Multimodality Intervention for Function and Metabolism in SCI

The proposed phase 2 trial a randomized, placebo-controlled, parallel group trial in persons with cervical or thoracic SCI, AIS grade A, B, C, or D, 6 months or later after injury. The trial will test the hypothesis that a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that addresses multiple pathophysiologic factors in SCI and includes functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry and an androgen will be more efficacious than functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry plus placebo in improving aerobic capacity, function, metabolism, bone health, and wellbeing.

Study Description: The proposed phase 2 trial a randomized, placebo-controlled, parallel group trial in persons with cervical or thoracic SCI, AIS grade A, B, C, or D, 6 months or later after injury. The trial will test the hypothesis that a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that addresses multiple pathophysiologic factors in SCI and includes functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry and an androgen will be more efficacious than functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry plus placebo in improving aerobic capacity, function, metabolism, bone health, and wellbeing.

Objectives:

Primary Objective:

• To determine whether the multimodality intervention is more efficacious in improving peak aerobic capacity, and muscle mass and strength than placebo plus functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry alone.

Secondary Objectives:

* To determine whether the multimodality intervention is more efficacious than placebo plus functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry in improving metabolic health, as reflected in fasting glucose, hemoglobin A1C, insulin sensitivity, fat mass and distribution, plasma lipids, and inflammation markers.
* To determine whether the multimodality intervention is more efficacious than placebo plus functional electrical stimulation during leg cycling (FES-LC) plus arm ergometry in improving volumetric and areal bone density, bone microarchitecture, and bone strength.

To determine the efficacy of the multimodality intervention in improving self-reported physical function (using SCI-FI AT and wellbeing (mood, anxiety, pain, loneliness and life satisfaction)

• To assess safety by structured monitoring of adverse events, and determining the proportion of participants experiencing injury, erythrocytosis, or other androgen-related or exercise-related adverse events.

Endpoints: Primary Endpoint:

Our primary outcome is peak aerobic capacity because it is an excellent marker of overall health, physical function, and mortality. Aerobic capacity is closely related to metabolic health, insulin sensitivity and cardiovascular outcomes. It can be measured accurately in SCI patients and would be expected to improve with the proposed interventions.

Secondary endpoints. Whole body skeletal muscle and fat mass and intraabdominal fat will be assessed by magnetic resonance imaging (MRI), using the Dixon method for separation of water/ fat signals. Body composition will also be measured by DEXA.

Maximal voluntary strength and muscle fatigability in the upper extremity will be assessed using the 1-repetition maximum in chest press.

Total, trabecular and cortical volumetric bone density; trabecular and cortical microarchitecture, both measured using high resolution peripheral quantitative computed tomography (HR-pQCT) at the ultradistal tibia, proximal tibia, and ultradistal radius.

Estimated bone strength of the ultradistal tibia and radius, assessed using microfinite element analysis of the HR-pQCT data.

Areal bone mineral density of the hip and lumbar spine using dual-energy X-ray absorptiometry (DEXA). (aBMD will be measured because DEXA is a clinically used and accepted measure of bone density, and aBMD is predictive of fracture risk.) Serum bone turnover markers, including markers of bone formation (osteocalcin, bone specific alkaline phosphatase (BSAP), (PINP) and bone resorption (CTX).

Spinal Cord Injury - Functional Index (SCI-FI) will be used to assess self-reported function and mobility. SCI-FI is specific for persons with SCI that assesses functional capacity in basic mobility, ambulation, self-care, and fine motor function, and wheelchair ambulation.

Measures of Metabolism: Fasting glucose, A1C; insulin sensitivity using HOMA-IR; IL-6 and hsCRP as inflammation markers; and plasma lipids, apolipoproteins B, C and A, and lipoprotein particles as markers of atherogenicity - all measured in the Brigham Research Assay Laboratory. Visceral fat will be assessed using Dixon MRI technique.

Wellbeing: We will assess mood, anxiety, pain, and life satisfaction as measures of wellbeing. Mood will be assessed using Patient Health Questionnaire (PHQ-9), a 9-item scale that assesses mood and depressive symptoms. We will assess anxiety using GAD-7. Modified Brief Pain Inventory (BPI), a validated measure of pain in SCI, assesses pain intensity (sensory dimension) and interference with function (reactive dimension). Satisfaction with Life Scale is a 5-item scale that assesses happiness with life. Loneliness will be assessed using the Three-Item Loneliness Scale.

Study Population: This proof-of-concept trial will enroll 88 community dwelling men and women with SCI, 19 to 70 years of age, motor C7-T12 cervical and thoracic, AIS A, B, C, or D, 6 months or later after a SCI.

The trial plans to randomize 84 eligible subjects at a single trial site.

Phase: Phase 2

Description of Sites/Facilities Enrolling Participants: This is a single site study that will take place at the Brigham and Women's Hospital in Boston, MA.

Description of Study Intervention: The Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program includes training at home consisting of FES-LC plus arm ergometry plus testosterone undecanoate. Testosterone injections will be administered by study staff in the research clinic or by a visiting nurse in the participant's home. The control group will receive FES-LC plus arm ergometry plus placebo injections.

Study Duration: Approximately 54 months

Participant Duration: Approximately 33 weeks (14 weeks for screening, baseline studies, and Day 1, 16 weeks of intervention, and up to 3 weeks of end of study assessments)

Eligibility Criteria:
INCLUSION CRITERIA

1. Men and women, 19 to 70 years
2. Confirmed cervical and thoracic, AIS A-D who are at least 6 months post-injury and who use a wheelchair as their primary mobility mode
3. Medically stable, able to follow directions
4. Able to provide informed consent.
5. For females of reproductive potential who are sexually active: use of highly effective contraception for at least 1 month prior to Day 1 and agreement to use such a method during study participation and for an additional 12 weeks after the end of intervention.

EXCLUSION CRITERIA

1. Upper extremity musculoskeletal conditions (such as advanced rotator cuff pathology or carpal tunnel syndrome) or neurological disorder that in the assessment of the study investigator would prevent the participant from performing the prescribed arm ergometry.
2. Current fractures in the upper and lower extremity
3. In accordance with the Endocrine Society and ISSAM Guidelines25,52, we will exclude individuals with a contraindication for androgen use:

   * History of prostate or breast cancer
   * Prostate nodule or induration on digital rectal examination (DRE)
   * Prostate specific antigen (PSA) \> 4 ng/ml or \> 3 ng/ml in individuals at high risk of prostate cancer such as African Americans or those with family history of prostate cancer in first degree relatives, unless there has been a negative prostate biopsy within 3 months
   * Hematocrit \> 48%
4. Conditions that would render exercise and FES unsafe or unfeasible such as severe autonomic dysreflexia, severe pressure sores, severe spasticity and severe pain.
5. Body mass index (BMI) \> 45 kg/m2
6. Renal dysfunction as indicated by GFR of \<50 ml/min, estimated by using the Modification of Diet in Kidney Disease (MDRD) Study equation, in accordance with K/DOQI guidelines
7. Use of testosterone or other anabolic therapies, including DHEA and androstenedione, or rhGH in the preceding 6 months
8. Active cancer requiring therapy and which may limit life expectancy to less than 5 years
9. Psychosis, bipolar disorder, or major untreated depression
10. Dementia (Mini-Mental Status Exam \[MMSE\] \<24)
11. Myocardial infarction (MI) or stroke within 3 months of entry
12. Pacemaker
13. ALT and AST \> 3 x upper limit of normal
14. Poorly controlled diabetes as indicated by hemoglobin (Hb)-A1c greater than 9.0% or diabetes requiring insulin therapy
15. Blood thinners such as Coumadin, heparin, rivaroxaban (Xarelto), dabigatran (Pradaxa), lovenox (subcutaneous heparin), apixaban (Eliquis) (aspirin, plavix and other anti-platelet agents are allowed)
16. Systolic blood pressure (BP) \> 170 or diastolic BP \> 100 mm Hg
17. Current grade 2 or greater pressure ulcers at relevant contact sites
18. Pressure sores or open wounds on the areas that restricts their participation
19. Because the safety of testosterone has not been established in pregnancy and lactation, we will exclude pregnant or lactating women and women of childbearing potential who are sexually active but are unwilling or unable to use a reliable form of contraception. We will perform a blood test to exclude pregnancy at the time of enrollment.
20. Participation in a structured exercise program currently or in the past 2 months and unwilling to stop the structured exercise program if ongoing at time of screening. Specifically, participation in a structured exercise program, currently or in the past 2 months, that involves progressive resistance exercise training of moderate to high intensity or regular endurance exercise of moderate to high intensity, and unwillingness to stop the structured exercise program if ongoing at time of screening.
21. Inability or unwillingness to participate in the exercise training or the assessments of muscle performance and physical performance