Vulvovaginal Candidiasis (VVC) Clinical Trial
Official title:
A Phase IIa Randomized, Active-controlled, Double-blind, Dose-escalation Study in Patients With Vulvovaginal Candidiasis to Evaluate Dose Response Relationship of Clinical Efficacy, Safety and Tolerability of Topically Administered ProF-001
| Verified date | September 2017 |
| Source | ProFem GmbH |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 84 |
| Est. completion date | July 30, 2018 |
| Est. primary completion date | July 30, 2018 |
| Accepts healthy volunteers | No |
| Gender | Female |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: - 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 Exclusion Criteria: - Known hypersensitivity to any ingredient of the investigational medicinal product - Pregnancy or breast feeding at time of screening - Menstrual bleeding (spotting is not an exclusion criterion) during the first three days of treatment - 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 |
| Country | Name | City | State |
|---|---|---|---|
| Austria | Medical University Innsbruck | Innsbruck | |
| Austria | Bezirkskrankenhaus Schwaz | Schwaz | |
| Austria | Medical University Vienna | Vienna |
| Lead Sponsor | Collaborator |
|---|---|
| ProFem GmbH |
Austria,
Achkar JM, Fries BC. Candida infections of the genitourinary tract. Clin Microbiol Rev. 2010 Apr;23(2):253-73. doi: 10.1128/CMR.00076-09. Review. — View Citation
Alem MA, Douglas LJ. Prostaglandin production during growth of Candida albicans biofilms. J Med Microbiol. 2005 Nov;54(Pt 11):1001-5. — View Citation
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. Epub 2002 Jul 11. — View Citation
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. — View Citation
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. Review. — View Citation
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. — View Citation
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. — View Citation
Haynes K. Virulence in Candida species. Trends Microbiol. 2001 Dec;9(12):591-6. Review. — View Citation
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. — View Citation
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. Review. — View Citation
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. Epub 2007 Sep 13. — View Citation
Mathé 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. Review. — View Citation
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. — View Citation
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. Review. — View Citation
Naglik J, Albrecht A, Bader O, Hube B. Candida albicans proteinases and host/pathogen interactions. Cell Microbiol. 2004 Oct;6(10):915-26. Review. — View Citation
Noverr MC, Huffnagle GB. Regulation of Candida albicans morphogenesis by fatty acid metabolites. Infect Immun. 2004 Nov;72(11):6206-10. — View Citation
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. — View Citation
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. — View Citation
Ray WA, Varas-Lorenzo C, Chung CP, Castellsague J, Murray KT, Stein CM, Daugherty JR, Arbogast PG, García-Rodríguez LA. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes. 2009 May;2(3):155-63. doi: 10.1161/CIRCOUTCOMES.108.805689. Epub 2009 May 5. — View Citation
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. — View Citation
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):672-6. — View Citation
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. — View Citation
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. — View Citation
Théraud M, Bédouin Y, Guiguen C, Gangneux JP. Efficacy of antiseptics and disinfectants on clinical and environmental yeast isolates in planktonic and biofilm conditions. J Med Microbiol. 2004 Oct;53(Pt 10):1013-8. — View Citation
Thompson DS, Carlisle PL, Kadosh D. Coevolution of morphology and virulence in Candida species. Eukaryot Cell. 2011 Sep;10(9):1173-82. doi: 10.1128/EC.05085-11. Epub 2011 Jul 15. Review. — View Citation
* Note: There are 25 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | Number of patients with local adverse events and serious adverse events (SAEs) with causal relationship to study medication | All local adverse events and serious adverse events with causal relationship to study medication (drug reaction) will be documented in a descriptive manner. | overall study period (max. 65 days) | |
| Secondary | Symptom relief within the first 60 minutes (after application of investigational product or active control, reduction of the subjective symptom score = 2) | Symptom relief within the first 60 minutes will be documented. A reduction of the subjective symptom score = 2 is expected. | within 60 minutes after drug application | |
| Secondary | Clinical cure (absence of signs and symptoms of VVC) at the TOC visit (=day 7/ accepted time window ±3days) | Clinical cure at day 7 will be documented. Clinical cure is defined as absence of signs and symptoms of VVC. | day 7 ±3 days after drug application | |
| Secondary | Mycological outcome: Vaginal swab culture negative for growth of Candida albicans and/or Candida species at the TOC visit (day 7 / ±3days) | A vaginal swab culture will be taken on day 7 / ±3days. The test result is expected to be negative for growth of Candida albicans and/or Candida species.visit (day 7 / ±3days) | day 7 ±3 days after drug application | |
| Secondary | 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) | Presence or absence of signs and symptoms will be documented. Vaginal swab culture is expected to be negative for growth of Candida albicans and/or Candida species at the TOC visit. | day 7 ±3 days after drug application | |
| Secondary | Time to improvement of symptoms after first intervention | The time to improvement of symptoms after the first intervention will be documented. | overall study period (max. 65 days) | |
| Secondary | Time to termination of clinical symptoms | The time to termination of clinical symptoms will be documented. | overall study period (max. 65 days) | |
| Secondary | Clinical relapse of VVC during follow-up period | Every clinical relapse of VVC during the follow-up period will be documented. | follow-up period (from day 8 to day 60) |