Femur Head Necrosis, Hip Fracture, Osteoarthritis
Conditions
Keywords
Hip Replacement Arthroplasty, Hip Replacement Surgery, Hip Surgery, Hip Rehabilitation, Avascular Necrosis, Knee replacement surgery, Total knee arthroplasty
Brief summary
The purpose of this study is to determine the effects of two postoperative interventions designed to preserve muscle protein after major hip or knee surgery.
Detailed description
Hip fractures among the elderly are a major health concern. Nearly one-third of elderly hip fracture patients die within 1 year of the injury. Events surrounding the actual injury and any necessary surgical repair often lead to reduced muscle protein, and eventually, muscle strength. Loss in everyday function and independence may follow, especially in elderly or frail individuals. The decrease in protein synthesis may be caused by two main events following injury and surgery: prolonged inactivity and an increase in stress hormone levels. Preventing a loss in protein may help to improve outcomes for individuals undergoing hip surgery and rehabilitation. The purpose of this study is to determine the effects of two postoperative interventions designed to retain muscle protein after major hip or knee surgery in adults. This study will include two experiments. Experiment 1 will include individuals who are scheduled for hip or knee replacement surgery because of osteoarthritis (the need to repair or replace the affected joint), or avascular necrosis (bone tissue death caused by lack of blood supply). Experiment 1 participants will be randomly assigned to one of two groups: * Group 1 participants will receive daily supplements of essential amino acids, which are thought to stimulate protein synthesis. * Group 2 participants will receive standard rehabilitation care while in the hospital and will serve as controls for the effect of time on recovery. Participants will be in the hospital for about 4 days. On the morning of surgery, blood and urine collection will occur. During surgery, substances called tracers, measuring the extent of protein synthesis and breakdown, will be injected into a vein for the first metabolic study. Additional blood and muscle samples will also be taken. After surgery, when participants arrive in the surgical recovery unit and are able to eat, they will begin to record all food intake and will receive their assigned treatment. Treatment, in the form of gel capsules, will be taken 2.5 hours after each meal. Urine will be collected throughout hospitalization and blood will be collected each morning. Prior to discharge, a 24-hour metabolic study will be performed, including tracer injections and muscle biopsies. After discharge, participants will be provided with 6 weeks' worth of their assigned treatment. Follow-up visits will occur 2 and \ 6 to 8 weeks after surgery. These visits will include various muscle function and physical performance tests. Participants will also undergo a dual energy x-ray absorptiometry (DEXA) scan, which will be used to determine muscle mass. Experiment 2 participants will include individuals scheduled for either hip or knee replacement surgery or fracture repair surgery. Participants will be randomly assigned to one of two groups: * Group 1 participants will receive the antifungal drug ketoconazole, which is thought to reduce levels of the stress hormone cortisol. * Group 2 participants will receive placebo and standard rehabilitation care while in the hospital. Participants will begin taking their assigned treatments the day prior to surgery; those with a hip fracture will take their assigned treatment at least 4 hours prior to surgery. The same procedures that occurred in Experiment 1 during surgery and hospitalization will be carried out during Experiment 2. The second metabolic study, however, will last only 1 hour and will include a standard clinical meal.
Interventions
15g of essential amino acid in capsule form three times daily during hospitalization, continued through 6 weeks after discharge.
DRUGKetoconazole
200mg ketoconazole twice daily; started night before surgery and continued through hospitalization.
DRUGPlacebo
Placebo for Ketoconazole
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
for All Participants: * Scheduled for surgery because of osteoarthritis, avascular necrosis, fracture, or revision of total joint replacement in the hip or knee
Exclusion criteria
for All Participants: * Taking insulin, thiazolidinediones (TZD), or metformin * Kidney insufficiency, as indicated by serum creatinine of more than 2.0 mg/dl * Recently treated cancer other than basal cell carcinoma * Any other condition or event that would be considered as reason for exclusion by the study investigators * Pregnancy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Muscle Protein Synthesis | Perioperative and discharge |
Secondary
| Measure | Time frame |
|---|---|
| Change in Maximal Voluntary Contraction | Baseline and 6 weeks post surgery |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experiment 1 - Amino Acid Supplement Essential amino acid supplement : 15g of essential amino acid in capsule form three times daily during hospitalization, continued through 6 weeks after discharge. | 16 |
| Experiment 1 - Standard of Care Usual clinical care - no dietary intervention. | 9 |
| Experiment 2 - Ketoconazole 200mg ketoconazole twice daily; started night before surgery and continued through hospitalization. | 4 |
| Experiment 2 - Placebo Placebo for Ketoconazole twice daily; started night before surgery and continued through hospitalization. | 8 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Personal reasons | 0 | 0 | 2 | 0 |
| Overall Study | Surgical schedule | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Experiment 1 - Standard of Care | Experiment 2 - Ketoconazole | Experiment 1 - Amino Acid Supplement | Experiment 2 - Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 4 Participants | 13 Participants | 7 Participants | 31 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 8 | 44 years STANDARD_DEVIATION 15 | 55 years STANDARD_DEVIATION 7 | 46 years STANDARD_DEVIATION 15 | 51 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 9 participants | 4 participants | 16 participants | 8 participants | 37 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 7 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 9 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 9 | 0 / 6 | 0 / 9 |
| serious Total, serious adverse events | 0 / 16 | 1 / 9 | 0 / 6 | 0 / 9 |
Outcome results
Primary
Muscle Protein Synthesis
Time frame: Perioperative and discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experiment 1 - Amino Acid Supplement | Muscle Protein Synthesis | Perioperative MPS | 1.38 %/d | Standard Error 0.12 |
| Experiment 1 - Amino Acid Supplement | Muscle Protein Synthesis | Discharge MPS | 1.23 %/d | Standard Error 0.16 |
| Experiment 1 - Standard of Care | Muscle Protein Synthesis | Discharge MPS | 1.49 %/d | Standard Error 0.18 |
| Experiment 1 - Standard of Care | Muscle Protein Synthesis | Perioperative MPS | 0.84 %/d | Standard Error 0.11 |
| Experiment 2 - Ketoconazole | Muscle Protein Synthesis | Perioperative MPS | 1.42 %/d | Standard Error 0.48 |
| Experiment 2 - Ketoconazole | Muscle Protein Synthesis | Discharge MPS | NA %/d | — |
| Experiment 2 - Placebo | Muscle Protein Synthesis | Perioperative MPS | 1.36 %/d | Standard Error 0.22 |
| Experiment 2 - Placebo | Muscle Protein Synthesis | Discharge MPS | NA %/d | — |
Secondary
Change in Maximal Voluntary Contraction
Time frame: Baseline and 6 weeks post surgery
Population: Measure not performed in Experiment 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experiment 1 - Amino Acid Supplement | Change in Maximal Voluntary Contraction | 0.68 kg/kg leg lean mass | Standard Error 0.3 |
| Experiment 1 - Standard of Care | Change in Maximal Voluntary Contraction | 0.34 kg/kg leg lean mass | Standard Error 0.32 |