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

NCT05962333 | Recruiting Phase 2 DMC

• 1 other identifier: NL82815.000.22
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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).

Conditions

Mitochondrial Myopathies

Keywords

m.3243A>G; mesoangioblasts

Outcome Measures

Primary Outcomes (13)

• 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 Outcomes (4)

• Assess changes in muscle volume biceps brachii muscles of both arms following 3 i.a. deliveries of autologous MABs in left arm.

  baseline and 15 weeks after 1st administration

• Assess formation of new muscle fibers following 3 i.a. deliveries of autologous MABs

  baseline and 15 weeks after 1st administration

• Mitochondrial mutation load and functioning following 3 i.a. deliveries of autologous MABs

  baseline and 15 weeks after 1st administration

• Mitochondrial functioning following 3 i.a. deliveries of autologous MABs in left arm.

  baseline and 15 weeks after 1st administration

Other Outcomes (1)

• Assess creatine kinase level in blood plasma as marker for muscle damage following 3 i.a. deliveries of autologous MABs

  0 and 8 hours after each administration.

Study Arms (1)

Intra-arterial delivery of autologous MABs

EXPERIMENTAL

Autologous MABs will be injected three times in left arm to treat biceps brachii muscle

Biological: Intra-arterial delivery of autologous MABs

Interventions

Intra-arterial delivery of autologous MABs BIOLOGICAL

three times intra-arterial administration of autologous mesoangioblasts in biceps brachii of the left arm at 4-6 week interval

Intra-arterial delivery of autologous MABs

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Maastricht University: lead

Study Sites (1)

Maastricht University Medical Center

Maastricht, 6229ER, Netherlands

RECRUITING

Related Publications (1)

• 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.

  PMID: 31864395 RESULT

Related Links

• website Generate Your Muscle (GYM) project

MeSH Terms

Conditions

Mitochondrial Myopathies

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Janneke Hoeijmakers, MD, PhD

  Maastricht University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Florence van Tienen, PhD

CONTACT

00314331995; florence.vantienen@maastrichtuniversity.nl

Bert Smeets, Prof. PhD

CONTACT

00314331995; bert.smeets@maastrichtuniversity.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 23, 2023
• First Posted: July 27, 2023
• Study Start: August 1, 2023
• Primary Completion: August 1, 2024
• Study Completion: February 1, 2025
• Last Updated: April 15, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)