ProF-001_Phase_IIa

Profem GmbH

Riglergasse 4/I, Vienna, Austria, 1180

Sponsor representative, Profem GmbH DDr. Marion Noe-Letschnig E-mail: marion.noe@profem.at , +43 676 7203070, office@profem.at

Sponsor representative, Profem GmbH DDr. Marion Noe-Letschnig E-mail: marion.noe@profem.at , +43 676 7203070, office@profem.at

No

No

No

Final

20 Nov 2018

Yes

30 Jul 2018

Yes

30 Jul 2018

No

To determine the dose-response and the clinical efficacy of a cream containing a combination of clotrimazole and diclofenac sodium for the topical treatment of acute episodes of vulvovaginal candidiasis (VVC) after vaginal administration. Three different doses of diclofenac sodium in combination with clotrimazole were compared with clotrimazole alone as reference.

Adverse event monitoring included subjective and objective symptom assessments applying an established symptom score as defined in the FDA guidance for treatment of VVC from 2016 and by Sobel and co-workers in 2001: • Subjective symptoms: itching, burning pain and irritation/soreness classified as mild, moderate and severe, • Objective symptoms: erythma, edema and excoriation as assessed by the gynecologist (classified as mild, moderate and severe). Study subjects were asked to self-rate their physical condition and adverse reactions associated with the study medication at each visit. Subjective grading of local reactions has been documented by patients in the diary according to severity based on a visual analogue scale (VAS). The treating physician assessed the symptoms itching, burning pain and irritation/soreness according to the above mentioned symptom score (categorized into mild, moderate and severe) and objectively confirmed by gynecological examination. Special attention of participating subjects has been drawn to document in the diary and to report the occurrence of local irritations such as erythema, peeling, itching or burning.

09 May 2017

No

No

Austria: 54

Poland: 32

86

86

0

0

0

0

0

0

86

0

0

Active treatment period

Randomised - controlled

Central blinding of IMP was performed at manufacturing site - blinding was kept throughout the study until database lock

Yes

clotrimazole 1%

comparator

Cream

Vaginal use

cream containing 1% clotrimazole (Fungizid-ratiopharm® 1% Vaginalcreme) for intravaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.2%

clotrimazole 1% + diclofenac 0.2%

ProF-001 0.2%

Cream

Topical use , Vaginal use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.3%

clotrimazole 1% + diclofenac 0.3%

ProF-001 0.3%

Cream

Topical use , Vaginal use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.4%

clotrimazole 1% + diclofenac 0.4%

ProF-001 0.4%

Cream

Vaginal use, Topical use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Follow up period

Randomised - controlled

Yes

clotrimazole 1%

comparator

Cream

Vaginal use

cream containing 1% clotrimazole (Fungizid-ratiopharm® 1% Vaginalcreme) for intravaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.2%

clotrimazole 1% + diclofenac 0.2%

ProF-001 0.2%

Cream

Topical use , Vaginal use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.3%

clotrimazole 1% + diclofenac 0.3%

ProF-001 0.3%

Cream

Topical use , Vaginal use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Candiplus 0.4%

clotrimazole 1% + diclofenac 0.4%

ProF-001 0.4%

Cream

Vaginal use, Topical use

2.5 ml + 2 cm cream twice daily (days 1, 2 and 3) followed by 2.5 ml + 2 cm cream once daily (days 4, 5 and 6) to be administered as vaginal application (2.5 ml cream) and topical application (2 cm cream in the vulvar region)

Control

Candiplus 0.2%

Candiplus 0.3%

Candiplus 0.4%

Full analysis set

The full analysis set will comprise all randomized subjects who received at least six doses (3 days) of investigational product and who have sufficient data of the co-efficacy endpoint of: (i) Symptom relief within the first 60 minutes (after application of investigational product or active control, with reduction of the subjective symptom score ≥2) and (ii) clinical cure (absence of signs and symptoms of VVC) at the TOC visit (=day 7 ± 3). Analyses on the FAS will be performed according to the randomized dose group (intention to treat principle).

Safety population

The safety population comprises all subjects who were randomized and received at least one dose of the IMP. Analyses based on the safety analyses were performed according to the actual dose the patients received.

Control

Candiplus 0.2%

Candiplus 0.3%

Candiplus 0.4%

Control

Candiplus 0.2%

Candiplus 0.3%

Candiplus 0.4%

Full analysis set

The full analysis set will comprise all randomized subjects who received at least six doses (3 days) of investigational product and who have sufficient data of the co-efficacy endpoint of: (i) Symptom relief within the first 60 minutes (after application of investigational product or active control, with reduction of the subjective symptom score ≥2) and (ii) clinical cure (absence of signs and symptoms of VVC) at the TOC visit (=day 7 ± 3). Analyses on the FAS will be performed according to the randomized dose group (intention to treat principle).

Safety population

The safety population comprises all subjects who were randomized and received at least one dose of the IMP. Analyses based on the safety analyses were performed according to the actual dose the patients received.

Composite primary endpoint combining two parameters: 1. Symptom relief within the first 60 minutes after application of the investigational medicinal product (IMP) defined as reduction of the subjective symptom score ≥2 in combination with 2. Clinical cure (absence of signs and symptoms of VVC) at the test of cure (TOC) visit at day 7 (±3 days)

Primary

Symptom assessment 60 minutes after application of IMP in combination with cure at the test of cure (TOC) visit at day 7 (±3 days)

The logistic regression was performed to test effects of dose-concentration on the primary endpoint. Results indicated that the model did not provide a statistically significant effect (p=0.39). The Nagelkerke R2 indicated that model accounted for 1.3% of the total variance. The correct prediction rate was about 66.2%. The wald test showed that the predictor did not significantly predict the primary endpoint.

Control v Candiplus 0.2% v Candiplus 0.3% v Candiplus 0.4% v Full analysis set

166

Pre-specified

2-sided

Day of randomization until end of follow-up period (day 60 ± 5 days after randomization)

21.1

Control

Candiplus 0.2%

Candiplus 0.3%

Candiplus 0.4%