The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue

• ClinicalTrials.gov Identifier: NCT01661595
• Recruitment Status: Completed
• First Posted: August 9, 2012
• Results First Posted: July 17, 2018
• Last Update Posted: July 17, 2018
• Sponsor: The University of Texas Medical Branch, Galveston
• Information provided by (Responsible Party): The University of Texas Medical Branch, Galveston

Tracking Information

• First Submitted Date: August 7, 2012
• First Posted Date: August 9, 2012
• Results First Submitted Date: April 24, 2018
• Results First Posted Date: July 17, 2018
• Last Update Posted Date: July 17, 2018
• Study Start Date: November 2012
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 19, 2018)

• Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo [ Time Frame: 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.
• Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug [ Time Frame: 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.
• Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo [ Time Frame: 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.
• Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug [ Time Frame: 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.

Original Primary Outcome Measures (submitted: August 8, 2012)

Fatigue [ Time Frame: Acutely at 1 week and 4 weeks ]

Determining if fatigue changes acutely between the two groups (Sildenafil, Tadalafil) at 1 week and 4 weeks.

Current Secondary Outcome Measures (submitted: June 19, 2018)

• Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: week 4 ]
  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 8. [ Time Frame: 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 0. [ Time Frame: 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. [ Time Frame: week 4 ]
  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 8. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: August 8, 2012)

Fractional Synthetic Rate [ Time Frame: Acutely - 1 day ]

Determining whether there is a difference between Sildenafil and Tadalafil at one day and at week 1.

Current Other Pre-specified Outcome Measures (submitted: June 19, 2018)

• Hemoglobin Level at Week 0 [ Time Frame: week 0 ]
  Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
• Hemoglobin Level Measured at Week 4 [ Time Frame: week 4 ]
  Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
• Hemoglobin Level Measured at Week 8 [ Time Frame: week 8 ]
  Hemoglobin was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 11.6 - 15.0 g/dL.
• Hematocrit Level Measured at Week 0 [ Time Frame: week 0 ]
  Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%.
• Hematocrit Level Was Measured at 4 Weeks [ Time Frame: 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 8 [ Time Frame: week 8 ]
  Hematocrit was measured by University of Texas Medical Branch Clinical Laboratory. Normal ranges are 35.7 - 45.2%.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue
• Official Title: The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue.
• 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
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
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.

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Fatigue

Intervention

• Drug: Sildenafil
  50 mg/day for 4 weeks
  Other Names:

  • Viagra
  • Revatio
• Drug: tadalafil
  10 mg/day for 4 weeks.
  Other Names:

  • Cialis
  • Adcirca
• Drug: Placebo
  Placebo 1 capsule per day for four weeks.

Study Arms

• Active Comparator: Sildenafil / Placebo
  50 mg/day Sildenafil: (Other Name: Viagra, Revatio) for weeks 0-4. Placebo for weeks 5-8.
  Interventions:

  • Drug: Sildenafil
  • Drug: Placebo
• Active Comparator: Tadalafil / Placebo
  10 mg/day Tadalafil: (Other Name: Cialis, Adcirca) for weeks 0-4. Placebo for weeks 5-8.
  Interventions:

  • Drug: tadalafil
  • Drug: Placebo
• Active Comparator: Placebo / Sildenafil
  Placebo for weeks 0-4. 50 mg/day Sildenafil: (Other Name: Viagra, Revatio) for weeks 5-8.
  Interventions:

  • Drug: Sildenafil
  • Drug: Placebo
• Active Comparator: Placebo / Tadalafil
  Placebo for weeks 0-4. 10 mg/day Tadalafil: (Other Name: Cialis, Adcirca) for weeks 5-8.
  Interventions:

  • Drug: tadalafil
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 3, 2015): 30
• Original Estimated Enrollment (submitted: August 8, 2012): 72
• Actual Study Completion Date: June 2015
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01661595
• Other Study ID Numbers: 12-153
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: The University of Texas Medical Branch, Galveston
• Original Responsible Party: Same as current
• Current Study Sponsor: The University of Texas Medical Branch, Galveston
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Melinda Sheffield-Moore, PhD; University of Texas Medical Branch, Galveston

• PRS Account: The University of Texas Medical Branch, Galveston
• Verification Date: April 2018