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Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Primary Purpose

Cutaneous Leiomyomas, Hereditary Leiomyomatosis and Renal Cell Cancer

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Botulinum toxin type A

Placebo

About this trial

This is an interventional treatment trial for Cutaneous Leiomyomas focused on measuring Cutaneous Leiomyomas, Skin Pain, Botox Therapy, Hereditary Leiomyomatosis, Renal Cell Cancer, Cutaneous Leiomyoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:
1. Subjects must be age greater than or equal to18 years.
2. Subjects must have a prior biopsy-proven diagnosis of cutaneous leiomyoma.
3. Subjects must have at least 1 symptomatic leiomyomas or regions less than or equal to 60 cm^2 of leiomyomas with pain characterized as greater than 4 based on a 10-point scale, indicating pain of at least moderate severity.
4. Pain episodes must occur at least once a week.
5. Subjects must have the ability to participate fully and comply with the procedures of the protocol in the opinion of the investigator.
6. Written informed consent has been obtained including consenting to have tissue samples stored, however subjects are allowed to refuse sample storage.
7. Negative urine or serum pregnancy test in females of childbearing potential.
8. Subjects who are clinically stable such that they can be expected to complete the 24-week study.

EXCLUSION CRITERIA:

Subjects with allergies to BTX-A.
Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study.
Subjects with neuromuscular junction disorders (ie. myasthenia gravis or Lambert-Eaton syndrome) or peripheral motor neuropathic diseases (ie. amyotrophic lateral sclerosis or motor neuropathy).
Subjects with infection at the intended sites of injection.
Subjects who have had prior Botulinum toxin product within the past 6 months.
Subjects with pain resulting from other disease(s), specifically:
- pain that requires intermittent or ongoing treatment with narcotics
- severe, debilitating, or acute pain originating from sources other than leiomyomas
Subjects taking pain medications, neuroactive agents, or other therapy directed toward treatment of cutaneous leiomyomas concurrently or within 5 days or 5 half-lives (whichever is longer) of BTX-A treatment, other than specified rescue pain medications). Patients currently on therapy directed toward OTHER mild to moderate chronic pain will be evaluated on a case-by-case basis for inclusion. Patients with well-controlled mild to moderate chronic pain such as that associated with osteoarthritis, who do not require narcotic therapy, will NOT be excluded. Aspirin for pain relief or for other indications is also acceptable.
Subjects with late-stage cancers or unstable disease (such as hemodynamic instability, i.e., systolic or diastolic blood pressure fall of 20 mm Hg or greater from the stable patient s baseline measurement).
A condition or situation that, in the investigator's opinion, may put the subject at significant risk or interfere significantly with the subject's participation in the study.

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

BTX-A

Placebo/Saline

Arm Description

BTX-A intralesional injection

Saline intralesional injection

Outcomes

Primary Outcome Measures

Change in Worst Lesional Pain in the Past Week Based on Brief Pain Inventory

Change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls. The BPI uses an arbitrary units on a 0-10 scale. For the purposes of the statistical calculation, a difference of 1 standard deviation between groups at baseline vs. week 4 was considered significant. Any BPI value above zero (no pain) is abnormal. The mean change indicates mean change in pain score.

Median Change in Average Pain Between Two Arms

Change in average pain was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)).

Secondary Outcome Measures

Number of Participants With Adverse Events

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Visual Analog Scale (VAS) of Patient Perceived Pain at Leiomyoma Site Prior to Ice Provocation at Week 0 vs. Week 4

The VAS is a commonly used validated tool for assessment of pain. For this measure, a 10-cm VAS was used to assess current patient pain/discomfort before application of ice to study lesions at week 0 and week 4. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Range is 0-10; 0 is no pain and 10 is worst possible pain.

Comparison of Change in Skin Related Quality of Life by Total Dermatology Life Quality Index (DLQI) at Week 0 vs. Week 4

Specific Skin Pain-Related Question on the Dermatology Life Quality Index

The DLQI is a 10-question quality of life survey which has been extensively validated and frequently used in dermatologic disorders such as atopic dermatitis, acne, and psoriasis. Participants response to the question "Over the last week, how itchy, sore, painful or stinging has your skin been?" was assessed by the Dermatology Life Quality Index. This outcome refers to a single specific question on the DLQI, so the range for this outcome is 0-3. Lower values in the DLQI indicate less impairment (or greater improvement) in life quality from the skin disease.

Change in Post-Ice Provocation Visual Analog Score (VAS) Between Week 12 and Week 24

The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale is 0-10. 10 denotes worse pain than 0.

Immunohistochemical Staining of Cutaneous Leiomyomas for Acetylcholinesterase (AchE) Before (i.e.,Week 0) and 12 Weeks After Botulinum Toxin Administration

AchE staining was scored as 0 (none), 1 (rare), 2 (scattered), or 3 (focal or greater).

Immunohistochemical Staining of Cutaneous Leiomyomas for C-fos Before (i.e., Week 0) and 12 Weeks After Botulinum Toxin Administration

c-fos, a marker of neuronal activation after pain stimulation, was scored as 0 (none), 1 (scattered), 2 (<66% of tumor cells), or 3 (≥66% of tumor cells).

Percentage of Patients With a Change in Average Pain Score

Average pain was determined from a 0-10 scale question on the Brief Pain Inventory (BPI). 10 denotes worse pain.

Percentage of Patients With a Change in Pre-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Percentage of Patients With a Change in Post-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Worst Pain Severity

Pain severity was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)). This outcome was based on a single 0-10 question on the BPI.

Full Information

NCT ID

NCT00971620

First Posted

September 3, 2009

Last Updated

February 23, 2017

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00971620

Brief Title

Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Official Title

Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Study Type

Interventional

2. Study Status

Record Verification Date

February 2017

Overall Recruitment Status

Completed

Study Start Date

November 17, 2008 (Actual)

Primary Completion Date

January 9, 2014 (Actual)

Study Completion Date

October 12, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

Cutaneous leiomyomas are benign tumors of smooth muscle origin. They can be very painful, and current treatments for the tumors and for the associated pain do not produce satisfactory results. One potential treatment for localized severe muscle pain involves injections with botulinum toxin A. This study will investigate the effectiveness, side effects, and dosage of botulinum toxin A (BOTOX) as a treatment for patients with pain associated with cutaneous leiomyomas. This study will include 18 subjects, all of whom will be 18 years of age and older, who have pain associated with cutaneous leiomyomas. For the 24-week study, patients will be randomly assigned to one of two treatment groups. Neither the study team nor the patient will know to which group patients have been assigned. Before the study begins, all participants must provide a full medical history for research and evaluation purposes, fill out pain and quality-of-life questionnaires, and undergo an ice test in which researchers will apply ice to the site of the cutaneous leiomyomas and ask participants to evaluate the level of pain before and after ice application. Both groups will be required to keep a pain diary throughout the study to record their level of pain on a daily basis, and will be asked to avoid or restrict the use of specific medications or other remedies to treat the pain. At the first visit (Week 0), one group will receive a prescribed dose of botulinum toxin A, which will be administered as an injection into the leiomyoma, and the other (control) group will receive a placebo injection of a saline solution. Patients will return 4 weeks later, at which time they will undergo a medical examination, and the ice test, and complete questionnaires to assess responses and level of pain. Patients will return in Week 12, at which time the group assignment will be revealed (un-blinded) to investigators and patients. Patients who received placebo injections will be offered the opportunity to receive injection of botulinum toxin A into their leiomyomas. All patients will undergo a medical examination, the ice test, complete questionnaires, and continue completing their daily pain diaries at home. The final visit, in Week 24, will follow the same procedure as the Week 4 visit. At the end of the study, patients may be eligible to have one or more of the painful cutaneous leiomyomas surgically removed if the researchers believe that the skin lesions can be removed with a reasonable cosmetic result.

Detailed Description

Background: Cutaneous leiomyomas are smooth muscle tumors that may arise sporadically or in association with an inherited cancer-related genodermatosis. Leiomyomas may be severely painful, and current management is generally unsatisfactory. Studies demonstrate increased nerve density within and around leiomyomas as well as increased acetylcholinesterase staining of associated nerves. Botulinum toxin-A has been used in the treatment of pain syndromes. Based on the known mechanisms of action of botulinum toxin-A, treatment with botulinum toxin-A (BOTOX; Allergan, Inc.), may ameliorate the severe paroxysmal pain of symptomatic cutaneous leiomyomas. Objectives: Primary: To assess change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls. Primary: To assess improvement in pain based on Visual Analog Scale (VAS) after application of ice at Week 4 compared to baseline in treated patients versus controls. Secondary: To assess change in magnitude and in frequency of painful episodes based on a weekly patient diary in treated patients versus controls. Secondary: To assess persistence of pain control at Weeks 12 based on the BPI and VAS. Secondary: To assess the frequency of rescue pain medication use in treated patients versus controls during the 24 week study period. Secondary: To determine the impact of leiomyoma treatment on quality of life. Secondary: To assess change in patient s condition based on the Patient Global Impression of Change. Secondary: To evaluate the immunohistochemical staining of nerve fibers and muscle in cutaneous leiomyomas in control and treated lesions following the conclusion of the study. Eligibility: Subjects greater than or equal to18 years with at least 1 symptomatic cutaneous leiomyoma. Pain symptoms must occur at least once a week and be characterized as greater than or equal to 5 out of 10. Design: A 12-week double-blind placebo controlled pilot study of 18 subjects with symptomatic leiomyomas will include initial assessment with BPI, photography, and skin biopsies, followed by treatment of subjects who initially received placebo. Cutaneous leiomyomas will undergo intralesional injection with botulinum toxin-A. Subjects will return at Weeks 4 and 12 for repeat assessment using pain and quality of life questionnaires and photography. Skin biopsies will be performed at week 12.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cutaneous Leiomyomas, Hereditary Leiomyomatosis and Renal Cell Cancer

Keywords

Cutaneous Leiomyomas, Skin Pain, Botox Therapy, Hereditary Leiomyomatosis, Renal Cell Cancer, Cutaneous Leiomyoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

BTX-A

Arm Type

Experimental

Arm Description

BTX-A intralesional injection

Arm Title

Placebo/Saline

Arm Type

Experimental

Arm Description

Saline intralesional injection

Intervention Type

Biological

Intervention Name(s)

Botulinum toxin type A

Other Intervention Name(s)

BTX-A

Intervention Description

Given as an intralesional injection.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Given as an intralesional injection

Primary Outcome Measure Information:

Title

Change in Worst Lesional Pain in the Past Week Based on Brief Pain Inventory

Description

Time Frame

Between week 0 and week 4

Title

Median Change in Average Pain Between Two Arms

Description

Time Frame

Between weeks 0 and week 4

Secondary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Time Frame

37 months

Title

Visual Analog Scale (VAS) of Patient Perceived Pain at Leiomyoma Site Prior to Ice Provocation at Week 0 vs. Week 4

Description

Time Frame

Week 0 vs. week 4

Title

Comparison of Change in Skin Related Quality of Life by Total Dermatology Life Quality Index (DLQI) at Week 0 vs. Week 4

Description

Time Frame

Week 0 vs. week 4

Title

Specific Skin Pain-Related Question on the Dermatology Life Quality Index

Description

Time Frame

Week 0 vs. week 4

Title

Change in Post-Ice Provocation Visual Analog Score (VAS) Between Week 12 and Week 24

Description

Time Frame

Between week 12 and 24

Title

Immunohistochemical Staining of Cutaneous Leiomyomas for Acetylcholinesterase (AchE) Before (i.e.,Week 0) and 12 Weeks After Botulinum Toxin Administration

Description

AchE staining was scored as 0 (none), 1 (rare), 2 (scattered), or 3 (focal or greater).

Time Frame

Week 0 vs. week 12

Title

Immunohistochemical Staining of Cutaneous Leiomyomas for C-fos Before (i.e., Week 0) and 12 Weeks After Botulinum Toxin Administration

Description

c-fos, a marker of neuronal activation after pain stimulation, was scored as 0 (none), 1 (scattered), 2 (<66% of tumor cells), or 3 (≥66% of tumor cells).

Time Frame

Week 0 vs. week 12

Title

Percentage of Patients With a Change in Average Pain Score

Description

Average pain was determined from a 0-10 scale question on the Brief Pain Inventory (BPI). 10 denotes worse pain.

Time Frame

Week 0 score vs. week 4 score

Title

Percentage of Patients With a Change in Pre-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Description

Time Frame

Week 0 vs. week 4

Title

Percentage of Patients With a Change in Post-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Description

Time Frame

Week 0 vs. week 4

Title

Worst Pain Severity

Description

Time Frame

Week 0 vs. week 4

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Subjects must be age greater than or equal to18 years. Subjects must have a prior biopsy-proven diagnosis of cutaneous leiomyoma. Subjects must have at least 1 symptomatic leiomyomas or regions less than or equal to 60 cm^2 of leiomyomas with pain characterized as greater than 4 based on a 10-point scale, indicating pain of at least moderate severity. Pain episodes must occur at least once a week. Subjects must have the ability to participate fully and comply with the procedures of the protocol in the opinion of the investigator. Written informed consent has been obtained including consenting to have tissue samples stored, however subjects are allowed to refuse sample storage. Negative urine or serum pregnancy test in females of childbearing potential. Subjects who are clinically stable such that they can be expected to complete the 24-week study. EXCLUSION CRITERIA: Subjects with allergies to BTX-A. Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study. Subjects with neuromuscular junction disorders (ie. myasthenia gravis or Lambert-Eaton syndrome) or peripheral motor neuropathic diseases (ie. amyotrophic lateral sclerosis or motor neuropathy). Subjects with infection at the intended sites of injection. Subjects who have had prior Botulinum toxin product within the past 6 months. Subjects with pain resulting from other disease(s), specifically: pain that requires intermittent or ongoing treatment with narcotics severe, debilitating, or acute pain originating from sources other than leiomyomas Subjects taking pain medications, neuroactive agents, or other therapy directed toward treatment of cutaneous leiomyomas concurrently or within 5 days or 5 half-lives (whichever is longer) of BTX-A treatment, other than specified rescue pain medications). Patients currently on therapy directed toward OTHER mild to moderate chronic pain will be evaluated on a case-by-case basis for inclusion. Patients with well-controlled mild to moderate chronic pain such as that associated with osteoarthritis, who do not require narcotic therapy, will NOT be excluded. Aspirin for pain relief or for other indications is also acceptable. Subjects with late-stage cancers or unstable disease (such as hemodynamic instability, i.e., systolic or diastolic blood pressure fall of 20 mm Hg or greater from the stable patient s baseline measurement). A condition or situation that, in the investigator's opinion, may put the subject at significant risk or interfere significantly with the subject's participation in the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Edward W Cowen, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

3348971

Citation

Archer CB, Whittaker S, Greaves MW. Pharmacological modulation of cold-induced pain in cutaneous leiomyomata. Br J Dermatol. 1988 Feb;118(2):255-60. doi: 10.1111/j.1365-2133.1988.tb01783.x.

Results Reference

background

PubMed Identifier

15099382

Citation

Batchelor RJ, Lyon CC, Highet AS. Successful treatment of pain in two patients with cutaneous leiomyomata with the oral alpha-1 adrenoceptor antagonist, doxazosin. Br J Dermatol. 2004 Apr;150(4):775-6. doi: 10.1111/j.0007-0963.2004.05880.x. No abstract available.

Results Reference

background

PubMed Identifier

9056647

Citation

Raj S, Calonje E, Kraus M, Kavanagh G, Newman PL, Fletcher CD. Cutaneous pilar leiomyoma: clinicopathologic analysis of 53 lesions in 45 patients. Am J Dermatopathol. 1997 Feb;19(1):2-9. doi: 10.1097/00000372-199702000-00002.

Results Reference

background

PubMed Identifier

26244563

Citation

Naik HB, Steinberg SM, Middelton LA, Hewitt SM, Zuo RC, Linehan WM, Kong HH, Cowen EW. Efficacy of Intralesional Botulinum Toxin A for Treatment of Painful Cutaneous Leiomyomas: A Randomized Clinical Trial. JAMA Dermatol. 2015 Oct;151(10):1096-102. doi: 10.1001/jamadermatol.2015.1793.

Results Reference

result

Links:

URL

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2009-C-0072.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

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