Treatment of Frostbite Sequelae With Botulinum Toxin A

June 10, 2024 updated by: University Hospital of North Norway

Botulinum Toxin A in the Treatment of Frostbite Sequelae - a Randomized, Double Blind, Placebo-controlled Study

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Background Frostbite sequelae can have a significant negative impact on quality of life. Depending on the type of frostbite, sequelae such as cold hypersensitivity, sensory loss, chronic pain, hyperhidrosis, growth plate disturbances and osteoarthritis may develop. Long-term paraesthesia with occasional electric shock-type sensations have also been repored. The pathophysiology of these sequelae is still poorly understood although peripheral neurovascular dysfunction plays an important role. This may result in a vasospastic disorder similar as in Raynaud's phenomenon.

Recently, the use of Botulinum toxin type A (BTX-A) for the treatment of vasospastic disorders of the hand has shown to result in great benefits for the patients by reducing the severity and number of vasospastic disorders. BTX-A injections are targeting the neurovascular bundle at or slightly proximal to the A1 pulley in the palm of the hand.

A case history has described the off-label use of BTX-A to treat a Norwegian soldier who suffered from long-term sequelae of frostbite to his hands after a military exercise. He was successfully treated with BTX-A injections in each palm of the hand. At follow up, the patient reported less pain, warmer hands and improved sensory function. Dynamic Infrared thermography (DIRT) showed improved rewarming of all fingers compared to the pre-treatment examination, while Quantattive sensory testing (QST) showed a normalization of sensory function.

Aim of this pilot study To investigate the effect of Botulinum toxin type A for frostbite sequelae in fingers.

Hypothesis The null hypothesis 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 two armed, randomized, double-blind, placebo-controlled study design, performed at one single centre will be used. The study population consists of four soldiers with frostbite sequelae who will be recruited from the Norwegian Armed Forces Health Registry. These four soldiers are randomized to either treatment with Botulinum toxin type A or placebo according to computer-generated random numbers provided by the research unit at the University Hospital of North Norway. Two soldiers in the primary treatment group will receive Botulinum toxin type A at their first injection at inclusion, while the two soldires 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 BTX- A on peripheral microcirculation will be evaluated with dynamic infrared thermography (DIRT) of the dorsal side of the hands. DIRT of the dorsal side of the hands encompass a pre-cooling phase (T1), a cooling phase of one minute (T2), and a four-minute recovery phase (T3, T4, T5 and T6). The pre-cooling phase include baseline measurements before the DIRT takes place and includes also the time from the initial image (T1) until the hands are immersed in water.

The DIRT procedure follows international standards and recommendations involving a cold challenge followed by a rewarming phase with both hands were positioned palms down on a grid made of thin nylon netting strung on a plastic frame. The nylon grid is positioned 7 cm (+/- 0.5 cm) above a uniformly heated base plate (40 +/-2°C) to ensure a thermally uniform background for the thermal imaging.

Quantitative sensory testing will be used to evaluate the effect of BTX- A on peripheral nerve function. Thermal tests will be performed with a device TSA (Medoc, Israel) attaching a thermode to the investigated body part. Thermal tests include detection thresholds for warm and cold sensation, sensory limen (i.e., perception of changing temperatures, pain thresholds for heat and cold pain as well paradoxical cold or heat sensation. It is important to notice, that the maximum temperatures produced by the device are 0° or 50° for cold and warm, respectively. The test system automatically cancels the run, when the participant did not respond with pain up to these temperatures. Mechanical tests include also detection thresholds and pain thresholds. Mechanical detection is evaluated by von Frey hairs (pressure) and a standardized tuning fork (vibration). Pain thresholds are assessed by pin prick stimulation, pressure algometry. Additional tests for allodynia are included as well. Finally, there is a test to assess temporary summation using wind-up ratio to a repeated stimulation with pinprick (10 stimuli with 1/s).

Both DIRT and QST will be performed prior to the treatment with BTX- A and placebo at the start of the pilot study, at 6 weeks as well as 6 weeks after the last injections. At 6 months follow up after the first injection DIRT and QST will be repeated again.

The patient's subjective symptoms are monitored by comparing Patient-Subjective-Symptom-Score (PSSS) after 6 weeks with the baseline values for each patient.

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.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Tromsø, Norway, 9038
        • University Hospital of North Norway

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:- Sequela following 2nd degree frostbite injury in the Norwegian Armed Forces

  • 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.

Exclusion Criteria:- Patients who do not return the signed informed consent form

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Botulinum toxin
100 IU botulinum toxin injection in the palm of the hand
Drug: Botuinum toxin
Injection of botulinum toxin in the palm of the hand
Other Names:
  • Botox
Placebo Comparator: Placebo
Saline injection in the palm of the hand
Drug: Botuinum toxin
Injection of botulinum toxin in the palm of the hand
Other Names:
  • Botox

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Subjective symptoms between injection of Botox and placebo at 6 weeks follow up
Time Frame: 6 weeks
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
Time Frame: 6 weeks

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital of North Norway

Investigators

  • Principal Investigator: Arne J Norheim, PhD, University Hospital of North Norway

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 1, 2022

Primary Completion (Estimated)

July 1, 2023

Study Completion (Actual)

June 10, 2024

Study Registration Dates

First Submitted

March 14, 2019

First Submitted That Met QC Criteria

June 10, 2024

First Posted (Actual)

June 14, 2024

Study Record Updates

Last Update Posted (Actual)

June 14, 2024

Last Update Submitted That Met QC Criteria

June 10, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018/1961(REK)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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