Effect and Safety MABs Administration m.3243A>G Mutation Carriers

Assess Effect and Safety of Intra-arterial Autologous Mesoangioblast Administration to the Upper Arm of m.3243A>G Mutation Carriers

The first primary objective is to assess the effect of three intra-arterial administrations of autologous mesoangioblasts (MABs) with respect to improving muscle strength and reduce fatigue of the treated biceps brachii (BB) compared to the untreated BB.

The second primary objective is safety of three intra-arterial administrations of autologous MABs, which the investigators will assess by monitoring (serious) adverse events ((S)AEs), blood flow in left arm pre- and post-intervention, and neurological vital signs during 8h post-intervention observation in the hospital.

Secondary objectives are to assess changes in muscle mass of the treated and untreated BB muscle, and microscopic changes and m.3243A>G mutation load at tissue level in treated biceps brachii (BB) muscle at baseline and after treatment.

Up to 20 adult m.3243A>G patients will undergo a ~30mg m. biceps brachii muscle biopsy at visit 1. The first six eligible patients will enroll the clinical study based on their m.3243A>G mutation load in skeletal muscle (50-90%) and mesoangioblasts (<10%), and on a decreased BB muscle strength and increased fatigue.

These 6 selected patients will visit the Maastricht University Medical Center for 8 additional times. From each patient, during visit 2 till 9:

• BB muscle biopsies of the left arm will be collected (1x ~130 mg at visit 2 and 1x ~30mg at visit 9)
• MRI of the BB muscles in both arms will be performed (visit 2 and 9).
• Autologous MABs will be injected into the left arm via axillary artery delivery. Angiography will be performed before and after infusion to assess vascular obstructions, and the participant will be monitored in the hospital for 8 hours (visit 4,6,8).
• Tc99m macroaggregated albumin (MAA) is infused to quantify blood flow to the BB muscle (visit 4).
• A bout of maximal eccentric exercise of BB muscles on both sides will be executed at visit 3, 5 and 7.
• BB muscle strength will be assessed using a Biodex dynamometer (visit 3-9)
• venous blood samples will be taken for assessing muscle damage and inflammation markers (visit 3-9), kidney functioning, coagulation and viral screening (visit 1 and 2).

Study Overview

• Status: Recruiting
• Conditions: Mitochondrial Myopathies
• Intervention / Treatment: Biological: Intra-arterial delivery of autologous MABs

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Florence van Tienen, PhD; Phone Number: 00314331995; Email: florence.vantienen@maastrichtuniversity.nl
• Study Contact Backup: Name: Bert Smeets, Prof. PhD; Phone Number: 00314331995; Email: bert.smeets@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229ER
    • Recruiting
    • Maastricht University Medical Center
    • Contact: Florence van Tienen, PhD; Phone Number: 0031433882918

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• Age: 18-64
• Sex: male/female
• Patients with the m.3243A>G mutation load of 50%-90% determined in skeletal muscle or derived from age-corrected calculation of blood m.3243A>G mutation load

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Use of dabigatran, apixaban, edoxaban or rivaroxaban (DOACs) as anti-coagulants
• Have a weekly alcohol intake of ≥ 35 units (men) or ≥ 24 units (women)
• Current history of drug abuse
• Deficient immune system or autoimmune disease
• Significant concurrent illness
• Ongoing participation in other clinical trials with intervention
• Pregnant or lactating women
• Psychiatric or other disorders likely to impact on informed consent
• Patients unable and/or unwilling to comply with treatment and study instructions
• A history of strokes with signs of extra-pyramidal or pyramidal syndrome
• Allergy for contrast fluid
• Peripheral signs of ischemia or vasculopathy
• Claustrophobia
• Metal implants
• Any other factor that in the opinion of the investigator excludes the patient from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intra-arterial delivery of autologous MABs; Autologous MABs will be injected three times in left arm to treat biceps brachii muscle	Biological: Intra-arterial delivery of autologous MABs; three times intra-arterial administration of autologous mesoangioblasts in biceps brachii of the left arm at 4-6 week interval

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess blood flow in left arm following i.a. arterial delivery of autologous MABs	Assess blood flow in left arm using digital subtraction angiography (DSA) before and directly after MABs administration in week 1, 5 and 10.	before and directly after each administration in week 1,5 and 10
Assess (serious) adverse events following 3 i.a. deliveries of autologous MABs	Assessment of (serious) adverse events	15 weeks
Assess temperature following 3 i.a. deliveries of autologous MABs	Temperature will be checked 0,1,2,3,4,6 and 8 hours after administration in week 1,5 and 10.	0,1,2,3,4,6 and 8 hours after each administration.
Assess oxygen saturation following 3 i.a. deliveries of autologous MABs	Oxygen saturation will be checked 0,1,2,3,4,6 and 8 hours after administration in week 1,5 and 10.	0,1,2,3,4,6 and 8 hours after each administration.
Muscle strength arm following 3 i.a. deliveries of autologous MABs	Using Medical Research Council (MRC) scale for muscle strength, muscle strength of left arm will be assessed 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10. MRC scale ranges from 0 (no visible contraction) to 5 (normal)).	0,1,2,3,4,6 and 8 hours after each administration.
Assess breathing frequency following 3 i.a. deliveries of autologous MABs	Breathing frequency will be checked 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10.	0,1,2,3,4,6 and 8 hours after each administration.
Assess vital signs following 3 i.a. deliveries of autologous MABs	Heart rate will be checked 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10.	0,1,2,3,4,6 and 8 hours after each administration.
Assess systolic and diastolic blood pressure following 3 i.a. deliveries of autologous MABs	Systolic and Diastolic blood pressure will be checked 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10.	0,1,2,3,4,6 and 8 hours after each administration.
Assess Glasgow Coma scale (GCS) score following 3 i.a. deliveries of autologous MABs	Glasgow Coma Scale (GCS) score will be determined 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10. GCS score ranges from 3 to 15, 3 being the worst and 15 being the best score.	0,1,2,3,4,6 and 8 hours after each administration.
Assess if pupil size is symmetrical in both eyes following 3 i.a. deliveries of autologous MABs	Pupil size of both eyes will be assessed 0,1,2,3,4,6 and 8 hours after administration in week 1, 5 and 10. If pupil size is not equal, this can indicate disease or trauma.	0, 1,2,3,4,6 and 8 hours after each administration.
Assess pupil reaction following 3 i.a. deliveries of autologous MABs	To assess brain functioning, reaction of pupils to light will be determined 0,1,2,3,4,6 and 8 hours after administration. Upon light, both pupils should become smaller in week 1, 5 and 10. No reaction or only reaction in one eye can indicate nerve damage.	0,1,2,3,4,6 and 8 hours after each administration.
Assess changes in muscle strength of biceps brachii muscle in both arms at baseline and 4-6 weeks after third i.a. delivery of autologous MABs in left arm, which is 12-16 weeks after baseline measurements.	Determine maximum muscle force generating capacity (peak torque N/m) of the biceps brachii muscle in both arms using Biodex dynamometer measurements. Measurements will be performed in left (intervention) and right (no intervention) biceps brachii muscle using Biodex dynamometer measurements at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration
Assess changes in muscle fatigue of biceps brachii muscle in both arms at baseline and 4-6 weeks after third i.a. delivery of autologous MABs in left arm, which is 12-16 weeks after baseline measurements.	Asses changes in muscle fatigue by measuring percentage decrease in maximum muscle force generating capacity (peak torque N/m) between first and sixth repetition. Measurements will be performed in left (intervention) and right (no intervention) biceps brachii muscle using Biodex dynamometer measurements at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess changes in muscle volume biceps brachii muscles of both arms following 3 i.a. deliveries of autologous MABs in left arm.	MRI T3 analysis to assess changes in muscle volume in both arms at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration
Assess formation of new muscle fibers following 3 i.a. deliveries of autologous MABs	Perform embryonic myosin heavy chain (MHC)+ immunostaining to assess percentage of new / regenerating muscle fibers in muscle biopsies collected at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration
Mitochondrial mutation load and functioning following 3 i.a. deliveries of autologous MABs	Assess changes in m.3243A>G mutation load in new/regenerating muscle fibers compared to existing muscle fibers isolated via laser microdissection from muscle biopsies left arm collected at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration
Mitochondrial functioning following 3 i.a. deliveries of autologous MABs in left arm.	Assess changes in mitochondrial functioning by performing Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) staining in muscle biopsies from left arm collected at baseline and 5 weeks after the third autologous MABs administration, which is 15 weeks after baseline measurements.	baseline and 15 weeks after 1st administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess creatine kinase level in blood plasma as marker for muscle damage following 3 i.a. deliveries of autologous MABs	Assess creatine kinase (CK) in blood plasma following eccentric exercise prior and 8 hours after administration in week 1,5 and 10.	0 and 8 hours after each administration.

Collaborators and Investigators

• Sponsor: Maastricht University
• Investigators: Principal Investigator: Janneke Hoeijmakers, MD, PhD, Maastricht University Medical Center

Publications and helpful links

General Publications

• van Tienen F, Zelissen R, Timmer E, van Gisbergen M, Lindsey P, Quattrocelli M, Sampaolesi M, Mulder-den Hartog E, de Coo I, Smeets H. Healthy, mtDNA-mutation free mesoangioblasts from mtDNA patients qualify for autologous therapy. Stem Cell Res Ther. 2019 Dec 21;10(1):405. doi: 10.1186/s13287-019-1510-8.

Helpful Links

• website Generate Your Muscle (GYM) project

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: May 23, 2023
• First Submitted That Met QC Criteria: July 24, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: m.3243A>G; mesoangioblasts
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Mitochondrial Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: NL82815.000.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No