Ignite Creation Date:
2024-05-05 @ 12:11 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00260143
Status:
COMPLETED
Last Update Posted:
2018-03-09
First Post:
2005-11-29
Brief Title:
Testosterone and Physical Function in HIV Men
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
Testosterone and Physical Function in HIV Associate Weight Loss
Status:
COMPLETED
Status Verified Date:
2018-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Men infected with the HIV virus the virus that causes AIDS often lose weight even though they may try to eat more food to gain weight The reasons for this weight loss are not clear Many men with HIV have low levels of testosterone in their blood Testosterone is a hormone that is naturally produced in the bodies of both men and women and has important effects on building muscle and bone mass The purpose of this study is to find out if providing additional testosterone to HIV infected men who have low testosterone can help them gain weight increase their muscle mass and feel better The study will also help see if testosterone improves the efficiency with which your body produces and uses energy including fat The dose of testosterone being used in this study will raise testosterone levels in the blood to higher than normal levels 2-3 times normal level
Detailed Description:
Purpose Although the prevalence of weight loss in HIV-infected individuals has decreased in the developed world with the availability of highly active antiretroviral therapy it continues to be a significant problem worldwide and in the USA The pathophysiology of weight loss in HIV-infected individuals is undoubtedly complex decreased energy intake metabolic dysregulation intercurrent opportunistic infections gastrointestinal infections and malabsorption and hormonal abnormalities all contribute to the multifactorial origin of weight loss Although patients with HIV-infection may lose both fat and lean tissue the loss of lean body mass is an important aspect of the weight loss associated with wasting Weight loss in HIV-infected patients is a good predictor of survival risk of hospitalization and opportunistic infections The magnitude of depletion of nonfat tissues is an important determinant of the time of death in AIDS One correctable factor in the complex pathophysiology of sarcopenia in HIV-infection is androgen deficiency There is a high prevalence of low testosterone levels in HIV-infected men Spontaneous and experimentally-induced androgen-deficiency in young men is associated with decreased muscle mass and strength Testosterone replacement increases lean body mass muscle strength and muscle protein synthesis in androgen-deficient young men The studies supported by this grant in the previous budget period and others have demonstrated that testosterone replacement of HIV-infected men with weight loss and low testosterone levels is associated with an increase in fat-free mass and maximal voluntary muscle strength Similarly testosterone replacement of older men with low testosterone levels is associated with gains in fat-free mass and grip strength However it remains unknown whether testosterone-induced increases in fat-free mass and maximal voluntary strength are associated with clinically meaningful improvements in physical function and perceptions of physical function Therefore the primary objective of this competing renewal application is to determine if testosterone replacement of HIV-infected men with weight loss and low testosterone levels will improve objective measures of physical function perceptions of physical function and body image Our previous study demonstrated that testosterone replacement in HIV-infected men with low testosterone levels is associated with an increase in maximal muscle strength However testosterone effects on other important measures of muscle performance such as power and fatigability that are important determinants of physical function are not known A second objective is to determine if testosterone replacement improves lower extremity power and fatigability
The mechanisms by which testosterone increases muscle mass also remain unknown Therefore a third objective is to elucidate the mechanisms by which testosterone increases muscle mass and to determine its effects on energy balance
Design The study will be a randomized placebo-controlled double-blind study of HIV-infected men
Sample Size Estimate We estimate that approximately 50 men will be needed in each treatment group to test the proposed hypotheses total 100 subjects
Location Subjects will be seen at the KingDrew Medical Center CRC 1720 E 120th Street Los Angeles CA 90059 for all their visits
Randomization and Subject Assignment Subjects who meet the eligibility criteria will be randomly assigned to receive either testosterone enanthate 300 mgweekly intramuscularly or placebo
Experimental Protocol The study will consist of a screening phase a 2-week control period a 16-week treatment phase and a 4-month recovery phase We have selected a 16-week treatment period because the effects of testosterone on fat-free mass and muscle strength become manifest within this time period in healthy hypogonadal men eugonadal men and in HIV-infected men with weight loss
Inclusion criteria A Is the subject HIV positive male and 18-60 years
B Is the subject wasting
a progressive weight loss within the previous 6 months of between 5-15 of body weight calculated by the equation a-ba x 100 ahighest weight in last6 months and b present weight at screening or a BMI between 17 and 20 an actual body weight at screening of 85-95 of the lower limit of ideal weight C Is there an energy intake of calories of at least 80 of the estimated energy requirements D Is the subject On stable and potent antiretroviral therapy for at least 12 weeks and in whom in the opinion of the primary care provider a change in antiretroviral therapy is unlikely in the next 4 months Stable therapy may include those not on any antiretroviral therapies and whom in the opinion of the primary care provider will not be starting antiretroviral therapy in the next 4 months E Does the subject have a CD4 cell count 50mm3 or a viral load HIV- copy number 10000ml F Is the subject able and willing to comply with the trial protocol G Is the subjects testosterone levels 400ngdL H Is the subject able and willing to give informed consent in writing
Exclusion criteria
A Does the subject have concurrent severe lipodystrophy according to the subject and the investigator B Does the subject have a history of hypersensitivity to anabolic steroids or to growth hormone C Does the subject have a history of prostatic or mammary cancer D Did the subject use nandrolone decanoate growth hormone androgen treatment or any other anabolic or appetite stimulating agents with the past 6 months E Did the subject chronically use systematic corticosteroids at least one month in the previous 6 months except for topical applications F Does the subject have significant cardiac renal hepatic or other diseases that in the opinion of the Investigator may put the subject at risk if entered onto the trial or prevent successful completion of the trial 15 Has the subject had an AIDS defining illness CDC HIV Classification 1993 Clinical Category Cwithin the previous 3 months except HIV wasting syndrome G Does the subject have a malignancy other that Kaposis Sarcoma localized to the skin H Has the subject been involved in vigorous resistance exercise training programs body buildingin the last 3 months 18 Dose the subject have diabetes mellitus I Is the active drug andor alcohol use which would interfere with compliance for the study according to the investigator J Did the subject receive investigational treatment except stable antiretroviral investigational drug in the last 12 weeks
K Has the subject any of the following blood tests results
Liver function test ALATSGPT ASATSCOT 5x the upper limit of the normal range ULN Cholesterol total 3x ULN Alkaline Phosphotase 5 ULN or 3xULN if bilirubin is above normal Serum Creatine 2x ULN Platelet count 50x 109 L Haemoglobin 80 gL 18gdL PSA 4 ngml Hct 48 L Concomitant meds as exclusion rhGh IGF-1 other anabolic agents appetite simulants testosterone ketoconazole dilantin phenobarbital creatin high dose of amino-acid supplements protein supplements androstenedione DHEA marinol M Severe symptoms of BPH American Urological Association AUA symptom index score of 14prostate nodule or induration on digital rectal examination DRE unless there has been a negative trans-rectal biopsy with last 3 months N Untreated severe obstructive sleep apnea as assessed by Berlin Symptom score O Limited neuromuscular joint or some disease or history of stroke with residual neurological defect that would preclude measurements of muscle strength of physical function P Significant diarrhea defined as 6 or more stools per day with recent change in bowel habits towards more frequent stools especially if associated with weight loss and fever
Outcome Measures
Our primary outcome measure is change from baseline in three important measures of physical function stair climbing power walking speed and lifting task These measures were selected because they are important for activities of daily living
We will measure changes in maximal voluntary muscle strength power and muscle fatigability using the leg press exercise This exercise was selected because it utilizes large muscle groups of the lower extremity that are important for functional activities and is androgen-responsive 39
Change in fat-free mass by dual energy X-ray absorptiometry DEXA Previous studies have already established that testosterone replacement increases fat-free mass This study is focused on measures of muscle performance and physical function therefore we have not included more detailed assessment of body composition by deuterium water and sodium bromide
Muscle volume of the non-dominant thigh will be measured by magnetic resonance imaging
Intramuscular concentrations of myostatin IGF-I and IGFBP-4 mRNA will be measured by RT-PCR and protein by western blot analysis The ubiquitin and C3 and C9 proteasome mRNA will be measured by northern analysis
Changes in perceptions of physical function and body image In addition to using global health related quality of life instruments which have many domains that are not androgen-responsive we will focus on assessment of perceptions of physical function fatigue and body image These instruments have been demonstrated to be responsive to androgen replacement in older men with low testosterone levels 48
Total and free testosterone and dihydrotestosterone levels will be measured as markers of testosterone bioavailability Serum LH FSH and SHBG levels will be measured as markers of androgen action
Safety Measures Plasma lipids apolipoproteins and lipoprotein particles will be measured to assess testosterone effects on these markers of cardiovascular risk profile Hemoglobin liver enzymes ALT AST bilirubin GGT alkaline phosphatase serum PSA digital rectal examination and AUA BPH symptom score will be monitored as safety parameters
Energy Expenditure We will measure resting energy expenditure by indirect calorimetry using a novel handheld device known as the MedGem HealtheTech Golden Colorado Neiman et al Neiman DC Trone GA Austin MD A new handheld device for measuring resting metabolic rate and oxygen consumption J Am Diet Assoc 2003 1035 588-593 have validated this device in 63 males adult men and women with BMI between 19 and 56 kgm2 against Douglas bags with duplicate measurements on each of two nonconsecutive days within a 14 day period Since there were no differences between tests or between days for either the MedGem or the Douglas bags the four tests for each device were pooled The mean difference for the pooled results between MedGem and Douglas bags was 7 Kcalday 04 The thermic effect of food will be measured by indirect calorimetry using the same MedGem apparatus with measurements during the last 15 minutes of each of five hours after ingestion of a standardized meal We will also measure resting energy expenditure by use of the Deltatrac II device After subjects have rested in bed for at least 5 minutes oxygen consumption and carbon dioxide production will be measured using a ventilated canopy system for 20 minutes Deltatrac II
The rates of ATP synthesis will be measured by 31P and 13C nuclear magnetic resonance NMR spectroscopy The rates of substrate oxidation in the citric acid cycle will be estimated from the specific activity of 4-13C glutamate during steady state infusion of 13C-1 acetate The ratio of ATP synthesis measured by NMR spectroscopy and fuel oxidation measured by steady state 13-1 acetate infusion will be used as a measure of mitochondrial coupling of oxidation and phosphorylation In addition we will also measure mitochondrial energy coupling in isolated muscle fibers obtained from biopsies of vastus lateralis directly by measuring PO ration using an oxygen electrode
Body core temperature will be measured by obtaining rectal temperature using a precise and accurate thermo-couple thermister
Free fatty acid flux and adipose tissue lipolysis will be measured using 1-13C palmitate and2H5 glycerol isotope infusion respectively Fat oxidation will be measured by the release and quantitation of 1-13C-CO2 released during exhalation after infusion of the 1-13C palmitate 2H2 glucose isotope will be used to measure insulin sensitivity One to two weeks before the second palmitate infusion a single injection of sodium 1-13C bicarbonate 176 µmolkg 90 enriched sterile and pyrogen free Mass Trace will be used to calculate the acetate correction factor ACF The ACF accounts for 13C-label lost in exchange reactions in the tricarboxylic acid cycle After 135 min of tracer equilibration breath samples will be obtained in 15-min intervals up to 150 minutes and 5 minute intervals from 150 to 180 minutes Non-esterified free fatty acid levels will be measured at baseline mid-study day 56 and at the end of treatment by a fasting blood measurement
The mechanisms by which testosterone increases muscle mass also remain unknown Therefore a third objective is to elucidate the mechanisms by which testosterone increases muscle mass and to determine its effects on energy balance
Design The study will be a randomized placebo-controlled double-blind study of HIV-infected men
Sample Size Estimate We estimate that approximately 50 men will be needed in each treatment group to test the proposed hypotheses total 100 subjects
Location Subjects will be seen at the KingDrew Medical Center CRC 1720 E 120th Street Los Angeles CA 90059 for all their visits
Randomization and Subject Assignment Subjects who meet the eligibility criteria will be randomly assigned to receive either testosterone enanthate 300 mgweekly intramuscularly or placebo
Experimental Protocol The study will consist of a screening phase a 2-week control period a 16-week treatment phase and a 4-month recovery phase We have selected a 16-week treatment period because the effects of testosterone on fat-free mass and muscle strength become manifest within this time period in healthy hypogonadal men eugonadal men and in HIV-infected men with weight loss
Inclusion criteria A Is the subject HIV positive male and 18-60 years
B Is the subject wasting
a progressive weight loss within the previous 6 months of between 5-15 of body weight calculated by the equation a-ba x 100 ahighest weight in last6 months and b present weight at screening or a BMI between 17 and 20 an actual body weight at screening of 85-95 of the lower limit of ideal weight C Is there an energy intake of calories of at least 80 of the estimated energy requirements D Is the subject On stable and potent antiretroviral therapy for at least 12 weeks and in whom in the opinion of the primary care provider a change in antiretroviral therapy is unlikely in the next 4 months Stable therapy may include those not on any antiretroviral therapies and whom in the opinion of the primary care provider will not be starting antiretroviral therapy in the next 4 months E Does the subject have a CD4 cell count 50mm3 or a viral load HIV- copy number 10000ml F Is the subject able and willing to comply with the trial protocol G Is the subjects testosterone levels 400ngdL H Is the subject able and willing to give informed consent in writing
Exclusion criteria
A Does the subject have concurrent severe lipodystrophy according to the subject and the investigator B Does the subject have a history of hypersensitivity to anabolic steroids or to growth hormone C Does the subject have a history of prostatic or mammary cancer D Did the subject use nandrolone decanoate growth hormone androgen treatment or any other anabolic or appetite stimulating agents with the past 6 months E Did the subject chronically use systematic corticosteroids at least one month in the previous 6 months except for topical applications F Does the subject have significant cardiac renal hepatic or other diseases that in the opinion of the Investigator may put the subject at risk if entered onto the trial or prevent successful completion of the trial 15 Has the subject had an AIDS defining illness CDC HIV Classification 1993 Clinical Category Cwithin the previous 3 months except HIV wasting syndrome G Does the subject have a malignancy other that Kaposis Sarcoma localized to the skin H Has the subject been involved in vigorous resistance exercise training programs body buildingin the last 3 months 18 Dose the subject have diabetes mellitus I Is the active drug andor alcohol use which would interfere with compliance for the study according to the investigator J Did the subject receive investigational treatment except stable antiretroviral investigational drug in the last 12 weeks
K Has the subject any of the following blood tests results
Liver function test ALATSGPT ASATSCOT 5x the upper limit of the normal range ULN Cholesterol total 3x ULN Alkaline Phosphotase 5 ULN or 3xULN if bilirubin is above normal Serum Creatine 2x ULN Platelet count 50x 109 L Haemoglobin 80 gL 18gdL PSA 4 ngml Hct 48 L Concomitant meds as exclusion rhGh IGF-1 other anabolic agents appetite simulants testosterone ketoconazole dilantin phenobarbital creatin high dose of amino-acid supplements protein supplements androstenedione DHEA marinol M Severe symptoms of BPH American Urological Association AUA symptom index score of 14prostate nodule or induration on digital rectal examination DRE unless there has been a negative trans-rectal biopsy with last 3 months N Untreated severe obstructive sleep apnea as assessed by Berlin Symptom score O Limited neuromuscular joint or some disease or history of stroke with residual neurological defect that would preclude measurements of muscle strength of physical function P Significant diarrhea defined as 6 or more stools per day with recent change in bowel habits towards more frequent stools especially if associated with weight loss and fever
Outcome Measures
Our primary outcome measure is change from baseline in three important measures of physical function stair climbing power walking speed and lifting task These measures were selected because they are important for activities of daily living
We will measure changes in maximal voluntary muscle strength power and muscle fatigability using the leg press exercise This exercise was selected because it utilizes large muscle groups of the lower extremity that are important for functional activities and is androgen-responsive 39
Change in fat-free mass by dual energy X-ray absorptiometry DEXA Previous studies have already established that testosterone replacement increases fat-free mass This study is focused on measures of muscle performance and physical function therefore we have not included more detailed assessment of body composition by deuterium water and sodium bromide
Muscle volume of the non-dominant thigh will be measured by magnetic resonance imaging
Intramuscular concentrations of myostatin IGF-I and IGFBP-4 mRNA will be measured by RT-PCR and protein by western blot analysis The ubiquitin and C3 and C9 proteasome mRNA will be measured by northern analysis
Changes in perceptions of physical function and body image In addition to using global health related quality of life instruments which have many domains that are not androgen-responsive we will focus on assessment of perceptions of physical function fatigue and body image These instruments have been demonstrated to be responsive to androgen replacement in older men with low testosterone levels 48
Total and free testosterone and dihydrotestosterone levels will be measured as markers of testosterone bioavailability Serum LH FSH and SHBG levels will be measured as markers of androgen action
Safety Measures Plasma lipids apolipoproteins and lipoprotein particles will be measured to assess testosterone effects on these markers of cardiovascular risk profile Hemoglobin liver enzymes ALT AST bilirubin GGT alkaline phosphatase serum PSA digital rectal examination and AUA BPH symptom score will be monitored as safety parameters
Energy Expenditure We will measure resting energy expenditure by indirect calorimetry using a novel handheld device known as the MedGem HealtheTech Golden Colorado Neiman et al Neiman DC Trone GA Austin MD A new handheld device for measuring resting metabolic rate and oxygen consumption J Am Diet Assoc 2003 1035 588-593 have validated this device in 63 males adult men and women with BMI between 19 and 56 kgm2 against Douglas bags with duplicate measurements on each of two nonconsecutive days within a 14 day period Since there were no differences between tests or between days for either the MedGem or the Douglas bags the four tests for each device were pooled The mean difference for the pooled results between MedGem and Douglas bags was 7 Kcalday 04 The thermic effect of food will be measured by indirect calorimetry using the same MedGem apparatus with measurements during the last 15 minutes of each of five hours after ingestion of a standardized meal We will also measure resting energy expenditure by use of the Deltatrac II device After subjects have rested in bed for at least 5 minutes oxygen consumption and carbon dioxide production will be measured using a ventilated canopy system for 20 minutes Deltatrac II
The rates of ATP synthesis will be measured by 31P and 13C nuclear magnetic resonance NMR spectroscopy The rates of substrate oxidation in the citric acid cycle will be estimated from the specific activity of 4-13C glutamate during steady state infusion of 13C-1 acetate The ratio of ATP synthesis measured by NMR spectroscopy and fuel oxidation measured by steady state 13-1 acetate infusion will be used as a measure of mitochondrial coupling of oxidation and phosphorylation In addition we will also measure mitochondrial energy coupling in isolated muscle fibers obtained from biopsies of vastus lateralis directly by measuring PO ration using an oxygen electrode
Body core temperature will be measured by obtaining rectal temperature using a precise and accurate thermo-couple thermister
Free fatty acid flux and adipose tissue lipolysis will be measured using 1-13C palmitate and2H5 glycerol isotope infusion respectively Fat oxidation will be measured by the release and quantitation of 1-13C-CO2 released during exhalation after infusion of the 1-13C palmitate 2H2 glucose isotope will be used to measure insulin sensitivity One to two weeks before the second palmitate infusion a single injection of sodium 1-13C bicarbonate 176 µmolkg 90 enriched sterile and pyrogen free Mass Trace will be used to calculate the acetate correction factor ACF The ACF accounts for 13C-label lost in exchange reactions in the tricarboxylic acid cycle After 135 min of tracer equilibration breath samples will be obtained in 15-min intervals up to 150 minutes and 5 minute intervals from 150 to 180 minutes Non-esterified free fatty acid levels will be measured at baseline mid-study day 56 and at the end of treatment by a fasting blood measurement
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01DK049296 | NIH | Charles R Drew University | httpsreporternihgovquickSearchR01DK049296 |
| CDU IRB 00-11-153-04 | OTHER | None | None |