HIV-1 Infection
Conditions
Brief summary
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
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.
Interventions
DRUGGentian Violet
Participants were administered topical Gentian violet solution, orally, twice daily for 14 days.
Participants were administered Nystatin oral suspension 4 times a day for 14 days.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Efficacy | After 14 days of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Yeast Colony Counts | At weeks 0, 2, 6 | If quantitative yeast culture yielding \< 20 CFU/mL of Candida spp., then we call this mycological success |
| Tolerance | After 14 days of treatment | 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.) |
| Number of Participant With Symptom | after 14 days of treatment | 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. |
| Self-Assessment of General Health | Weeks 0, 6 | 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) |
| Number of Participants Who Found GV and Nystatin Acceptable. | After 14 days of treatment | 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. |
| Number of Participants Who Were Adherent. | After 14 days of treatment | 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. |
Countries
Botswana, India, Kenya, Malawi, South Africa, Uganda, Zimbabwe
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Topical GV Solution Topical GV 0.00165% solution (5 mL swish and gargle for 1 minute and expectorate \[spit\] 2 times per day \[BID\]) for 14 days
Gentian Violet: Participants will be administered topical Gentian violet solution, orally, twice daily for 14 days. | 110 |
| Arm B: Nystatin Oral Suspension Nystatin oral suspension (5 mL of 100,000 units/mL swish for 1 minute and swallow 4 times per day \[QID\]) for 14 days
Nystatin oral suspension: Participants will be administered Nystatin oral suspension 4 times a day for 14 days. | 111 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 12 | 9 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Severe debilitation, unable to continue | 0 | 1 |
| Overall Study | Subject not willing to adhere to reqs | 1 | 2 |
| Overall Study | Subject unable to get to clinic | 5 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Arm A: Topical GV Solution | Arm B: Nystatin Oral Suspension | Total |
|---|---|---|---|
| Age, Customized 10-19 years | 0 participants | 1 participants | 1 participants |
| Age, Customized 20-29 years | 17 participants | 30 participants | 47 participants |
| Age, Customized 30-39 years | 54 participants | 52 participants | 106 participants |
| Age, Customized 40-49 years | 21 participants | 17 participants | 38 participants |
| Age, Customized 50-59 years | 16 participants | 9 participants | 25 participants |
| Age, Customized Over 60 years | 2 participants | 2 participants | 4 participants |
| Antiretroviral Therapy Usage Not on ART | 83 participants | 83 participants | 166 participants |
| Antiretroviral Therapy Usage On ART | 27 participants | 28 participants | 55 participants |
| CD4 Count 0-200 cells/microliter | 87 participants | 88 participants | 175 participants |
| CD4 Count > 200 cells/microliter | 23 participants | 23 participants | 46 participants |
| HIV RNA Viral Load | 4.89 log10(copies/ml) STANDARD_DEVIATION 1.31 | 5.03 log10(copies/ml) STANDARD_DEVIATION 1.21 | 4.96 log10(copies/ml) STANDARD_DEVIATION 1.26 |
| Race/Ethnicity, Customized Asian, Pacific Islander | 13 participants | 5 participants | 18 participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 97 participants | 106 participants | 203 participants |
| Sex: Female, Male Female | 62 Participants | 66 Participants | 128 Participants |
| Sex: Female, Male Male | 48 Participants | 45 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 110 | 101 / 111 |
| serious Total, serious adverse events | 18 / 110 | 17 / 111 |
Outcome results
Primary
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.
Time frame: After 14 days of treatment
Population: Out of 221 subjects,17 had oral exams at entry but not week 2: 11 premature discontinuation, 2 missed visits, and 4 without specific reasons. 204 subjects received oral exams at both entry and week 2. 2 more participants were excluded from the final analysis because they had no pseudomem candi at entry, which led to a total of 202 subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Topical GV Solution | Number of Participants With Clinical Efficacy | 76 participants |
| Arm B: Nystatin Oral Suspension | Number of Participants With Clinical Efficacy | 73 participants |
Comparison: Repeated confidence intervals (RCIs) were used to control type I error.A interim analysis was conducted by a 99.7% CI. The final analyses use a 95.1% CI, based on the Lan-DeMets error-spending function corresponding to the O'Brien-Fleming boundary.76% of 100 participant in arm GV had cure or improvement of OC after 14 days of treatment, and 71.6% of 102 in arm nystatin had cure or improvement of OC. Difference in clinical efficacy rates between GV and nystatin 95.1% CI is 0.044 (-0.077, 0.166).95.1% CI: [-0.077, 0.166]
Secondary
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.
Time frame: After 14 days of treatment
Population: The analysis for acceptability of treatment was based on 209 subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Topical GV Solution | Number of Participants Who Found GV and Nystatin Acceptable. | 100 participants |
| Arm B: Nystatin Oral Suspension | Number of Participants Who Found GV and Nystatin Acceptable. | 98 participants |
Secondary
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.
Time frame: After 14 days of treatment
Population: The analysis for adherence was based on 209 observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Topical GV Solution | Number of Participants Who Were Adherent. | Adherent | 95 participants |
| Arm A: Topical GV Solution | Number of Participants Who Were Adherent. | Non-adherent | 9 participants |
| Arm B: Nystatin Oral Suspension | Number of Participants Who Were Adherent. | Adherent | 95 participants |
| Arm B: Nystatin Oral Suspension | Number of Participants Who Were Adherent. | Non-adherent | 10 participants |
Secondary
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.
Time frame: after 14 days of treatment
Population: At entry, a total of 217 observations (106 in GV arm; 111 in nystatin arm) were available to evaluate the symptoms (pain and discomfort) associated with OC. At the end of treatment, a total of 204 observations were available to evaluate the symptoms associated with OC using extended Mantel-Haenszel test between GV and nystatin arms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Topical GV Solution | Number of Participant With Symptom | Pain at entry | 106 participants |
| Arm A: Topical GV Solution | Number of Participant With Symptom | Pain at end of treatment | 102 participants |
| Arm A: Topical GV Solution | Number of Participant With Symptom | Discomfort at entry | 106 participants |
| Arm A: Topical GV Solution | Number of Participant With Symptom | Discomfort at end of treatment | 102 participants |
| Arm B: Nystatin Oral Suspension | Number of Participant With Symptom | Discomfort at end of treatment | 102 participants |
| Arm B: Nystatin Oral Suspension | Number of Participant With Symptom | Pain at entry | 111 participants |
| Arm B: Nystatin Oral Suspension | Number of Participant With Symptom | Discomfort at entry | 111 participants |
| Arm B: Nystatin Oral Suspension | Number of Participant With Symptom | Pain at end of treatment | 102 participants |
Secondary
Quantitative Yeast Colony Counts
If quantitative yeast culture yielding \< 20 CFU/mL of Candida spp., then we call this mycological success
Time frame: At weeks 0, 2, 6
Population: At entry, 210 observations were available (182 had positive culture result for Candida specimen, and 175 of those had colony count performed) to evaluate quantitative yeast colony counts.~N= 78 (GV), 70 (Nystatin) at end of treatment; N= 51 (GV), 35 (Nystatin) at week 6;
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Topical GV Solution | Quantitative Yeast Colony Counts | At entry, week 0 | 7.2497 CFU/mL | Standard Deviation 2.2382 |
| Arm A: Topical GV Solution | Quantitative Yeast Colony Counts | At end of treatment (week 2) | 6.9374 CFU/mL | Standard Deviation 2.1438 |
| Arm A: Topical GV Solution | Quantitative Yeast Colony Counts | At week 6 | 6.7388 CFU/mL | Standard Deviation 2.3469 |
| Arm B: Nystatin Oral Suspension | Quantitative Yeast Colony Counts | At entry, week 0 | 7.0037 CFU/mL | Standard Deviation 2.0584 |
| Arm B: Nystatin Oral Suspension | Quantitative Yeast Colony Counts | At end of treatment (week 2) | 5.8888 CFU/mL | Standard Deviation 2.397 |
| Arm B: Nystatin Oral Suspension | Quantitative Yeast Colony Counts | At week 6 | 6.5929 CFU/mL | Standard Deviation 2.3668 |
Secondary
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)
Time frame: Weeks 0, 6
Population: N=110 (GV), 110 (Nystatin) wk 0 N= 96 (GV), 95 (Nystatin) wk 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 0: Excellent | 1 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 6: Fair | 18 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 0: Very Good | 13 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 6: Good | 42 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 0: Good | 52 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 6: Poor | 2 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 0: Fair | 39 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 6: Very Good | 29 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 0: Poor | 5 participants |
| Arm A: Topical GV Solution | Self-Assessment of General Health | Week 6: Excellent | 5 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 0: Poor | 9 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 6: Very Good | 25 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 6: Good | 42 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 6: Fair | 18 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 6: Poor | 3 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 0: Excellent | 4 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 0: Very Good | 11 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 0: Good | 56 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 0: Fair | 30 participants |
| Arm B: Nystatin Oral Suspension | Self-Assessment of General Health | Week 6: Excellent | 7 participants |
Secondary
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.)
Time frame: After 14 days of treatment
Population: The analysis for tolerance was based on 208 observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Topical GV Solution | Tolerance | No side effects, no changes in treatment | 100 participants |
| Arm A: Topical GV Solution | Tolerance | Some side effects, no changes in treatment | 3 participants |
| Arm A: Topical GV Solution | Tolerance | Some side effects, treatment interruption | 0 participants |
| Arm B: Nystatin Oral Suspension | Tolerance | No side effects, no changes in treatment | 98 participants |
| Arm B: Nystatin Oral Suspension | Tolerance | Some side effects, no changes in treatment | 6 participants |
| Arm B: Nystatin Oral Suspension | Tolerance | Some side effects, treatment interruption | 1 participants |