Study Protocol for "Psilocybin as a Treatment for Anorexia Nervosa: A Pilot Study".

Background: Anorexia nervosa (AN) is a serious and life-threatening psychiatric condition. With a paucity of approved treatments, there is a desperate need for novel treatment avenues to be explored. Here, we present (1) an overview of the ways through which Public Patient Involvement (PPI) has informed a trial of psilocybin-assisted therapy for AN and (2) a protocol for a pilot study of psilocybin-assisted therapy in AN currently underway at Imperial College London. The study aims to assess the feasibility, brain mechanisms and preliminary outcomes of treating anorexia nervosa with psilocybin. Methods: (1) PPI: Across two online focus groups, eleven individuals with lived experience of AN were presented with an overview of the protocol. Their feedback not only identified solutions to possible barriers for future participants, but also helped the research team to better understand the concept of "recovery" from the perspective of those with lived experience. (2) Protocol: Twenty female participants [21-65 years old, body mass index (BMI) 15 kg/m2 or above] will receive three oral doses of psilocybin (up to 25 mg) over a 6-week period delivered in a therapeutic environment and enveloped by psychological preparation and integration. We will work with participant support networks (care teams and an identified support person) throughout and there will be an extended remote follow-up period of 12 months. Our two-fold primary outcomes are (1) psychopathology (Eating Disorder Examination) across the 6-month follow-up and (2) readiness and motivation to engage in recovery (Readiness and Motivation Questionnaire) across the 6-week trial period. Neurophysiological outcome measures will be: (1) functional magnetic resonance imaging (fMRI) brain changes from baseline to 6-week endpoint and (2) post-acute changes in electroencephalography (EEG) activity, including an electrophysiological marker of neuronal plasticity. Discussion: The results of this pilot study will not only shed light on the acceptability, brain mechanisms, and impression of the potential efficacy of psilocybin as an adjunct treatment for AN but will be essential in shaping a subsequent Randomised Control Trial (RCT) that would test this treatment against a suitable control condition. Clinical Trial Registration: identifier: NCT04505189.

Trial of Psilocybin versus Escitalopram for Depression.

BACKGROUND: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).

Self-blinding citizen science to explore psychedelic microdosing.

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a 'self-blinding' citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

Psychedelic psychotherapy, therapy enhanced with psychedelic drugs such as LSD or psilocybin (the active ingredient of 'magic mushrooms'), has been suggested to improve psychological well-being. For this reason, trials on psychedelic therapy for the treatment of depression, addiction and other conditions are ongoing. Recently, 'microdosing' ­ a way of administering psychedelics that involves taking about 10% of a recreational dose two or three times per week ­ has gained popularity. Unlike taking large doses of psychedelics, microdosing does not induce hallucinations, but anecdotal reports suggest that it yields similar benefits as psychedelic therapy. A key feature of modern medicine are 'placebo control' studies that compare two groups of patients: one that takes a drug and another that takes inactive pills, known as placebos. Crucially, neither group knows whether they are taking drug or placebo. This control ensures that observed effects are due to the drug itself and not to unrelated psychological causes. For example, in trials of mood medicines, participants often expect to feel happier, which in itself improves their mood even when taking a placebo. This is known as the placebo effect. Restrictive drug policies make placebo-controlled studies on psychedelics difficult and expensive, in particular for microdosing, which involves taking psychedelics over a longer time period. To overcome this problem, Szigeti et al. developed a new citizen-science approach, where microdosers implemented their own placebo control based on online instructions. The advantages are the low cost and the ability to recruit participants globally. The experiment was completed by 191 microdosers, making it the largest placebo-controlled study on psychedelics to-date, for a fraction of the cost of an equivalent clinical study. The trial examined whether psychedelic microdosing can improve cognitive function and psychological well-being. The team found that microdosing significantly increased a number of psychological measures, such as well-being and life satisfaction. However, participants taking placebo also improved: there were no significant differences between the two groups. The findings confirmed positive anecdotes about microdosing improving people's moods, but at the same time show that taking empty capsules, knowing they might be microdoses, have the same benefits. This result suggests that the observed benefits are not caused by the microdose, but rather by psychological expectations. The study's innovative 'do-it-yourself' approach to placebo control may serve as a template for future citizen science studies on other popular phenomena where positive expectations and social factors could play a role, such as cannabidiol (CBD) oils, nootropics and nutrition.

Cardiovascular Safety of Degarelix Versus Leuprolide for Advanced Prostate Cancer: The PRONOUNCE Trial Study Design.

OBJECTIVES: This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist. BACKGROUND: Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist. METHODS: PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses. RESULTS: As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease. CONCLUSIONS: PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908).

Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

IMPORTANCE: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. OBJECTIVE: To test whether selepressin improves outcome in septic shock. DESIGN, SETTING, AND PARTICIPANTS: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 µg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. INTERVENTIONS: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. MAIN OUTCOMES AND MEASURES: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. RESULTS: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). CONCLUSIONS AND RELEVANCE: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02508649.

Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial.

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size. Clinical Trial registered with www.clinicaltrials.gov (NCT02508649).

Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients.

BACKGROUND: Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. METHODS: This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. RESULTS: A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 µg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 µg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. CONCLUSIONS: In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.

Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Extended 5-year follow-up of a RCT.

BACKGROUND: This study compares the outcome 5 years after treatment of varicose veins with endovenous radiofrequency ablation (RFA), endovenous laser ablation (EVLA), ultrasound guided foam sclerotherapy (UGFS) or high ligation and stripping (HL/S) by assessing technical efficacy, clinical recurrence and the rate of reoperations. METHODS: Five hundred patients (580 legs) with Great Saphenous Vein (GSV) reflux and varicose veins were randomized to one of the 4 treatments. Follow-up included clinical and duplex ultrasound examinations. RESULTS: During 5 years there was a difference in the rate of GSV recanalization, recurrence and reoperations across the groups, KM P<0.001, P<0.01, P<0.001 respectively. Thus 8 in the RFA group (Kaplan Meier [KM] estimate 5.8%), 8 in the EVLA group (KM estimate 6.8%), 37 (KM estimate 31.5%) in the UGFS group and 8 in the HL/S group (KM estimate 6.3%) of GSVs recanalized or had a failed stripping procedure. Nineteen (RFA) (KM estimate 18.7%), 42 (EVLA) (KM estimate 38.6%), 28 (UGFS) (KM estimate 31.7%) and 38 (HL/S) (KM estimate 34.6%) legs developed recurrent varicose veins. Within 5 years after treatment, 19 (RFA) (KM estimate 17%), 19 (EVLA) (KM estimate 18.7%), 43 (UGFS) (KM estimate 37.7%) and 25 (HL/S) (KM estimate 23.4%) legs were retreated. CONCLUSIONS: More recanalization's of the GSV occurred after UGFS and no difference in the technical efficacy was found between the other modalities during 5-year follow-up. The higher frequency of clinical recurrence after EVLA and HL/S cannot be explained and requires confirmation in other studies.

Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years.

OBJECTIVE: This is the first randomized controlled trial with a 5-year follow-up comparing endovenous laser ablation (EVLA) with high ligation and pin-stripping in patients with great saphenous vein (GSV) incompetence. METHODS: One hundred twenty-one consecutive patients (137 legs) with GSV incompetence were randomized to EVLA (980 nm bare fiber) or high ligation and stripping using tumescent local anesthesia with light sedation. Mini-phlebectomies were performed in all patients. The patients were examined with duplex scanning before treatment and after 12 days, and then after 1, 3, and 6 months, and yearly thereafter for up to 5 years. The primary end point was open refluxing GSV. Secondary end points were recurrent varicose veins, frequency of reoperations, Venous Clinical Severity Score, and quality of life scores (Aberdeen Varicose Vein Symptoms Severity Score and Short Form-36). RESULTS: In the EVLA and stripping group, nine (Kaplan-Meier [KM] estimate, 17.9%) and four (KM estimate, 10.1%) of GSVs had open refluxing segments of 5 cm or more (ns). Clinical recurrence was recorded in 24 (KM estimate, 46.6%) and 25 (KM estimate, 54.6%), whereas reoperations were performed in 17 (KM estimate, 38.6%) and 15 (KM estimate, 37.7%) legs (ns). Venous Clinical Severity Score and Aberdeen Varicose Vein Symptoms Severity Score improved whereas Medical Outcomes Study Short Form-36 quality of life score improved in several domains in both groups with no difference between the groups. CONCLUSIONS: Five-year follow-up of our randomized controlled trial comparing EVLA with open surgery in patients with GSV incompetence did not show any significant difference between the two groups in primary or secondary end points, perhaps because of the small sample size. EVLA seems to be a valid alternative to open surgery.

Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy, and surgical stripping for great saphenous varicose veins with 3-year follow-up.

INTRODUCTION: This study compares the outcome 3 years after treatment of varicose veins by endovenous laser ablation (EVLA), radiofrequency ablation, ultrasound-guided foam sclerotherapy (UGFS), or surgery by assessing recurrence, Venous Clinical Severity Score (VCSS), and quality of life (QOL). METHODS: A total of 500 patients (580 legs) were randomized to one of the three endovenous treatments or high ligation and stripping of the great saphenous vein (GSV). Follow-up included clinical and duplex ultrasound examinations and VCSS and QOL questionnaires. Kaplan-Meier (KM) life-table analysis was used. P values below .05 were considered statistically significant. RESULTS: At 3 years, eight (KM estimate, 7%), eight (KM estimate, 6.8%), 31 (KM estimate, 26.4%), and eight (KM estimate, 6.5%) of GSVs recanalized or had a failed stripping procedure (more than 10 cm open refluxing part of the treated GSV; CLF, EVLA, UGFS, and stripping, respectively; P < .01). Seventeen (KM estimate, 14.9%), 24 (KM estimate, 20%), 20 (KM estimate, 19.1%), and 22 (KM estimate, 20.2%) legs developed recurrent varicose veins (P = NS). The patterns of reflux and location of recurrent varicose veins were not different between the groups. Within 3 years after treatment, 12 (KM estimate, 11.1%), 14 (KM estimate, 12.5%), 37 (KM estimate, 31.6%), and 18 (KM estimate, 15.5%) legs were retreated in the CLF, EVLA, UGFS, and stripping groups, respectively (P < .01). VCSS, SF-36, and Aberdeen QOL scores improved significantly in all the groups with no difference between the groups. CONCLUSIONS: All treatment modalities were efficacious and resulted in a similar improvement in VCSS and QOL. However, more recanalization and reoperations were seen after UGFS.

Randomized trial comparing endovenous laser ablation of the great saphenous vein with high ligation and stripping in patients with varicose veins: short-term results.

BACKGROUND: Endovenous laser (EVL) ablation of the great saphenous vein (GSV) is thought to minimize postoperative morbidity and reduce work loss compared with high ligation and stripping (HL/S). However, the procedures have not previously been compared in a randomized trial with parallel groups where both treatments were performed in tumescent anesthesia on an out-patient basis. METHODS: Patients with varicose veins due to GSV insufficiency were randomized to either EVL (980 nm) or HL/S in tumescent anesthesia. Miniphlebectomies were also performed. Patients were examined preoperatively and at 12 days, and 1, 3, and 6 months postoperatively. Sick leave, time to normal physical activity, pain score, use of analgesics, Aberdeen score, Medical Outcomes Study Short Form-36 quality-of-life score, Venous Clinical Severity Score (VCSS), and complication rates were investigated. The total cost of the procedures, including lost wages and equipment, was calculated. Cost calculations were based on the standard fee for HL/S with the addition of laser equipment and the standard salary and productivity level in Denmark. RESULTS: A follow-up of 6 months was achieved in 121 patients (137 legs). The groups were well matched for patient and GSV characteristics. Two HL/S procedures failed, and three GSVs recanalized in the EVL group. The groups experienced similar improvement in quality-of-life scores and VCSS score at 3 months. Only one patient in the HL/S group had a major complication, a wound infection that was treated successfully with antibiotics. The HL/S and EVL groups did not differ in mean time to resume normal physical activity (7.7 vs 6.9 calendar days) and work (7.6 vs 7.0 calendar days). Postoperative pain and bruising was higher in the HL/S group, but no difference in the use of analgesics was recorded. The total cost of the procedures, including lost wages, was euro 3084 ($3948 US) in the HL/S and euro 3396 ($4347 US) in the EVL group. CONCLUSIONS: This study suggests that the short-term efficacy and safety of EVL and HL/S are similar. Except for slightly increased postoperative pain and bruising in the HL/S group, no differences were found between the two treatment modalities. The treatments were equally safe and efficient in eliminating GSV reflux, alleviating symptoms and signs of GSV varicosities, and improving quality of life. Long-term outcomes, particularly with respect to recurrence rates, shall be investigated in future studies, including the continuation of the present.