Fatigue
Conditions
Keywords
Fatigue, Fatigability, Surface Electromyography (sEMG), cyclic guanosine monophosphate (cGMP), Nitric Oxide (NO), NO-cGMP, Phosphodiesterase (PDE), Sildenafil, Tadalafil, Isotope, Infusion, Anabolism, Upregulation, Accelerometer, Placebo, Nitrosylation
Brief summary
This study is funded by the Moody Endowment. In this project, we will investigate the potential effect of skeletal muscle nitric oxide (NO) production on skeletal muscle anabolism, muscle strength, physical function, and body composition in older individuals. Further, we will determine whether augmentation of NO-mediated signaling reduces fatigue and fatigability.
Detailed description
The Investigators hypothesize that upregulation of skeletal muscle NO-cGMP mediated responses through phosphodiesterase (PDE) inhibition by sildenafil or tadalafil causes an acute anabolic response of skeletal muscle protein synthesis. NO is well-known to elicit vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle perfusion may influence both skeletal muscle anabolism and perceptual fatigue. To measure skeletal muscle protein synthesis, we will infuse a stable isotope tracer of phenylalanine and measure its incorporation into skeletal muscle proteins following a dose of sildenafil, tadalafil, or placebo. The Investigators will also determine whether differences exist between men and women in response to PDE inhibition. As skeletal muscle NO-cGMP signaling has been implicated in fatigue responses, we will assess the acute effect of sildenafil and tadalafil on fatigue. Fatigue can be manifested both as a performance deficit at a local level (e.g., a reduced ability of skeletal muscle to produce power or force) as well as a subjective experience of lacking physical or mental energy. Accordingly, we will use more than one means (skeletal muscle performance, fatigue questionnaires, accelerometers) to study fatigue. The Investigators hypothesize that sildenafil or tadalafil will acutely reduce exercise-associated fatigability and skeletal muscle fatigue development
Interventions
DRUGSildenafil
50 mg/day for 4 weeks
DRUGtadalafil
10 mg/day for 4 weeks.
DRUGPlacebo
Placebo 1 capsule per day for four weeks.
Sponsors
The University of Texas Medical Branch, Galveston
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Subjects were assigned to one of 4 arms: 1. Sildenafil (50mg/day) for weeks 0-4. Placebo for weeks 5-8. 2. Tadalafil (10mg/day) for weeks 0-4. Placebo for weeks 5-8. 3. Placebo for weeks 0-4. Sildenafil (50mg/day) for weeks 5-8. 4. Placebo for weeks 0-4. Tadalafil (10mg/day) for weeks 5-8.
Eligibility
Sex/Gender
ALL
Age
50 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 50-60 years of age 2. Ability to sign consent form (score\>23 on the 30-item Mini Mental Status examination, MMSE) 3. Stable body weight for at least three months.
Exclusion criteria
1. Physical dependence or frailty (impairment in any of the Activities of Daily Living (ADL), history of falls (\>2/year) or significant weight loss in the past year). 2. Pregnancy 3. Significant heart, liver, kidney, blood or respiratory disease. 4. Peripheral vascular disease. 5. Diabetes mellitus or other untreated endocrine disease. 6. Active cancer 7. Use of nitrates. 8. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids. 9. Alcohol or drug abuse. 10. Severe depression (\>5 on the 15-item Geriatric Depression Scale, GDS). 11. Cardiac abnormalities such as cardiac shunt or previously diagnosed pulmonary hypertension. 12. Systolic blood pressure \<100 or\>150, diastolic blood pressure \<60 or 90\>. This range is smaller than the acceptable range stated in the prescribing information for sildenafil/tadalafil (90/50 and \<170/110).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo | after 4 weeks of placebo | Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks. |
| Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug | after 4 weeks of active drug | The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue. |
| Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo | after 4 weeks of placebo | The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test after 4 weeks of placebo. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue. |
| Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug | after 4 weeks of active drug | Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | week 8 | Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
| Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | week 8 | Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
| Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo | after 4 weeks of placebo | Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug | after 4 weeks of active drug | Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0 | Week 0 | Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue. |
| Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4 | week 4 | Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue. |
| Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8 | week 8 | Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue. |
| Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo | after 4 weeks of placebo | Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug. | after 4 weeks of active drug | Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo. | after 4 weeks of placebo | Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug | after 4 weeks of active drug | Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. |
| Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | week 0 | Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
| Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | week 4 | Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
| Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | week 0 | Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
| Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | week 4 | Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hematocrit Level Measured at Week 8 | week 8 | Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%. |
| Hemoglobin Level Measured at Week 4 | week 4 | Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL. |
| Hemoglobin Level at Week 0 | week 0 | Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL. |
| Hematocrit Level Was Measured at 4 Weeks | 4 weeks | Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%. |
| Hematocrit Level Measured at Week 0 | week 0 | Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%. |
| Hemoglobin Level Measured at Week 8 | week 8 | Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the community via flyers and local postings.
Pre-assignment details
30 subjects enrolled in this study. 6 subjects failed the screening and were withdrawn. 6 subjects chose to withdraw participation before the study began. 18 subjects began the study. 2 subjects were withdrawn during the study. 16 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil, Then Placebo Sildenafil (50mg/day) daily for weeks 0-4, then Placebo daily weeks 5-8. | 5 |
| Tadalfil, Then Placebo Tadalafil (10mg/day) daily for weeks 0-4, then Placebo daily for weeks 5-8. | 4 |
| Placebo, Then Sildenafil Placebo daily for weeks 0-4, then Sildenafil (50mg/day) daily for weeks 5-8. | 5 |
| Placebo, Then Tadalafil Placebo daily for weeks 0-4, then Tadalafil (10mg/day) daily for weeks 5-8. | 4 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1: Week 0-4 | Adverse Event | 1 | 0 | 0 | 0 |
| Phase 2: Week 5-8. | Protocol Violation | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sildenafil, Then Placebo | Tadalfil, Then Placebo | Placebo, Then Sildenafil | Placebo, Then Tadalafil | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 4.16 | 56 years STANDARD_DEVIATION 1.41 | 52.4 years STANDARD_DEVIATION 1.51 | 57.25 years STANDARD_DEVIATION 2.99 | 54.6 years STANDARD_DEVIATION 3.22 |
| Region of Enrollment United States | 5 Participants | 4 Participants | 5 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 3 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 | 0 / 18 |
| other Total, other adverse events | 2 / 10 | 0 / 8 | 0 / 18 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 | 0 / 18 |
Outcome results
Primary
Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug
The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue.
Time frame: after 4 weeks of active drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug | 4.5 units on a scale | Standard Deviation 2.38 |
| Tadalafil, Then Placebo | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug | 3.5 units on a scale | Standard Deviation 1.73 |
| Placebo, Then Sildenafil | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug | 5.25 units on a scale | Standard Deviation 4.27 |
| Placebo, Then Tadalafil | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug | 6.0 units on a scale | Standard Deviation 1.83 |
Primary
Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo
The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test after 4 weeks of placebo. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue.
Time frame: after 4 weeks of placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo | 4.33 units on a scale | Standard Deviation 1.53 |
| Tadalafil, Then Placebo | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo | 2.5 units on a scale | Standard Deviation 0.58 |
| Placebo, Then Sildenafil | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo | 7.0 units on a scale | Standard Deviation 1.83 |
| Placebo, Then Tadalafil | Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo | 4.75 units on a scale | Standard Deviation 0.96 |
Primary
Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug
Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks.
Time frame: after 4 weeks of active drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug | 60.90 Newton-Meters | Standard Deviation 35.6 |
| Tadalafil, Then Placebo | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug | 42.48 Newton-Meters | Standard Deviation 6.3 |
| Placebo, Then Sildenafil | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug | 62.68 Newton-Meters | Standard Deviation 24.88 |
| Placebo, Then Tadalafil | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug | 63.25 Newton-Meters | Standard Deviation 15.12 |
Primary
Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo
Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks.
Time frame: after 4 weeks of placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo | 59.69 Newton-Meters | Standard Deviation 33.71 |
| Tadalafil, Then Placebo | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo | 42.07 Newton-Meters | Standard Deviation 5.19 |
| Placebo, Then Sildenafil | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo | 67.17 Newton-Meters | Standard Deviation 26.87 |
| Placebo, Then Tadalafil | Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo | 63.24 Newton-Meters | Standard Deviation 8.34 |
Secondary
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 32.35 kilograms | Standard Deviation 11.4 |
| Tadalafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 37.21 kilograms | Standard Deviation 6.81 |
| Placebo, Then Sildenafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 32.72 kilograms | Standard Deviation 5.92 |
| Placebo, Then Tadalafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 32.10 kilograms | Standard Deviation 6.9 |
Secondary
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 33.16 kilograms | Standard Deviation 12.42 |
| Tadalafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 37.12 kilograms | Standard Deviation 6.35 |
| Placebo, Then Sildenafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 32.30 kilograms | Standard Deviation 5.55 |
| Placebo, Then Tadalafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 32.47 kilograms | Standard Deviation 7.08 |
Secondary
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 33.60 kilograms | Standard Deviation 12.51 |
| Tadalafil, Then Placebo | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 37.02 kilograms | Standard Deviation 6.21 |
| Placebo, Then Sildenafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 32.40 kilograms | Standard Deviation 5.83 |
| Placebo, Then Tadalafil | Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 32.79 kilograms | Standard Deviation 7.12 |
Secondary
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 44.60 kilograms | Standard Deviation 11.62 |
| Tadalafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 41.43 kilograms | Standard Deviation 4.72 |
| Placebo, Then Sildenafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 49.93 kilograms | Standard Deviation 10.63 |
| Placebo, Then Tadalafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0. | 54.45 kilograms | Standard Deviation 14.28 |
Secondary
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 46.29 kilograms | Standard Deviation 14.4 |
| Tadalafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 41.02 kilograms | Standard Deviation 4.05 |
| Placebo, Then Sildenafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 50.61 kilograms | Standard Deviation 10.67 |
| Placebo, Then Tadalafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4. | 54.85 kilograms | Standard Deviation 14.71 |
Secondary
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 46.22 kilograms | Standard Deviation 14.68 |
| Tadalafil, Then Placebo | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 40.76 kilograms | Standard Deviation 4.38 |
| Placebo, Then Sildenafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 52.09 kilograms | Standard Deviation 10.03 |
| Placebo, Then Tadalafil | Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8. | 55.10 kilograms | Standard Deviation 14.42 |
Secondary
Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug
Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug | 106.79 Newton-Meters | Standard Deviation 49.69 |
| Tadalafil, Then Placebo | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug | 79.33 Newton-Meters | Standard Deviation 11.69 |
| Placebo, Then Sildenafil | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug | 116.48 Newton-Meters | Standard Deviation 37.83 |
| Placebo, Then Tadalafil | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug | 114.75 Newton-Meters | Standard Deviation 36.49 |
Secondary
Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo.
Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo. | 105.15 Newton-Meters | Standard Deviation 49.46 |
| Tadalafil, Then Placebo | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo. | 78.59 Newton-Meters | Standard Deviation 10.25 |
| Placebo, Then Sildenafil | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo. | 117.71 Newton-Meters | Standard Deviation 39.86 |
| Placebo, Then Tadalafil | Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo. | 111.67 Newton-Meters | Standard Deviation 23.43 |
Secondary
Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug.
Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug. | 140.09 Newton-Meters | Standard Deviation 82.29 |
| Tadalafil, Then Placebo | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug. | 110.39 Newton-Meters | Standard Deviation 21.26 |
| Placebo, Then Sildenafil | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug. | 133.81 Newton-Meters | Standard Deviation 58.04 |
| Placebo, Then Tadalafil | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug. | 139.96 Newton-Meters | Standard Deviation 50.47 |
Secondary
Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo
Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo | 145.86 Newton-Meters | Standard Deviation 97.73 |
| Tadalafil, Then Placebo | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo | 104.17 Newton-Meters | Standard Deviation 23.66 |
| Placebo, Then Sildenafil | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo | 149.14 Newton-Meters | Standard Deviation 62.67 |
| Placebo, Then Tadalafil | Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo | 148.34 Newton-Meters | Standard Deviation 47.26 |
Secondary
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: Week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0 | 9.66 scores on a scale | Standard Deviation 19.55 |
| Tadalafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0 | -7.5 scores on a scale | Standard Deviation 5.45 |
| Placebo, Then Sildenafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0 | -8 scores on a scale | Standard Deviation 3.61 |
| Placebo, Then Tadalafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0 | -3.75 scores on a scale | Standard Deviation 9.54 |
Secondary
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: week 4
Population: 1 subject did not complete the week 4 MFSI questionnaire
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4 | 6.33 scores on a scale | Standard Deviation 26.08 |
| Tadalafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4 | -3.33 scores on a scale | Standard Deviation 10.97 |
| Placebo, Then Sildenafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4 | -6.33 scores on a scale | Standard Deviation 2.31 |
| Placebo, Then Tadalafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4 | -3.5 scores on a scale | Standard Deviation 12.66 |
Secondary
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8 | 9.67 scores on a scale | Standard Deviation 19.09 |
| Tadalafil, Then Placebo | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8 | 3.25 scores on a scale | Standard Deviation 27.54 |
| Placebo, Then Sildenafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8 | -9.67 scores on a scale | Standard Deviation 6.81 |
| Placebo, Then Tadalafil | Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8 | -9.25 scores on a scale | Standard Deviation 1.26 |
Secondary
Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug
Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
Population: 1 subject did not complete the walking test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug | 197.01 meter | Standard Deviation 32.72 |
| Tadalafil, Then Placebo | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug | 178.56 meter | Standard Deviation 17.84 |
| Placebo, Then Sildenafil | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug | 200.19 meter | Standard Deviation 13.99 |
| Placebo, Then Tadalafil | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug | 203.46 meter | Standard Deviation 31.11 |
Secondary
Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo
Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
Population: 1 subject did not complete the walking test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo | 203.82 meters | Standard Deviation 30.51 |
| Tadalafil, Then Placebo | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo | 189.79 meters | Standard Deviation 38.12 |
| Placebo, Then Sildenafil | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo | 198.41 meters | Standard Deviation 14.04 |
| Placebo, Then Tadalafil | Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo | 202.80 meters | Standard Deviation 37.84 |
Other Pre-specified
Hematocrit Level Measured at Week 0
Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%.
Time frame: week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hematocrit Level Measured at Week 0 | 39.53 percent of red blood cells | Standard Deviation 2.16 |
| Tadalafil, Then Placebo | Hematocrit Level Measured at Week 0 | 38.55 percent of red blood cells | Standard Deviation 1.42 |
| Placebo, Then Sildenafil | Hematocrit Level Measured at Week 0 | 37.25 percent of red blood cells | Standard Deviation 2.07 |
| Placebo, Then Tadalafil | Hematocrit Level Measured at Week 0 | 31.88 percent of red blood cells | Standard Deviation 13.09 |
Other Pre-specified
Hematocrit Level Measured at Week 8
Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%.
Time frame: week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hematocrit Level Measured at Week 8 | 40.38 percent of red blood cells | Standard Deviation 0.44 |
| Tadalafil, Then Placebo | Hematocrit Level Measured at Week 8 | 36.6 percent of red blood cells | Standard Deviation 1.94 |
| Placebo, Then Sildenafil | Hematocrit Level Measured at Week 8 | 38.1 percent of red blood cells | Standard Deviation 1.19 |
| Placebo, Then Tadalafil | Hematocrit Level Measured at Week 8 | 38.4 percent of red blood cells | Standard Deviation 3.24 |
Other Pre-specified
Hematocrit Level Was Measured at 4 Weeks
Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hematocrit Level Was Measured at 4 Weeks | 39.08 percent of red blood cells | Standard Deviation 0.84 |
| Tadalafil, Then Placebo | Hematocrit Level Was Measured at 4 Weeks | 37.38 percent of red blood cells | Standard Deviation 0.82 |
| Placebo, Then Sildenafil | Hematocrit Level Was Measured at 4 Weeks | 38.13 percent of red blood cells | Standard Deviation 0.77 |
| Placebo, Then Tadalafil | Hematocrit Level Was Measured at 4 Weeks | 39.1 percent of red blood cells | Standard Deviation 1.81 |
Other Pre-specified
Hemoglobin Level at Week 0
Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
Time frame: week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hemoglobin Level at Week 0 | 13.42 g/dL | Standard Deviation 0.97 |
| Tadalafil, Then Placebo | Hemoglobin Level at Week 0 | 12.78 g/dL | Standard Deviation 0.71 |
| Placebo, Then Sildenafil | Hemoglobin Level at Week 0 | 12.4 g/dL | Standard Deviation 0.53 |
| Placebo, Then Tadalafil | Hemoglobin Level at Week 0 | 13.05 g/dL | Standard Deviation 0.9 |
Other Pre-specified
Hemoglobin Level Measured at Week 4
Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
Time frame: week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hemoglobin Level Measured at Week 4 | 13.05 g/dL | Standard Deviation 0.49 |
| Tadalafil, Then Placebo | Hemoglobin Level Measured at Week 4 | 12.03 g/dL | Standard Deviation 0.43 |
| Placebo, Then Sildenafil | Hemoglobin Level Measured at Week 4 | 12.6 g/dL | Standard Deviation 0.37 |
| Placebo, Then Tadalafil | Hemoglobin Level Measured at Week 4 | 13.2 g/dL | Standard Deviation 0.47 |
Other Pre-specified
Hemoglobin Level Measured at Week 8
Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
Time frame: week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil, Then Placebo | Hemoglobin Level Measured at Week 8 | 13.55 g/dL | Standard Deviation 0.35 |
| Tadalafil, Then Placebo | Hemoglobin Level Measured at Week 8 | 11.97 g/dL | Standard Deviation 0.76 |
| Placebo, Then Sildenafil | Hemoglobin Level Measured at Week 8 | 12.5 g/dL | Standard Deviation 0.08 |
| Placebo, Then Tadalafil | Hemoglobin Level Measured at Week 8 | 12.95 g/dL | Standard Deviation 1.17 |