Cost-Effectiveness of perioperative Vaginally Administered estrogen in postmenopausal women undergoing prolapse surgery (EVA trial): study protocol for a multicenter double-blind randomized placebo-controlled trial

Research design and setting

The EVA trial is a multicenter, double-blind randomized placebo managed medical trial. Postmenopausal girls present process major POP surgical procedure with a POP-Q stage of ≥ 2, are eligible for the examine and will likely be requested for knowledgeable consent to take part. After enrollment, contributors are randomized and administer both vaginal estriol or placebo from 4 to six weeks earlier than POP surgical procedure until 12 months postoperative.

Recruitment will happen in a multicenter setting in 22 taking part facilities within the Netherlands, i.e. college, instructing and non-teaching hospitals. A listing of present examine websites may be obtained through the web site [27]. Gynecologists and residents, supported by analysis nurses, will counsel girls, ask knowledgeable consent, carry out randomization and accumulate information. Each contributors and investigators will likely be blinded for allocation. The examine design is introduced in Fig. 1. The examine is carried out in cooperation with the urogynecology consortium of the Netherlands and the Dutch NVOG Consortium 2.0 (Dutch Consortium for Healthcare Analysis and Analysis in Obstetrics and Gynecology).

Members and eligibility standards

Inclusion standards

Postmenopausal girls (> 1 yr amenorrhea)
Pelvic organ prolapse; POP-Q stage ≥ 2 [28]
Girls that can bear major POP surgical procedure with native tissue restore, together with no less than anterior OR posterior vaginal wall restore

Exclusion standards

Earlier POP surgical procedure in regarding compartment;
Prolapse restore utilizing mesh
Present vaginal an infection
Use of estrogens prior to now 12 months
Contraindications for topical estrogen
Identified, previous or suspected estrogen-dependent malignant tumors
Inadequate information or understanding of the Dutch language

Interventions

After acquiring knowledgeable consent, eligible girls will likely be assigned to both estriol cream (Synapause-E3; 1 mg/g) or placebo cream. Each lotions are vaginally administered, ante noctem and include a particular applicator. The applicator permits the participant to insert the correct quantity of cream deep into the vagina. Subsequently, the participant lies on her again with barely bent, unfold legs. The cream-filled applicator is utilized deep into the vagina. Then the applicator will likely be emptied and faraway from the vagina. Throughout the first 2 weeks of use, 0.5 g cream will likely be used as soon as a day. Thereafter, 0.5 g cream will likely be used vaginally twice per week. The primary 2 weeks postoperative, no cream will likely be used. The overall period of this intervention will likely be 58 weeks; 6 weeks previous to POP surgical procedure (with a minimal of 4 weeks) and 52 weeks after POP surgical procedure. This dosage schedule corresponds with the usual dosage schedule utilized in medical observe. Girls will obtain routine medical care and stay blinded to therapy allocation till the first evaluation has been accomplished.

Preparation and labelling of examine treatment will likely be performed in response to Good Manufacturing Observe tips. Manufacturing and packaging of each estriol vaginal cream (1 mg/g) and placebo cream is carried out by Aspen Pharmacare. Throughout the manufacturing means of estriol vaginal cream and placebo cream, the very same elements have been used, besides from estriol. The lively product ingredient estriol isn’t any part within the placebo cream. Labelling is carried out by the pharmacy of the Educational Medical Heart Amsterdam.

Low-dose vaginal estrogen

The low-dose vaginal estrogen used on this examine is most popular over systemic (oral) estrogens, as a result of systemic use is related to an elevated danger of thrombosis and endometrial, breast and ovarian most cancers. Low-dose regimens are additionally most popular over intermediate- or excessive dose strategies since absorption and systemic results happen with high-dose vaginal estrogen preparations [29,30,31,32,33,34]. Though vaginally administered low-dose estrogen may end in a minimal systemic uptake, serum estrogen ranges stay throughout the regular vary for postmenopausal girls and no endometrial or myometrial results are seen [22, 35,36,37,38,39,40]. Subsequently, vaginal estrogens are an efficient and secure technique and is in keeping with the worldwide consensus assertion on menopausal hormonal remedy, the place low-dose estrogen is most popular [41].

Consequence measures

The first consequence is subjective enchancment of POP signs at 1 yr follow-up; the proportion of girls with a lot or very a lot enchancment of POP signs, measured with the Affected person International Impression of Enchancment (PGI-I) scale [42]. PGI-I is a 7-point Likert scale, with scores starting from very a lot worse to very a lot improved. Success is outlined as ‘a lot or very a lot’ enchancment.

Secondary outcomes are surgical success, POP-Q anatomy in all compartments, surgical procedure associated issues, normal high quality of life, illness particular high quality of life (micturition and defecation), sexual perform, indicators and complaints of vaginal atrophy, vaginal pH, adversarial occasions, prices, and adherence to therapy. Surgical success is outlined because the absence of POP past the hymen (POP-Q at gynecological examination), the absence of bulge signs (absence of bulge signs is outlined as a damaging response to the query, “Do you see or really feel a bulge within the vaginal space”), and absence of reoperation or further pessary remedy for POP [43]. Comply with up is scheduled at 6 weeks, 6 months and 12 months postoperative. Knowledge will likely be collected utilizing validated questionnaires (See additionally ‘Knowledge assortment’ and Fig. 1) and out-patient visits together with gynecological examination are carried out by an impartial gynecologist.

Affected person recruitment and consent

Eligible girls obtain oral and written info on examine participation throughout a daily hospital go to for POP complaints. Girls will likely be contacted by phone for additional info by the gynecologist, resident or analysis nurse. Girls will likely be given adequate time to learn the affected person info and the knowledgeable consent kind and get the chance to ask questions. If a lady agrees to take part within the examine, written knowledgeable consent will likely be obtained and countersigned by the investigator the place after randomization will likely be carried out, in response to Good Medical Observe (GCP).

Randomization

Girls will likely be randomized in a 1:1 ratio to perioperative therapy with estriol or perioperative therapy with placebo utilizing computer-generated randomly permuted blocks of sizes 4, 6 and eight. Blinded randomization will likely be carried out by the taking part middle utilizing on-line software program (Castor Digital Knowledge Seize, Amsterdam, the Netherlands [online] obtainable at: http://castoredc.com). The central coordinating pharmacy of the Educational Medical Heart Amsterdam receives an robotically generated electronic mail containing the allotted therapy for every randomized affected person from the Castor system. After additionally receiving a health care provider’s prescription, the pharmacy will ship examine treatment on the participant’s house deal with by courier service.

Blinding

Research treatment will likely be blinded. Each estriol cream and placebo cream are supplied to the participant in an identical clean white tubes, marked with a examine label. All physicians, researchers, analysis nurses, consequence assessors and contributors will stay blinded to therapy allocation till the first evaluation has been accomplished. Throughout the conduct of the examine, solely the pharmacy of the Educational Medical Heart Amsterdam can have entry to the blinding info of the examine. With the approval of the principal investigator, a neighborhood investigator may resolve to disclose a participant’s allocation for pressing medical causes solely. Unblinding will likely be carried out by the central coordinating pharmacy on the Educational Medical Heart Amsterdam.

Knowledge assortment

All information will likely be systematically recorded by skilled analysis nurses or gynecologists in an digital Case Report Type in web-based information administration software program: Castor EDC. Castor EDC permits researchers to gather and handle information in accordance with the GCP tips [44]. To enhance information high quality, vary checks are included within the digital Case Report Type. The software program will randomly assign an distinctive numeric code for each topic that bears no relation to initials or date of start. Knowledge dealing with will likely be performed with coded information, with the important thing (code to private info linkage) solely obtainable to the native investigator and the analysis nurse working within the taking part middle. Individuals who’ve entry to the coded information embody: investigators, analysis workers, monitoring and high quality assurance private. Knowledge will likely be preserved in the course of 15 years. The dealing with of non-public information complies with the European Common Knowledge Safety Regulation. Members will likely be adopted from baseline (pre-operatively) as much as 1 yr after POP surgical procedure. Throughout the observe up interval the next information will likely be collected:

Hospital visits

The participant will go to the hospital previous to beginning with the examine treatment, 6 weeks postoperative and 12 months postoperative. Historical past and gynecological examination together with POP-Q, vaginal pH and evaluation of vaginal atrophy will likely be carried out. To scale back interviewer bias, the POP-Q measurement at 12 months postoperative will likely be performed by an impartial examiner—as a substitute of the surgeon. Unscheduled visits and telephone calls are additionally recorded in respect to further prices.

Surgical procedure and postoperative information

Surgical procedure time, blood loss, surgical procedure associated issues (together with extreme blood loss, hematoma, lesion of the intestine, bladder, ureter or urethra, urinary retention, urinary tract an infection, and extended hospitalization) are recorded.

Questionnaires and diary

Members will likely be requested to finish on-line questionnaires, generated in Castor EDC (when most popular, it’s potential to finish the questionnaires on paper). Members will obtain 2 or extra of the next questionnaires at baseline and 6 weeks, 6 months and 12 months postoperative (See additionally Fig. 1):

Questionnaire on baseline traits and medical historical past (together with age, size, weight, parity, training, historical past of diabetes, respiratory ailments and smoking, household historical past of POP).
Affected person International Impression of Enchancment (PGI-I): to evaluate subjective enchancment of POP signs [42].
EuroQoL (EQ-5D-5L): a normal high quality of life questionnaire, to guage well being utilities and the corresponding high quality adjusted life years (QALYs) [45].
Pelvic Ground Incapacity Index-20 (PFDI-20): to measure symptom misery on illness particular high quality of life, specializing in POP, urinary incontinence, and fecal incontinence [46].
Pelvic Ground Influence Questionnaire-7 (PFIQ-7): to measure impression on particular high quality of life, specializing in POP, urinary incontinence, and fecal incontinence [46].
Most Bothersome Symptom questionnaire: to evaluate probably the most bothersome urogenital signs [47].
The Pelvic organ prolapse Incontinence Sexual Questionnaire-IR (PISQ-IR): a condition-specific measure of sexual perform in girls with pelvic ground dysfunction, together with urinary and anal incontinence and pelvic organ prolapse [48].
Medical Consumption Questionnaire (iMCQ): for value effectiveness evaluation [49].
Productiveness Price Questionnaire (iPCQ) to evaluate productiveness loss [50].
Adherence questionnaire: on adherence to therapy, expertise utilizing perioperative vaginal cream and influencing components on compliance. This questionnaire has been developed for this examine and is supplied as Extra file 1.
Adherence diary: a perioperative diary will likely be stored on using vaginal cream, from begin until 6 weeks postoperative. Adversarial reactions related to vaginally administered estriol cream (e.g. momentary itch or irritation of the appliance website) may be reported within the diary as properly.
Adherence to therapy: Research treatment will likely be delivered on the participant’s house deal with at two time factors; 2 tubes at randomization and three tubes at 5 months post-randomization. Members are requested to return the examine treatment at 5 months post-randomization and on the finish of the examine—12 months post-operative. In an effort to asses adherence to therapy, tubes will likely be weighted on a scale (Denver Instrument Firm, TR-602, digit: 0.01 g) and recorded in Castor EDC.

In case of non-completion of questionnaires, a primary reminder will likely be despatched by electronic mail after two weeks. If crucial, a second reminder will likely be despatched after 3 weeks. In case of persistent non-completion after 4 weeks, the participant is contacted by phone by the analysis nurse.

Lengthy-term outcomes

The intention is to guage the long-term outcomes of the contributors as properly (e.g. 3 or 5 years postoperative). When this appears precious after the 1 yr evaluation, MEC approval will likely be obtained in a separate modification. Permission to strategy the contributors for this follow-up analysis is obtained on the time of the knowledgeable consent process.

Monitoring and security

To guarantee top quality analysis information and safe affected person security, sufficient monitoring will likely be carried out in accordance with the GCP tips. Monitoring will likely be coordinated by the Dutch NVOG Consortium 2.0 and will likely be executed by a professional impartial monitor. Primarily based on the NVOG Website Monitoring Plan 3.1 of the Dutch NVOG Consortium, distant initiation visits and monitoring visits in every taking part middle will likely be carried out yearly. The impartial monitor can have entry to the information and supply paperwork of the trial to assessment the standard of the taking part facilities. Extra detailed info may be discovered within the monitoring plan of the examine through www.zorgevaluatienederland.nl/eva. Severe adversarial occasions and every other vital issues will likely be reported to the medical ethics committee of the Amsterdam Medical Heart. A knowledge security monitoring board is not going to be put in for this examine since perioperative topical estrogens are generally utilized in every day observe and use inside this examine is just not perceived to pose an extra danger. Additionally no interim evaluation for efficacy will likely be carried out.

Insurance coverage

Based on nationwide tips, a legal responsibility insurance coverage and in addition an insurance coverage that covers damage to contributors attributable to this examine are taken out. These insurances cowl accidents as much as 4 years after the top of the examine.

Statistical evaluation

Pattern measurement

The pattern measurement relies on the first endpoint of subjective treatment charge (PGI-I) at 12 months postoperative. A distinction in subjective treatment of greater than 15% is taken into account clinically related. Assuming a subjective treatment of 80% within the intervention group and a subjective treatment of 65% within the management group; 136 girls in every trial arm are wanted to evaluate superiority of the intervention, with an influence of 80% and an α of 0.05. With an anticipated 10% loss to observe up, various 150 girls will likely be included in every trial arm (whole pattern measurement 300 girls).

Knowledge evaluation

Each an intention-to-treat evaluation and per protocol evaluation will likely be carried out to guage the impact of perioperative estrogen; taking potential confounders in consideration reminiscent of examine withdrawal and lacking information. Analyses will likely be performed utilizing SPSS model 26.0. A p worth of < 0.05 is taken into account a threshold for significance. Baseline traits will likely be introduced utilizing descriptive statistics, with frequencies (numbers, imply or median with respectively percentages, customary deviation or quartiles).

Main examine parameter

The first consequence, subjective treatment (PGI-I), will likely be reported as frequency with share and relative danger with 95% confidence interval along with a p worth for a chi-squared take a look at. Sufferers are thought-about to be cured once they state to be “significantly better” and “very significantly better” on a 7 level Likert scale.

Secondary examine parameters

All of the secondary outcomes will likely be introduced as frequencies with percentages for dichotomous outcomes, means with customary deviations for steady usually distributed variables and medians with interquartile ranges for non-normally distributed variables.

We plan to calculate the variations inside teams between baseline and 12 months utilizing both a paired t-test, Wilcoxon signed rank take a look at or McNemar take a look at for PFIQ, PFDI-20, PISQ-IR, the compound measure, vaginal pH, vaginal atrophy (goal and subjective outcomes), adversarial occasions, gynecological interventions carried out, prices and compliance. Variations between teams (together with relative dangers with 95% confidence interval) will likely be analyzed utilizing one-sample t-test for usually distributed numerical information, Mann–Whitney U checks for not usually distributed numerical information, chi-square testing for categorical information and Fisher’s precise testing for uncommon outcomes.

The secondary consequence high quality of life at 1 yr after the process, will likely be measured with the EQ-5D-5L and will likely be analyzed utilizing the utility calculation that was utilized in different research [51]. High quality of life outcomes will likely be described and analyzed accordingly. Distinction in utilities between teams will likely be estimated utilizing a linear regression. For every time level, QALYs will likely be calculated by multiplying the utilities by time (as fraction of a yr) [52, 53]. Outcomes will likely be additional included within the cost-effectiveness analyses.

Adherence to remedy will likely be assessed by evaluating tube weights to the anticipated weight if used in response to protocol. Members may even preserve a perioperative diary on using vaginal cream to calculate adherence to remedy till 6 weeks postoperative. Furthermore, adherence to remedy will likely be calculated at 6 and 12 months postoperative from the adherence questionnaire.

Financial analysis

A price-effectiveness evaluation (CEA) will likely be carried out based mostly on empirical information obtained within the examine. The CEA will take a societal and well being care perspective, involving direct medical (well being care associated), non-medical (journey, over-the-counter treatment, time prices), and oblique (productiveness) prices. The first consequence measure within the CEA would be the PFDI-20, whereas cost-effectiveness will likely be expressed as prices per unit enhance on the PFDI-20-scale. As most anatomical failures happen within the first yr after surgical procedure, we are going to assess the first endpoint at 12 months after surgical procedure. According to the medical endpoints, secondary consequence measures will likely be satisfaction with therapy and QALY, with cost-effectiveness ratios expressed as prices per girl happy with therapy and prices per QALY. The medical outcomes will likely be derived from the trial information. Well being state utilities to estimate QALYs will likely be derived from EQ-5D measurements at baseline, in addition to 12 months. Utility values for EQ-5D scores will likely be based mostly on Dutch estimates. The associated fee-utility evaluation will estimate Incremental prices per QALYs will likely be calculated to find out cost-utility [54]. Prices will likely be calculated by multiplying useful resource use per affected person with unit-cost estimates. Useful resource use will likely be obtained from trial data, complemented with affected person administered cost-questionnaires. Unit prices will likely be based mostly on publicly obtainable standardized prices, price schedules, and estimates reported within the medical literature. The selection of costing methodology will depend upon the provision of applicable value estimates. Incremental prices and results will likely be illustrated in a scatter plot to proven cost-effectiveness of the interventon as in comparison with management [54]. Neither prices nor results will likely be discounted because the time horizon of the analyses is proscribed to 1 yr. Sensitivity analyses will likely be carried out to evaluate robustness of the outcomes for uncertainties and assumptions relating to unit prices and useful resource use: bootstrap evaluation (1000 replicates) will likely be used to estimate uncertainty [54]. Long run outcomes (for each prices and medical outcomes) will likely be evaluated utilizing modelling strategies. Penalties for the Dutch well being care finances will likely be estimated in a finances impression evaluation.

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