ProF-001_Phase IIa

NCT03115073 | Completed Phase 2 DMC

• 1 other identifier: ProF-001_Phase IIa
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 3

Brief Summary

This is a multi-center, randomized, prospective, active-controlled, double-blind, dose-escalation study comparing dose response of clinical efficacy, safety, local tolerability of three different doses of ProF-001/Candiplus® (Candiplus® 0.2%, Candiplus® with 0.3%, Candiplus® with 0.4%) to 1% clotrimazole vaginal cream. Patients with acute episode of vulvovaginal candidiasis (VVC) will be randomized to receive a daily dose of either 5 ml (intravaginal) of Candiplus® at three different doses for the first 3 days and 2.5 ml for the remaining 3 days or 5 ml (intravaginal) application of 1% clotrimazole cream over the first 3 days and 2.5 ml for the remaining 3 days according to the following scheme (with each application 2 cm of cream will be applied to the vulvar region): Cohort 1: Candiplus® 0.2% versus clotrimazole mono Cohort 2: Candiplus® 0.3% versus clotrimazole mono Cohort 3: Candiplus® 0.4% versus clotrimazole mono Randomization into the cohorts will occur consecutively from the lowest dose to the highest dose, i.e. patients will be randomized first in cohort 1 and finally in cohort 3. The proposed study is - after a pilot study to assess critical pharmacokinetic data - the second study within a clinical trial program with the objective to develop a new combination therapy for the treatment of vulvovaginal candidiasis. The new combination consists of two registered drug substances.

Conditions

Vulvovaginal Candidiasis (VVC)

Keywords

Vulvovaginal candidiasis; Candiplus; Clotrimazole; Safety; Tolerability; Clinical efficacy

Outcome Measures

Primary Outcomes (1)

• Combined outcome measure of: Symptom relief within the first 60 minutes (after application of investigational product or active control) and clinical cure at day 7 (± 3 days).

  As the primary outcome symptom relief within the first 60 minutes will be documented. A reduction of the subjective symptom score ≥ 2 is expected. Furthermore clinical cure at day 7 will be documented. Clinical cure is defined as absence of signs and symptoms of VVC.

  within 60 minutes after application and at day 7 (± 3 days) after drug application

Secondary Outcomes (8)

• Number of patients with local adverse events and serious adverse events (SAEs) with causal relationship to study medication

  overall study period (max. 65 days)

• Symptom relief within the first 60 minutes (after application of investigational product or active control, reduction of the subjective symptom score ≥ 2)

  within 60 minutes after drug application

• Clinical cure (absence of signs and symptoms of VVC) at the TOC visit (=day 7/ accepted time window ±3days)

  day 7 ±3 days after drug application

• Mycological outcome: Vaginal swab culture negative for growth of Candida albicans and/or Candida species at the TOC visit (day 7 / ±3days)

  day 7 ±3 days after drug application

• Responder outcome: absence of signs and symptoms plus vaginal swab culture negative for growth of Candida albicans and/or Candida species at the TOC visit (day 7 / ±3days)

  day 7 ±3 days after drug application

Study Arms (4)

0,2% Candiplus

EXPERIMENTAL

Candiplus® 0.2%

Drug: Candiplus

0,3% Candiplus

EXPERIMENTAL

Candiplus® 0.3%

Drug: Candiplus

0,4% Candiplus

EXPERIMENTAL

Candiplus® 0.4%

Drug: Candiplus

Clotri mono

ACTIVE COMPARATOR

Clotrimazole mono

Drug: Clotrimazole

Interventions

Candiplus DRUG

Administration of Candiplus

0,2% Candiplus; 0,3% Candiplus; 0,4% Candiplus

Clotrimazole DRUG

Administration of Clotrimazole

Clotri mono

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Premenopausal female patients ≥ 18 years old
• Patients suffering from an acute episode of vulvovaginal candidiasis, characterized by:
• Positive vaginal smear (native, KOH) for budding yeasts and/or fungal (pseudo-) hyphae, normal or intermediate flora (G I and G II)
• Positive clinical symptoms (itching, burning, irritation, edema, erythema, excoriations), with a subjective symptom score of at least 3 (0=absent, 1=mild, 2=moderate, and 3=severe), with score being at least moderate for at least 1 subjective symptom and itching being present, and a total sign and symptom score of at least 4
• Readiness for sexual abstinence from start of treatment until test of cure (TOC) - visit
• Sufficient knowledge of German language to understand trial instructions and rating scales, and ability to comply with treatment
• Written informed consent prior to enrolment

You may not qualify if:

• Known hypersensitivity to any ingredient of the investigational medicinal product
• Pregnancy or breast feeding at time of screening
• Acute cystitis
• Patients with clinical signs of other infectious causes of vulvovaginitis: bacterial vaginosis (GIII), trichomonas vaginalis, herpes simplex genitalis
• Treatment with antimycotics (systemic or vaginal) within 7 days of randomization
• Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs)
• Patients with other clinical gynecological abnormalities, such as infections of the upper urogenital tract (pelvic inflammatory disease, adnexitis)
• Subjects with another vaginal or vulvar condition that would confound the interpretation of clinical response (e.g. Lichen sclerosus, neuropathic pain)
• Subjects who will be under treatment or surgery for gynecological pathologies during the study period, i.e, cervical intraepithelial neoplasia, cervical carcinoma, other neoplasms
• Known alcohol, drug or medication abuse
• Any clinically relevant concomitant condition that could compromise the objectives of this study and/ or the patient's compliance (eg. known immune deficiency syndrome with clinical relevance at time of screening)
• Participation in another interventional clinical trial within the last 30 days
• Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub-investigators, or study nurse) or relationship to the sponsor

Sponsors & Collaborators

• ProFem GmbH: lead

Study Sites (3)

Medical University Innsbruck

Innsbruck, Austria

Location

Bezirkskrankenhaus Schwaz

Schwaz, Austria

Location

Medical University Vienna

Vienna, Austria

Location

Related Publications (25)

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• Donders G, Bellen G, Byttebier G, Verguts L, Hinoul P, Walckiers R, Stalpaert M, Vereecken A, Van Eldere J. Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial). Am J Obstet Gynecol. 2008 Dec;199(6):613.e1-9. doi: 10.1016/j.ajog.2008.06.029. Epub 2008 Oct 30.

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• Dovnik A, Golle A, Novak D, Arko D, Takac I. Treatment of vulvovaginal candidiasis: a review of the literature. Acta Dermatovenerol Alp Pannonica Adriat. 2015;24(1):5-7. doi: 10.15570/actaapa.2015.2.

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• Cannom RR, French SW, Johnston D, Edwards JE Jr, Filler SG. Candida albicans stimulates local expression of leukocyte adhesion molecules and cytokines in vivo. J Infect Dis. 2002 Aug 1;186(3):389-96. doi: 10.1086/341660. Epub 2002 Jul 11.

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• Filler SG, Pfunder AS, Spellberg BJ, Spellberg JP, Edwards JE Jr. Candida albicans stimulates cytokine production and leukocyte adhesion molecule expression by endothelial cells. Infect Immun. 1996 Jul;64(7):2609-17. doi: 10.1128/iai.64.7.2609-2617.1996.

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• Gale CA, Bendel CM, McClellan M, Hauser M, Becker JM, Berman J, Hostetter MK. Linkage of adhesion, filamentous growth, and virulence in Candida albicans to a single gene, INT1. Science. 1998 Feb 27;279(5355):1355-8. doi: 10.1126/science.279.5355.1355.

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• Haynes K. Virulence in Candida species. Trends Microbiol. 2001 Dec;9(12):591-6. doi: 10.1016/s0966-842x(01)02237-5.

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• King RD, Lee JC, Morris AL. Adherence of Candida albicans and other Candida species to mucosal epithelial cells. Infect Immun. 1980 Feb;27(2):667-74. doi: 10.1128/iai.27.2.667-674.1980.

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• Klotz SA. Fungal adherence to the vascular compartment: a critical step in the pathogenesis of disseminated candidiasis. Clin Infect Dis. 1992 Jan;14(1):340-7. doi: 10.1093/clinids/14.1.340.

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• Kolachala VL, Bajaj R, Wang L, Yan Y, Ritzenthaler JD, Gewirtz AT, Roman J, Merlin D, Sitaraman SV. Epithelial-derived fibronectin expression, signaling, and function in intestinal inflammation. J Biol Chem. 2007 Nov 9;282(45):32965-73. doi: 10.1074/jbc.M704388200. Epub 2007 Sep 13.

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• Mathe L, Van Dijck P. Recent insights into Candida albicans biofilm resistance mechanisms. Curr Genet. 2013 Nov;59(4):251-64. doi: 10.1007/s00294-013-0400-3. Epub 2013 Aug 25.

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• Mendling W, Krauss C, Fladung B. A clinical multicenter study comparing efficacy and tolerability of topical combination therapy with clotrimazole (Canesten, two formats) with oral single dose fluconazole (Diflucan) in vulvovaginal mycoses. Mycoses. 2004 Apr;47(3-4):136-42. doi: 10.1111/j.1439-0507.2004.00970.x.

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• Muzny CA, Schwebke JR. Biofilms: An Underappreciated Mechanism of Treatment Failure and Recurrence in Vaginal Infections. Clin Infect Dis. 2015 Aug 15;61(4):601-6. doi: 10.1093/cid/civ353. Epub 2015 May 1.

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• Naglik J, Albrecht A, Bader O, Hube B. Candida albicans proteinases and host/pathogen interactions. Cell Microbiol. 2004 Oct;6(10):915-26. doi: 10.1111/j.1462-5822.2004.00439.x.

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• Noverr MC, Phare SM, Toews GB, Coffey MJ, Huffnagle GB. Pathogenic yeasts Cryptococcus neoformans and Candida albicans produce immunomodulatory prostaglandins. Infect Immun. 2001 May;69(5):2957-63. doi: 10.1128/IAI.69.5.2957-2963.2001.

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• Noverr MC, Huffnagle GB. Regulation of Candida albicans morphogenesis by fatty acid metabolites. Infect Immun. 2004 Nov;72(11):6206-10. doi: 10.1128/IAI.72.11.6206-6210.2004.

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• Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991 Feb;29(2):297-301. doi: 10.1128/jcm.29.2.297-301.1991.

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• Schaller M, Mailhammer R, Korting HC. Cytokine expression induced by Candida albicans in a model of cutaneous candidosis based on reconstituted human epidermis. J Med Microbiol. 2002 Aug;51(8):672-676. doi: 10.1099/0022-1317-51-8-672.

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• Schaller M, Mailhammer R, Grassl G, Sander CA, Hube B, Korting HC. Infection of human oral epithelia with Candida species induces cytokine expression correlated to the degree of virulence. J Invest Dermatol. 2002 Apr;118(4):652-7. doi: 10.1046/j.1523-1747.2002.01699.x.

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• Sobel JD, Schmitt C, Stein G, Mummaw N, Christensen S, Meriwether C. Initial management of recurrent vulvovaginal candidiasis with oral ketoconazole and topical clotrimazole. J Reprod Med. 1994 Jul;39(7):517-20.

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• Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D, Nyirjesy P, Heine MW, Willems J, Panzer H, Wittes H. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol. 2001 Aug;185(2):363-9. doi: 10.1067/mob.2001.115116.

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Related Links

• Lisa A. Bero, February 15, 2005, Expert Committee on Selection and Use of Essential Medicines, Review of Application of Clotrimazole for topical or intravaginal use in vulvovaginal candidiasis.
• FDA draft Guidance for Industry Vulvovaginal Candidiasis -Developing Drugs for Treatment, 2016.
• Newcombe, R.G. "Interval estimation for the difference between independent proportions: comparison of eleven methods" Statistics in Medicine 17(1988) pp. 873-890
• Santoni G, Gismondi A, Liu JH, et al. Candida albicans expresses a fibronectin receptor antigenically related to a5b1 integrin. Microbiology. 1994 Nov;140 ( Pt 11):2971-9.
• Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004b Aug 26;351(9):876-83.
• Voltarol Suppositories 12.5 mg, 25 mg, 50 mg, 100 mg, UK SmPC 2013

MeSH Terms

Conditions

Candidiasis, Vulvovaginal

Interventions

Clotrimazole

Condition Hierarchy (Ancestors)

Candidiasis; Mycoses; Bacterial Infections and Mycoses; Infections; Vulvovaginitis; Vaginitis; Vaginal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Vulvitis; Vulvar Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Herbert Kiss, Ao.Univ.Prof.Dr.

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2017
• First Posted: April 14, 2017
• Study Start: April 4, 2017
• Primary Completion: July 30, 2018
• Study Completion: July 30, 2018
• Last Updated: March 14, 2019

Record last verified: 2017-09

Locations

AU (3)