Tolerability and Pharmacokinetic Study of Econazole Nitrate Plus Benzydamine HCl Vaginal Pessary

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the local tolerability of the new Econazole/Benzydamine pessary, in comparison with Econazole and Benzydamine stand-alone products and placebo. Pharmacokinetics of the study products after single and multiple applications o.d. for 3 days, overall local and general tolerability, safety and comfort of use will also be evaluated.

Official Title
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A Phase I Study of a Novel Antimycotic Vaginal Pessary Formulation (Econazole Nitrate 150 mg + Benzydamine HCl 6 mg) Administered Once Daily for 3 Days to Healthy Women

Conditions
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Healthy Women

Intervention / Treatment
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* Drug: Econazole nitrate 150 mg plus Benzydamine HCl 6 mg vaginal pessary
* Drug: Placebo plus Econazole nitrate 150 mg vaginal pessary
* Drug: Placebo plus Benzydamine HCl 6 mg vaginal pessary
* Drug: Placebo vaginal pessary


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study. Sex and age: healthy women, aged 18-55 years old inclusive. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest (sitting position). Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the Investigator and to comply with the requirements of the entire study. Sexual abstinence: agreement to sexual abstinence during the study. Contraception and fertility: women of child-bearing potential, even if sexually abstinent during the study as required by the study inclusion criteria, must be using at least one reliable method of contraception, as follows: hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit; a non-hormonal intrauterine device [IUD] for at least 2 months before the screening visit; a male sexual partner who agrees to use a male condom; a vasectomised sexual partner. Female participants of non-child-bearing potential will be admitted. For all female subjects, pregnancy test result must be negative at screening and on day 1. PAP test: negative PAP test result (i.e. normal PAP test result without atypical cells) at screening. Exclusion Criteria: ECG (12-leads, supine position): clinically significant abnormalities. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study as judged by the Investigator. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness. Allergies: ascertained or presumptive hypersensitivity (including allergies) to the active ingredients (econazole nitrate and/or benzydamine HCl) and/or formulations' excipients or related drugs, e.g. other azoles; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the study. Diseases: relevant history of renal, hepatic, gastrointestinal, genitourinary, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study or affect the subject's safety. Genitourinary diseases: presence of any specific genitourinary symptoms detected at visit 2 with the relevant questionnaire (genitourinary symptoms questionnaire). Infection history: history of bacterial urinary tract or bacterial or fungal vaginal infections for 3 weeks before the screening visit. Systemic and/or local infections: bacterial or fungal infections that may interfere with the aim of the study or affect the subject's safety. If the results of the microbiological analyses concerning Ureaplasma/Mycoplasma and Actinomyces are positive, the subject can be enrolled only if asymptomatic and without any clinical evidence (gynaecological visit, PAP test and vaginal pH measurement) of vaginal infections. Gynaecological findings: clinically significant abnormal findings at the gynaecological visit performed by the study Gynaecologist. Mucosa conditions: altered mucosa conditions affecting the site of insertion (e.g. open lesions or other). Habits: use of vaginal detergents, soaps and washes that, in the Investigator's opinion, may have an influence on vaginal pH and/or change the vaginal flora. Medications: any medication (topical or systemic), including over the counter, herbal medication, topical drugs on the application area, and anticoagulants, such as warfarin, acenocoumarol and rivaroxaban, for 2 weeks before the start of the study. Hormonal contraceptives and hormonal replacement therapies are allowed. Paracetamol will be allowed as a counter-measure for adverse events, on a case by case basis, if deemed appropriate by the Investigator. Investigative drug studies: participation in the evaluation of any drug for 3 months before this study, calculated from the first day of the month following the last visit of a previous study and the first day of the present study (date of the informed consent signature). Blood donation: blood donations for 3 months before this study. Drug, alcohol, caffeine, tobacco: history of drug, alcohol (> 1 drink/day, defined according to USDA Dietary Guidelines 2010), tobacco (≥ 10 cigarettes/day) or caffeine (> 5 cups coffee/tea/day) abuse. Diet: Abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians. Pregnancy: positive or missing pregnancy test at screening or day 1, pregnant or lactating women or females of child-bearing potential not following adequate contraceptive procedures. Non-compliance: subjects suspected to have a high potential for non-compliance to the study procedures according to the Investigator's judgement, including non-compliance to sexual abstinence during the study. Drug test (cocaine, amphetamine, methamphetamine, cannabinoids, opiates and ecstasy): positive result at the drug test at screening. Alcohol test: positive alcohol breath test at day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Econazole nitrate 150 mg plus Benzydamine HCl 6 mg<br>One vaginal pessary (2.7 g) of Econazole nitrate 150 mg plus Benzydamine HCl 6 mg, once daily, for 3 consecutive days | Drug: Econazole nitrate 150 mg plus Benzydamine HCl 6 mg vaginal pessary<br>* Econazole nitrate 150 mg plus Benzydamine HCl 6 mg vaginal pessary<br>|
| Active Comparator: Placebo plus Econazole nitrate 150 mg<br>One vaginal pessary (2,7 g) of Placebo plus Econazole nitrate 150 mg, once daily, for 3 consecutive days | Drug: Placebo plus Econazole nitrate 150 mg vaginal pessary<br> <br> |
| Active Comparator: Placebo plus Benzydamine HCl 6 mg<br>One vaginal pessary (2,7 g) of Placebo plus Benzydamine HCl 6 mg, once daily, for 3 consecutive days | Drug: Placebo plus Benzydamine HCl 6 mg vaginal pessary<br> <br> |
| Placebo Comparator: Placebo<br>One vaginal pessary (2.7 g) of Placebo, once daily, for 3 consecutive days | Drug: Placebo vaginal pessary<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Adverse Drug Reactions (ADRs) | Occurence of local ADRs reported by the subjects as 1-3 scores for pruritus, burning sensation, pain, stinging and dryness; occurrence of all the other local Adverse Events (AEs) referred by the subjects; occurrence of all the local ADRs revealed by the Investigator/ Gynaecologist | Up to 7 days after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Econazole (free base), benzydamine (free base) and benzydamine N-oxide (free base) plasma concentrations |  | At pre-dose (0), 1, 2, 3, 4, 6, 8, 12, 24 hours after the first (day 1) and the last dose (day 3) | 
| Area under the plasma concentration versus time curve [AUC(0-t)] of econazole (free base), benzydamine (free base) and benzydamine N-oxide (free base) |  | At pre-dose (0), 1, 2, 3, 4, 6, 8, 12, 24 hours after the first (day 1) and the last dose (day 3) | 
| Overall local tolerability assessment scale |  | At final visit (from day 5 to day 8) | 
| Occurrence of all AEs and ADRs |  | 5-8 days | 
| Change from screening in laboratory parameters |  | From screening (from day -21 to day -7) at final visit (from day 5 to day 8) | 
| Questionnaire for the comfort of use |  | At final visit (from day 5 to day 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Econazole nitrate 150mg, Benzydamine HCl 6mg, Vaginal pessary, Tolerability