Effectiveness of Two Types of Treatment in Restoring Muscle After Hip or Knee Surgery

Restoration of Muscle Following Hip Surgery

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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis; Femur Head Necrosis; Hip Fracture
• Intervention / Treatment: Drug: Ketoconazole; Drug: Essential amino acid supplement; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Exclusion Criteria for Experiment 1 Participants:

• Severe hypertension as indicated by requiring more than two drugs for blood pressure control
• History of hypo- or hypercoagulation disorders, including individuals who have taken warfarin (Coumadin)
• Atrial fibrillation, angina, or congestive heart failure

Exclusion Criteria for Experiment 2 Participants:

• Liver disease or abnormal liver function tests
• HIV infected
• Active hepatitis
• Any uncontrolled metabolic disease, including liver or kidney disease
• Taking medications that use the cytochrome P450 pathway for metabolism and unable to discontinue their use for the duration of the study
• Require certain medications. More information on this criterion can be found in the protocol.
• Gastrointestinal absorption disorders that affect nutrient uptake

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experiment 2 - Experimental Group	Drug: Ketoconazole; 200mg ketoconazole twice daily; started night before surgery and continued through hospitalization.
No Intervention: Experiment 1 - Standard of care Group
Experimental: Experiment 1 - Experimental Group	Drug: Essential amino acid supplement; 15g of essential amino acid in capsule form three times daily during hospitalization, continued through 6 weeks after discharge.
Placebo Comparator: Experiment 2 - Placebo Group	Drug: Placebo; Placebo for Ketoconazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Muscle Protein Synthesis	Perioperative and discharge

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in Maximal Voluntary Contraction	Baseline and 6 weeks post surgery

Collaborators and Investigators

• Sponsor: University of Arkansas
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Arny Ferrando, PhD, University of Arkansas

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: October 27, 2006
• First Submitted That Met QC Criteria: October 27, 2006
• First Posted (Estimate): October 29, 2006

Study Record Updates

• Last Update Posted (Estimate): June 2, 2014
• Last Update Submitted That Met QC Criteria: May 30, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Total knee arthroplasty; Avascular Necrosis; Hip Surgery; Knee replacement surgery; Hip Replacement Arthroplasty; Hip Replacement Surgery; Hip Rehabilitation
• Additional Relevant MeSH Terms: Pathologic Processes; Fractures, Bone; Wounds and Injuries; Leg Injuries; Musculoskeletal Diseases; Bone Diseases; Femoral Fractures; Hip Injuries; Osteonecrosis; Necrosis; Hip Fractures; Femur Head Necrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Ketoconazole
• Other Study ID Numbers: R01AR052293 (U.S. NIH Grant/Contract); 70451; 1R01AR052293-01A2 (U.S. NIH Grant/Contract)