HIV Infection
Conditions
Keywords
HIV, women, androgen, Treatment Experienced
Brief summary
Androgen deficiency in HIV-infected women is associated with sarcopenia and may cause critical reductions in physical functioning and reduced bone density. The effects of long-term androgen therapy on lean body mass, bone density and other clinical endpoints including quality of life, functional status and neurocognitive function in HIV-infected women are not known.
Detailed description
We will perform an 18-month randomized, double-blinded, placebo-controlled study among relatively androgen deficient women with HIV, to determine the effects of testosterone administration on lean body mass. The administered dose will be 300 micrograms twice a week vs. identical placebo in the form of a transdermal preparation. Secondary endpoints include effects on bone density, quality of life, neurocognitive function and menstrual function. Open label administration at 300 micrograms twice a week will be initiated for 12 months in all subjects following the randomized portion of the study. Assuming a 15% dropout rate and 25 randomized patients, the probability is 80 percent that the study will detect a treatment difference at a two sided 5.000 percent significance level, if the true difference between the treatments is 2.7 kg. This is based on the assumption that the standard deviation of the response variable, lean body mass by DEXA, is 2.3 kg, as was shown by Choi et al1 over 12 weeks in HIV-infected women at the same dose of 300 ug 2x/week.
Interventions
DRUG1 Transdermal Testosterone (Patch)
300 micrograms twice a week
DRUG2 Placebo Patch
Placebo patch (0 micrograms of testosterone) applied twice a week
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Female 18 - 55 * BMI less than or equal to 26 * HIV-infected * Androgen deficient, with free testosterone \< 3 pg/mL * Stable antiretroviral regimen for 3 months prior to study * Tubal ligation, hysterectomy, or verbalized understanding of appropriate barrier contraception methods. Subjects will be counseled in appropriate barrier contraception methods and the counseling will be documented.
Exclusion criteria
* Use of anabolic agent, including testosterone, GH or other preparations within 3 months of the study. * Use of megestrol acetate within 3 months of the study * Use of estrogen or any preparation known to affect bone density or bone turnover.This includes oral contraceptives, depo provera or combined progesterone-estrogen injections, and transdermal contraceptive patches. * Pregnant or breast-feeding * Hgb \< 9.0 mg/dL * Current participation in another research study conducted by this investigator or past participation in the DHEA study funded by the same grant as this protocol. * Creatinine \> 1.5 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lean Body Mass | Baseline (time 0) to 18 months | Represents change in measure from baseline to 18 months. 18 month mean and standard error of the mean for lean body mass measured by dual energy absorptiometry (DEXA)scan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life/Depression: Becks Depression Inventory | Baseline (time 0) to 18 months | Represents change in the mean score from baseline to 18 months. Depression was evaluated with the Beck's Depression Inventory (BDI). The BDI is a 21-item self-report instrument used to assess the presence and severity of symptoms of depression. A Total score in the range of 0-13 is considered minimal, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. |
| Quality of Life/Sexual Function: Brief Index of Sexual Function (BISF-W) Domain 7: Problems Affecting Sexual Function | Baseline (time 0) to 18 months | Represents change in measure from baseline to 18 months. The BISF is 22 items with seven domains: Thoughts and Desires, Arousal, Frequency of Sexual Activity, Receptivity/Initiation, Pleasure, Relationship Satisfaction, and Problems Affecting Sexual Function. Data from Domain 7: Problems Affecting Sexual Function is reported. The score range for this domain is -16 to 75,a higher score indicates greater sexual function. |
| Safety: Number of Subjects Reporting a Skin Reaction to the Patch | Baseline (time 0) to 18 months | Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant. |
| Safety: Number of Subjects Reporting a Change in Hair Pattern (Increased Hair on Chin, Upper Lip, Chest, Abdomen, Fore Arms, and Legs) | Baseline (time 0) to 18 months | Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant. |
| Bone Mineral Density of the Hip | Baseline (time 0) to 18 months | Represents change in measure from baseline to 18 months. 18 month mean and standard error of the mean for bone mineral density of the hip measured by dual energy absorptiometry (DEXA)scan. |
| Safety: Number of Subjects Reporting a Change in Menstrual Status (Reported More Than One Period in 1 Month or Missed a Period During a Monthly Cycle) | Baseline (time 0) to 18 months | Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant. |
| Neurocognitive Function: Hopkins Verbal Learning Test-revised,Total Recall Z Score Represents Change in Z Score From Baseline to 18 Months. | Baseline (time 0) to 18 months | This test assesses verbal learning and memory. Subjects are given a list of 12 words and asked to repeat as many words as they can recall during 3 separate trials. The Total Recall Z score is calculated based on the sum of total correct responses for Trials 1,2,& 3. A Z score of 0 equals the 50 percentile, a Z score of 1 is 1 standard deviation above the mean and a Z score of -1 is 1 standard deviation below the mean. The lowest and highest T scores for the HVLT-R are ≤20 and ≥80. This correlates to lowest and highest Z scores of ≤ -3.0 and ≥3.0. A lower Z score is indicative of poor recall. |
| Strength: Total Knee Flexion Performed Via Quantitative Muscle Function Testing. | Baseline (time 0) to 18 months | Represents change in isometric force (measured in kilograms) from baseline to 18 months. Peak isometric force of total knee flexion and extension were measured on the best of 2 repetitions for which subjects held a maximum contraction for 5 seconds. |
| Strength: Total Knee Extension Performed Via Quantitative Muscle Function Testing. | Baseline (time 0) to 18 months | Represents change in isometric force (measured in kilograms) from baseline to 18 months. Peak isometric force of total knee flexion and extension were measured on the best of 2 repetitions for which subjects held a maximum contraction for 5 seconds. |
| Safety: Number of Subjects Reporting Acne | Baseline (time 0) to 18 months | Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in August, 2004 and continued through October, 2006. Subjects were recruited via poster advertisement at community health centers, hospitals, and AIDS Service Organizations, as well as newspaper advertisement and provider referral.
Pre-assignment details
Prior to randomization at the baseline visit, each subject's doctor was contacted to confirm safety of study enrollment. Subjects age 40 and older were required to have a mammogram performed within one year of study enrollment and provide results. Eligible subjects completed a pregnancy test at each visit and were excluded for a positive test.
Participants by arm
| Arm | Count |
|---|---|
| Transdermal Testosterone (Patch) 300 micrograms applied twice a week | 13 |
| Placebo Patch (Identical in Appearance) placebo patch (0 micrograms of testosterone)applied twice a week | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo Patch (Identical in Appearance) | Transdermal Testosterone (Patch) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 13 Participants | 25 Participants |
| Age Continuous | 43 years STANDARD_DEVIATION 1 | 45 years STANDARD_DEVIATION 2 | 44 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 12 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 13 | 6 / 12 |
| serious Total, serious adverse events | 1 / 13 | 1 / 12 |
Outcome results
Primary
Lean Body Mass
Represents change in measure from baseline to 18 months. 18 month mean and standard error of the mean for lean body mass measured by dual energy absorptiometry (DEXA)scan.
Time frame: Baseline (time 0) to 18 months
Population: Responses at 9 and 18 months were pooled as the post treatment repeated measures. All data were included in the analysis, including 9 month data from the 4 subjects who discontinued after the 9 month visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Lean Body Mass | 1.8 kilograms | Standard Error 0.5 |
| Placebo Patch (Identical in Appearance) | Lean Body Mass | 0.8 kilograms | Standard Error 0.9 |
p-value: 0.04longitudinal linear mixed effects model
Secondary
Bone Mineral Density of the Hip
Represents change in measure from baseline to 18 months. 18 month mean and standard error of the mean for bone mineral density of the hip measured by dual energy absorptiometry (DEXA)scan.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Bone Mineral Density of the Hip | 0.01 grams per centimeter squared | Standard Error 0.01 |
| Placebo Patch (Identical in Appearance) | Bone Mineral Density of the Hip | -0.01 grams per centimeter squared | Standard Error 0.01 |
Comparison: The study was powered at 80% to detect a significant treatment difference of 2.7 kg in lean body mass between the two groups with 25 randomized patients and a 15% assumed dropout rate, using a two sided 5.0 percent significance level.p-value: 0.02Longitudinal linear mixed effects model
Secondary
Neurocognitive Function: Hopkins Verbal Learning Test-revised,Total Recall Z Score Represents Change in Z Score From Baseline to 18 Months.
This test assesses verbal learning and memory. Subjects are given a list of 12 words and asked to repeat as many words as they can recall during 3 separate trials. The Total Recall Z score is calculated based on the sum of total correct responses for Trials 1,2,& 3. A Z score of 0 equals the 50 percentile, a Z score of 1 is 1 standard deviation above the mean and a Z score of -1 is 1 standard deviation below the mean. The lowest and highest T scores for the HVLT-R are ≤20 and ≥80. This correlates to lowest and highest Z scores of ≤ -3.0 and ≥3.0. A lower Z score is indicative of poor recall.
Time frame: Baseline (time 0) to 18 months
Population: data not available for all subjects as some did not wish to complete the testing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Neurocognitive Function: Hopkins Verbal Learning Test-revised,Total Recall Z Score Represents Change in Z Score From Baseline to 18 Months. | -0.21 Units on a scale | Standard Error 0.41 |
| Placebo Patch (Identical in Appearance) | Neurocognitive Function: Hopkins Verbal Learning Test-revised,Total Recall Z Score Represents Change in Z Score From Baseline to 18 Months. | 0.50 Units on a scale | Standard Error 0.37 |
p-value: 0.26t-test, 2 sided
Secondary
Quality of Life/Depression: Becks Depression Inventory
Represents change in the mean score from baseline to 18 months. Depression was evaluated with the Beck's Depression Inventory (BDI). The BDI is a 21-item self-report instrument used to assess the presence and severity of symptoms of depression. A Total score in the range of 0-13 is considered minimal, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Quality of Life/Depression: Becks Depression Inventory | -6.8 Units on a scale | Standard Error 2.2 |
| Placebo Patch (Identical in Appearance) | Quality of Life/Depression: Becks Depression Inventory | -1.9 Units on a scale | Standard Error 3.1 |
Comparison: The study was powered at 80% to detect a significant treatment difference of 2.7 kg in lean body mass between the two groups with 25 randomized patients and a 15% assumed dropout rate, using a two sided 5.0 percent significance level.p-value: 0.02Longitudinal mixed methods model
Secondary
Quality of Life/Sexual Function: Brief Index of Sexual Function (BISF-W) Domain 7: Problems Affecting Sexual Function
Represents change in measure from baseline to 18 months. The BISF is 22 items with seven domains: Thoughts and Desires, Arousal, Frequency of Sexual Activity, Receptivity/Initiation, Pleasure, Relationship Satisfaction, and Problems Affecting Sexual Function. Data from Domain 7: Problems Affecting Sexual Function is reported. The score range for this domain is -16 to 75,a higher score indicates greater sexual function.
Time frame: Baseline (time 0) to 18 months
Population: data not available for all subjects as some did not wish to complete the questionnaire
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Quality of Life/Sexual Function: Brief Index of Sexual Function (BISF-W) Domain 7: Problems Affecting Sexual Function | -1.8 Units on a scale | Standard Error 0.8 |
| Placebo Patch (Identical in Appearance) | Quality of Life/Sexual Function: Brief Index of Sexual Function (BISF-W) Domain 7: Problems Affecting Sexual Function | 0.5 Units on a scale | Standard Error 0.5 |
Comparison: The study was powered at 80% to detect a significant treatment difference of 2.7 kg in lean body mass between the two groups with 25 randomized patients and a 15% assumed dropout rate, using a two sided 5.0 percent significance level.p-value: 0.01Longitudinal mixed methods model
Secondary
Safety: Number of Subjects Reporting a Change in Hair Pattern (Increased Hair on Chin, Upper Lip, Chest, Abdomen, Fore Arms, and Legs)
Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transdermal Testosterone (Patch) | Safety: Number of Subjects Reporting a Change in Hair Pattern (Increased Hair on Chin, Upper Lip, Chest, Abdomen, Fore Arms, and Legs) | 2 participants |
| Placebo Patch (Identical in Appearance) | Safety: Number of Subjects Reporting a Change in Hair Pattern (Increased Hair on Chin, Upper Lip, Chest, Abdomen, Fore Arms, and Legs) | 4 participants |
p-value: 0.29Chi-squared
Secondary
Safety: Number of Subjects Reporting a Change in Menstrual Status (Reported More Than One Period in 1 Month or Missed a Period During a Monthly Cycle)
Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transdermal Testosterone (Patch) | Safety: Number of Subjects Reporting a Change in Menstrual Status (Reported More Than One Period in 1 Month or Missed a Period During a Monthly Cycle) | 6 participants |
| Placebo Patch (Identical in Appearance) | Safety: Number of Subjects Reporting a Change in Menstrual Status (Reported More Than One Period in 1 Month or Missed a Period During a Monthly Cycle) | 9 participants |
p-value: 0.14Chi-squared
Secondary
Safety: Number of Subjects Reporting Acne
Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transdermal Testosterone (Patch) | Safety: Number of Subjects Reporting Acne | 4 participants |
| Placebo Patch (Identical in Appearance) | Safety: Number of Subjects Reporting Acne | 3 participants |
p-value: 0.75Chi-squared
Secondary
Safety: Number of Subjects Reporting a Skin Reaction to the Patch
Represents number of subjects who reported this symptom from baseline to 18 months. Every 6 weeks,subjects were counseled on appropriate barrier contraception methods and a urine pregnancy was performed. Subjects who experienced increased hair growth (facial hair) could remain in the study on a lower dose of testosterone (1 patch per week), but dose reductions were not necessary and full dosing was continued throughout the study for all subjects. Changes in menstrual status, missed periods and/or irregular bleeding, were noted and reported back to the primary care physician if significant.
Time frame: Baseline (time 0) to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transdermal Testosterone (Patch) | Safety: Number of Subjects Reporting a Skin Reaction to the Patch | 4 participants |
| Placebo Patch (Identical in Appearance) | Safety: Number of Subjects Reporting a Skin Reaction to the Patch | 1 participants |
p-value: 0.16Chi-squared
Secondary
Strength: Total Knee Extension Performed Via Quantitative Muscle Function Testing.
Represents change in isometric force (measured in kilograms) from baseline to 18 months. Peak isometric force of total knee flexion and extension were measured on the best of 2 repetitions for which subjects held a maximum contraction for 5 seconds.
Time frame: Baseline (time 0) to 18 months
Population: data not available for all subjects due to malfunctioning equipment at some sessions, and some subjects did not wish to complete testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Strength: Total Knee Extension Performed Via Quantitative Muscle Function Testing. | 28.0 kilograms | Standard Error 7.6 |
| Placebo Patch (Identical in Appearance) | Strength: Total Knee Extension Performed Via Quantitative Muscle Function Testing. | 26.9 kilograms | Standard Error 10.7 |
p-value: 0.94t-test, 2 sided
Secondary
Strength: Total Knee Flexion Performed Via Quantitative Muscle Function Testing.
Represents change in isometric force (measured in kilograms) from baseline to 18 months. Peak isometric force of total knee flexion and extension were measured on the best of 2 repetitions for which subjects held a maximum contraction for 5 seconds.
Time frame: Baseline (time 0) to 18 months
Population: data not available for all subjects due to malfunctioning equipment at some sessions, and some subjects did not wish to complete testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone (Patch) | Strength: Total Knee Flexion Performed Via Quantitative Muscle Function Testing. | 28.5 kilograms | Standard Error 11 |
| Placebo Patch (Identical in Appearance) | Strength: Total Knee Flexion Performed Via Quantitative Muscle Function Testing. | 11.0 kilograms | Standard Error 4.9 |
p-value: 0.22t-test, 2 sided