Tolerability and Pharmacokinetic Study of Econazole Nitrate and Benzydamine HCl Intravaginal Cream

A Phase I Study of a Novel Intravaginal Antimycotic Cream (Econazole Nitrate 1% Plus Benzydamine HCl 0.12%) Administered Once Daily for 15 Days to Healthy Women

The primary objective of the study is to evaluate local tolerability of the new Econazole/Benzydamine product, in comparison with the Econazole and Benzydamine stand-alone products and placebo. Pharmacokinetics of the study products after single and repeated applications once a day for 15 days, safety of the investigational products and comfort of use will also be evaluated as secondary objectives.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Econazole nitrate 1% plus Benzydamine HCl 0.12% intravaginal cream; Drug: Placebo plus Econazole nitrate 1% intravaginal cream; Drug: Placebo plus Benzydamine HCl 0.12% intravaginal cream; Drug: Placebo intravaginal cream

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Arzo, Switzerland, CH-6864
    • CROSS Research S.A., Phase I Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Informed consent: signed written informed consent before inclusion in the study;
2. Sex and age: females, aged 18-55 years old inclusive;
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive;
4. 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);
5. 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;
6. Sexual abstinence: agreement to sexual abstinence during the study;

7. Contraception and fertility: women of child-bearing potential, even if sexual abstinent during the study as required by the study inclusion criteria, must be using at least one reliable method of contraception, as follows:

   1. hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit;
   2. a non-hormonal intrauterine device [IUD] for at least 2 months before the screening visit;
   3. a male sexual partner who agrees to use a male condom;
   4. 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 at each scheduled evaluation;
8. PAP test: negative result at PAP test (i.e. normal PAP test result without atypical cells) at screening.

Exclusion Criteria:

1. ECG (12-leads, supine position): clinically significant abnormalities;
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study as judged by the investigator;
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness;
4. Allergy: ascertained or presumptive hypersensitivity (including allergies) to the active ingredients (econazole and/ or benzydamine) 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;
5. 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;
6. Genitourinary disease: presence of any specific genitourinary symptoms detected at Visit 2 with the relevant questionnaire (genitourinary symptoms questionnaire);
7. Infection history: history of bacterial urinary tract or bacterial and fungal vaginal infections for 3 weeks before the screening visit;
8. Infections: bacterial or fungal infections (microbiology assessment);
9. Gynaecological findings: clinically significant abnormal findings at the gynaecological visit performed by the study gynaecologist;
10. Mucosa conditions: altered mucosa conditions affecting the site of application (e.g. open lesion or other);
11. Vaginal conditions: 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;
12. Medications: any medication (topical or systemic), including over the counter, herbal medication, topical drugs on the application area and anticoagulants, such as warfarin and acenocoumarol, 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;
13. 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);
14. Blood donation: blood donations for 3 months before this study;
15. 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;
16. Diet: Abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
17. 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;
18. 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;
19. Drug test (cocaine, amphetamine, methamphetamine, cannabinoids, opiates and ecstasy): positive result at the drug test at screening
20. Alcohol test: positive alcohol breath test at day 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Econazole nitrate 1% plus Benzydamine HCl 0.12%; 5 grams of Econazole nitrate 1% plus Benzydamine HCl 0.12% intravaginal cream, once daily for 15 consecutive days	Drug: Econazole nitrate 1% plus Benzydamine HCl 0.12% intravaginal cream
Active Comparator: Placebo plus Econazole nitrate 1%; 5 grams of Placebo plus Econazole nitrate 1% intravaginal cream, once daily for 15 consecutive days	Drug: Placebo plus Econazole nitrate 1% intravaginal cream
Active Comparator: Placebo plus Benzydamine HCl 0.12%; 5 grams of Placebo plus Benzydamine HCl 0.12% intravaginal cream, once daily for 15 consecutive days.	Drug: Placebo plus Benzydamine HCl 0.12% intravaginal cream
Placebo Comparator: Placebo; 5 grams of Placebo intravaginal cream, once daily for 15 consecutive days.	Drug: Placebo intravaginal cream

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Adverse Events (AEs)	Occurrence of local Adverse Events (AEs) reported in the subject's diary as 1-3 scores for pruritus, burning sensation, pain, stinging, dryness; occurrence of all the other local AEs referred by the subject; occurrence of all the local Adverse Drug Reactions (ADRs) revealed by the Investigator	Up to 7 days after administration

Secondary Outcome Measures

Outcome Measure	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 (days 1-2) and the last dose (days 15-16) and at pre-dose (0) on day 6±1, day 9±1 and day 12±1
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 (days 1-2) and the last dose (days 15-16) and at pre-dose (0) on day 6±1, day 9±1 and day 12±1
Treatment Emergent Adverse Events (TEAEs)	15-16 days
Change from screening in vital signs	From screening (from day -21 to day -7) at days 1 and 15 at pre-dose (0), 12 and 24 hours post-dose
Change from screening in 12-leads ECG	From screening (from day -21 to day -7) at final visit (from day 17 to day 20)
Change from screening in laboratory parameters	From screening (from day -21 to day -7) and at final visit (from day 17 to day 20)
Change from screening in vaginal pH measurement	From screening (from day -21 to day -7), before the application on days 1, 2, 15, on days 6±1, 9±1, 12±1 at final visit (from day 17 to day 20)
Change from screening in gynaecological examination findings	From screening (from day -21 to day -7) at final visit (from day 17 to day 20)
Overall tolerability assessment scale	At final visit (from day 17 to day 20)
Questionnaire for the comfort of use	At final visit (from day 17 to day 20)

Collaborators and Investigators

• Sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A
• Collaborators: Cross Research S.A.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 15, 2016

Study Registration Dates

• First Submitted: August 7, 2015
• First Submitted That Met QC Criteria: March 18, 2016
• First Posted (Estimate): March 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 15, 2018
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Tolerability; Econazole nitrate 1%; Benzydamine HCl 0.12%; Intravaginal cream; Antimycotic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Benzydamine; Econazole
• Other Study ID Numbers: 030(4A)HO14387; CRO-PK-14-289 (Other Identifier: CROSS Research S.A., Phase I Unit)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No