo plaster (n = 68). Plasters were administered once daily for five consecutive days. The primary assessment was the area under the curve (AUC) of the visual analogue scale (VAS) of pain on movement (POM) over 0 to 72 h (VAS0-72). RESULTS: The ibuprofen medicated plaster was associated with a reduction in pain on movement (POM) based on lower VAS AUC0-72h (2399.4 mm*h) compared with placebo (4078.9 mm*h) (least squares mean difference: - 1679.5 mm*h; P < 0.0001). The reduction in AUC of POM was also significantly greater for the ibuprofen medicated plaster compared with placebo at 12, 48, 24, and 120 h (P < 0.0001). Algometry/tenderness measurements found that the ibuprofen medicated plaster was associated with greater reduction in tenderness/pain than placebo at each timepoint (P values <0.0001). Seven patients experienced drug-related adverse events (n = 1 [1.6%] for the ibuprofen plaster, and n = 6 [8.8%] for placebo). All drug-related AEs were administration site reactions and were mild in intensity. CONCLUSIONS: The results of this study indicate that ibuprofen medicated plaster results in rapid and clinically relevant reduction of pain in patients suffering from blunt musculoskeletal injuries or recurrent pain. The ibuprofen medicated plaster was well tolerated.

How Dextran Sulfate Affects C1-inhibitor Activity: A Model for Polysaccharide Potentiation.

C1-inhibitor is a key inhibitor of the complement and contact activation systems, and mutations in the protein can cause hereditary angioedema. Through an unknown mechanism, polysaccharides can increase C1-inhibitor activity against some of its target proteases. Here we present the crystal structures of the serine protease inhibitor (serpin) domain of active C1-inhibitor by itself and in complex with dextran sulfate. Unlike previously described interactions of serpins with polysaccharides, the structures and isothermal titration calorimetry experiments together reveal that dextran sulfate binds to C1-inhibitor's F1 helix with low affinity and does not invoke an allosteric change. Furthermore, one dextran sulfate molecule can bind multiple C1-inhibitor molecules. We propose that in a C1-inhibitor/protease/polysaccharide ternary complex, negatively charged polysaccharides link C1-inhibitor's positively charged F1 helix to positively charged autolysis loops of proteases. The proposed mechanism elegantly explains previous experiments showing that polysaccharide potentiation is increased against proteases with a greater positive charge in their autolysis loop.

A randomized, double-blind, placebo-controlled multicentre study to evaluate the efficacy and safety of diclofenac 4% spray gel in the treatment of acute uncomplicated ankle sprain.

OBJECTIVE: A prospective, randomized, double-blind, placebo-controlled, parallel-group multicentre study to evaluate the efficacy and safety of diclofenac 4% spray gel for the treatment of acute, uncomplicated ankle sprain. METHODS: Outpatients with acute, uncomplicated, one-sided ankle sprain were randomly assigned to receive diclofenac 4% spray gel or placebo (vehicle) three times daily for 14 ± 1 days. The main efficacy endpoint was the intra-individual response to treatment (≥ 50% decrease in swelling of the injured ankle after a treatment period of ≤ 10 days). RESULTS: The response rate was significantly higher in the diclofenac group (n = 118) than the placebo group (n = 114) (91.5% vs. 82.5%). After 3-4 days' treatment, diclofenac spray significantly reduced swelling, spontaneous pain, pain on active movement and tenderness compared with placebo. Diclofenac spray was well tolerated, with a low overall rate of adverse events. CONCLUSIONS: Diclofenac 4% spray gel rapidly relieves pain and improves mobility in patients with acute, uncomplicated ankle sprain and is well tolerated. It may be a useful treatment option for other acute soft tissue injuries.

Efficacy and safety of diclofenac diethylamine 2.32% gel in acute ankle sprain.

BACKGROUND: Topical diclofenac diethylamine (DDEA) 2.32% gel achieves lasting efficacy in localized pain with two applications per day, while maintaining the favorable safety profile of topical diclofenac and potentially improving convenience and patient compliance. METHODS: This randomized double-blind controlled study enrolled patients with acute ankle sprain treated with DDEA 2.32% gel two times per day (bid) (n = 80) or three times per day (tid) (n = 80) or placebo (n = 82). Efficacy (including pain and swelling) and local tolerability were evaluated during 8 ± 1 d. RESULTS: By day 5, the reduction in pain on movement (POM) (primary efficacy variable) with DDEA bid and tid (49.1 and 49.7 mm, respectively; 100-mm visual analog scale) was almost double that with placebo (25.4 mm) (P < 0.0001). In patients with severe baseline POM (≥ 80 mm), mean change in POM from baseline to day 5 with DDEA bid or tid was 30-40 mm greater than that with placebo, which was double the difference (15-20 mm) in patients with mild-moderate baseline POM (<80 mm). More than 70% of all DDEA patients experienced ≥ 50% reduction in POM between days 1 and 5 versus 21% of placebo patients (P < 0.0001). By study end (day 8), ankle swelling in patients treated with DDEA (0.3 cm) was one-third that in those treated with placebo (0.9 cm) (P < 0.0001), which had still not achieved the level of ankle joint function seen with DDEA on day 5 (P < 0.0001). At day 5, treatment satisfaction was "good" to "excellent" in almost 90% of DDEA patients but only "good" or "very good" in 23% of placebo patients (P < 0.0001). DDEA 2.32% gel was well tolerated. CONCLUSIONS: DDEA 2.32% gel twice daily (applied in the morning and evening) was well tolerated and provided lasting relief from pain, improved function, and reduced symptomatic healing time in uncomplicated ankle sprain.

Comfrey extract ointment in comparison to diclofenac gel in the treatment of acute unilateral ankle sprains (distortions).

OBJECTIVES: A previously published study comparing the efficacy of comfrey extract to a commercial diclofenac (CAS 78213-16-8) preparation in the treatment of unilateral ankle sprains is critically re-evaluated. The study was designed to show non-inferiority of the comfrey extract. The data were re-evaluated for superiority according to CPMP guidelines. The study was an observer-blind, randomised, multi-centre clinical trial with two independent treatment groups "comfrey extract" and "diclofenac gel" (parallel group design) and included a total of 164 patients (82 in the comfrey group and 82 in the diclofenac group, intention-to-treat (ITT) analysis). Key variables were the area under the curve (AUC) from Visits 1 to 2 of the difference of the tenderness values contra-lateral minus injured side (primary variable), pain assessment (Visual Analogue Scale, VAS) at rest and on movement by patient, swelling (figure-of-eight method) and ankle movement (neutral zero method). On average (mean difference comfrey extract minus diclofenac), the AUC was +61.1 h x N/cm2 greater for patients treated with comfrey extract compared to diclofenac treated patients (95% confidence interval: 19.08; 103.09 h x N/cm2). The difference between the two treatment groups was statistically significant (analysis of variance with factors "study drug", "centre", and "drug x centre interaction"). Safety was excellent in both treatment groups. The re-evaluation of the data showed superiority of the plant based ointment over the diclofenac gel in the treatment of distortions. It is encouraging and impressive to realize that a natural product seems to be an effective and safe alternative to the standard topical treatment with diclofenac.