Applying pGz in Mitochondrial Disease

Mitochondrial Diseases Clinical Trial

Official title:

The Utility of pGz in Primary Mitochondrial Disorders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05569122
• Other study ID #: 21-018532
• Status: Recruiting
• Phase: Phase 1
• Start date: March 22, 2023
• Est. completion date: October 2024

Study information

• Verified date: February 2024
• Source: Children's Hospital of Philadelphia
• Contact: Katelynn Stanley, BS
• Phone: 215-426-0225
• Email: stanleyk2[@]chop.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 10 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Mitochondrial Diseases
• Mitochondrial Myopathies

Intervention

Diagnostic Test:
• Cardiopulmonary Exercise Testing
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

Device:
• pGz Bed
Participants will lay down on a passive exercise (pGz) bed for 45 minutes during which the bed will administer passive exercise through periodic acceleration
• Gentle Jogger
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)
• Exercise Pedal
Participants will exercise while laying down for 20 minutes with an exercise pedal that attaches to the bed

Drug:
• Lumason® contrast agent
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.

Locations

Country	Name	City	State
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia	United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (20)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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.

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Aim 1 and 2: Oxygen Consumption	Measured During the study interventions	1 hour per study intervention
Secondary	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
Secondary	Aim 1 and 2: Heart Rate	To measure hemodynamic physiologic marker of cardiac output (CO)	1 hour per study intervention
Secondary	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
Secondary	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
Secondary	Aim 1 and 2: Vasodilatation	Measured through a vascular ultrasound with contrast	30 minute ultrasound that occurs pre and immediately after each study intervention
Secondary	NO release	Measured through Plethsymography	15 minutes, before and immediately after each study intervention
Secondary	Plasma Nom Levels	Measured through venous blood draws	15 minute blood draws that occur pre and immediately after each study intervention
Secondary	Post-operative Patient Satisfaction Survey	Participant tolerance to pGz compared to CPET	15 minutes, taken after each study intervention
Secondary	Borg Scale	Participant tolerance to pGz compared to CPET	15 minutes, taken after each study intervention