Clinical trial NCT05569122: Applying pGz in Mitochondrial Disease
Official title: The Utility of pGz in Primary Mitochondrial Disorders
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Mitochondrial Myopathies
Mitochondrial Diseases
Keywords: Passive Exercise
periodic acceleration
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2022-10-06
Enrollment: 90
Sex: ALL
Minimum age (years): 10
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Aim 1: Mean Difference in Maximal Oxygen Consumption between primary mitochondrial disease patients and healthy volunteers
timeFrame: During Cardiopulmonary Exercise Testing, which will last 1 hour
measure: Aim 2: Arterial-Venous (A-V) O2 difference
timeFrame: A total of 4 15 minute blood draws
measure: Aim 1 and 2: Oxygen Consumption
timeFrame: 1 hour per study intervention
Secondary outcomes:
measure: Aim 1 and 2: A/B ratio measurement through EKG or Plethsymography
timeFrame: 1 hour per study intervention
measure: Aim 1 and 2: Heart Rate
timeFrame: 1 hour per study intervention
measure: Aim 1 and 2: OXPHOS Capacity
timeFrame: Aim 1 subjects will complete 2 1 hour MRIs, Aim 2 Subjects will complete 1 1-hour MRI
measure: Aim 1 and 2: Plasma Lactate Levels
timeFrame: 15 minute blood draws that occur pre and and immediately after each study intervention
measure: Aim 1 and 2: Vasodilatation
timeFrame: 30 minute ultrasound that occurs pre and immediately after each study intervention
measure: NO release
timeFrame: 15 minutes, before and immediately after each study intervention
measure: Plasma Nom Levels
timeFrame: 15 minute blood draws that occur pre and immediately after each study intervention
measure: Post-operative Patient Satisfaction Survey
timeFrame: 15 minutes, taken after each study intervention
measure: Borg Scale
timeFrame: 15 minutes, taken after each study intervention
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Attending Physician
name: Zuela Zolkipli-Cunningham, MBChB, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sackner MA, Lopez JR, Banderas V, Adams JA. Can Physical Activity While Sedentary Produce Health Benefits? A Single-Arm Randomized Trial. Sports Med Open. 2020 Oct 2;6(1):47. doi: 10.1186/s40798-020-00278-3.
citation: Sackner MA, Patel S, Adams JA. Changes of blood pressure following initiation of physical inactivity and after external addition of pulses to circulation. Eur J Appl Physiol. 2019 Jan;119(1):201-211. doi: 10.1007/s00421-018-4016-7. Epub 2018 Oct 22.
citation: Burstein DS, McBride MG, Min J, Paridon AA, Perelman S, Huffman EM, O'Malley S, Del Grosso J, Groepenhoff H, Paridon SM, Brothers JA. Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents. J Pediatr. 2021 Feb;229:61-69.e5. doi: 10.1016/j.jpeds.2020.09.018. Epub 2020 Sep 11.
citation: Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain. 2003 Feb;126(Pt 2):413-23. doi: 10.1093/brain/awg028.
citation: Tarnopolsky M. Exercise testing in metabolic myopathies. Phys Med Rehabil Clin N Am. 2012 Feb;23(1):173-86, xii. doi: 10.1016/j.pmr.2011.11.011. Epub 2011 Dec 11.
citation: Tarnopolsky M. Exercise testing as a diagnostic entity in mitochondrial myopathies. Mitochondrion. 2004 Sep;4(5-6):529-42. doi: 10.1016/j.mito.2004.07.011. Epub 2004 Sep 30.
citation: Taivassalo T, Haller RG. Exercise and training in mitochondrial myopathies. Med Sci Sports Exerc. 2005 Dec;37(12):2094-101. doi: 10.1249/01.mss.0000177446.97671.2a.
citation: Adams JA, Uryash A, Bassuk J, Sackner MA, Kurlansky P. Biological basis of neuroprotection and neurotherapeutic effects of Whole Body Periodic Acceleration (pGz). Med Hypotheses. 2014 Jun;82(6):681-7. doi: 10.1016/j.mehy.2014.02.031. Epub 2014 Mar 12.
citation: Adams JA, Mangino MJ, Bassuk J, Kurlansky P, Sackner MA. Regional blood flow during periodic acceleration. Crit Care Med. 2001 Oct;29(10):1983-8. doi: 10.1097/00003246-200110000-00022.
citation: M. Fujita et al., "Periodic acceleration enhances release of nitric oxide in healthy adults," Int. J. Angiol., vol. 14, no. 1, pp. 11-14, Feb. 2005, doi: 10.1007/s00547-005-2013-2.
citation: Uryash A, Bassuk J, Kurlansky P, Altamirano F, Lopez JR, Adams JA. Antioxidant Properties of Whole Body Periodic Acceleration (pGz). PLoS One. 2015 Jul 2;10(7):e0131392. doi: 10.1371/journal.pone.0131392. eCollection 2015.
citation: Uryash A, Bassuk J, Kurlansky P, Altamirano F, Lopez JR, Adams JA. Non-invasive technology that improves cardiac function after experimental myocardial infarction: Whole Body Periodic Acceleration (pGz). PLoS One. 2015 Mar 25;10(3):e0121069. doi: 10.1371/journal.pone.0121069. eCollection 2015.
citation: Adams JA, Patel S, Lopez JR, Sackner MA. The Effects of Passive Simulated Jogging on Short-Term Heart Rate Variability in a Heterogeneous Group of Human Subjects. J Sports Med (Hindawi Publ Corp). 2018 Oct 1;2018:4340925. doi: 10.1155/2018/4340925. eCollection 2018.
citation: Sackner MA, Gummels E, Adams JA. Nitric oxide is released into circulation with whole-body, periodic acceleration. Chest. 2005 Jan;127(1):30-9. doi: 10.1378/chest.127.1.30.
citation: Adams JA, Bassuk J, Wu D, Grana M, Kurlansky P, Sackner MA. Periodic acceleration: effects on vasoactive, fibrinolytic, and coagulation factors. J Appl Physiol (1985). 2005 Mar;98(3):1083-90. doi: 10.1152/japplphysiol.00662.2004. Epub 2004 Oct 22.
citation: Betik AC, Parker L, Kaur G, Wadley GD, Keske MA. Whole-Body Vibration Stimulates Microvascular Blood Flow in Skeletal Muscle. Med Sci Sports Exerc. 2021 Feb 1;53(2):375-383. doi: 10.1249/MSS.0000000000002463.
citation: Sjoberg KA, Rattigan S, Hiscock N, Richter EA, Kiens B. A new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and rat. Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H450-8. doi: 10.1152/ajpheart.01174.2010. Epub 2011 May 27.
citation: Kogan F, Haris M, Debrosse C, Singh A, Nanga RP, Cai K, Hariharan H, Reddy R. In vivo chemical exchange saturation transfer imaging of creatine (CrCEST) in skeletal muscle at 3T. J Magn Reson Imaging. 2014 Sep;40(3):596-602. doi: 10.1002/jmri.24412. Epub 2013 Oct 31.
citation: DeBrosse C, Nanga RPR, Wilson N, D'Aquilla K, Elliott M, Hariharan H, Yan F, Wade K, Nguyen S, Worsley D, Parris-Skeete C, McCormick E, Xiao R, Cunningham ZZ, Fishbein L, Nathanson KL, Lynch DR, Stallings VA, Yudkoff M, Falk MJ, Reddy R, McCormack SE. Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders. JCI Insight. 2016 Nov 3;1(18):e88207. doi: 10.1172/jci.insight.88207.
citation: Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Duno M, Hauerslev S, Vissing J. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006 Dec;129(Pt 12):3402-12. doi: 10.1093/brain/awl149. Epub 2006 Jun 30.