Botulinum Toxin A (Botox) in Tissue Expander Breast Reconstruction

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01591746
• Collaborator: Allergan (Industry)
• Enrollment: 131
• Location: 1
• Arms: 2
• Actual Duration (Months): 59.5
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

Each year, the number of breast cancer survivors who choose post-mastectomy breast reconstruction keeps rising. Among women who elect to pursue breast reconstruction, approximately 75% will choose prosthetic breast reconstruction. Implant-based breast reconstruction is frequently achieved in two-stages. The first stage consists of the placement of a tissue expander after mastectomy. This is followed by a period of biweekly tissue expansions that can last several months. In the second stage, the tissue expander is removed in a surgical procedure and replaced with a permanent breast implant. Tissue expansion is a well-established breast reconstruction technique characterized by high success rates and high patient satisfaction. Despite the well-recognized advantages of this successful breast reconstruction technique, the subpectoral placement of a tissue expander is associated with significant pain and discomfort in the immediate post-operative period and during the phase of tissue expansion. Pectoralis major muscle spasm is a frequently reported problem during tissue expansion. Legeby et al. recently showed that women who underwent prosthetic breast reconstruction had higher pain scores and took more analgesics that those who did not choose post-mastectomy reconstruction.

In the past 10 years, publications on the use of botulinum toxin A (BTX-A) for pain relief in a wide array of clinical conditions have increased tremendously. BTX-A is one of the neurotoxins produced by Clostridium botulinum bacteria. By reversibly inhibiting neurotransmitter release, BTX-A has both analgesic and paralytic properties. The analgesic action of BTX-A was initially thought to be related to its effects on muscular contraction. However, a recent in vitro study of embryonic rat dorsal neurons did confirm that BTX-A inhibits release of substance P, a neurotransmitter associated with pain and inflammatory reactions. The presence of analgesic properties of BTX-A is increasingly supported by several clinical observations: pain relief with BTX-A injections has been reported for migraine headaches, chronic pelvic, chronic tennis elbow, and post-operative pain control for lower limb lengthening correction, among others.

This aspect has never been studied in breast cancer survivors who elect to pursue breast reconstruction with tissue expanders. Furthermore, physical function outcomes are important to consider with BTX-A use because the link between temporary muscle paralysis and improvements in participation in daily activities is not a given.

The investigators propose to complete a double-blinded prospective randomized controlled trial of women undergoing unilateral and bilateral mastectomies with immediate placement of tissue expanders, to establish the efficacy and safety of BTX-A in alleviating pain and in improving physical well-being during the expansion period.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Pain, Postoperative; BRCA1 Mutation; BRCA2 Mutation; Breast Diseases; Neoplasms	Drug: Botulinum Toxin Type A; Drug: Placebo	Phase 3

Detailed Description

Consecutively enrolled eligible women will be randomized into one of two different treatment groups: 1) Group receiving BTX-A, and 2) Group receiving a placebo. All consenting subjects will be randomized to receive either a single injection of 100 units of BTX-A, or a placebo (saline water), during surgery in the pectoralis major muscle on the operated side once the mastectomy and the breast reconstruction have been completed. Expected duration of subject participation is 4 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 131 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Botulinum Toxin A in Tissue Expander Breast Reconstruction: A Double-Blinded Randomized Controlled Trial
• Actual Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Jul 18, 2017
• Actual Study Completion Date: Jul 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A - Botulinum Toxin Type A 100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast	Drug: Botulinum Toxin Type A; Other Names: BOTOX
Placebo Comparator: Group B - Placebo 5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast	Drug: Placebo; 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A; Other Names: Sodium chloride solution

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale [preoperative visit, first postoperative visit (1-2 weeks post surgery)]

   The numeric pain intensity scale (NPIS) will be completed at the preoperative visit and again at the first postoperative visit. The NPIS is a visual analog scale (VAS) commonly used to assess clinical pain. Subjects are asked to rate their pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable.

2. Physical Well-Being Using the BREAST-Q, Reconstruction Module [first post-operative visit (1-2 weeks post surgery)]

   The Physical Well-Being scale of the BREAST-Q, Reconstruction module, will be used for this purpose. The BREAST-Q is a validated patient-reported outcome measure to accurately assess quality of life and patient satisfaction. The Reconstruction module Physical Well-Being scale has questions on the function and participation in activities before and after breast reconstruction. For this study, subjects were asked to answer 16 questions on how often they experienced each symptom, using score of 1 to 5, where 1 was none of the time and 5 was very often. Answers from these questions were combined to provide a total physical well-being score (for a total possible range of 16-80) for each patient at each visit. Lower scores reflected fewer symptoms and higher satisfaction where higher scores reflected more symptoms and less satisfaction.

Secondary Outcome Measures

1. Initial Intraoperative Fill Volume in Milliliters (mL) [Single intra-operative measurement at first surgery]

   The amount of initial intraoperative fill volume in milliliters (mL) in the tissue expander at the time of surgery divided by the manufacturers recommended total tissue expander volume will be measured. Each breast will be measured separately.

2. Number of Tissue Expansion Visits [up to 24 weeks post-operatively]

   The total number of tissue expansion visits completed post-operatively.

3. Total Volume of Tissue Expansion [Up to 24 weeks post-operatively]

   Measurement of total expansion volume in milliliters (mL).

4. Rate of Reconstruction Failure [6 months after first surgery]

   The rate of reconstruction failure will be measured by the number of subjects who have tissue expander removal.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Women at least 18 years of age, who will undergo immediate unilateral or bilateral tissue expander breast reconstruction following therapeutic skin-sparing or nipple-sparing mastectomy

• Women at least 18 years of age, who will undergo immediate bilateral tissue expanders breast reconstruction following risk-reduction (prophylactic) skin-sparing or nipple-sparing mastectomy

Exclusion Criteria:

• Subjects who are unable to read or speak English

• Breast reconstruction using the latissimus dorsi flap combined with a tissue expander

• Documented diagnosis of chronic pain, upper limb spasticity, cervical dystonia, axillary hyperhidrosis, strabismus or blepharospasm

• Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation

• Infection at the proposed site of injection

• Pre-existing neuromuscular disorders (including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis)

• Aminoglycosides intake at the time of surgery (these antibiotics can potentiate the effect of BTX-A)

• Women who are pregnant or breast feeding

• Presence of breast implants from previous breast surgery

• Reported use of Botox within 4 months prior to planned surgical date

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Allergan

Investigators

• Principal Investigator: Valerie Lemaine, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 4, 2018

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Valerie Lemaine, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01591746
• Other Study ID Numbers: 11-001687
• First Posted: May 4, 2012
• Last Update Posted: Oct 10, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Valerie Lemaine, Principal Investigator, Mayo Clinic: Mastectomy; Mammaplasty; Breast reconstruction; Tissue expansion; Botulinum toxins, Type A; Quality of Life; Acellular dermal matrix
• Additional relevant MeSH terms: Breast Diseases; Pain, Postoperative; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA

Study Results

Participant Flow

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Period Title: Overall Study
STARTED	68	63
COMPLETED	68	63
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo	Total
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A	Total of all reporting groups
Overall Participants	68	63	131
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.9 (11.1)	48.4 (11.5)	49.1 (11.3)
Sex: Female, Male (Count of Participants)
Female	68 100%	63 100%	131 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	68 100%	63 100%	131 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.6 (5.9)	26.6 (8.1)	27.1 (7)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale
Description	The numeric pain intensity scale (NPIS) will be completed at the preoperative visit and again at the first postoperative visit. The NPIS is a visual analog scale (VAS) commonly used to assess clinical pain. Subjects are asked to rate their pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable.
Time Frame	preoperative visit, first postoperative visit (1-2 weeks post surgery)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	68	63
Median (Inter-Quartile Range) [score on a scale]	2	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Physical Well-Being Using the BREAST-Q, Reconstruction Module
Description	The Physical Well-Being scale of the BREAST-Q, Reconstruction module, will be used for this purpose. The BREAST-Q is a validated patient-reported outcome measure to accurately assess quality of life and patient satisfaction. The Reconstruction module Physical Well-Being scale has questions on the function and participation in activities before and after breast reconstruction. For this study, subjects were asked to answer 16 questions on how often they experienced each symptom, using score of 1 to 5, where 1 was none of the time and 5 was very often. Answers from these questions were combined to provide a total physical well-being score (for a total possible range of 16-80) for each patient at each visit. Lower scores reflected fewer symptoms and higher satisfaction where higher scores reflected more symptoms and less satisfaction.
Time Frame	first post-operative visit (1-2 weeks post surgery)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	68	63
Median (Inter-Quartile Range) [score on a scale]	63	60

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Initial Intraoperative Fill Volume in Milliliters (mL)
Description	The amount of initial intraoperative fill volume in milliliters (mL) in the tissue expander at the time of surgery divided by the manufacturers recommended total tissue expander volume will be measured. Each breast will be measured separately.
Time Frame	Single intra-operative measurement at first surgery

Outcome Measure Data

Analysis Population Description

Volume measurements were not captured for all subjects.

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	60	60
Right breast	63.5 (23.0)	60.4 (20.0)
Left breast	60.1 (23.1)	60.0 (21.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments	Right breast initial percent volume expansion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments	Left breast initial percent volume expansion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Number of Tissue Expansion Visits
Description	The total number of tissue expansion visits completed post-operatively.
Time Frame	up to 24 weeks post-operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	66	62
Median (Inter-Quartile Range) [visits]	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Total Volume of Tissue Expansion
Description	Measurement of total expansion volume in milliliters (mL).
Time Frame	Up to 24 weeks post-operatively

Outcome Measure Data

Analysis Population Description

Volume measurement were not captured on all subjects.

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	61	59
Median (Inter-Quartile Range) [mL]	80	75

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Rate of Reconstruction Failure
Description	The rate of reconstruction failure will be measured by the number of subjects who have tissue expander removal.
Time Frame	6 months after first surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Botulinum Toxin Type A	Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A	5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Measure Participants	68	63
Count of Participants [Participants]	1 1.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Botulinum Toxin Type A, Group B - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Adverse events were collected from baseline until four months postoperatively for each subject, a total average of five years.
Arm/Group Title	Group A - Botulinum Toxin Type A		Group B - Placebo
Arm/Group Description	100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast Botulinum Toxin Type A		5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
All Cause Mortality
	Group A - Botulinum Toxin Type A		Group B - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/63 (0%)
Serious Adverse Events
	Group A - Botulinum Toxin Type A		Group B - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/63 (0%)
Other (Not Including Serious) Adverse Events
	Group A - Botulinum Toxin Type A		Group B - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/68 (22.1%)		14/63 (22.2%)
Blood and lymphatic system disorders
Seroma	0/68 (0%)	0	4/63 (6.3%)	4
Infections and infestations
Surgical site infection	1/68 (1.5%)	1	2/63 (3.2%)	2
Skin and subcutaneous tissue disorders
Hematoma requiring reoperation	1/68 (1.5%)	1	2/63 (3.2%)	2
Mastectomy skin flap necrosis	1/68 (1.5%)	1	0/63 (0%)	0
Delayed wound healing	5/68 (7.4%)	5	2/63 (3.2%)	2
Surgical and medical procedures
Unplanned reoperation	7/68 (10.3%)	7	4/63 (6.3%)	4

Limitations/Caveats

A practice change from patients receiving paravertebral blocks preoperatively to intraoperative field blocks with liposomal bupivacaine;data not collected on postoperative oral narcotic consumption;study designed to detect 25% decrease in pain score.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.