AIDS, Histoplasmosis
Conditions
Keywords
Histoplasmosis, AIDS, Liposomal amphotericin B, High dose therapy
Brief summary
Disseminated histoplasmosis (DH) is one of the major AIDS-defining infections responsible for high mortality rates in HIV-infected patients. Liposomal amphotericin B (L-AmB) is considered the therapy of choice for AIDS-associated histoplasmosis.However, many patients in Latin America are still treated with high doses of deoxycholate amphotericin B (d-AmB) for long periods. These regimens are associated with toxicity and thus reduced efficacy. Therefore, a better treatment strategy is necessary to improve the activity of this amphotericin B treatment. Treatment with a high dose of L-AmB for short periods (rather than standard doses for longer periods) is a promising approach considering that the antifungal effect of amphotericin B depends on peak concentrations. This randomized open-label Phase II study aims to determinate and to compare the activity and safety of three L-AmB regimens, as induction therapy for DH in AIDS patients.
Detailed description
This is a prospective randomized non-comparative multicenter open label trial of induction therapy with LAmB for DH in AIDS patients, followed by oral therapy with itraconazole. The sample size planned is 99 patients of both sexes, older than 18 years (33 patients per study arm), infected with HIV and with confirmed diagnosis for DH. This sample size considers 10% of dropout. The study will be conducted in accordance with the Helsinki Declaration, as well as the Standards national and international Guidelines for Good Clinical Practices. Eight research centres in Brazil will competitively recruit patients: Santa Casa de Misericórdia de Porto Alegre (Porto Alegre; Dr Alessandro C. Pasqualotto), Hospital de Clínicas de Porto Alegre (Porto Alegre; Dr Diego R. Falci), Hospital Nossa Senhora da Conceição (Porto Alegre; Dr Marineide Melo), Hospital de Doenças Tropicais (Goiânia; Dr Cassia S. de Miranda Godoy), Hospital São José de Doenças Infecciosas (Fortaleza; Dr Terezinha M. J. Silva Leitão), and Hospital Giselda Trigueiro (Natal, Dr Monica B. Bay), Hospital Universitário Osvaldo Cruz (Recife, Dr. Filipe Prohaska Batista) e Instituto de Infectologia Emília Ribas (São Paulo, Dr. José Ernesto Vidal Bermudez). AIDS patients with DH will be randomized to one of three study arms: (i) single IV dose of 10 mg/kg of L-AmB; (ii) single IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3; (iii) IV dose of 3 mg/kg of L-AmB for 2 weeks. Induction therapy will be followed in all patients by oral therapy with itraconazole capsules at 400 mg/daily for a year, azole drug which is already therapy of choice for consolidation of histoplasmosis, according to national and international Guidelines.
Interventions
DRUG2 doses of L-AmB
(ii) IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3;
DRUG2 weeks of L-AmB
(iii) IV dose of 3 mg/kg of L-AmB for 2 weeks.
DRUGsingle dose of L-AmB
(i) single IV dose of 10 mg/kg of L-AmB on day 1;
Sponsors
Hospital de Clinicas de Porto Alegre
Hospital Nossa Senhora da Conceicao
Irmandade Santa Casa de Misericórdia de Porto Alegre
Alessandro Pasqualotto
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
* Adult (\> 18 years) HIV-infected hospitalized patients diagnosed with HD by the means of (i) urine Histoplasma positive antigen (IMMY® monoclonal antibody test); (ii) confirmation by classical mycological methods (microscopy, culture or histopathology); or (iii) Histoplasma positive qualitative polymerase chain reaction (PCR) in bronchoalveolar lavage samples, bone marrow aspirates or tissue samples. * Patients will be included despite of the use of antiretroviral therapy (ART). * Understanding and signed the Informed Consent Form.
Exclusion criteria
* Patients with previous diagnosis of histoplasmosis. * Pregnant or lactating women. * Patients with renal insufficiency (serum creatinine and urea \> 1.5x the upper limit of normal). * Abnormal aminotransferases (up to \> 3x the upper limit of normal) and patients with a severe prior reaction to polyene antifungal. * Patients who have received more than one dose of a polyene antifungal in the last 48 hours. * Patients who refuse to participate in the study. * Patients diagnosed with histoplasmosis that affect the central nervous system. * Patients who, at the trial of the attending physician, are expected to die within 48 hours. * Patients diagnosed with tuberculosis. * Patients with any disease or condition that, in the opinion of the investigator, may interfere with the assessments or participation in the study. * Patients receiving drugs that cause significant (relative or absolute) drug interaction with Itraconazole.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response | day 14 | Maximum daily temperature lower than 37.8 °C |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Mortality | day 14 | Mortality rates attributed to the cause of death that is not directly and only related to histoplasmosis |
Countries
Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Dose of L-AmB single IV dose of 10 mg/kg of L-AmB on day 1;
N=40 | 40 |
| 2 Doses of L-AmB IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3;
N=39 | 39 |
| 2 Weeks of L-AmB IV dose of 3 mg/kg of L-AmB for 2 weeks.
N=39 | 39 |
| Total | 118 |
Baseline characteristics
| Characteristic | Single Dose of L-AmB | Total | 2 Weeks of L-AmB | 2 Doses of L-AmB |
|---|---|---|---|---|
| Age, Continuous | 40 years | 39 years | 39 years | 39 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 40 Participants | 118 Participants | 39 Participants | 39 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Brazil | 40 participants | 118 participants | 39 participants | 39 participants |
| Sex: Female, Male Female | 5 Participants | 21 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 35 Participants | 97 Participants | 34 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 38 | 8 / 37 | 3 / 38 |
| other Total, other adverse events | 34 / 38 | 27 / 37 | 34 / 38 |
| serious Total, serious adverse events | 1 / 38 | 6 / 37 | 4 / 38 |
Outcome results
Primary
Clinical Response
Maximum daily temperature lower than 37.8 °C
Time frame: day 14
Population: Clinical response on day 14 was 84.0% for the single-dose L-AmB arm-(32/38-1 patient was excluded due to concomitant tuberculosis, and another was lost to follow-up), 69.0% (25/36) for the 2-dose L-AmB arm, with 3 patients being excluded from efficacy analysis (1 individual with central nervous system histoplasmosis, 1 patient with concomitant tuberculosis, and another patient lost to follow-up); in the control group, response rate was 74.0% (28/38), with 1 patient being lost to follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of L-AmB | Clinical Response | 32 Participants |
| 2 Doses of L-AmB | Clinical Response | 25 Participants |
| 2 Weeks of L-AmB | Clinical Response | 28 Participants |
Secondary
Overall Mortality
Mortality rates attributed to the cause of death that is not directly and only related to histoplasmosis
Time frame: day 14
Population: Overall survival on day 14 were, respectively: 89.0% (34/38) (single-dose L-AmB-with 2 patients being excluded from efficacy analysis); 78.0% (29/37) (2-dose L-AmB arm-2 patients excluded from efficacy analysis); and 89.7% (35/38) (control group-1 patient excluded from efficacy analysis).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of L-AmB | Overall Mortality | 4 Participants |
| 2 Doses of L-AmB | Overall Mortality | 8 Participants |
| 2 Weeks of L-AmB | Overall Mortality | 3 Participants |