Principal Investigator: Colby Hansen
Keywords: Hyperhidrosis , Botox , Amputation Department: Physical Medicine & Rehab
IRB Number: 00107999 Co Investigator: Bradeigh  Godfrey
Specialty: Physical Medicine and Rehabilitation
Sub Specialties: Amputee Rehabilitation
Recruitment Status: Not yet recruiting

Contact Information

Heidi Hansen

Simple Summary

Looking at hyperhidrosis treatment in the amputation population.

Detailed Description

The investigator(s) have applied for and granted an FDA IND (IND #135330) for the drug Botulinum toxin Type A (Botox) in an off label setting to study the effectiveness of Botox to treat residual limb hyperhidrosis in patients with amputation. While there are other BTX-A products on the market, Botox is the only FDA approved toxin for the treatment of axillary hyperhidrosis. There are a few considerations to make when dosing Botox for hyperhidrosis. These include the total dose, the dose per injection site, and the distribution of injection sites. Typical doses for axillary hyperhidrosis are 50-100 units per axilla. However, for clinical trials used to support the FDA-approved labeling in focal spasticity, doses up to 400 units were used. There are reports of off label dosing exceeding this amount, including the case series reported by Charrow for residual limb hyperhidrosis, which used doses ranging from 300 – 500 units of Botox. There was no mention of adverse events in this series. It has been suggested that doses greater than 600 units pose a greater risk of serious adverse events including systemic weakness. Regarding dose per injection site, hyperhidrosis guidelines suggest 1 unit per site for the axilla, and 1.5 – 2 units per site for the palm or sole. The largest case series in amputees used doses of 2-3 units per site. Regarding the distribution of injection sites, guidelines recommend injections every 1 – 2 cm in a grid-like fashion.PurposeThis project will address a problem that has troubled Service members, Veterans, and civilians with amputations for decades, impacting satisfaction with prosthetic use, residual limb skin health, and negatively affecting quality of life. Prior research in this area has been limited and insufficient. We plan to conduct an open label study of Botox, up to 400 units, to treat limb hyperhidrosis in patients with amputations. The actual dose of Botox used will be based on individual results with the Iodine-Starch test to identify areas on the residual limb that are producing excessive sweat. Botulinum Toxin A (BTX-A): Botulinum toxin therapy is well-established for use in excessive sweating of several body areas (axillary, palmar, plantar, and facial) in individuals with hyperhidrosis and inadequate response to topical treatments. Extensive research has been conducted on the efficacy and safety of BTX-A for hyperhidrosis of other areas, and it has been shown to improve both objective and subjective measures of ​sweating, and lead to improved quality of life measures.HypothesisTreatment of residual limb Hyperhidrosis with Botox will result in improved patient reports of excessive sweating as measured by the HDSS and as measured by subjects’ response to iodine-starch testing. We are confident that improving the evaluation and treatment of residual limb hyperhidrosis will reduce the secondary health consequences of amputation and will lead to improved quality of life.Brief DiscriptionThere is insufficient evidence to support the widespread use of botulinum toxin to treat excessive sweating in amputees. It is not known if the botulinum toxin can be effectively localized and administered with the help of the iodine-starch test, although our published case report suggests that it is. The iodine-starch test will be utilized in amputees to identify potential sites for injection, thus helping us use the lowest necessary dose to adequately treat the residual limb.The intended study population will be healthy amputees, age > 18, at least 6 months post-amputation surgery, with a prosthetic device, who complain of excessive residual limb sweating. Excessive sweating will be defined by a score of 2 or greater on the Hyperhidrosis Disease Severity Scale (HDSS).There is no universally accepted standard for assessing the burden and precise location of sweating in amputee patients. Among the several subjective scales of hyperhidrosis severity in the dermatology literature, the most commonly used and rigorously validated one is the Hyperhidrosis Disease Severity Scale (HDSS) (Solish et al., 2007). The HDSS provides a qualitative measure for the severity of the patient’s condition based on the extent to which hyperhidrosis affects daily activities. The HDSS is simple to administer and scored as follows:Hyperhidrosis Disease Severity Scale (Solish et al., 2007)Condition:ScoreMy sweating is never noticeable and never interferes with my daily activities1My sweating is tolerable but sometimes interferes with my daily activities2My sweating is barely tolerable and frequently interferes with my daily activities3My sweating is intolerable and always interferes with my daily activities4 In the general hyperhidrosis patient population (non-amputee), the HDSS exhibits moderate to strong correlations with other quality of life and disease impact metrics, as well as with gravimetric sweat production. A 1 point improvement on the HDSS correlates with a 50% reduction in sweat production, while a 2 point improvement correlates with an 80% reduction in sweat production (Solish et al., 2007). Our survey data shows the HDSS correlates well with amputees’ perception of the impact of sweating on their prosthesis fit and function, and is therefore a valid outcome measure in the amputee population (Hansen et al., 2015). While the HDSS gives a global, patient-reported outcome of the significance of hyperhidrosis in the patient’s life, it does not inform the treating clinician on the precise location of the problem. Dermatologists treating hyperhidrosis of other regions (i.e. axillary, palmar, plantar) use the Minor iodine-starch test to identify the area of hyperhidrosis in order to guide subsequent treatments (Solish et al., 2007). This test consists of an application of iodine, which is allowed to dry and then dusted with cornstarch. Sweat will react with the iodine and starch and produce a black/purple color. While this test is primarily used to identify the areas of hyperhidrosis, a grading scale has been proposed for test interpretation and monitoring response to treatments (Hexsel, Rodrigues, Soirefmann, & Zechmeister-Prado, 2010). There is scant literature describing the iodine-starch test in amputees(Garcia-Morales, Perez-Bernal, & Camacho, 2007; Gratrix & Hivnor, 2010), and our early experience suggests that it is insufficient to simply apply iodine and starch on a residual limb without then donning the patient’s prosthesis. It appears necessary to recreate the environment that produces the excessive sweating by donning the prosthesis and ambulating. It is not known, however, what method is safe and effective, without causing harm to the patient’s skin and/or prosthetic materials.As part of the scope of the research proposed herein, we have done pilot work with 9 subjects and 11 amputation sites, utilizing the iodine-starch test under a variety of conditions to assess which method is most feasible to allow the patient to use their prosthesis in the test. Preliminary results suggest that plastic wrap is adequate to protect the prosthesis from significant iodine stain and does not cause new skin irritation, but is more often viewed as uncomfortable. It also appears to induce a very rapid and diffuse pattern sweating, raising concern for creating too much of a false positive effect. A prosthetic sheath appears to protect the liner from dense stain, though some light iodine stain has been observed to seep onto the liner in some cases. This method, though, is generally viewed as comfortable to the patient, does not cause new skin irritation, and does produce a positive test after 10 - 15 minutes of walking in focal areas more consistent with the patient’s described experience with sweat and sweat location. We believe that applying the iodine-starch combination, donning a prosthetic sheath, the patient’s own prosthesis, followed by a period of ambulation is the best method for future studies.Subjects will have needed to demonstrate a prior failure to respond adequately to topical Aluminum Chloride, as evidenced by either a lack of response (no change in HDSS score), in adequate response (HDSS score of 2 or greater after treatment), or intolerance of the topical Aluminum Chloride. The primary outcome will be change in HDSS score, but there will also be administered a report of interference of sweating on prosthetic fit and function (on a 5-point Likert scale). The iodine-starch test will be administered to help define where the medication will be injected, and will also be applied at subsequent visits with a sweating intensity visual score obtained as a secondary outcome measure. Willingness to comply with all study procedures and availability for the duration of the study will be expected. Study Participants will be excluded if they have any open sores or wounds on the residual limb. Subjects must have no prior hypersensitivity or contraindications to Botox therapy this includes anaphylaxis, serum sickness, urticarial, soft tissue edema, and dyspnea. Exclusions also include any and all allergy to Botox, infections at the injections site, known neuromuscular junction disorder. Women who are pregnant or currently breastfeeding will be excluded. Those subjects with compromised respiratory status including the use of oxygen, recent hospitalization for respiratory illness, recent antibiotic treatment within the past 8 weeks for pneumonia, bronchitis or other respiratory tract infections will not be allowed to participate. Participants with overactive bladder and a history of recurrent urinary tract infection (UTI) or two or more UTI’s in the past six months or chronic antibiotics for suppression of UTI’s will also be excluded.Patient enrollment in study activities is for twenty weeks; enrollment completion will take approximately three years. Study design is a single cohort, open-label.It is planned to recruit 25 participants between the University of Utah and the Salt Lake VA.

Inclusion Criteria

Inclusion Criteria

  • Provision of signed and dated informed consent form (ICF)
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • Male or female, age 18 or older
  • At least 6 months post-amputation surgery 
  • Have a prosthetic device  
  • In good general health as evidenced by medical history 
  • HDSS score of 2 or greater AND failed prior treatment with topical Aluminum Chloride.
  • At least  6 months from last injection with any botulinum toxin

Exclusion Criteria

Exclusion Criteria 

  • Open sores or wounds on the residual limb  
  • Known sensitivity or allergy to iodine 
  • Pregnancy or lactation  
  • Any prior Hypersensitivity reaction to Botox including anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea
  • Infection at the injection site 
  • Known neuromuscular junction disorder 
  • Inflammation at the injection site 
  • A known compromised respiratory status which may include the use of oxygen, recent hospitalization for respiratory illness, including but not limited to recent antibiotic treatment for pneumonia, bronchitis or other respiratory tract infections will not be allowed to participate
  •  Overactive bladder with a history of recurrent urinary tract infection (UTI) or two or more UTI’s

Participant Reimbursement

There will be a one time payment of $50.00 following the completion of the screening, assessment, enrollment and Botox injection. A second payment of $50.00 will be made following Week #1, Week #2, Week#4 and Week #12 in person clinic office visits and a Week #8 follow-up phone call. There will be an additional $50.00 if the participant completes Week #16 & Week #20 follow-up phone call visits. If the participant completes all clinic visits from enrollment to the final phone call assessment the participant will be paid a total of $150.00.