Gentian Violet Vs. Nystatin Oral Suspension for Treatment of Oropharyngeal Candidiasis

Study Overview
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Brief Summary
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The purpose of this study was to see which one of two medicines (topical gentian violet [GV] or nystatin oral suspension) was better than the other in treating Oral Candidiasis (OC). This was measured by whether the study participant still had OC or sores in his/her mouth after 14 days of treatment. Also, safety and tolerability of GV and nystatin in the treatment of OC were assessed.

Detailed Description
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A5265 was a phase III, open-label (both the researchers and participants know which treatment was being administered) clinical trial to compare the safety and efficacy of topical GV to that of oral nystatin suspension. Male and female HIV-1 positive participants ≥ 18 years of age were randomized (as if by the toss of a coin) with equal probability and stratified by CD4+ T-cell counts and the use of antiretroviral therapy at the time of study entry to receive either topical GV solution (5 mL swish and gargle for 1 minute and spit two times daily) or nystatin oral suspension (5 mL swish for 1 minute and swallow four times daily) for 14 days. Therapy was considered as failed if participants have no clinical improvement (assessed by severity of pseudomembranous candidiasis) during either treatment regimen. Evaluation of signs and symptoms of oral candidiasis was done by an evaluator who was blinded to the treatment assignment. A total of 494 participants was expected to enroll in the study but due to early study closure only 221 enrolled; and participants are expected to be on the study for about 13 weeks.

Official Title
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A Phase III, Open-Label, Randomized, Assessment-Blinded Clinical Trial to Compare the Safety and Efficacy of Gentian Violet Oral Solution to That of Nystatin Oral Suspension for the Treatment of Oropharyngeal Candidiasis in HIV-1 Infected Participants in Non-U.S. Settings

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Gentian Violet
* Drug: Nystatin oral suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. Pseudomembranous candidiasis documented by a complete oral exam (i.e., white or yellow spots or plaques with an underlying erythematous base, located in any part of the oral cavity) at the screening visit. Participants with documented angular chelitis and/or erythematous candidiasis without pseudomembranous candidiasis were not eligible to enroll in the study. If on an antiretroviral therapy (ART), initiation of regimen at least 12 weeks prior to study entry, and willingness of participant to remain on current ART regimen until the study-defined 14-day treatment period was complete. NOTE: Participants who were not ART-naïve and not on ART were eligible to participate in the study if they did not intend to initiate ART during the study- defined 14-day treatment period. CD4+ cell count obtained within 30 days prior to study entry at a DAIDS-approved laboratory. Exclusion Criteria: Documented or presumptive signs or symptoms of esophageal candidiasis (e.g., dysphagia) during the screening period unless endoscopic examination of the esophagus was performed, and fungal esophagitis were excluded. Use of any investigational drug currently or within 30 days prior to study entry. NOTE: For purposes of this study, drugs available under an FDA-authorized expanded access program was NOT considered investigational. Concurrent vaginal candidiasis within 21 days prior to study entry. Use of inhaled or systemic corticosteroids within 14 days prior to study entry. Use of any antifungal agents within 30 days prior to study entry. Anticipated need for systemic or oral/topical antifungal agents for other diagnoses within the study-defined 14-day treatment period. Intend to initiate ART during the screening period, at study entry, or within the study-defined 14-day treatment period. Intend to use any additional oral topical treatments within the study- defined 14-day treatment period. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Serious illness, in the opinion of the site investigator, requiring systemic treatment. Hospitalization within 30 days prior to study entry for HIV or HIV-related conditions. Previous or current history of porphyria. Presence of oral warts during the screening period or at the study entry visit before randomization. Current wearing of full dentures or a maxillary partial denture at study entry

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Topical GV solution<br>Topical GV 0.00165% solution (5 mL swish and gargle for 1 minute and expectorate [spit] 2 times per day [BID]) for 14 days | Drug: Gentian Violet<br>* Participants were administered topical Gentian violet solution, orally, twice daily for 14 days.<br>|
| Active Comparator: Arm B: Nystatin oral suspension<br>Nystatin oral suspension (5 mL of 100,000 units/mL swish for 1 minute and swallow 4 times per day [QID]) for 14 days | Drug: Nystatin oral suspension<br>* Participants were administered Nystatin oral suspension 4 times a day for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Efficacy | The primary endpoint is clinical efficacy defined as cure (absence of lesions) or improvement (a decrease in severity of lesions) after 14 days of treatment. The oral cavity will be split arbitrarily into 6 sites: left lower and upper labial mucosa and buccal mucosa, right lower and upper labial mucosa and buccal mucosa, hard palate, soft palate, tongue (dorsum, lateral, and ventral), and floor of mouth. Severity is scored using a scoring system from 0 to 3 (0 corresponds to absence of lesions, and 3 corresponds to presence of extensive confluent lesions) which leads to a composite severity score ranging from 0 to 18 after adding up the scores from all 6 sites. Complete success is assigned if the composite score after treatment equals to 0. Improved/partial response is assigned if the composite score after treatment is less than the baseline score. The blinded evaluator scores the severity of lesions by examining different lesion characteristics. | After 14 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant With Symptom | Symptoms were assessed using a visual analog scale where the level of discomfort and pain were recorded and quantified using a scoring system from 0 to 3. 0=no discomfort/pain; 1=mild discomfort/pain; 2=Moderate discomfort/pain; 3=Severe discomfort/pain. | after 14 days of treatment | 
| Quantitative Yeast Colony Counts | If quantitative yeast culture yielding < 20 CFU/mL of Candida spp., then we call this mycological success | At weeks 0, 2, 6 | 
| Tolerance | The investigators will measure tolerance using a scale from 0 to 3 (0=No side effects experienced, no changes in treatment; 1=Some side effects experienced, but not enough to modify treatment; 2=Some side effects experienced, resulted in treatment interruption; 3=Side effects experienced, resulted in treatment discontinuation.) | After 14 days of treatment | 
| Number of Participants Who Were Adherent. | Adherence was reported as a dichotomous variable (adherence vs. non-adherence). Participants who have missing doses less than 15% will be considered as adherent, i.e., if a participant is in the GV arm, then the cutoff point is 28*0.15=4 doses; and for the nystatin arm is 56*0.15=8 doses. | After 14 days of treatment | 
| Self-Assessment of General Health | Participants rated their general health on two scales. One is a five point scale ranging from 1 to 5 (1=Excellent; 2=Very Good; 3=Good; 4=Fair; 5=Poor) | Weeks 0, 6 | 
| Number of Participants Who Found GV and Nystatin Acceptable. | Acceptability was defined as the willingness to use the drug if it is proven effective to treat oral candidiasis. Participants were asked whether or not they would be willing to use the assigned treatment via questionnaires. | After 14 days of treatment |