Safety and Effectiveness of EN3835 in the Treatment of EFP in Women

• Sponsor: Endo Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03329989
• Collaborator: (none)
• Enrollment: 158
• Locations: 11
• Arm: 1
• Actual Duration (Months): 9.6
• Patients Per Site: 14.4
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

An open-label study of safety and effectiveness of EN3835 in the treatment of cellulite in adult women.

Condition or Disease	Intervention/Treatment	Phase
Edematous Fibrosclerotic Panniculopathy; Cellulite	Biological: Collagenase Clostridium Histolyticum	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 158 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Open-Label Study of EN3835 In The Treatment of Edematous Fibrosclerotic Panniculopathy
• Actual Study Start Date: Nov 17, 2017
• Actual Primary Completion Date: Sep 5, 2018
• Actual Study Completion Date: Sep 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EN3835 Active EN3835 0.84mg (Collagenase Clostridium Histolyticum)	Biological: Collagenase Clostridium Histolyticum; During 3 treatment visits 12 injections will be given per treatment area; Other Names: Xiaflex

Outcome Measures

Primary Outcome Measures

1. Investigator Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) 2-level Responders [Day 22, 43, 90, and 180]

   Percentage of responders defined as participants with an improvement in cellulite severity from baseline of at least 2-levels of severity of at least one buttock (left or right) on the Investigator-rated Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) with ratings ranging from "0" (None) to "4" (Severe). A 2-level responder is a participant with a reduction in severity of at least 2-levels from Baseline at that particular visit. Number of participants analyzed is determined by observed participants at each visit.

Secondary Outcome Measures

1. Investigator Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) 1-level Responders [Day 22, 43, 90, and 180]

   Percentage of responders defined as participants with an improvement in cellulite severity from baseline of at least 1-level of severity of at least one buttock (left or right) on the Investigator-rated Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) with ratings ranging from "0" (None) to "4" (Severe). A 1-level responder is a participant with a reduction in severity of at least 1-level from Baseline at that particular visit. Percentages are based on the observed counts. Number of participants analyzed is determined by observed participants at each visit.

2. Subject Satisfaction With Cellulite Treatment Assessment at End of Study [Day 180]

   At Day 180, participants rated their satisfaction with cellulite treatment using the 5-point subject satisfaction scale. Ratings range from Very Satisfied with Treatment (2), Satisfied with Treatment (1), Neither Dissatisfied nor Satisfied with Treatment (0), Dissatisfied with Treatment (-1), and Very Dissatisfied with Treatment (-2). Percentages are based on the observed counts.

Other Outcome Measures

1. Overall Anti-AUX-I Serum Antibody by Visit [Day 1 to Day 180]

   Percent of participants that are seropositive. Descriptive statistics were based on log10 transformation of titer levels. Percentages were based on the number of subjects who had immunogenicity lab samples drawn at the visit. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.

2. Overall Anti-AUX-I Antibody Log Titer Levels by Visit [Day 1 to Day 180]

   Descriptive statistics were based on log10 transformation of titer levels. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.

3. Overall Anti-AUX-II Serum Antibody by Visit [Day 1 to Day 180]

   Percent of participants that are seropositive. Descriptive statistics were based on log10 transformation of titer levels. Percentages were based on the number of subjects who had immunogenicity lab samples drawn at the visit. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.

4. Overall Anti-AUX-II Antibody Log Titer Levels by Visit [Day 1 to Day 180]

   Descriptive statistics were based on log10 transformation of titer levels. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.

5. Anti-AUX-I Neutralizing Antibodies by Visit [Day 1 to Day 180]

   A subset of all CCH Treated participants who had positive binding antibody titer levels were tested for the presence or absence of Neutralizing Antibodies. Overall Number of Participants Analyzed is determined by the number of participants in the highest and lowest quartiles at Day 90 (Q1 and Q4) of seropositive participants at each of two visits (Day 90 and Day 180).

6. Anti-AUX-II Neutralizing Antibodies by Visit [Day 1 to Day 180]

   A subset of all CCH Treated participants who had positive binding antibody titer levels were tested for the presence or absence of Neutralizing Antibodies. Overall Number of Participants Analyzed is determined by the number of participants in the study. Number of Participants Analyzed is determined by observed participants that had a seropositive sample at each visit and the antibody level at Day 71 in Q1 and Q4.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Voluntarily sign and date an informed consent agreement

2. Be a female ≥18 years of age

3. At Screening visit, have at least 2 bilateral quadrants with each quadrant having:

4. a score of 2 (mild) or greater as reported by the Investigator (CR-PCSS), and

5. a Hexsel CSS score no greater than 13

6. At Day 1 visit, have assigned bilateral quadrants with each quadrant having:

7. a score of 2 (mild) or greater as reported by the Investigator (CR-PCSS), and

8. a Hexsel CSS score no greater than 13

9. Be willing to apply sunscreen to the assigned treatment quadrants before each exposure to the sun while participating in the study (i.e., Screening through end of study)

10. Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile at Screening

11. Have a negative serum pregnancy test at Screening and a negative urine pregnancy test before injection of study drug and be using a stable and effective contraception method (e.g., abstinence, intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or double barrier method) for at least 1 menstrual cycle prior to study enrollment and for the duration of the study; or be menopausal defined as 12 months of amenorrhea in the absence of other biological or physiological causes, as determined by the Investigator; or post-menopausal for at least 1 year; or be surgically sterile

12. Be willing and able to cooperate with the requirements of the study

13. Be able to read, complete and understand the patient-reported outcomes rating instruments in English

Exclusion Criteria:

1. Has any of the following systemic conditions:

2. Coagulation disorder

3. Evidence or history of malignancy (other than excised basal-cell carcinoma) unless there has been no recurrence in at least 5 years

4. History of keloidal scarring or abnormal wound healing

5. Concurrent diseases or conditions that might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the subject's well-being. Any questions about concurrent diseases should be discussed with the Medical Monitor.

6. Evidence of clinically significant abnormalities on physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory values.

7. Has any of the following local conditions in the area to be treated:

8. History of lower extremity thrombosis or post-thrombosis syndrome

9. Vascular disorder (e.g., varicose veins, telangiectasia) in area to be treated

10. Inflammation or active infection

11. Active cutaneous alteration including rash, eczema, psoriasis, or skin cancer

12. Has a tattoo and/or a mole located within 2 cm of the site of injection

13. Requires the following concomitant medications before or during participation in the trial:

1. Anticoagulant or antiplatelet medication or has received anticoagulant or antiplatelet medication (except for ≤150 mg aspirin daily) within 7 days before injection of study drug

1. Has used any of the following for the treatment of EFP on the legs or buttock within the timelines identified below or intends to use any of the following at any time during the course of the study:

2. Liposuction in the areas of the body selected for treatment during the 12-month period before injection of study drug

3. Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; buttock and/or thigh implant treatment, or surgery (including subcision and/or powered subcision) within the assigned treatment quadrants during the 12-month period before injection of study drug

4. Endermologie or similar treatments within the assigned treatment quadrants during the 6 month period before injection of study drug

5. Massage therapy within the assigned treatment quadrants during the 3-month period before injection of study drug

6. Creams (eg, Celluvera™, TriLastin®) to prevent or mitigate EFP within the assigned treatment quadrants during the 2-week period before injection of study drug

7. Is presently nursing or providing breast milk

8. Intends to become pregnant during the study

9. Intends to initiate an intensive sport or exercise program during the study

10. Intends to initiate a weight reduction program during the study

11. Intends to use tanning spray or tanning booths during the study

12. Has received an investigational drug or treatment within 30 days before injection of study drug

13. Has a known systemic allergy to collagenase or any other excipient of study drug

14. Has received any collagenase treatments at any time prior to treatment

15. Was a subject in a previous cellulite clinical trial of collagenase clostridium histolyticum (CCH) : AUX-CC-830, AUX-CC-831, EN3835-102, EN3835-104, EN3835-201, and/or EN3835-202

16. Any other condition(s) that, in the Investigator's opinion, might indicate the subject to be unsuitable for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Endo Clinical Trial Site #1	Scottsdale	Arizona	United States	85258
2	Endo Clinical Trial Site #2	Huntington Beach	California	United States	92647
3	Endo Clinical Trial Site #3	San Diego	California	United States	92121
4	Endo Clinical Trial Site #4	Santa Monica	California	United States	90404
5	Endo Clinical Trial Site #5	Coral Gables	Florida	United States	33146
6	Endo Clinical Trial Site #6	Tampa	Florida	United States	33626
7	Endo Clinical Trial Site #7	West Palm Beach	Florida	United States	33401
8	Endo Clinical Trial Site #8	Alpharetta	Georgia	United States	30022
9	Endo Clinical Trial Site #9	New York	New York	United States	10003
10	Endo Clinical Trial Site #10	Franklin	Tennessee	United States	37067
11	Endo Clinical Trial Site #11	Austin	Texas	United States	78746

Sponsors and Collaborators

• Endo Pharmaceuticals

Investigators

• Study Director: Mike McLane, PhD, Endo Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Aug 31, 2017
• Statistical Analysis Plan - Aug 30, 2018

More Information

Publications

None provided.

• Responsible Party: Endo Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03329989
• Other Study ID Numbers: EN3835-205
• First Posted: Nov 6, 2017
• Last Update Posted: Dec 29, 2020
• Last Verified: Oct 1, 2020

• 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
• Additional relevant MeSH terms: Cellulite; Edema

Study Results

Participant Flow

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Period Title: Overall Study
STARTED	158
COMPLETED	135
NOT COMPLETED	23

Baseline Characteristics

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Overall Participants	158
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.8 (10.41)
Sex: Female, Male (Count of Participants)
Female	158 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	44 27.8%
Not Hispanic or Latino	114 72.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 1.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	17 10.8%
White	135 85.4%
More than one race	4 2.5%
Unknown or Not Reported	0 0%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.74 (5.259)
Skin Category (Fitzpatrick Scale) (Count of Participants)
I (Pale White)	3 1.9%
II (Fair)	34 21.5%
III (Darker White)	53 33.5%
IV (Light Brown)	48 30.4%
V (Brown)	10 6.3%
VI (Dark Brown)	10 6.3%

Outcome Measures

1. Primary Outcome

Title	Investigator Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) 2-level Responders
Description	Percentage of responders defined as participants with an improvement in cellulite severity from baseline of at least 2-levels of severity of at least one buttock (left or right) on the Investigator-rated Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) with ratings ranging from "0" (None) to "4" (Severe). A 2-level responder is a participant with a reduction in severity of at least 2-levels from Baseline at that particular visit. Number of participants analyzed is determined by observed participants at each visit.
Time Frame	Day 22, 43, 90, and 180

Outcome Measure Data

Analysis Population Description

Effectiveness Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	144
Yes	6 3.8%
No	131 82.9%
Yes	8 5.1%
No	125 79.1%
Yes	17 10.8%
No	110 69.6%
Yes	20 12.7%
No	111 70.3%

2. Secondary Outcome

Title	Investigator Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) 1-level Responders
Description	Percentage of responders defined as participants with an improvement in cellulite severity from baseline of at least 1-level of severity of at least one buttock (left or right) on the Investigator-rated Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) with ratings ranging from "0" (None) to "4" (Severe). A 1-level responder is a participant with a reduction in severity of at least 1-level from Baseline at that particular visit. Percentages are based on the observed counts. Number of participants analyzed is determined by observed participants at each visit.
Time Frame	Day 22, 43, 90, and 180

Outcome Measure Data

Analysis Population Description

Effectiveness Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	144
Yes	55 34.8%
No	82 51.9%
Yes	87 55.1%
No	46 29.1%
Yes	96 60.8%
No	31 19.6%
Yes	90 57%
No	41 25.9%

3. Secondary Outcome

Title	Subject Satisfaction With Cellulite Treatment Assessment at End of Study
Description	At Day 180, participants rated their satisfaction with cellulite treatment using the 5-point subject satisfaction scale. Ratings range from Very Satisfied with Treatment (2), Satisfied with Treatment (1), Neither Dissatisfied nor Satisfied with Treatment (0), Dissatisfied with Treatment (-1), and Very Dissatisfied with Treatment (-2). Percentages are based on the observed counts.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed is the number participants in effectiveness population at Day 180.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	130
Very Satisfied with Treatment (2)	25 15.8%
Satisfied with Treatment (1)	48 30.4%
Neither Dissatisfied nor Satisfied with Treatment	32 20.3%
Dissatisfied with Treatment (-1)	12 7.6%
Very Dissatisfied with Treatment (-2)	13 8.2%

4. Other Pre-specified Outcome

Title	Overall Anti-AUX-I Serum Antibody by Visit
Description	Percent of participants that are seropositive. Descriptive statistics were based on log10 transformation of titer levels. Percentages were based on the number of subjects who had immunogenicity lab samples drawn at the visit. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	158
Seropositive	4 2.5%
Seronegative	152 96.2%
Seropositive	104 65.8%
Seronegative	43 27.2%
Seropositive	141 89.2%
Seronegative	2 1.3%
Seropositive	134 84.8%
Seronegative	0 0%
Seropositive	134 84.8%
Seronegative	1 0.6%

5. Other Pre-specified Outcome

Title	Overall Anti-AUX-I Antibody Log Titer Levels by Visit
Description	Descriptive statistics were based on log10 transformation of titer levels. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	158
Anti-AUX-I: Day 1 positive	2.046 (1.012)
Anti-AUX-I: Day 22 positive	2.268 (1.076)
Anti-AUX-I: Day 43 positive	4.681 (0.924)
Anti-AUX-I: Day 90 positive	5.937 (0.686)
Anti-AUX-I: Day 180 positive	5.556 (0.981)

6. Other Pre-specified Outcome

Title	Overall Anti-AUX-II Serum Antibody by Visit
Description	Percent of participants that are seropositive. Descriptive statistics were based on log10 transformation of titer levels. Percentages were based on the number of subjects who had immunogenicity lab samples drawn at the visit. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	158
Seropositive	6 3.8%
Seronegative	150 94.9%
Seropositive	50 31.6%
Seronegative	98 62%
Seropositive	138 87.3%
Seronegative	5 3.2%
Seropositive	131 82.9%
Seronegative	0 0%
Seropositive	130 82.3%
Seronegative	5 3.2%

7. Other Pre-specified Outcome

Title	Overall Anti-AUX-II Antibody Log Titer Levels by Visit
Description	Descriptive statistics were based on log10 transformation of titer levels. Overall number of participants analyzed is determined by the number of participants in the study. At each visit, the number of participants analyzed is determined by observed participants that had a seropositive sample.
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	158
Anti-AUX-II: Day 1 positive	1.607 (0.947)
Anti-AUX-II: Day 22 positive	1.942 (1.068)
Anti-AUX-II: Day 43 positive	3.641 (1.068)
Anti-AUX-II: Day 90 positive	5.255 (0.809)
Anti-AUX-II: Day 180 positive	5.141 (0.913)

8. Other Pre-specified Outcome

Title	Anti-AUX-I Neutralizing Antibodies by Visit
Description	A subset of all CCH Treated participants who had positive binding antibody titer levels were tested for the presence or absence of Neutralizing Antibodies. Overall Number of Participants Analyzed is determined by the number of participants in the highest and lowest quartiles at Day 90 (Q1 and Q4) of seropositive participants at each of two visits (Day 90 and Day 180).
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	34
Positive	0 0%
Negative	1 0.6%
Positive	26 16.5%
Negative	8 5.1%
Positive	19 12%
Negative	14 8.9%

9. Other Pre-specified Outcome

Title	Anti-AUX-II Neutralizing Antibodies by Visit
Description	A subset of all CCH Treated participants who had positive binding antibody titer levels were tested for the presence or absence of Neutralizing Antibodies. Overall Number of Participants Analyzed is determined by the number of participants in the study. Number of Participants Analyzed is determined by observed participants that had a seropositive sample at each visit and the antibody level at Day 71 in Q1 and Q4.
Time Frame	Day 1 to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	12 injections of CCH (Collagenase Clostridium Histolyticum) were administered per treatment area at each treatment visit during 3 visits.
Measure Participants	32
Positive	1 0.6%
Negative	0 0%
Positive	24 15.2%
Negative	8 5.1%
Positive	20 12.7%
Negative	11 7%

Adverse Events

Time Frame	All (serious and non-serious) AEs, from Day 1 up to Day 180
Adverse Event Reporting Description	All (serious and nonserious) AEs, whether elicited or observed during study visits or spontaneously reported by the participant, including events that occurred from the time the participant signed the study-specific consent form until completion of or discharge from the study.
Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)
Arm/Group Description	EN3835 0.84mg (Collagenase Clostridium Histolyticum) Collagenase Clostridium Histolyticum: During 3 treatment visits 12 injections is given per treatment area
All Cause Mortality
	Collagenase Clostridium Histolyticum (CCH)
	Affected / at Risk (%)	# Events
Total	0/158 (0%)
Serious Adverse Events
	Collagenase Clostridium Histolyticum (CCH)
	Affected / at Risk (%)	# Events
Total	1/158 (0.6%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/158 (0.6%)
Other (Not Including Serious) Adverse Events
	Collagenase Clostridium Histolyticum (CCH)
	Affected / at Risk (%)	# Events
Total	158/158 (100%)
General disorders
Injection site bruising	136/158 (86.1%)
Injection site pain	76/158 (48.1%)
Injection site swelling	35/158 (22.2%)
Injection site pruritus	27/158 (17.1%)
Injection site discolouration	26/158 (16.5%)
Injection site nodule	23/158 (14.6%)
Injection site warmth	18/158 (11.4%)
Injection site haemorrhage	17/158 (10.8%)
Injection site mass	10/158 (6.3%)
Skin and subcutaneous tissue disorders
Hemosiderin stain	8/158 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.