Clinical trial NCT05962333: Effect and Safety MABs Administration m.3243A>G Mutation Carriers
Official title: Assess Effect and Safety of Intra-arterial Autologous Mesoangioblast Administration to the Upper Arm of m.3243A>G Mutation Carriers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Mitochondrial Myopathies
Keywords: m.3243A>G
mesoangioblasts
Lead sponsor: Maastricht University
Sponsor class: OTHER
First posted: 2023-07-27
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Intra-subjected controlled clinical study. Treatment is performed in left arm of the subjects and right arm (no intervention), measurements are performed before the first and after the last administration.
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Assess blood flow in left arm following i.a. arterial delivery of autologous MABs
timeFrame: before and directly after each administration in week 1,5 and 10
measure: Assess (serious) adverse events following 3 i.a. deliveries of autologous MABs
timeFrame: 15 weeks
measure: Assess temperature following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess oxygen saturation following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Muscle strength arm following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess breathing frequency following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess vital signs following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess systolic and diastolic blood pressure following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess Glasgow Coma scale (GCS) score following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: Assess if pupil size is symmetrical in both eyes following 3 i.a. deliveries of autologous MABs
timeFrame: 0, 1,2,3,4,6 and 8 hours after each administration.
measure: Assess pupil reaction following 3 i.a. deliveries of autologous MABs
timeFrame: 0,1,2,3,4,6 and 8 hours after each administration.
measure: 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.
timeFrame: baseline and 15 weeks after 1st administration
measure: 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.
timeFrame: baseline and 15 weeks after 1st administration
Secondary outcomes:
measure: Assess changes in muscle volume biceps brachii muscles of both arms following 3 i.a. deliveries of autologous MABs in left arm.
timeFrame: baseline and 15 weeks after 1st administration
measure: Assess formation of new muscle fibers following 3 i.a. deliveries of autologous MABs
timeFrame: baseline and 15 weeks after 1st administration
measure: Mitochondrial mutation load and functioning following 3 i.a. deliveries of autologous MABs
timeFrame: baseline and 15 weeks after 1st administration
measure: Mitochondrial functioning following 3 i.a. deliveries of autologous MABs in left arm.
timeFrame: baseline and 15 weeks after 1st administration
Other outcomes:
measure: Assess creatine kinase level in blood plasma as marker for muscle damage following 3 i.a. deliveries of autologous MABs
timeFrame: 0 and 8 hours after each administration.
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
Study officials:
affiliation: Maastricht University Medical Center
name: Janneke Hoeijmakers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.