Phase 3 Study of Deoxycholic Acid Injection (ATX-101) Versus Placebo for the Reduction of Localized Subcutaneous Fat in the Submental Area (REFINE-1)

• ClinicalTrials.gov Identifier: NCT01542034
• Recruitment Status: Completed
• First Posted: March 1, 2012
• Results First Posted: June 15, 2015
• Last Update Posted: June 15, 2015
• Sponsor: Kythera Biopharmaceuticals
• Information provided by (Responsible Party): Kythera Biopharmaceuticals

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Moderate or Severe Submental Fullness
• Interventions: Drug: Deoxycholic acid injection; Drug: Placebo
• Enrollment: 506

Participant Flow

Recruitment Details	The study was performed at 35 investigational centers in the United States (US) and Canada.
Pre-assignment Details

Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Period Title: Overall Study
Started	256	250
Received Treatment	256	249
Completed	226 [1]	227 [1]
Not Completed	30	23
Reason Not Completed
Consent Withdrawn (Subject Convenience)	20	12
Administrative decision	0	3
Subject Noncompliance	1	0
Adverse Event	2	2
Lost to Follow-up	7	6
[1] Participants who completed long-term follow-up 24 weeks after the last treatment

Baseline Characteristics

Arm/Group Title		Deoxycholic Acid Injection	Placebo	Total
Arm/Group Description		Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Total of all reporting groups
Overall Number of Baseline Participants		256	250	506
Baseline Analysis Population Description		Intention-to-treat population
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	256 participants	250 participants	506 participants
		49.5 (9.30)	49.4 (9.33)	49.5 (9.30)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	256 participants	250 participants	506 participants
18 - 50 years		122	121	243
51 - 65 years		134	129	263
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	256 participants	250 participants	506 participants
	Female	213 83.2%	208 83.2%	421 83.2%
	Male	43 16.8%	42 16.8%	85 16.8%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	256 participants	250 participants	506 participants
White		218	227	445
Black or African American		24	13	37
Asian		7	5	12
American Indian or Alaskan Native		0	2	2
Native Hawaiian or Pacific Islander		0	1	1
Multiple		2	0	2
Other		5	2	7
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	256 participants	250 participants	506 participants
Hispanic or Latino		28	17	45
Non-Hispanic or Latino		228	233	461
Weight [1]; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	256 participants	250 participants	506 participants
		81.15 (14.549)	80.98 (14.296)	81.07 (14.411)
		[1] Measure Description: Data available for 256 and 249 participants in each treatment group respectively
Body Mass Index (BMI) [1]; Mean (Standard Deviation); Unit of measure: Kg/m²
	Number Analyzed	256 participants	250 participants	506 participants
		29.23 (4.406)	29.26 (4.281)	29.25 (4.340)
		[1] Measure Description: Data available for 256 and 249 participants in each treatment group respectively
Fitzpatrick Skin Type [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	256 participants	250 participants	506 participants
I - III		180	187	367
IV - VI		76	63	139
		[1] Measure Description: Fitzpatrick Skin Type is a numerical classification schema for human skin color and typical response to ultraviolet (UV) light: Type I: Pale white skin, blue/hazel eyes, blond/red hair; Always burns, does not tan.; Type II: Fair skin, blue eyes; Burns easily, tans poorly.; Type III: Darker white skin; Tans after initial burn.; Type IV: Light brown skin; Burns minimally, tans easily.; Type V: Brown skin; Rarely burns, tans darkly easily.; Type VI: Dark brown or black skin; Never burns, always tans darkly.

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved a Composite 1-grade Response
Description	A composite 1-grade response is defined as at least a 1-grade improvement from Baseline on both the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and Patient-Reported Submental Fat Rating Scale (PR-SMFRS) 12 weeks after the last treatment. The CR-SMFRS score is based on the investigator's clinical evaluation of the participant, where submental fullness is scored on a 5-point ordinal scale (0-4) with 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme. The PR-SMFRS is based on the participant's response to the question "How much fat do you have under your chin right now?" answered on a 5-point ordinal scale (0-4) with 0 = no chin fat at all, 1 = a slight amount of chin fat, 2 = a moderate amount of chin fat, 3 = a large amount of chin fat, and 4 = a very large amount of chin fat.
Time Frame	Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population; missing values were imputed using a multiple imputation process.

Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description:	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed	256	250
Measure Type: Number; Unit of Measure: percentage of participants
	70.0	18.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deoxycholic Acid Injection, Placebo
	Comments	The primary analysis was satisfied if both null hypotheses (there is no treatment difference in 1-grade or 2-grade response rate) were rejected in favor of the two-tailed alternative at the 0.05 level of significance for both primary efficacy endpoints, and the response rates were higher for the deoxycholic acid injection treatment group than the placebo group. Because both hypotheses must be rejected, the type I error was preserved when testing the primary endpoints.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel (CMH) method stratified by pooled study center.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	3.702
	Confidence Interval	(2-Sided) 95%; 2.808 to 4.880
	Estimation Comments	A risk ratio greater than 1 favors deoxycholic acid injection treatment, and between 0 and 1 favors placebo.

2. Primary Outcome

Title	Percentage of Participants Who Achieved a Composite 2-grade Response
Description	A composite 2-grade response is defined as at least a 2-grade improvement from Baseline on both the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and Patient-Reported Submental Fat Rating Scale (PR-SMFRS) 12 weeks after the last treatment. The CR-SMFRS score is based on the investigator's clinical evaluation of the participant, where submental fullness is scored on a 5-point ordinal scale (0-4) with 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme. The PR-SMFRS is based on the participant's response to the question "How much fat do you have under your chin right now?" answered on a 5-point ordinal scale (0-4) with 0 = no chin fat at all, 1 = a slight amount of chin fat, 2 = a moderate amount of chin fat, 3 = a large amount of chin fat, and 4 = a very large amount of chin fat.
Time Frame	Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; missing values were imputed using a multiple imputation process.

Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description:	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed	256	250
Measure Type: Number; Unit of Measure: percentage of participants
	13.4	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deoxycholic Acid Injection, Placebo
	Comments	The primary analysis was satisfied if both null hypotheses (there is no treatment difference in 1-grade or 2-grade response rate) were rejected in favor of the two-tailed alternative at the 0.05 level of significance for both primary efficacy endpoints, and the response rates were higher for the deoxycholic acid injection treatment group than the placebo group. Because both hypotheses must be rejected, the type I error was preserved when testing the primary endpoints.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	CMH method stratified by pooled study center.

3. Secondary Outcome

Title	Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response
Description	An MRI responder is a participant who exhibited at least a 10% reduction in submental fat volume as measured by MRI from Baseline to 12 weeks after last treatment. Magnetic resonance imaging was evaluated in a subset of participants at selected centers.
Time Frame	Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)

Outcome Measure Data

Analysis Population Description

The ITT-MRI population consisted of all randomized participants who participated in the MRI cohort and had evaluable Baseline MRI data. A multiple imputation process was used.

Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description:	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed	113	111
Measure Type: Number; Unit of Measure: percentage of participants
	46.3	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deoxycholic Acid Injection, Placebo
	Comments	If both primary endpoints were statistically significant, testing continued to the 2 secondary endpoints using the Bonferroni-Holm method. The smaller of the 2 p-values for the treatment difference was tested at the 0.025 level. If significant, testing proceeded for the remaining secondary endpoint at the 0.05 level. If the smaller p-value was > 0.025, the null hypothesis for the associated variable would not be rejected, and testing of the second endpoint would not proceed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	CMH method stratified by pooled study center
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	8.541
	Confidence Interval	(2-Sided) 95%; 3.620 to 20.148
	Estimation Comments	A risk ratio greater than 1 favors deoxycholic acid injection treatment, and between 0 and 1 favors placebo.

4. Secondary Outcome

Title	Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS)
Description	The PR-SMFIS assesses the impact of submental fat on self-perception of 6 emotional and visual characteristics related to the appearance of submental fullness (unhappy, bothered, self-conscious, embarrassed, look older, and look overweight) as evaluated by the participant. Each item is rated on an 11-point numeric scale from 0 to 10. Scores for the 6 items were averaged to generate a PR-SMFIS total scale score ranging from 0 to 10 where 0 is a positive outcome and 10 is a negative outcome. A negative change from Baseline indicates improvement.
Time Frame	Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; missing values were imputed using a multiple imputation process.

Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description:	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed	256	250
Mean (Standard Deviation); Unit of Measure: units on a scale
	-3.56 (2.793)	-1.16 (2.064)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deoxycholic Acid Injection, Placebo
	Comments	If both primary endpoints were statistically significant, testing continued to the 2 secondary endpoints using the Bonferroni-Holm method. The smaller of the 2 p-values for the treatment difference was tested at the 0.025 level. If significant, testing proceeded for the remaining secondary endpoint at the 0.05 level. If the smaller p-value was > 0.025, the null hypothesis for the associated variable would not be rejected, and testing of the second endpoint would not proceed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model included treatment and Baseline PR-SMFIS total scale score.

Adverse Events

Time Frame	From the first dose of study drug until 24 weeks after the last dose (up to 44 weeks after first treatment).
Adverse Event Reporting Description	The safety population consisted of all participants who received at least 1 injection of study drug. One participant was randomized to placebo, received deoxycholic acid injection at Visit 4 (Week 8), and was included in the deoxycholic acid injection arm for safety analyses.
Arm/Group Title	Deoxycholic Acid Injection	Placebo
Arm/Group Description	Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.	Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
All-Cause Mortality
	Deoxycholic Acid Injection	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Deoxycholic Acid Injection	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/257 (2.33%)	12/248 (4.84%)
Cardiac disorders
Cardiac arrest † 1	0/257 (0.00%)	1/248 (0.40%)
Gastrointestinal disorders
Colitis microscopic † 1	1/257 (0.39%)	0/248 (0.00%)
Gastrointestinal haemorrhage † 1	0/257 (0.00%)	1/248 (0.40%)
Gastrooesophageal reflux disease † 1	0/257 (0.00%)	1/248 (0.40%)
Hiatus hernia † 1	0/257 (0.00%)	1/248 (0.40%)
Infections and infestations
Abdominal abscess † 1	1/257 (0.39%)	0/248 (0.00%)
Abscess oral † 1	0/257 (0.00%)	1/248 (0.40%)
Diverticulitis † 1	0/257 (0.00%)	1/248 (0.40%)
Injury, poisoning and procedural complications
Concussion † 1	1/257 (0.39%)	0/248 (0.00%)
Contusion † 1	1/257 (0.39%)	0/248 (0.00%)
Head injury † 1	1/257 (0.39%)	0/248 (0.00%)
Humerus fracture † 1	0/257 (0.00%)	1/248 (0.40%)
Skull fracture † 1	1/257 (0.39%)	0/248 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/257 (0.00%)	1/248 (0.40%)
Musculoskeletal and connective tissue disorders
Osteoarthritis † 1	1/257 (0.39%)	1/248 (0.40%)
Intervertebral disc protrusion † 1	0/257 (0.00%)	1/248 (0.40%)
Spinal column stenosis † 1	1/257 (0.39%)	0/248 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	0/257 (0.00%)	1/248 (0.40%)
Multiple myeloma † 1	0/257 (0.00%)	1/248 (0.40%)
Nervous system disorders
Meningism † 1	1/257 (0.39%)	0/248 (0.00%)
Renal and urinary disorders
Urethral disorder † 1	0/257 (0.00%)	1/248 (0.40%)
Respiratory, thoracic and mediastinal disorders
Respiratory distress † 1	0/257 (0.00%)	1/248 (0.40%)
Respiratory failure † 1	1/257 (0.39%)	0/248 (0.00%)
Surgical and medical procedures
Hip arthroplasty † 1	0/257 (0.00%)	1/248 (0.40%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (14.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Deoxycholic Acid Injection	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	246/257 (95.72%)	196/248 (79.03%)
General disorders
Injection site haematoma † 1	180/257 (70.04%)	167/248 (67.34%)
Injection site pain † 1	168/257 (65.37%)	58/248 (23.39%)
Injection site oedema † 1	136/257 (52.92%)	54/248 (21.77%)
Injection site anaesthesia † 1	172/257 (66.93%)	11/248 (4.44%)
Injection site swelling † 1	96/257 (37.35%)	39/248 (15.73%)
Injection site erythema † 1	46/257 (17.90%)	25/248 (10.08%)
Injection site induration † 1	47/257 (18.29%)	4/248 (1.61%)
Injection site paraesthesia † 1	33/257 (12.84%)	8/248 (3.23%)
Injection site nodule † 1	32/257 (12.45%)	2/248 (0.81%)
Injection site pruritus † 1	22/257 (8.56%)	9/248 (3.63%)
Infections and infestations
Nasopharyngitis † 1	23/257 (8.95%)	26/248 (10.48%)
Nervous system disorders
Headache † 1	19/257 (7.39%)	11/248 (4.44%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (14.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.

The Clinical Study Agreement requires that the investigator or institution obtain written consent from Kythera prior to presenting and/or publishing results of this study.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure
• Organization: Kythera
• EMail: clinical_trials@kythera.com

• Responsible Party: Kythera Biopharmaceuticals
• ClinicalTrials.gov Identifier: NCT01542034
• Other Study ID Numbers: ATX-101-11-22
• First Submitted: February 24, 2012
• First Posted: March 1, 2012
• Results First Submitted: May 28, 2015
• Results First Posted: June 15, 2015
• Last Update Posted: June 15, 2015