Applying pGz in Mitochondrial Disease

Study Overview
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Brief Summary
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This is a multi-aim study, studying the effects of conventional exercise (measured through Cardiopulomary Exercises Testing or an in-bed pedal exercise) and passive exercise through periodic acceleration (pGz). Aim 1 will focus on the differences between primary mitochondrial disease (PMD) patients and healthy volunteers. Aim 2 is an exploratory aim, which will be studying the effects in patients admitted to the Children's Hospital of Philadelphia Pediatric Intensive Care Unit (PICU).

Detailed Description
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Aim 1: Primary Mitochondrial Disease Patients and Healthy Controls Individuals will be screened for eligibility for study entry, and answer questions relating to their ability to perform study procedures and their physical activity levels. Individuals who meet study criteria will have 3 study visits, and each study visit will involve a different intervention. At each of these study visits, individuals will complete one of the following interventions: Cardiopulmonary Exercise Testing (CPET), pGz administration through a bed or recliner, and pGz through a device called a Gentle Jogger. While participants will complete all three study visits, the order of the study visits will occur in random order. During the study visits, participants will have blood draws before and after the study intervention, a vascular ultrasound with a Lumason contrast agent before and after the study intervention, and a Creatine Chemical Exchange Saturation Transfer (CrCEST) MRI of the lower leg. Aim 2: Patients in the Pediatric Intensive Care Unit (PICU) Individuals will be screened for eligibility for study entry. Individuals who meet study criteria will have 2 study visits during their admission to the PICU. The first study visit will involve a pedal exercise and the second study visit will involve pGz administration through a device called a Gentle Jogger. During the study visits, participants will have blood draws before and after the study intervention, a vascular ultrasound with a Lumason contrast agent before and after the study intervention, and if able to safely complete, an CrCEST MRI of the lower leg.

Official Title
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The Utility of pGz in Primary Mitochondrial Disorders

Conditions
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Mitochondrial Myopathies, Mitochondrial Diseases

Intervention / Treatment
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* Drug: Lumason® contrast agent
* Diagnostic Test: Cardiopulmonary Exercise Testing
* Device: pGz Bed
* Device: Gentle Jogger
* Device: Exercise Pedal


Participation Criteria
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Eligibility Criteria
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Aim 1 Enrollment Criteria Inclusion Criteria for Healthy Controls Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm Ambulatory and able to complete routine clinical exercise testing Willing and able to complete all study procedures For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent For individuals over the age of 18 the ability to provide informed consent Inclusion Criteria for PMD Patients Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm Ambulatory and able to complete routine clinical exercise testing Willing and able to complete all study procedures Genetically confirmed mitochondrial myopathy (MM) as defined by a diagnosis of primary mitochondrial disease (PMD) with predominant symptoms of myopathy as expressed by exercise intolerance and muscle weakness and fatigue Parental/guardian permission (informed consent) and as appropriate, child assent Exclusion Criteria for All Aim 1 Participants General Exclusion Criteria Tracheostomy Non-ambulatory Unable to complete routine exercise testing Diagnosed with or have symptoms of vertigo Within 1 month of a recent hospital admission for acute illness Severe co-existing cardiac or pulmonary disease Cognitive impairment that may preclude ability to comply with study procedures Pregnant or lactating females Active alcohol and/or substance abuse At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures Use of investigational agent(s) within 4 weeks Individuals who are employed by the U.S. Department of Defense, including U.S military personal Patients with biliary atresia with asplenia or polysplenia. Patients with prior liver transplant. Patients with cystic fibrosis. Patients with chronic lung disease. Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein. Patients with significant heart disease or severe congenital heart disease. Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite) Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces Inability to lie flat in an MRI scanner for up to 45 minutes Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study Aim 2 Enrollment Criteria Inclusion Criteria for PICU PMD Non-Ambulatory Patients Males or females ages 10 to 23 years (children and adults) Non-ambulatory Genetically confirmed mtDNA-PMD Cooperative and capable of following research procedures Have cognitive ability to enable cooperation with study procedures Admitted to the PICU with an anticipated length of stay for >24 hours Willing and able to complete all study procedures For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent For individuals over the age of 18 the ability to provide informed consent Inclusion Criteria for PICU non-PMD neuromuscular diagnosis Males or females ages 10 to 23 years (children and adults) Non-ambulatory Genetically confirmed non-PMD neuromuscular diagnosis Cooperative and capable of following research procedures Have cognitive ability to enable cooperation with study procedures Admitted to the PICU with an anticipated length of stay for >24 hours For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent For individuals over the age of 18 the ability to provide informed consent Inclusion Criteria for all other PICU Participants Males or females ages 10 to 23 years (children and adults) Non-ambulatory No known genetic diagnosis with healthy pre-morbid status, admitted to PICU Cooperative and capable of following research procedures Have cognitive ability to enable cooperation with study procedures Admitted to the PICU with an anticipated length of stay for >24 hours Willing and able to complete all study procedures For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent For individuals over the age of 18 the ability to provide informed consent Exclusion Criteria for All Aim 2 Participants Have cognitive impairment that may preclude ability to comply with study procedures Have cardiorespiratory instability Patients in whom are so sick that they will not be able to cooperate with the study procedures Have clear contraindications to mobilization Have fixed lower limb deformities/contractures that would prohibit lower extremity exercise Pregnant or lactating females Active alcohol and/or substance abuse At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study Use of investigational agent(s) within 4 weeks Individual who are employed by the U.S. Department of Defense, including U.S military personal Patients with biliary atresia with asplenia or polysplenia. Patients with prior liver transplant. Patients with cystic fibrosis. Patients with chronic lung disease. Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein. Patients with significant heart disease or severe congenital heart disease. Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent Exclusion Criteria Specific to study procedure: CrCEST MRI Scan: Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite) Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces Inability to lie flat in an MRI scanner for up to 45 minutes Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Aim 1 will have the 3 study interventions/study visits occur in random order. The interventions will be performed in primary mitochondrial disease patients and healthy controls Aim 2 will have all participants complete the study interventions/visits in the same order. Patients will be from the PICU
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aim 1: Primary Mitochondrial Disease Patients<br>The participant has the interventions/study visits occur in a random order: CPET pGz administration through pGz Bed pGz administration through Gentle Jogger | Diagnostic Test: Cardiopulmonary Exercise Testing<br>* Testing with an exercise bicycle that is considered standard of care for determination of exercise capacity. Participants will complete about 20 minutes of pedaling in a stationary exercise bike<br>Device: pGz Bed<br>* Participants will lay down on a passive exercise (pGz) bed for 45 minutes during which the bed will administer passive exercise through periodic acceleration<br>Device: Gentle Jogger<br>* Participants will have passive exercise delivered through the gentle jogger device for 45 minutes. This may be sitting down (aim 1 participants) or laying down (aim 2 participants)<br>Drug: Lumason® contrast agent<br>* Contrast agent used during a vascular ultrasound of the upper leg. Will occur at each study visit twice before and after pGz bed, gentle jogger, exercise pedal or CPET. Drug Administration will be through an IV line and take about 5 - 10 minutes.<br>|
| Experimental: Aim 1: Healthy Controls<br>The participant has the interventions/study visits occur in a random order: pGz administration through Gentle Jogger CPET pGz administration through pGz Bed | Diagnostic Test: Cardiopulmonary Exercise Testing<br>* Testing with an exercise bicycle that is considered standard of care for determination of exercise capacity. Participants will complete about 20 minutes of pedaling in a stationary exercise bike<br>Device: pGz Bed<br>* Participants will lay down on a passive exercise (pGz) bed for 45 minutes during which the bed will administer passive exercise through periodic acceleration<br>Device: Gentle Jogger<br>* Participants will have passive exercise delivered through the gentle jogger device for 45 minutes. This may be sitting down (aim 1 participants) or laying down (aim 2 participants)<br>Drug: Lumason® contrast agent<br>* Contrast agent used during a vascular ultrasound of the upper leg. Will occur at each study visit twice before and after pGz bed, gentle jogger, exercise pedal or CPET. Drug Administration will be through an IV line and take about 5 - 10 minutes.<br>|
| Experimental: Aim 2: PICU Patients<br>All participants in Aim 2 will have the interventions/study visits occur in the same order: Exercise Pedal and Gentle Jogger | Device: Gentle Jogger<br>* Participants will have passive exercise delivered through the gentle jogger device for 45 minutes. This may be sitting down (aim 1 participants) or laying down (aim 2 participants)<br>Device: Exercise Pedal<br>* Participants will exercise while laying down for 20 minutes with an exercise pedal that attaches to the bed<br>Drug: Lumason® contrast agent<br>* Contrast agent used during a vascular ultrasound of the upper leg. Will occur at each study visit twice before and after pGz bed, gentle jogger, exercise pedal or CPET. Drug Administration will be through an IV line and take about 5 - 10 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aim 1: Mean Difference in Maximal Oxygen Consumption between primary mitochondrial disease patients and healthy volunteers | Maximal Oxygen Consumption will be measured only during CPET | During Cardiopulmonary Exercise Testing, which will last 1 hour | 
| Aim 2: Arterial-Venous (A-V) O2 difference | This will be measured through blood draws that occur before and after study interventions | A total of 4 15 minute blood draws | 
| Aim 1 and 2: Oxygen Consumption | Measured During the study interventions | 1 hour per study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aim 1 and 2: A/B ratio measurement through EKG or Plethsymography | To measure hemodynamic physiologic marker of cardiac output (CO) | 1 hour per study intervention | 
| Aim 1 and 2: Heart Rate | To measure hemodynamic physiologic marker of cardiac output (CO) | 1 hour per study intervention | 
| Aim 1 and 2: OXPHOS Capacity | Measured through a CrCEST Leg MRI, which measures creative levels and recovery in the leg | Aim 1 subjects will complete 2 1 hour MRIs, Aim 2 Subjects will complete 1 1-hour MRI | 
| Aim 1 and 2: Plasma Lactate Levels | Measured through venous blood draws | 15 minute blood draws that occur pre and and immediately after each study intervention | 
| Aim 1 and 2: Vasodilatation | Measured through a vascular ultrasound with contrast | 30 minute ultrasound that occurs pre and immediately after each study intervention | 
| NO release | Measured through Plethsymography | 15 minutes, before and immediately after each study intervention | 
| Plasma Nom Levels | Measured through venous blood draws | 15 minute blood draws that occur pre and immediately after each study intervention | 
| Post-operative Patient Satisfaction Survey | Participant tolerance to pGz compared to CPET | 15 minutes, taken after each study intervention | 
| Borg Scale | Participant tolerance to pGz compared to CPET | 15 minutes, taken after each study intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Passive Exercise, periodic acceleration