Treatment of Frostbite Sequelae With Botulinum Toxin A

NCT06460194 | Withdrawn Phase 2 DMC

• 1 other identifier: 2018/1961(REK)
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background Digital vasospasm as part of frostbite sequelae is comparable to the vasospastic disorders found in Raynaud's phenomenon which has been successfully treated with Botulinum toxin type A injections in the palm of the hands. Aim of this pilot study To investigate the effect of Botulinum toxin type A for frostbite sequelae in the fingers. Hypothesis The null hypothesis which is that all study-subjects will have equal distribution of symptoms and measurements after treatment, regardless of injection with Botulinum toxin type A or placebo. Methodology A randomized, double-blind, placebo-controlled study design, The study population consists of four patients with frostbite sequelae. The patients are randomized to either treatment with Botulinum toxin type A or placebo Two patients in the primary treatment group will receive Botulinum toxin type A at their first injection at inclusion, while the two patients in the secondary treatment group will receive normal saline (placebo) as their first injection at inclusion. At 6 weeks follow up, the primary treatment group will receive their second injection of Botulinum toxin type A and the secondary treatment group now will receive their second injection, but this will be their first injection of Botulinum toxin type A. By using the described study-design, all participating soldiers will get treatment. However, the secondary treatment group will have a delayed onset of treatment with Botulinum toxin type A and serves as a control for the primary treatment group during the initial 6 weeks observation. Botulinum toxin A and placed will be injected near the neurovascular bundle at the A1 pulley in the palm of the hand using a total dosage 100 U per hand (concentration 50 U per ml), 8-12 U/ injection site. The effect of Botulinum toxin type A on subjective symptoms will be measured by Patients Subjective Symptom Score (PSSS) The effect of Botulinum toxin type A on peripheral microcirculation will be evaluated with dynamic infrared thermography (DIRT) of the dorsal side of the hands. Quantitative sensory testing will be used to evaluate the effect of Botulinum toxin type A on peripheral nerve function. Both DIRT and QST will be performed prior to the treatment with Botulinum toxin type A and placebo at the start of the pilot study, at 6 weeks as well as 6 weeks after the last injections. Statistical methods and data analysis will be performed according to the EMA guidelines for biostatistics. Statistical analysis will be performed according to the null hypothesis.

Conditions

Cold Hypersensitivity; Vascular System Injuries; Vibration; Disorder; Sensory Disorders; Pain, Nerve

Keywords

cold hypersensitivity; cold intolerance; vasospastic disorder; Raynauds phenomenon; botulinum toxin; infrared thermography; Quantative sensory testing

Outcome Measures

Primary Outcomes (2)

• Subjective symptoms between injection of Botox and placebo at 6 weeks follow up

  According to clinical experience, the patient s experience improvement in subjective symptoms after 4-6 weeks follow-up. The patient's subjective symptoms are monitored in a questionnaire of neurological and vasoactive sensations by comparing Patient-Subjective-Symptom-Score (PSSS) wustionnaire after 6 weeks with the baseline values for each patient.

  6 weeks

• Rewarming before and 6 weeks after treatment with Botulinum toxin

  According to clinical experience, an improvement is found in the rewarming ability after 4-6 weeks follow-up after injection of Botox. The patients rewarming ability is monitored by comparing the results from Dynamic Infrared Thermography (DIRT) after 6 weeks with the baseline values for each patient. The DIRT examines the dynamic regulation of peripheral micro-vascularization. Examination of the dorsal side of the hands encompasses a pre-cooling phase (T1), a cooling phase with hands immersed in water for one minute (T2), and a four-minute recovery phase (T3, T4, T5 and T6).

  6 weeks

Study Arms (2)

Botulinum toxin

ACTIVE COMPARATOR

100 IU botulinum toxin injection in the palm of the hand

Drug: Botuinum toxin

Placebo

PLACEBO COMPARATOR

Saline injection in the palm of the hand

Drug: Botuinum toxin

Interventions

Botuinum toxin DRUG

Injection of botulinum toxin in the palm of the hand

Also known as: Botox

Botulinum toxin; Placebo

Eligibility Criteria

• Age: 20 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Entering the Norwegian Armed Forces Health Registry (NAFHR) between 01.01.2010-31.12.2014
• Still suffering from sequelae related to frostbite injury in their fingers at least four years after their initial frostbite
• Have agreed on receiving a request to participate in the NAFHR quality assurance study.

You may not qualify if:

• Patients who cannot read Norwegian information or answer questions in the study
• Patients who are unable to comply the examination and treatment procedures
• Patients who are unable to travel to University Hospital North Norway in Tromsø for examination and treatment
• Patients who have undergone/is undergoing surgical treatment of hands/fingers
• Patients with known allergy/anaphylaxis in relation to the injection of BTX-A
• Patients who have used/are using drugs that interact with BTX-A injection (anticoagulants)
• Patients who are pregnant before start of the trial and/or during the trial

Sponsors & Collaborators

• University Hospital of North Norway: lead

Study Sites (1)

University Hospital of North Norway

Tromsø, 9038, Norway

Location

Related Publications (11)

• Schaefer G, Huguet J, Zhu SY, Plassmann P, Ring F. Adopting the DICOM standard for medical infrared images. Conf Proc IEEE Eng Med Biol Soc. 2006;2006:236-9. doi: 10.1109/IEMBS.2006.259523.

  PMID: 17946389 BACKGROUND

• Iorio ML, Masden DL, Higgins JP. Botulinum toxin A treatment of Raynaud's phenomenon: a review. Semin Arthritis Rheum. 2012 Feb;41(4):599-603. doi: 10.1016/j.semarthrit.2011.07.006. Epub 2011 Aug 24.

  PMID: 21868066 RESULT

• Imray C, Grieve A, Dhillon S; Caudwell Xtreme Everest Research Group. Cold damage to the extremities: frostbite and non-freezing cold injuries. Postgrad Med J. 2009 Sep;85(1007):481-8. doi: 10.1136/pgmj.2008.068635.

  PMID: 19734516 RESULT

• Fabregat G, De Andres J, Villanueva-Perez VL, Asensio-Samper JM. Subcutaneous and perineural botulinum toxin type a for neuropathic pain: a descriptive review. Clin J Pain. 2013 Nov;29(11):1006-12. doi: 10.1097/AJP.0b013e31827eafff.

  PMID: 23370086 RESULT

• Norheim AJ, Mercer J, Musial F, de Weerd L. A new treatment for frostbite sequelae; Botulinum toxin. Int J Circumpolar Health. 2017;76(1):1273677. doi: 10.1080/22423982.2016.1273677.

  PMID: 28452678 RESULT

• Segreto F, Marangi GF, Cerbone V, Persichetti P. The Role of Botulinum Toxin A in the Treatment of Raynaud Phenomenon. Ann Plast Surg. 2016 Sep;77(3):318-23. doi: 10.1097/SAP.0000000000000715.

  PMID: 26808752 RESULT

• Arnold PB, Campbell CA, Rodeheaver G, Merritt W, Morgan RF, Drake DB. Modification of blood vessel diameter following perivascular application of botulinum toxin-A. Hand (N Y). 2009 Sep;4(3):302-7. doi: 10.1007/s11552-009-9169-8. Epub 2009 Feb 5.

  PMID: 19194764 RESULT

• Ring EF, Ammer K. Infrared thermal imaging in medicine. Physiol Meas. 2012 Mar;33(3):R33-46. doi: 10.1088/0967-3334/33/3/R33. Epub 2012 Feb 28.

  PMID: 22370242 RESULT

• Moreira DG, Costello JT, Brito CJ, Adamczyk JG, Ammer K, Bach AJE, Costa CMA, Eglin C, Fernandes AA, Fernandez-Cuevas I, Ferreira JJA, Formenti D, Fournet D, Havenith G, Howell K, Jung A, Kenny GP, Kolosovas-Machuca ES, Maley MJ, Merla A, Pascoe DD, Priego Quesada JI, Schwartz RG, Seixas ARD, Selfe J, Vainer BG, Sillero-Quintana M. Thermographic imaging in sports and exercise medicine: A Delphi study and consensus statement on the measurement of human skin temperature. J Therm Biol. 2017 Oct;69:155-162. doi: 10.1016/j.jtherbio.2017.07.006. Epub 2017 Jul 18.

  PMID: 29037377 RESULT

• Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, Gierthmuhlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uceyler N, Valet M, Wasner G, Treede DR. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010 Sep;150(3):439-450. doi: 10.1016/j.pain.2010.05.002.

  PMID: 20627413 RESULT

• Aru RG, Songcharoen SJ, Seals SR, Arnold PB, Hester RL. Microcirculatory Effects of Botulinum Toxin A in the Rat: Acute and Chronic Vasodilation. Ann Plast Surg. 2017 Jul;79(1):82-85. doi: 10.1097/SAP.0000000000001054.

  PMID: 28509693 RESULT

MeSH Terms

Conditions

Cold Hypersensitivity; Vascular System Injuries; Sensation Disorders; Neuralgia; Raynaud Disease

Interventions

Botulinum Toxins, Type A

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Peripheral Nervous System Diseases; Neuromuscular Diseases; Pain; Livedoid Vasculopathy; Thrombosis; Embolism and Thrombosis; Peripheral Vascular Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Study Officials

• Arne J Norheim, PhD

  University Hospital of North Norway

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: double blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The methodology uses a two armed, randomized, double-blind, placebo-controlled studydesign, . All participating soldiers will get two injections, one first injection at inclusion and a second injection after 6 weeks. The injections contain either BTX -A or an inert placebo. Both patient and treating doctor is blinded to content of the injection. The two patients in the primary treatment group will receive Botox at their first injection at inclusion, while the two patients in the secondary group will receive placebo as their first injection at inclusion. At 6 weeks follow up, the patients in the primary treatment group will receive their second injection of botox. The patients in the secondary treatment group now will receive their second injection, but this will be their first injection of Botox, given at their 6 weeks follow-up.

Study Record Dates

• First Submitted: March 14, 2019
• First Posted: June 14, 2024
• Study Start: November 1, 2022
• Primary Completion: July 1, 2023
• Study Completion: June 10, 2024
• Last Updated: June 14, 2024

Record last verified: 2024-06

Locations

NO (1)