VARITHENA was evaluated in two randomized, blinded, multicenter clinical trials designed to assess the efficacy and safety of VARITHENA 0.5%, 1.0%, and 2.0% (VANISH-1) and VARITHENA 0.5% and 1.0% (VANISH-2) compared with placebo in the treatment of both symptoms and appearance in patients with SFJ incompetence as evidenced by reflux of the GSV or major accessory veins. In both studies, a VARITHENA 0.125% treatment group was included as a control for blinding of the duplex ultrasound assessment. Patients with history of deep vein thrombosis or pulmonary embolism; inability to comply with post-treatment compression due to severe peripheral arterial disease or leg obesity; incompetence of the small saphenous vein or deep venous reflux as a major source of reflux; or reduced mobility, major surgery, pregnancy, or prolonged hospitalization within 3 months were excluded. Patients were randomized in an equal distribution to each treatment group; the primary time point for analyses of the primary, secondary, and tertiary efficacy endpoints was Week 8.

In these clinical trials, the maximum volume of injectable foam or placebo to be administered per treatment session was 15 mL.

In VANISH-1, patients received one blinded treatment and in VANISH-2, patients received one blinded treatment with an option for a second blinded treatment 1 week later. In VANISH-2, patients in the VARITHENA 1.0% treatment group received an average of 1.4 blinded treatments. All patients received post-procedure compression therapy for 14 days following treatment.

Of the 519 patients randomized into VANISH-1 and VANISH-2, a total of 511 were treated with either VARITHENA 0.5% (n=111), 1.0% (n=110), or 2.0% (n=63), VARITHENA 0.125% as control (n=114), or placebo (n=113). Ninety-nine percent of the patients in VANISH-1 and VANISH-2 completed the blinded treatment period.

In the VARITHENA 1% group in VANISH-2, 23 of 58 patients received an additional blinded treatment. Two of these patients had retreatment of veins treated in the initial treatment session. The remaining 21 patients received treatment for additional veins not treated in the initial treatment session.

The mean age was approximately 50 years and approximately three-fourths of the patients were women. The mean BMI was similar in VANISH-1 and VANISH-2, at 28 kg/m2 (range 16 to 44 kg/m2) and 30 kg/m2 (range 17 to 48 kg/m2), respectively. The mean baseline GSV diameter was also similar in VANISH-1 and VANISH-2, at 7.6 mm (range 1.5 to 25.9 mm) and 8.7 mm (range 3.1 to 19.4 mm), respectively. Overall, 22% of patients in VANISH-1 and 25% of patients in VANISH-2 reported one or more prior varicose vein procedures in the leg to be treated.

For both clinical trials, the primary efficacy endpoint was improvement in patient symptoms, as measured by the change from baseline to Week 8 in the 7-day average electronic daily diary VVSymQ® score. The VVSymQ® score is a patient-reported outcome measure based on daily patient assessment of the varicose vein symptoms determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. VVSymQ® scores range from 0 to 25, where 0 represents no symptoms and 25 represents all 5 symptoms experienced all of the time. Results are shown in Table 2.

For both VANISH-1 and VANISH-2, treatment with 1.0% was superior to placebo in improving symptoms as measured by VVSymQ®, when either a duration or an intensity scale was used to measure patients’ symptoms.

The co-secondary endpoints in VANISH-1 and VANISH-2 were the improvement in appearance of visible varicosities from baseline to Week 8 as measured by 1) patients scoring the appearance of their varicose veins in the medial view of their study leg (PA-V3 score) from "Not at all noticeable" (a score of 0) to "Extremely noticeable" (a score of 4); and 2) an independent photography review panel rating the severity of the patient's varicose vein appearance in standardized digital photographs of the medial view of each patient's study leg (IPR-V3 score) from "None" (a score of 0) to "Very severe" (a score of 4). Results are shown in Table 3.

Tertiary endpoints in VANISH-1 and VANISH-2 included response to treatment as determined by change from baseline in Venous Clinical Severity Score (VCSS), by duplex ultrasound, and by change from baseline in Venous Insufficiency Epidemiologic and Economic Study – Quality of Life/Symptoms (VEINES-QOL) score.

VCSS is a clinician rating of severity of chronic venous insufficiency ranging from 0 to 30, where higher scores indicate more severe venous disease. In VANISH-1 and VANISH-2, the adjusted mean changes from baseline in VCSS in the 1% VARITHENA treatment groups were 3.70 and 5.05, respectively, at Week 8 compared with 0.75 and 1.52 points in the placebo groups, respectively. For both studies, the differences between these improvements are statistically significant (P<0.0001).

The physiological response to treatment as measured by duplex ultrasound (duplex response) was defined as elimination of reflux through the SFJ and/or complete occlusion of all incompetent GSV and major accessory veins at baseline. The primary comparison for duplex response in both studies was the pooled VARITHENA groups versus the VARITHENA 0.125% (control) group. Results are shown in Table 4.

VEINES-QOL is a disease-specific quality of life instrument, ranging from 0 (worst possible quality of life) to 100 (best possible quality of life). In VANISH-1 and VANISH-2, the adjusted mean changes from baseline in VEINES-QOL in the pooled VARITHENA treatment groups were 21.2 and 21.6, respectively, at Week 8 compared with 7.7 and 7.4 points in the placebo groups, respectively. For both studies, the differences between these improvements are statistically significant (P<0.0001).

For efficacy endpoints, VARITHENA treatment effects were consistent across subgroups of age, sex, BMI (up to 48 kg/m2), CEAP clinical class, GSV diameter (up to 25.9 mm), and VCSS.