INDICATIONS
VARITHENA™ (POLIDOCANOL INJECTABLE FOAM) IS INDICATED FOR THE TREATMENT OF INCOMPETENT GREAT SAPHENOUS VEINS, ACCESSORY SAPHENOUS VEINS, AND VISIBLE VARICOSITIES OF THE GREAT SAPHENOUS VEIN (GSV) SYSTEM ABOVE AND BELOW THE KNEE. VARITHENA™ IMPROVES THE SYMPTOMS OF SUPERFICIAL VENOUS INCOMPETENCE AND THE APPEARANCE OF VISIBLE VARICOSITIES.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
POLIDOCANOL SOLUTION, 180 MG/18 ML (10 MG/ML) MUST BE ACTIVATED BEFORE USE.
ONCE ACTIVATED, VARITHENA™ IS A WHITE, INJECTABLE FOAM DELIVERING A 1% POLIDOCANOL SOLUTION. EACH ML OF VARITHENA™ INJECTABLE FOAM CONTAINS 1.3 MG OF POLIDOCANOL.
VARITHENA™ (POLIDOCANOL INJECTABLE FOAM) PRODUCT IS SUPPLIED AS TWO COMPONENTS:
VARITHENA™ BI-CANISTER (NDC 60635-118-01)
A TYVEK® POUCH CONTAINING TWO STERILE, CONNECTED 303 ML ALUMINUM ALLOY CANISTERS: ONE CONTAINING POLIDOCANOL SOLUTION, 180 MG/18 ML (10 MG/ML), UNDER A CARBON DIOXIDE ATMOSPHERE, THE SECOND CONTAINING PRESSURIZED OXYGEN AT APPROXIMATELY 5.4 BAR ABSOLUTE. THE CONNECTOR JOINS THE TWO CANISTERS AND ALLOWS ACTIVATION OF THE PRODUCT. ONCE ACTIVATED, VARITHENA™ INJECTABLE FOAM DELIVERS A 1% POLIDOCANOL SOLUTION. EACH ML OF VARITHENA™ INJECTABLE FOAM CONTAINS 1.3 MG OF POLIDOCANOL. ONE CANISTER OF VARITHENA™ GENERATES 90 ML OF FOAM, WHICH FOLLOWING PURGING INSTRUCTIONS IN THE IFU, IS SUFFICIENT TO YIELD 45 ML OF USABLE FOAM FOR INJECTION.
PRESCRIBING INFORMATION
INSTRUCTIONS FOR USE
VARITHENA™ ADMINISTRATION PACK (NDC 60635-123-01)
ONE VARITHENA™ TRANSFER UNIT TO GENERATE AND DISPENSE FOAM.
INSTRUCTIONS FOR USE
PATIENT ANCILLARY COMPONENTS:
THREE 10 ML SILICONE-FREE LUER SYRINGES
ONE 20-INCH MANOMETER TUBE
TWO COMPRESSION PADS
VARITHENA™ IS ALSO SUPPLIED IN A CONVENIENCE BOX (NDC 60635-133-01) THAT CONTAINS:
A TYVEK® POUCH CONTAINING TWO STERILE, CONNECTED 303 ML ALUMINUM ALLOY CANISTERS: ONE CONTAINING POLIDOCANOL SOLUTION, 180 MG/18 ML (10 MG/ML), UNDER A CARBON DIOXIDE ATMOSPHERE, THE SECOND CONTAINING PRESSURIZED OXYGEN AT APPROXIMATELY 5.4 BAR ABSOLUTE. THE CONNECTOR JOINS THE TWO CANISTERS AND ALLOWS ACTIVATION OF THE PRODUCT. ONCE ACTIVATED, VARITHENA™ INJECTABLE FOAM DELIVERS A 1% POLIDOCANOL SOLUTION. EACH ML OF VARITHENA™ INJECTABLE FOAM CONTAINS 1.3 MG OF POLIDOCANOL. ONE CANISTER OF VARITHENA™ GENERATES 90 ML OF FOAM, WHICH FOLLOWING PURGING INSTRUCTIONS IN THE IFU, IS SUFFICIENT TO YIELD 45 ML OF USABLE FOAM FOR INJECTION.
THREE VARITHENA™ TRANSFER UNITS TO DISPENSE INJECTABLE FOAM;
THREE ADMINISTRATION PACKS EACH CONTAINING:
THREE 10 ML SILICONE-FREE LUER SYRINGES
ONE 20-INCH MANOMETER TUBE
TWO COMPRESSION PADS
STORAGE AND HANDLING
DO NOT SHAKE VARITHENA™ CANISTERS. AVOID CONTACT WITH EYES.
STORE THE VARITHENA™ BI-CANISTER OR CONVENIENCE BOX AT 68°F TO 77°F (20 °C TO 25°C); EXCURSIONS ARE PERMITTED TO BETWEEN 59°F TO 86 °F (15°C AND 30°C). DO NOT REFRIGERATE OR FREEZE.
UNUSED, NON-ACTIVATED VARITHENA™ CANISTERS MAY BE STORED IN THE FLAT OR UPRIGHT POSITION.
CONTAINS GAS UNDER PRESSURE: MAY EXPLODE IF HEATED. STORE IN A WELL-VENTILATED PLACE. STORE THE CANISTERS AWAY FROM SOURCES OF HEAT INCLUDING STRONG LIGHT CONDITIONS.
PRESSURIZED OXYGEN: MAY CAUSE OR INTENSIFY FIRE; OXIDIZER. STORE AWAY FROM COMBUSTIBLE MATERIALS.
ONCE ACTIVATED, THE CANISTER OF VARITHENA™ MUST BE USED WITHIN SEVEN (7) DAYS.
STORE ACTIVATED CANISTERS OF VARITHENA™ UPRIGHT, WITH THE VARITHENA™ TRANSFER UNIT ATTACHED, UNDER THE SAME TEMPERATURE CONDITIONS AS THE VARITHENA™ CONVENIENCE BOX. USE A NEW VARITHENA™ TRANSFER UNIT FOR EACH TREATMENT SESSION.
DISCARD AEROSOL CANISTERS AFTER USE IN ACCORDANCE WITH STATE AND LOCAL REQUIREMENTS.
FOR MORE INFORMATION, PLEASE REFER TO THE IFU.
MANUFACTURED FOR PROVENSIS LTD BY: BIOCOMPATIBLES UK LTD CHAPMAN HOUSE, WEYDON LANE, FARNHAM, UK, GU9 8QL. DISTRIBUTED BY: BIOCOMPATIBLES, INC. 115 HURLEY ROAD, BUILDING 3F, OXFORD, CT 06478. PROVENSIS LTD, BIOCOMPATIBLES UK LTD, AND BIOCOMPATIBLES, INC. ARE BTG INTERNATIONAL GROUP COMPANIES. REVISED: JAN 2015
DOSAGE AND ADMINISTRATION
FOR INTRAVENOUS USE ONLY.
VARITHENA™ IS INTENDED FOR INTRAVENOUS INJECTION USING ULTRASOUND GUIDANCE, ADMINISTERED VIA A SINGLE CANNULA INTO THE LUMEN OF THE TARGET INCOMPETENT TRUNK VEINS OR BY DIRECT INJECTION INTO VARICOSITIES. USE UP TO 5 ML PER INJECTION AND NO MORE THAN 15 ML PER SESSION.
PHYSICIANS ADMINISTERING VARITHENA™ MUST BE EXPERIENCED WITH VENOUS PROCEDURES, POSSESS A DETAILED WORKING KNOWLEDGE OF THE USE OF THE DUPLEX ULTRASOUND IN VENOUS DISEASE, AND BE TRAINED IN THE ADMINISTRATION OF VARITHENA™.
ACTIVATE VARITHENA™ USING THE VARITHENA™ OXYGEN CANISTER AND POLIDOCANOL CANISTER (SEE INSTRUCTIONS FOR USE). ONCE A VARITHENA™ TRANSFER UNIT IS IN PLACE, FOAM CAN BE GENERATED AND TRANSFERRED TO A SYRINGE. DISCARD THE SYRINGE CONTENTS IF THERE ARE ANY VISIBLE BUBBLES. ADMINISTER THE INJECTABLE FOAM WITHIN 75 SECONDS OF EXTRACTION FROM THE CANISTER TO MAINTAIN INJECTABLE FOAM PROPERTIES. USE A NEW STERILE SYRINGE AFTER EACH INJECTION. USE A NEW VARITHENA™ TRANSFER UNIT FOR EACH TREATMENT SESSION.
LOCAL ANESTHETIC MAY BE ADMINISTERED PRIOR TO CANNULA INSERTION BUT NEITHER TUMESCENT ANESTHESIA NOR PATIENT SEDATION IS REQUIRED. CANNULATE THE VEIN TO BE TREATED USING ULTRASOUND GUIDANCE TO CONFIRM VENOUS ACCESS.
INJECT FRESHLY GENERATED VARITHENA™ INJECTABLE FOAM SLOWLY (APPROXIMATELY 1 ML/SECOND IN THE GSV AND 0.5 ML/SECOND IN ACCESSORY VEINS OR VARICOSITIES) WHILE MONITORING USING ULTRASOUND. CONFIRM VENOSPASM OF THE TREATED VEIN USING ULTRASOUND.
WHEN TREATING THE PROXIMAL GSV, STOP THE INJECTION WHEN VARITHENA™ IS 3-5 CM DISTAL TO THE SAPHENOFEMORAL JUNCTION (SFJ).
APPLY COMPRESSION BANDAGING AND STOCKINGS AND HAVE THE PATIENT WALK FOR AT LEAST 10 MINUTES, WHILE BEING MONITORED. MAINTAIN COMPRESSION FOR 2 WEEKS AFTER TREATMENT.
REPEAT TREATMENT MAY BE NECESSARY IF THE SIZE AND EXTENT OF THE VEINS TO BE TREATED REQUIRE MORE THAN 15 ML OF VARITHENA™. SEPARATE TREATMENT SESSIONS BY A MINIMUM OF 5 DAYS.
RETAINED COAGULUM MAY BE REMOVED BY ASPIRATION (MICROTHROMBECTOMY) TO IMPROVE COMFORT AND REDUCE SKIN STAINING.
SIDE EFFECTS
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER CONTROLLED BUT WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN CLINICAL TRIALS OF VARITHENA™ CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF OTHER DRUGS OR PROCEDURES AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
A TOTAL OF 1333 PATIENTS IN 12 CLINICAL TRIALS WERE EVALUATED FOR SAFETY WHEN TREATED WITH VARITHENA™ AT DOSE CONCENTRATIONS OF 0.125%, 0.5%, 1.0%, OR 2.0%, INCLUDING 437 PATIENTS TREATED WITH VARITHENA™ IN PLACEBO-CONTROLLED CLINICAL TRIALS.
ADVERSE REACTIONS OCCURRING IN 3% MORE PATIENTS RECEIVING VARITHENA™ 1% THAN RECEIVING PLACEBO ARE SHOWN IN TABLE 1.
TABLE 1: TREATMENT-EMERGENT ADVERSE REACTIONS (3% MORE ON VARITHENA™ 1% THAN ON PLACEBO) THROUGH WEEK 8 (N=588)
ADVERSE REACTION
PLACEBO
(N=151)
VARITHENA™ 1.0%
(N=149)
POOLEDA VARITHENA™
(N=437)
PAIN IN EXTREMITY
14 (9.3)
25 (16.8)
65 (14.9)
INFUSION SITE THROMBOSISB
0
24 (16.1)
46 (10.5)
CONTUSION/INJECTION SITE HEMATOMA
9 (6.0)
23 (15.4)
38 (8.7)
LIMB DISCOMFORT
5 (3.3)
18 (12.1)
32 (7.3)
TENDERNESS/INJECTION SITE PAIN
5 (3.3)
16 (10.7)
30 (6.9)
VENOUS THROMBOSIS LIMBC
0
12 (8.1)
24 (5.5)
THROMBOPHLEBITIS SUPERFICIAL
2 (1.3)
8 (5.4)
40 (9.2)
DEEP VEIN THROMBOSIS
0
7 (4.7)
10 (2.3)
AINCLUDES VARITHENA™ 0.125%, 0.5%, 1.0%, AND 2.0% FROM THE PLACEBO-CONTROLLED TRIALS.
BRETAINED COAGULUM.
CCOMMON FEMORAL VEIN THROMBUS EXTENSION (NON-OCCLUSIVE THROMBI STARTING IN THE SUPERFICIAL VEIN AND EXTENDING INTO THE COMMON FEMORAL VEIN).
IN VARITHENA™-TREATED PATIENTS, 80% OF PAIN EVENTS IN THE TREATED EXTREMITY RESOLVED WITHIN 1 WEEK.
IN THE 1333 PATIENTS TREATED WITH VARITHENA™, THE FOLLOWING VENOUS THROMBUS ADVERSE EVENTS OCCURRED: COMMON FEMORAL VEIN THROMBUS EXTENSION (2.9%), PROXIMAL DEEP VEIN THROMBOSIS (DVT) (1.7%), DISTAL DVT (1.1%), ISOLATED GASTROCNEMIUS, AND SOLEAL VEIN THROMBOSIS (1.4%).
PROXIMAL SYMPTOMATIC VENOUS THROMBI OCCURRED IN < 1% OF PATIENTS TREATED WITH VARITHENA™. APPROXIMATELY HALF (49%) OF PATIENTS WITH THROMBI RECEIVED TREATMENT WITH ANTICOAGULANTS.
SINCE VARITHENA™ INDUCES THROMBOSIS IN THE TREATED SUPERFICIAL VEINS, D-DIMER IS COMMONLY ELEVATED POST-TREATMENT AND IS NOT USEFUL DIAGNOSTICALLY TO ASSESS PATIENTS FOR VENOUS THROMBUS FOLLOWING TREATMENT WITH VARITHENA™.
NEUROLOGIC ADVERSE EVENTS (CEREBROVASCULAR ACCIDENT, MIGRAINES) HAVE BEEN REPORTED IN PATIENTS FOLLOWING ADMINISTRATION OF PHYSICIAN COMPOUNDED FOAM SCLEROSANTS. NONE OF THE 1333 PATIENTS IN THE VARITHENA™ TRIALS EXPERIENCED CLINICALLY IMPORTANT NEUROLOGICAL OR VISUAL ADVERSE EVENTS SUGGESTIVE OF CEREBRAL GAS EMBOLISM. THE INCIDENCE OF NEUROLOGIC AND VISUAL ADVERSE EVENTS WITHIN 1 DAY OF TREATMENT IN THE PLACEBO-CONTROLLED STUDIES WAS 2.7% IN THE POOLED VARITHENA™ GROUP AND 4.0% IN THE PLACEBO GROUPS.
SKIN DISCOLORATION ADVERSE EVENTS WERE REPORTED IN 1.1% OF THE POOLED VARITHENA™ GROUP AND 0.7% OF THE PLACEBO GROUP IN THE PLACEBO-CONTROLLED STUDIES.
READ THE VARITHENA (POLIDOCANOL INJECTABLE FOAM) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THERE ARE NO KNOWN CASES OF OVERDOSAGE WITH VARITHENA™. IN CLINICAL STUDIES, TOTAL VOLUMES OF UP TO 60 ML OF VARITHENA™ PER TREATMENT SESSION HAVE BEEN ADMINISTERED.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
VARITHENA™ IS A DRUG/DEVICE COMBINATION PRODUCT THAT GENERATES INJECTABLE FOAM. THE INJECTABLE FOAM IS COMPOSED OF A LIQUID AND GAS PHASE, BOTH OF WHICH ARE NECESSARY TO HAVE ITS THERAPEUTIC EFFECT. VARITHENA™ IS INTENDED TO ACT AS FOLLOWS: (1) THE FOAM DISPLACES BLOOD FROM THE VEIN TO BE TREATED, AND (2) THE POLIDOCANOL THEN SCLEROSES THE ENDOTHELIUM.
THE ACTIVE PHARMACEUTICAL INGREDIENT OF VARITHENA™ IS POLIDOCANOL, A NON-IONIC SURFACTANT SCLEROSING AGENT. THE HYDROPHOBIC POLE OF THE POLIDOCANOL MOLECULE ATTACHES TO THE LIPID CELL MEMBRANE OF THE VENOUS ENDOTHELIUM, RESULTING IN DISRUPTION OF THE OSMOTIC BARRIER, DESTRUCTION OF THE VENOUS ENDOTHELIUM, AND VASOSPASM. FOLLOWING EXPOSURE TO POLIDOCANOL, THE INTERIOR SURFACE OF THE VEIN BECOMES THROMBOGENIC, WHICH LEADS TO THROMBUS FORMATION AND VENOUS OCCLUSION. THE OCCLUDED VEIN IS EVENTUALLY REPLACED BY FIBROUS CONNECTIVE TISSUE. POLIDOCANOL IS DEACTIVATED UPON CONTACT WITH BLOOD, THUS LIMITING THE SCLEROSANT ACTION TO THE ENDOTHELIUM NEAR THE SITE OF INJECTION.
PHARMACODYNAMICS
THE ACTIVE PHARMACEUTICAL INGREDIENT IN VARITHENA™ IS POLIDOCANOL. POLIDOCANOL HAS A CONCENTRATION DEPENDENT DAMAGING EFFECT ON THE ENDOTHELIUM OF BLOOD VESSELS.
PHARMACOKINETICS
THE PHARMACOKINETICS OF VARITHENA™ (AS A WEIGHTED SUM OF 4 OLIGOMERS: E5, E9, E12 AND E14) WERE EVALUATED AT TWO CONCENTRATIONS (1% AND 2%) RANDOMLY ASSIGNED WITHIN GENDER IN 20 PATIENTS WITH GSV INCOMPETENCE.
WHEN ADMINISTERED AS AN INTRAVENOUS INJECTABLE FOAM AS TWO FIXED 5 ML DOSES SEPARATED BY 10 MINUTES, POLIDOCANOL WAS RAPIDLY DETECTED IN PLASMA, REACHING MAXIMUM CONCENTRATION OF DRUG IN THE BODY AFTER DOSING (CMAX ) WITHIN 15 MINUTES OF THE FIRST INJECTION AND WITHIN 5 MINUTES OF RECEIVING THE SECOND INJECTION OF VARITHENA™ 1% OR VARITHENA™ 2%. THE MEAN VOLUME OF DISTRIBUTION (VD) OF POLIDOCANOL RANGED FROM 35 TO 82 L.
MEAN SYSTEMIC CLEARANCE (CL) OF POLIDOCANOL RANGED FROM 0.2 TO 0.4 L/MIN. THE CLEARANCE OF E5 WAS SIGNIFICANTLY GREATER THAN THAT OF LONGER OLIGOMERS. MEAN TERMINAL ELIMINATION HALF-LIFE (T ½ ) RANGED FROM 102 TO 153 MINUTES, WITH MOST PLASMA SAMPLES BELOW THE LIMIT OF QUANTITATION (BLQ) AT THE END OF THE 8HOUR COLLECTION PERIOD. THE INCREASE IN PLASMA POLIDOCANOL CONCENTRATIONS WAS LESS THAN PROPORTIONAL WITH INCREASING VARITHENA™ CONCENTRATION. WEIGHT-NORMALIZED DATA DEMONSTRATED NO CONSISTENT DIFFERENCES IN C MAX OR AUC BETWEEN MALES AND FEMALES.
CLINICAL STUDIES
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.
TABLE 2: IMPROVEMENT IN SYMPTOMS OF VARICOSE VEINS AS MEASURED BY VVSYMQ® AT WEEK 8, VANISH-1 AND VANISH-2
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.
TABLE 3: IMPROVEMENT IN APPEARANCE OF VISIBLE VARICOSITIES AS MEASURED BY IPR-V3AND PAV3AT WEEK 8, VANISH-1 AND VANISH-2
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.
TABLE 4: RESPONSE TO TREATMENT AS MEASURED BY DUPLEX ULTRASOUND AT WEEK 8, VANISH-1 AND VANISH-2
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.