Evaluation of rGH Therapy to Prevent Muscle Atrophy in Patients With ACL Tears

Study Overview
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Brief Summary
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Anterior cruciate ligament (ACL) tears are among the most frequent traumatic knee injuries that occur in physically active individuals. Despite advances in minimally invasive surgical reconstruction techniques and aggressive rehabilitation, this atrophy and loss of strength can persist even after patients return to full activity and can place them at considerable risk for re-injury and developing osteoarthritis (OA). The design of new therapeutic interventions to prevent muscle atrophy is needed to advance the care of patients who suffer from ACL injuries. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis plays an important role in promoting muscle growth and protecting muscle from atrophy. While GH therapy has shown promise in protecting immobilized muscle from various models of disuse atrophy, it remains unknown whether GH can help to restore strength and protect against the loss in strength that occurs after ACL tear. GH therapy may help to accelerate the safe return to play of patients that suffer ACL tears, and help to prevent the long-term OA and reduction in quality of life that occur after these traumatic knee injuries.

Official Title
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Evaluation of Recombinant Growth Hormone Therapy to Prevent Muscle Atrophy in Patients With Anterior Cruciate Ligament Tears

Conditions
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Rupture of Anterior Cruciate Ligament

Intervention / Treatment
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* Drug: Somatropin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males between the ages of 18 and 35 Have acute unilateral complete ACL tears with or without bucket handle medial meniscus tears that occurred within the past 6 months Consent to undergo an ACL reconstruction by an orthopaedic surgeon using a patellar tendon or hamstring autograft Will be performing supervised post-operative rehabilitation at UMHS MedSport at Dominos Farms Exclusion Criteria: Patients who are undergoing a revision ACL reconstruction Had a previous injury to the involved knee Have an allergy to recombinant GH Have a BMI<20 or >35 Have a growth disorder of bones or connective tissue, type 1 diabetes mellitus, type 2 diabetes mellitus, or who have a history of carpal tunnel syndrome, trigger finger, myopathy, cancer, endocrine disorder, hypertension or rheumatologic disorder. Systolic blood pressure >140mm Hg or diastolic blood pressure >90mm Hg, or with resting heart rate >110 BPM or <40 BPM at screening. Additionally, because GH is currently listed as a banned substance by the World Anti-Doping Agency (WADA), National Collegiate Athletics Association (NCAA) and most professional sports agencies, we will exclude patients who are current collegiate, professional or elite athletes.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Somatropin<br>Somatropin of rDNA origin | Drug: Somatropin<br>* GH dose will be calculated by nomogram estimation of body surface area, and will be administered via subcutaneous injection in the abdominal area twice per day (BID) at a dose of 0.5mg GH per body surface area (BSA) in m2 (0.5mg/m2). Patients will begin GH treatment one week prior to surgery and will continue through 5 weeks after surgery. On the day of surgery, patients will not take GH, but otherwise patients will take GH every day over this 6 week period.<br>|
| Placebo Comparator: Placebo<br>A placebo vehicle that contains somatropin diluent but no active hormone. | Drug: Placebo<br>* A placebo diluent that will be administered via subcutaneous injection in the abdominal area twice per day (BID) at a dose of the equivalent concentration of 0.5mg GH per body surface area (BSA) in m2 (0.5mg/m2). Patients will begin treatment one week prior to surgery and will continue through 5 weeks after surgery. On the day of surgery, patients will not take medication, but otherwise patients will take medication every day over this 6 week period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normative Isokinetic Knee Extension Strength, Measured in Newton Meters (Nm) at 26 Weeks Post-op | Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 wks post-op | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normative Isokinetic Extension (Nm) at Pre-op (Baseline) | Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Normative Isokinetic Flexion (Nm) at Pre-op (Baseline) | Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Normative Isokinetic Flexion (Nm) at 26 Weeks Post-op | Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| Normative Isometric Extension (Nm) at Pre-op (Baseline) | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Normative Isometric Extension (Nm) at 26 Weeks Post-op | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| Normative Isometric Flexion (Nm) at Pre-op (Baseline) | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Normative Isometric Flexion (Nm) at 26 Weeks Post-op | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Normalized values were calculated by dividing the value from the injured limb by the value from the contralateral, uninjured leg prior to surgery. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| Absolute Isokinetic Extension (Nm) at Pre-op (Baseline) | Absolute Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Absolute Isokinetic Extension (Nm) at 26 wk Post-op | Absolute Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Strength values were calculated by comparing the affected limb of each subject across study group. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 wk post-op | 
| Absolute Isokinetic Flexion (Nm) at Pre-op (Baseline) | Absolute Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Absolute Isokinetic Flexion (Nm) at 26 Weeks Post-op | Absolute Isokinetic knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isokinetic measurements were performed at a speed of 60º/sec from a range of 0º to 90º of knee flexion. Strength values were calculated by comparing the affected limb of each subject across study group. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| Absolute Isometric Extension (Nm) at Pre-op (Baseline) | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Absolute Isometric Extension (Nm) at 26 Weeks Post-op | Absolute Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Strength values were calculated by comparing the affected limb of each subject across study group. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| Absolute Isometric Flexion (Nm) at Pre-op (Baseline) | Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. For each measurement, the highest force from a series of 5 repetitions was used. | at pre-op (baseline) | 
| Absolute Isometric Flexion (Nm) at 26 Weeks Post-op | Absolute Isometric knee flexion and extension strength measurements were obtained in a System 3 dynamometer (BioDex, Shirley, New York). Isometric measurements were performed at 45º of knee flexion. Strength values were calculated by comparing the affected limb of each subject across study group. For each measurement, the highest force from a series of 5 repetitions was used. | at 26 weeks post-op | 
| VR12 Health Survey: Physical Health Summary Measure Score at Pre-op (Baseline) | The VR-12 includes 12 questions that do not give an overall score but yield a physical and mental component score. PCS and MCS summary scores are standardized using a t-score transformation and normalized to the U.S. population of a score of 50 and a standard deviation of 10. Higher PCS and MCS scores indicate better health. Medical Expenditure Panel Survey (MEPS) collected between 2000 and 2002 standard norms range as followed PCS maximum: 72.11; minimum: 0.59. | at pre-op (baseline) | 
| VR12 Health Survey: Physical Health Summary Measure Score at 26 Weeks Post-op | The VR-12 includes 12 questions that do not give an overall score but yield a physical and mental component score. PCS and MCS summary scores are standardized using a t-score transformation and normalized to the U.S. population of a score of 50 and a standard deviation of 10. Higher PCS and MCS scores indicate better health. Medical Expenditure Panel Survey (MEPS) collected between 2000 and 2002 standard norms range as followed PCS maximum: 72.11; minimum: 0.59. | at 26 weeks post-op | 
| VR12 Health Survey: Mental Health Summary Measure Score at Pre-op (Baseline) | The VR-12 includes 12 questions that do not give an overall score but yield a physical and mental component score. PCS and MCS summary scores are standardized using a t-score transformation and normalized to the U.S. population of a score of 50 and a standard deviation of 10. Higher PCS and MCS scores indicate better health. Medical Expenditure Panel Survey (MEPS) collected between 2000 and 2002 standard norms range as followed MCS Maximum: 76.09; Minimum: -2.47. | at pre-op (baseline) | 
| VR12 Health Survey: Mental Health Summary Measure Score at 26 Weeks Post-op | The VR-12 includes 12 questions that do not give an overall score but yield a physical and mental component score. PCS and MCS summary scores are standardized using a t-score transformation and normalized to the U.S. population of a score of 50 and a standard deviation of 10. Higher PCS and MCS scores indicate better health. Medical Expenditure Panel Survey (MEPS) collected between 2000 and 2002 standard norms range as followed MCS Maximum: 76.09; Minimum: -2.47. | at 26 weeks post-op | 
| International Knee Document Committee (IKDC) at Pre-op (Baseline) | The IKDC percentage score is a subjective patients reported outcome measure (PROM) that scores a participants over all score. The PROM looks at 3 categories: symptoms, sports activity, and knee function. Scores range from 0 to 100, the final score given is interpreted as a measure of function with higher scores representing higher levels of function. | at pre-op (baseline) | 
| International Knee Documentation Committee (IKDC) up to 26 wk Post-op | The IKDC percentage score is a subjective patients reported outcome measure (PROM) that scores a participants over all score. The PROM looks at 3 categories: symptoms, sports activity, and knee function. Scores range from 0 to 100, the final score given is interpreted as a measure of function with higher scores representing higher levels of function. | up to 26 wk post-op | 
| The Knee Injury and Osteoarthritis Outcome Score (KOOS): Patient Reported Outcome Measure: ADL at 26 Weeks Post-op | KOOS Function in daily living (ADL) (17 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at 26 weeks post-op | 
| KOOS Patient Reported Outcome Measure: ADL at Pre-op (Baseline) | KOOS Function in daily living (ADL) (17 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at pre-op (baseline) | 
| KOOS Patient Reported Outcome Measure: Pain at 26 Weeks Post-op | KOOS Pain (9 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at 26 weeks post-op | 
| KOOS Patient Reported Outcome Measure: Pain at Pre-op (Baseline) | KOOS Pain (9 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at pre-op (baseline) | 
| KOOS Patient Reported Outcome Measure: Quality of Life at 26 Weeks Post-op | KOOS Quality of Life (QoL) (4 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at 26 weeks post-op | 
| KOOS Patient Reported Outcome Measure: Quality of Life at Pre-op (Baseline) | KOOS Quality of Life (QoL) (4 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at pre-op (baseline) | 
| KOOS Patient Reported Outcome Measure: Sport and Recreation at 26 Weeks Post-op | KOOS Sport and Recreation (Sport/Rec) (5 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures. | at 26 weeks post-op | 
| KOOS Patient Reported Outcome Measure: Sports and Recreation at Pre-op (Baseline) | KOOS Sport and Recreation (Sport/Rec) (5 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures. | at pre-op (baseline) | 
| KOOS Patient Reported Outcome Measure: Symptoms at 26 Weeks Post-op | KOOS Symptoms (7 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at 26 weeks post-op | 
| KOOS Patient Reported Outcome Measure: Symptoms at Pre-op (Baseline) | KOOS Symptoms (7 items) A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five dimensions separately. Maximum score 100% / Minimum score 0%. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopaedic assessment scales and generic measures | at pre-op (baseline) | 
| Absolute Quadriceps Volume (L) at Pre-op (Baseline) | Bilateral MRI scans were obtained at specific time points to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at pre-op (baseline) | 
| Absolute Quadricep Volume (L) at 26 Week Post-op | Bilateral MRI scans were obtained at specific time points to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at 26 week post-op | 
| Absolute Hamstring Volume (L) at Pre-op (Baseline) | Bilateral MRI scans were obtained at specific time points to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at pre-op (baseline) | 
| Absolute Hamstring Volume (L) at 26 Weeks Post-op | Bilateral MRI scans were obtained at specific time points to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at 26 weeks post-op | 
| Normalized Quadriceps Volume (L) at Pre-op (Baseline) | Normalized volume relative to the pre-op measurements of the uninjured limb, used to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at pre-op (baseline) | 
| Normalized Quadriceps Volume (L) at 26 Weeks Post-op | Normalized volume relative to the pre-op measurements of the uninjured limb, used to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at 26 weeks post-op | 
| Normalized Hamstring Volume (L) at Pre-op (Baseline) | Normalized volume relative to the pre-op measurements of the uninjured limb, used to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at pre-op (baseline) | 
| Normalized Hamstring Volume (L) at 26 Weeks Post-op | Normalized volume relative to the pre-op measurements of the uninjured limb, used to assess the muscle volume of the quadriceps and hamstring muscle groups will be calculated using GE ImagePACS software (FDA cleared software which is the standard software used to read and analyze imaging studies in the UMHS). | at 26 weeks post-op | 
| Insulin Like Growth Factor (IGF1) at -1 and 5 Weeks Post-op | IGF1 was measured from serum using an IMMULITE 2000 system (Siemens). | Area under the curve between -1 and 5 weeks post-op | 
| Myostatin at -1 and 5 Weeks Post-op | Myostatin was measured from plasma using ELISAs (R&D Systems, Minneapolis, MN) following manufacturer recommendations. | Area under the curve between -1 and 5 weeks post-op | 
| MMP3 at -1 and 5 Weeks Post-op | Matrix metalloproteinase-3 (MMP3) was measured from serum using ELISAs (R&D Systems, Minneapolis, MN) following manufacturer recommendations. | Area under the curve between -1 and 5 weeks post-op | 
| Hyaluronic Acid at -1 and 5 Weeks Post-op | Hyaluronic acid was measured from plasma using ELISAs (R&D Systems, Minneapolis, MN) following manufacturer recommendations. | Area under the curve between -1 and 5 weeks post-op | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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muscle atrophy, growth hormone, ACL tear