Radiesse

CLINICAL PHARMACOLOGY

Clinical Studies

Nasolabial Fold Pre-Market Clinical Trial

Study Design

The safety and effectiveness of RADIESSE injectable implant for the treatment of nasolabial folds (NLFs) was evaluated in a multi-center, prospective, randomized clinical trial. Patients were randomized to receive RADIESSE injectable implant in one fold and a commercially available collagen implant in the contralateral fold.

Patients were eligible to receive up to three injections during the initial treatment phase (week 0, week 2 and week 4). At 2 weeks after each treatment, the level of correction was determined and if correction was less than optimal, the Investigator re-treated the nasolabial fold using the same respective treatment materials as in the initial treatment. A safety follow-up was conducted 1 month after any injection and at 3 and 6 months after the last injection. Effectiveness evaluations were conducted at 3 and 6 months after the last injection. Three blinded reviewers independently evaluated the severity of the subject's nasolabial folds using a validated 6-point wrinkle severity scale.

Study Endpoints

The primary effectiveness endpoint of the study was the blinded reviewers' Lemperle Rating Scale (LRS) score of wrinkle severity at 3 months after the last touch-up (at which optimal correction was achieved). In this assessment, LRS scores were determined, (using this validated 6-point scale), via blinded, photographic assessments by 3 board certified physicians. A change in LRS of 1 was considered to be clinically significant. Secondary effectiveness endpoints included the blinded reviewers' assessment of wrinkle severity at 6 months after treatment, and the volume of material injected.

Study Population

A total of 117 subjects (31-76 years of age) were randomized and treated and 115 (98.3%) completed the 3 month primary effectiveness evaluation and 113 (96.6%) completed the 6 month follow-up visit. The baseline demographics of the study population are presented in Table 7 which shows that the study enrolled a population of predominantly female, Caucasian nonsmokers.

Table 7: PATIENT DEMOGRAPHICS
N = 117

AGE (YEARS)  
Mean 54.7
Standard Deviation 8.9
Minimum 31.0
Maximum 76.0
GENDER
Female 105 (89.7%)
Male 12 (10.3%)
RACE
American Indian 0 (0.0%)
Asian 0 (0.0%)
Black 2 (1.7%)
Caucasian 102 (87.2%)
Hispanic 11 (9.4%)
Other 2 (1.7%)
SMOKING HISTORY
Quit Smoking 26 (22.2%)
Never Smoked 83 (70.0%)
Smokes 8 (6.8%)

Treatment Material Delivered

Volumes injected during the initial treatment phase are detailed in Table 8 below. The total mean volume for RADIESSE injectable implant was 1.2mL and 2.4mL for the Control.

Table 8: TOTAL VOLUME OF MATERIAL INJECTED (mL),
N = 117

  RADIESSE® CONTROL
Mean 1.2 2.4
Median 1.1 2.2
Standard Deviation 0.5 0.9
Minimum 0.3 0.8
Maximum 2.7 4.7

Effectiveness Results

Table 9 contains the mean LRS at baseline, 3 months and 6 months for the RADIESSE injectable implant treated nasolabial folds and the Control treated nasolabial folds with the difference between the means. Baseline scores for the RADIESSE injectable implant and Control groups were not statistically different.

Table 9: COMPARISON OF MEAN LRS SCORES* FOR RADIESSE INJECTABLE IMPLANT AND CONTROL
Nasolabial Folds - Baseline, 3 and 6 Months

  RADIESSE® CONTROL DIFFERENCE
Baseline 3.4 3.4 0.0
3 Months 1.9 3.5 1.6
6 Months 2.1 3.4 1.3
* Grading Scale: 0 = No wrinkles, 1 = Just perceptible wrinkle, 2 = Shallow wrinkle, 3 = Moderately deep wrinkle, 4 = Deep wrinkle, well-defined edges, 5 = Very deep wrinkle, redundant fold

Primary Effectiveness Endpoint

The primary effectiveness endpoint was to use mean LRS scores to evaluate whether RADIESSE injectable implant was non-inferior to Control for the correction of nasolabial folds 3 months after final treatment. At 3 months, 84.6% of the RADIESSE injectable implant treated nasolabial folds were scored at least 1-point higher than the Control, 12.8% were scored equally, and 2.6% were scored at least 1-point lower than the Control. RADIESSE injectable implant met the statistical criteria for non-inferiority to Control at 3 months (p < 0.0001), however, the Control scored no effectiveness at 3 months.

Secondary Effectiveness Endpoint

The pre-specified secondary superiority analyses at 6 months required a mean 1-point LRS difference between the improvements for the RADIESSE injectable implant treated nasolabial fold versus improvement on the Control treated nasolabial fold and that in at least 50% of patients, the RADIESSE injectable implant treated nasolabial fold be superior to the Control treated nasolabial fold. At 6 months after optimal correction was achieved, 78.6% of the RADIESSE injectable implant treated nasolabial folds were scored at least 1-point higher than the Control-treated folds, 16.2% were scored equally, and 5.1% were scored at least 1-point lower than the Control. The mean LRS for the RADIESSE injectable implant treated nasolabial folds demonstrated superiority when compared to the mean LRS for the Control-treated nasolabial folds at 6 months (p < 0.0001).

Nasolabial Folds Mixing Radiesse Injectable Implant With 2% Lidocaine Hcl Pre-Market Clinical Trial

CAUTION: The clinical study that evaluated the mixing of 2% lidocaine and RADIESSE injectable implant was conducted ONLY on nasolabial folds. The safety and effectiveness for the mixing of 2% lidocaine and RADIESSE injectable implant for restoration and/or correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus has not been studied.

In a prospective, randomized split-face single-blind clinical study, 50 patients were injected with syringes of 1.3cc of RADIESSE injectable implant mixed with 0.2cc of 2% lidocaine HCl (lidocaine) in one nasolabial fold (Treatment) and RADIESSE injectable implant without the 2% lidocaine (Control) in the contralateral nasolabial fold at two investigational sites in the United States. The purpose of this study was to assess the effectiveness of RADIESSE injectable implant mixed with 2% lidocaine for the reduction of pain during injection and the incidence of adverse events through the 1 month follow-up period.

Study Endpoints

The two primary effectiveness endpoints of the study were to evaluate if a statistically significant reduction in pain existed in the Treatment nasolabial fold when compared to the Control nasolabial fold immediately after treatment using a validated visual analog scale (VAS) and to assess whether the observed differences in pain in the Treatment nasolabial fold when compared to the Control nasolabial fold were clinically meaningful immediately after treatment.

The secondary effectiveness endpoints assessed pain in the Treatment nasolabial fold when compared to the Control nasolabial fold at various times out to 1 month post treatment, aesthetic effectiveness out to one month after treatment and subject preference by analyzing the percent of patients favoring one treatment over the other.

Study Population

The inclusion criteria for the clinical study were that the patient was at least 18 years of age, was a candidate for nasolabial fold treatment using RADIESSE injectable implant, understood and accepted the obligation not to receive any other facial procedures in the lower half of the face for 1 month, understood and accepted the obligation to present for all scheduled follow-up visits, was logistically able to meet all study requirements and had approximately symmetrical nasolabial folds.

The exclusion criteria for the clinical study were patients that had received any type of treatment or procedures including surgery in the nasolabial folds, had received neurotoxins in the lower half of the face in the past 6 months, had received hyaluronic acid, calcium hydroxylapatite (CaHA) or collagen injections in the lower half of the face within the past 1 ½ years, had received polylactic acid, PMMA, silicone or any other permanent filler injections in the lower half of the face, had nasolabial folds that were too severe to be corrected in one treatment session, had a history of chronic or recurrent infection or inflammation that would preclude participation in the study, had a known bleeding disorder or were receiving medication that would likely increase the risk of bleeding, was female and of child bearing potential and was pregnant or not using acceptable method of birth control, had any history of hypersensitivity to Lidocaine or anesthetics of the amide type, had a history of anaphylaxis or multiple severe allergies, or had received any investigational product within 30 days prior to study enrollment or is planning to participate in another investigation during the course of this study.

Study Results

The first primary effectiveness endpoint of the study was to assess pain using the Visual Analog Scale (VAS) in the Treatment fold compared to the Control fold. The mean VAS scores at time zero resulted in a statistically significant reduction in pain in the Treatment fold compared to the Control fold. The mean difference in VAS scores was -3.85 and a paired t-test resulted in a pvalue of < 0.0001 (see Table 10).

Table 10: VISUAL ANALOG SCALE (VAS) SCORE AT TIME ZERO

  TREATMENT CONTROL
Mean 2.8 6.6
Median 2.5 7.0
St. Deviation 1.9 2.2
Minimum 0.0 2.0
Maximum 8.5 10.0
Mean Difference 3.85
p-value < 0.0001

The second primary effectiveness endpoint of the study was to assess percentage of patients in which there was a clinically meaningful reduction in pain in the Treatment fold. Forty-five (45) of the 50 patients (90%) recorded VAS scores of at least 2.0cm lower for the Treatment fold compared to the Control fold, demonstrating a clinically meaningful reduction in pain (see Table 11).

Table 11: VAS SCORE ≥ 2.0cm LOWER IN TREATMENT VS. CONTROL
N = 50

N %
45 90.0% C.I. 78.2%-96.7%
p < 0.0001

A secondary effectiveness endpoint of the study was to assess pain in the Treatment fold compared to the Control fold at various times out to 1 month. The Treatment fold showed a statistically significant reduction in pain at four time points within the first hour (p < 0.0001) when compared to the Control fold. At 2 weeks and 1 month, there was no difference between the Treatment and Control folds as all pain ratings for both groups were 0 (no pain) (see Table 12).

Table 12: VAS SCORE AFTER TIME ZERO
N = 50

  15 MIN 30 MIN 45 MIN 60 MIN 2 WEEK 1 MONTH
TX CON- TROL TX CON- TROL TX CON- TROL TX CON- TROL TX CON- TROL TX CON- TROL
Mean 0.9 3.4 0.7 2.5 0.5 1.8 0.3 1.3 0.0 0.0 0.0 0.0
Median 0.5 3.0 0.5 2.3 0.0 1.0 0.0 0.5 0.0 0.0 0.0 0.0
SD 1.0 2.2 1.0 2.1 0.8 1.8 0.7 1.6 0.0 0.0 0.0 0.0
Minimum 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Maximum 4.0 8.0 5.0 7.5 3.5 6.5 3.0 6.0 0.0 0.0 0.0 0.0
p-value < 0.0001 < 0.0001 < 0.0001 < 0.0001 N/A N/A

Another effectiveness endpoint assessed aesthetic improvement on the Global Aesthetic Improvement Scale (GAIS) at 2 weeks and 1 month post treatment. All patients in both groups were at least “Improved” (see Table 13).

Table 13: GAIS DISTRIBUTION

RATING 2 WEEKS
N
(%)
1 MONTH
N
(%)
TREATMENT CONTROL TREATMENT CONTROL
Very Much Improved 29 (58.0) 26 (52.0) 31 (62.0) 28 (56.0)
Much Improved 16 (32.0) 18 (36.0) 12 (24.0) 20 (40.0)
Improved 5 (10.0) 6 (12.0) 0) 2 (4.0)
No Change 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Worse 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
TOTAL IMPROVED 50 (100.0) 50 (100.0) 50 (100.0) 50 (100.0)
p-value 1.0000 1.0000

Nasolabial Folds Long-Term Safety Post-Approval Study

Study Objective

A post approval study was performed to 1) collect long-term safety information on use of RADIESSE injectable implant injected into the nasolabial folds; and 2) to assess the effect of multiple injections.

Study Design

RADIESSE injectable implant was assessed in a prospective, open-label, multi-center study of patients whose nasolabial folds were corrected with RADIESSE injectable implant. 102 subjects (drawn from the 117 patients who participated in the premarket clinical trial) agreed to participate in the post approval study. Patients were requested to return for visits a minimum of 2 years and then a minimum of 3 years after their initial injection. At the beginning of the post marketing study, 8 patients were already 3 years from initial injection and, therefore, required only one visit. One hundred and two (102) patients were assessed a minimum of 2 years after initial injection and 99 were assessed a minimum of 3 years after initial injection. Three (3) patients were lost to follow up.

Study Population

The patient cohort in this post approval study was the continued follow-up of the pre-market cohort. Patient demographics are provided in Table 14.

Table 14: PATIENT DEMOGRAPHICS
N =102

AGE (YEARS)  
  Mean 55.1
  Standard Deviation  8.8
  Minimum 31.0
  Maximum 76.0
GENDER
  Female 94 (92.2%)
  Male 8 (7.8%)
RACE
  American Indian 1 (1.0%)
  Asian 0 (0.0%)
  Black   1 (1.0%)
  Caucasian 8 .8 %
  Hispanic 11 (10.8%)
  Other 2 (2.0%)
SMOKING HISTORY
  Quit Smoking 23 (22.6%)
  Never Smoked 73 (71.6%)
  Smokes 6 (5.9%)

The inclusion criterion for the study was participation in the pre-market clinical trial (Section I of the Nasolabial Folds CLINICAL STUDIES section) and signing a written informed consent for participation in the post-approval study. There were no additional exclusion criteria.

Study Endpoints

To collect long-term safety information of RADIESSE injectable implant injected into the nasolabial folds at a minimum of 2 and 3 years after initial injection and to assess the effect of multiple injections.

Study Results

102 study patients and 204 folds received a mean of 3.7 and 1.8 RADIESSE injections, respectively, from the time period covering initial pre market study injection through the last post approval study visit. 100% of patients and 98% of folds received RADIESSE treatment during the same time period with only 11% of patients receiving RADIESSE injections during the post approval study period alone. During the post approval study, 15% of patients received Botulinum toxin injections and 9% of patients received facial dermal fillers other than RADIESSE injectable implant in the nasolabial folds.

With respect to the long term safety of RADIESSE injectable implant, there were no reports of long term adverse events in this post approval study. The adverse events monitored in the postapproval study included allergic reaction, ecchymosis, edema, embolization, erosion, erythema, extrusion, granuloma, hematoma, infection, necrosis, needle jamming, nodule, and pain. These results demonstrate the long term safety and effectiveness of RADIESSE injectable implant up to 3 years after the date of first injection.

Study Limitations

RADIESSE injectable implant was studied in a limited number of predominately female patients. Safety of RADIESSE injectable implant following the correction of nasolabial folds beyond 3 years was not studied.

Nasolabial Folds Fitzpatrick Skin Type Iv-Vi Post-Approval Study

Study Objective

A post-approval study was performed to assess the safety of RADIESSE injectable implant following correction of the nasolabial folds in patients with Fitzpatrick Skin Types 4, 5, or 6, specifically to assess the likelihood of hypertrophic scarring, keloid formation and hyper- or hypopigmentation.

Study Design

The safety of RADIESSE injectable implant was assessed in a prospective, open-label, multicenter study in 100 patients with Fitzpatrick Skin Types 4, 5 or 6 whose nasolabial folds were corrected with subdermal injections of RADIESSE injectable implant.

Study Population

Patient demographics are provided in Table 15.

Table 15: PATIENT DEMOGRAPHICS
N = 100

AGE (YEARS)  
  Mean 52
  Standard Deviation 11.1
  Minimum 25
  Maximum 78
GENDER
  Male 6 (6.0%)
  Female 94 (94.0%)
RACE
  Caucasian 0 (0.0%)
  Black 85 (85.0%)
  Hispanic 12 (12.0%)
  Asian 2 (2.0%)
  Other 1 (1.0%)
FITZPATRICK SKIN TYPE
  4 24(24.0%)
  5 35(35.0%)
  6 41(41.0%)
INJECTION VOLUME (mL)
  Mean 1.24
  Standard Deviation 0.397
  Minimum 0.6
  Maximum 2.8

The Inclusion Criteria for the post-approval study were that the patient was at least 18 years of age, has Fitzpatrick Skin Type IV, V, or VI, and understands and accepts the obligation not to receive any other procedures or treatments in the nasolabial fold for 6 months.

The Exclusion Criteria for the post-approval study were that the patient has history of hyper- or hypo-pigmentation in the nasolabial folds, keloid formation, or hypertrophic scarring, has a known bleeding disorder or is receiving drug therapy that could increase the risk of bleeding, has nasolabial folds that are too severe to be corrected in one treatment session, has received any dermal filler or other injections, grafting or surgery in either nasolabial fold, is pregnant, lactating, or not using acceptable contraception.

Study Endpoints

The likelihood of hypertrophic scarring, keloid formation and hyper- or hypopigmentation was evaluated through 6 months from treatment with RADIESSE injectable implant in the nasolabial folds.

Length of Follow-up and Assessments

Patients were followed for 6 months from RADIESSE treatment (injection visit). Ninety days (90) ± 30 days from the injection visit, patients returned for a safety assessment of their nasolabial folds (3 month visit). One hundred eighty days (180) ± 30 days from the initial injection, patients returned for a safety assessment of their nasolabial folds (6 month visit).

Subject Accountability

One hundred (100) patients were enrolled in the post-approval study. 100 patients were assessed at the 3 month visit (100% follow-up rate). Ninety eight (98) patients were assessed at the 6 month visit (98% follow-up rate). Two (2) patients were lost to follow-up.

Study Results

At 3 months, 100% of patients were assessed and there were no reports of hypertrophic scarring, keloid formation, hyperpigmentation or hypopigmentation at the injection site. At 6 months 98% of patients were assessed. Two (2) patients were lost to follow-up. Of the 98 patients assessed, no occurrence of hypertrophic scarring, keloid formation, hyperpigmentation or hypopigmentation at the injection site was reported. One patient reported erythema in the upper left nasolabial fold that was treated with hydrocortisone and lasted for 111 days. Another patient experienced mild hyperpigmentation in the upper lip that lasted 159 days. No treatment was required.

The use of RADIESSE injectable implant did not cause hypertrophic scarring, keloid formation, hyperpigmentation or hypopigmentation at the injection site in persons with Fitzpatrick Skin Types of 4, 5 and 6 in this study throughout the follow-up period of 6 months.

Study Limitations

RADIESSE injectable implant was studied in a limited number of predominately female patients. Likelihood of keloid formation, hypertrophic scarring, and hypo- or hyperpigmentation after use of RADIESSE injectable implant for the correction of nasolabial folds in patients with Fitzpatrick Skin Type 4, 5 and 6 beyond 6 months was not studied.

Hiv-Associated Facial Lipoatrophy Pre-Market Clinical Trial

In a 12-month prospective, open label study of 100 patients at three U.S. sites, adverse events reported after RADIESSE injectable implant treatments are presented below. Adverse events reported in patient diaries during the 14 days after treatment are listed in Tables 16 and 17. Physician reported adverse events (those reported by Investigators and patients any time outside the 2 week diaries) are presented in Tables 18 and 19.

Table 16: PATIENT DIARY ADVERSE EVENTS
Reported Through Patient Diaries Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 64 34 (53.1) 25 (39.1) 5 (7.8)
Edema 99 46 (46.5) 49 (49.5) 4 (4.0)
Erythema 55 32 (58.2) 23 (41.8) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0)
Pain 37 24 (64.9) 13 (35.1) 0 (0.0)
Pruritis 21 18 (85.7) 4.3 ) 0 (0.0)
Contour Irregularity 11 8 (72.7) 3 (27.3) 0 (0.0)
Discoloration 5 2 (40.0) 3 (60.0) 0 (0.0)
Hardness 4 2 (50.0) 2 (50.0) 0 (0.0)
Headache 3 1 (33.3) 2 (66.7) 0 (0.0)
Lump 12 8 (66.7) 4 (33.3) 0 (0.0)
* Other - Miscellaneous 13 9 (69.2) 4 (30.8) 0 (0.0)
Numbness 4 4 (100) 0 (0.0) 0 (0.0)
Scab 2 1 (50.0) 1 (50.0) 0 (0.0)
Soreness 3 2 (66.7) 1 (33.3) 0 (0.0)
Tenderness 3 3 (100) 0 (0.0) 0 (0.0)
Tightness 2 1 (50.0) 0 (0.0) 1 (50.0)
* 13 patients with the following event types: flushed, bloodshot eyes, fever, black eye, ear running, backed up salivary gland, spot, nerve sensitivity, dry, sinus infection, burning sensation, warm cheeks, felt stretched, rash.

Table 17: PATIENT DIARY ADVERSE EVENTS
Reported Through Patient Diaries Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 142 29 (20.4) 51 (35.9) 50 (35.2) 12 (8.5)
Edema 431 206 (47.8) 153 (35.5) 52 (12.1) 20 (4.6)
Erythema 210 114 (54.3) 69 (32.9) 22 (10.5) 5 (2.4)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 110 54 (49.1) 32 (29.1) 18 (16.4) 6 (5.5)
Pruritis 54 28 (51.9) 9 (16.7) 6 (11.1) 11 (20.4)
Contour Irregularity 30 4 (13.3) 1 (3.3) 5 (16.7) 20 (66.7)
Discoloration 6 2 (33.3) 0 (0.0) 2 (33.3) 2 (33.3)
Hardness 8 2 (25.0) 1 (12.5) 2 (25.0) 3 (37.5)
Headache 3 2 (66.7) 0 (0.0) 0 (0.0) 1 (33.3)
Lump 18 6 (33.3) 2 (11.1) 4 (22.2) 6 (33.3)
* Other - Miscellaneous 18 9 (50.0) 4 (22.2) 2 (11.1) 3 (16.7)
Numbness 7 7 (100) 0 (0.0) 0 (0.0) 0 (0.0)
Scab 4 1 (25.0) 2 (50.0) 1 (25.0) 0 (0.0)
Soreness 6 3 (50.0) 3 (50.0) 0 (0.0) 0 (0.0)
Tenderness 8 3 (37.5) 5 (62.5) 0 (0.0) 0 (0.0)
Tightness 4 1 (25.0) 1 (25.0) 2 (50.0) 0 (0.0)
* 18 reports of the following event types: flushed, bloodshot eyes, fever, black eye, ear running, backed up salivary gland, spot, nerve sensitivity, dry, sinus infection, burning sensation, warm cheeks, felt stretched, rash.

Table 18: PHYSICIAN REPORTED ADVERSE EVENTS
Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 3 2 (66.7) 1 (33.3) 0 (0.0)
Edema 7 7 (100) 0 (0.0) 0 (0.0)
Erythema 3 3 (100) 0 (0.0) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0)
Pain 2 1 (50.0) 0 (0.0) 1 (50.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0)
Contour Irregularity 19 15 (78.9) 4 (21.1) 0 (0.0)
Discoloration 3 3 (100) 0 (0.0) 0 (0.0)
Lump 2 1 (50.0) 1 (50.0) 0 (0.0)
* Other - Miscellaneous 5 2 (40.0) 3 (60.0) 0 (0.0)
* 5 patients with the following event types: puffiness, hearing loss, skin tag/lesion excision, firmness.

Table 19: PHYSICIAN REPORTED ADVERSE EVENTS
Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 5 3 (60.0) 0 (0.0) 2 (40.0) 0 (0.0)
Edema 12 9 (75.0) 1 (8.3) 1 (8.3) 1 (8.3)
Erythema 4 1 (25.0) 2 (50.0) 0 (0.0) 1 (25.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 4 2 (50.0) 0 (0.0) 2 (50.0) 0 (0.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Contour Irregularity 44 22 (50.0) 0 (0.0) 1 (2.3) 21 (47.7)
Discoloration 6 0 (0.0) 0 (0.0) 0 (0.0) 6 (100)
Lump 3 1 (33.3) 0 (0.0) 0 (0.0) 2 (66.7)
* Other - Miscellaneous 10 5 (50.0) 0 (0.0) 0 (0.0) 5 (50.0)
* 10 reports of the following event types: puffiness, hearing loss, skin tag/lesion excision, firmness

Hiv-Associated Facial Lipoatrophy Long-Term Safety Study

Adverse events reported at 18 months are presented below. Adverse events reported in patient diaries during the 14 days after treatment are listed in Tables 20 and 21. Physician reported adverse events (those reported by Investigators and patients any time outside the 2 week diaries) are presented in Tables 22 and 23.

Table 20: PATIENT DIARY ADVERSE EVENTS - 18 MONTHS
Reported Through Patient Diaries Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 22 9 (40.9) 10 (45.5) 3 (13.6)
Edema 74 47 (63.5) 23 (31.1) 4 (5.4)
Erythema 40 25 (62.5) 14 (35.0) 1 (2.5)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0)
Pain 23 12 (52.2) 11 (47.8) 0 (0.0)
Pruritis 7 7 (100) 0 (0.0) 0 (0.0)
Contour Irregularity 2 1 (50.0) 1 (50.0) 0 (0.0)
Numbness 1 0 (0.0) 1 (100) 0 (0.0)

Table 21: PATIENT DIARY ADVERSE EVENTS - 18 MONTHS
Reported Through Patient Diaries Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 34 11 (32.4) 13 (38.2) 6 (17.6) 4 (11.8)
Edema 144 54 (37.5) 74 (51.4) 12 (8.3) 4 (2.8)
Erythema 75 51 (68.0) 20 (26.7) 4 (5.3) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 42 18 (42.9) 20 (47.6) 3 (7.1) 1 (2.4)
Pruritis 13 11 (84.6) 0 (0.0) 2 (15.4) 0 (0.0)
Contour Irregularity 2 0 (0.0) 0 (0.0) 1 (50.0) 1 (50.0)
Numbness 2 1 (50.0) 1 (50.0) 0 (0.0) 0 (0.0)

Table 22: PHYSICIAN REPORTED ADVERSE EVENTS - 18 MONTHS
Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 0 0 (0.0) 0 (0.0) 0 (0.0)
Edema 1 1 (100) 0 (0.0) 0 (0.0)
Erythema 0 0 (0.0) 0 (0.0) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0)
Pain 0 0 (0.0) 0 (0.0) 0 (0.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0)
Other 0 0 (0.0) 0 (0.0) 0 (0.0)

Table 23: PHYSICIAN REPORTED ADVERSE EVENTS - 18 MONTHS
Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Edema 1 1 (100) 0 (0.0) 0 (0.0) 0 (0.0)
Erythema 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 0 0(0.0) 0(0.0) 0(0.0) 0(0.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Other 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Adverse events reported at 30 months are presented below. Adverse events reported in patient diaries during the 14 days after treatment are listed in Tables 24 and 25. Physician reported adverse events (those reported by Investigators and patients any time outside the 2 week diaries) are presented in Tables 26 and 27.

Table 24: PATIENT DIARY ADVERSE EVENTS - 30 MONTHS
Reported Through Patient Diaries Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 19 12 (63.2) 7 (36.8) 0 (0.0)
Edema 70 43 (61.4) 22 (31.4) 5 (7.1)
Erythema 24 18 (75.0) 5 (20.8) 1 (4.2)
Granuloma 0 0(0.0) 0(0.0) 0(0.0)
Nodule 0 0(0.0) 0(0.0) 0(0.0)
Pain 19 11(57.9) 8(42.1) 0(0.0)
Pruritis 3 3(100) 0(0.0) 0(0.0)
Headache 1 1(100) 0(0.0) 0(0.0)
Lump 1 1(100) 0(0.0) 0(0.0)
* Other - Miscellaneous 4 3(75.0) 1(25.0) 0(0.0)
Numbness 1 0(0.0) 1(100) 0(0.0)
Soreness 1 1(100) 0(0.0) 0(0.0)
Tightness 1 1 (100) 0 (0.0) 0 (0.0)
* 4 patients with the following event types: black eye, nausea, abrasion, pimple.

Table 25: PATIENT DIARY ADVERSE EVENTS - 30 MONTHS
Reported Through Patient Diaries Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 34 8 (23.5) 12 (35.3) 10 (29.4) 4 (11.8)
Edema 147 57 (38.8) 68 (46.3) 16 (10.9) 6 (4.1)
Erythema 49 26 (53.1) 18 (36.7) 3 (6.1) 2 (4.1)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 34 21 (61.8) 12 (35.3) 1 (2.9) 0 (0.0)
Pruritis 5 3 (60.0) 2 (40.0) 0 (0.0) 0 (0.0)
Headache 2 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0)
Lump 1 0 (0.0) 1 (100) 0 (0.0) 0 (0.0)
* Other - Miscellaneous 5 0 (0.0) 3 (60.0) 1 (20.0) 1 (20.0)
Numbness 2 0 (0.0) 0 (0.0) 2 (100) 0 (0.0)
Soreness 2 1 (50.0) 1 (50.0) 0 (0.0) 0 (0.0)
Tightness 2 0 (0.0) 2 (100) 0 (0.0) 0 (0.0)
* 5 reports of the following event types: black eye, nausea, abrasion, pimple.

Table 26: PHYSICIAN REPORTED ADVERSE EVENTS - 30 MONTHS
Maximum Severity By Adverse Event Type N = 100

ADVERSE EVENT TYPE PATIENTS REPORTING SYMPTOMS MILD
N
(%)
MODERATE
N
(%)
SEVERE
N
(%)
Ecchymosis 1 0 (0.0) 1 (100) 0 (0.0)
Edema 6 5 (83.3) 1 (16.7) 0 (0.0)
Erythema 0 0 (0.0) 0 (0.0) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0)
Pain 0 0 (0.0) 0 (0.0) 0 (0.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0)
Other 0 0 (0.0) 0 (0.0) 0 (0.0)

Table 27: PHYSICIAN REPORTED ADVERSE EVENTS - 30 MONTHS
Duration By Adverse Event Type N = 100

ADVERSE EVENT TYPE TOTAL REPORTING SYMPTOMS NUMBER OF DAYS
1-3
N
(%)
4-7
N
(%)
8-14
N
(%)
> 14
N
(%)
Ecchymosis 2 2 (100) 0 (0.0) 0 (0.0) 0 (0.0)
Edema 12 7 (58.3) 4 (33.3) 1 (8.3) 0 (0.0)
Erythema 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Granuloma 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Needle Jamming 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nodule 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain 0 0(0.0) 0(0.0) 0(0.0) 0(0.0)
Pruritis 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Other 0 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Clinical Studies

Hiv-Associated Facial Lipoatrophy Pre-Market Clinical Trial

Study design

The safety and effectiveness of RADIESSE injectable implant for the treatment of facial lipoatrophy was evaluated in a prospective, open-label, multi-center study of 100 patients with facial lipoatrophy with human immunodeficiency virus. Patients received an initial treatment (initial injection and an additional injection at 1 month as needed). Six months later, all patients were assessed for the need for a touch up injection. Effectiveness was assessed at 3, 6 and 12 months from initial treatment by means of a Global Aesthetic Improvement Scale (GAIS) rating, cheek skin thickness measurements, and patient satisfaction assessment. Safety was assessed by the recording of adverse events through 12 months.

Study Endpoints

The primary endpoint of the study was to evaluate the correction of lipoatrophy 3 months after treatment by comparing changes from baseline on the GAIS. The GAIS is a 5-category scale (Very much improved, much improved, improved, no change and worse). The secondary endpoints of the study were to evaluate the correction of facial lipoatrophy 6 months after treatment by comparing changes from baseline on the GAIS, and 3 and 6 months after treatment by comparing changes from baseline in cheek skin thickness measurements.

Study Population

The inclusion criteria for the clinical study were that the patient was to be HIV positive, had a CD4 count ≥ 250 /mm³ and viral load ≤ 5000 copies/mL, had been receiving HAART therapy for a minimum of 3 years, had HIV-associated facial lipoatrophy that was a grade 2, 3, or 4 on the Facial Lipoatrophy Severity Scale, was at least 18 years of age, signed a written informed consent, understood and accepted the obligation not to receive any other facial procedures or treatment affecting facial lipoatrophy through 12 month follow-up and understood and accepted the obligation and was logistically able to present for all scheduled follow-up visits.

The exclusion criteria for the clinical study were patients that had a known bleeding disorder (e.g., thrombocytopenia, thrombasthenia, or von Willebrand's disease), had received or was anticipated to receive antiplatelets, anticoagulants, thrombolytics, vitamin E, anti-inflammatories, interferon, or prednisone from 1 week pre- to 1 month post-injection, was receiving systemic or topical corticosteroids or anabolic steroids, had another medical condition that would preclude study participation or suggested an AIDS diagnosis (e.g., Kaposi sarcoma, recurrent infection, recurrent pneumonia), had received silicone injections, facial tissue augmentation other than collagen, grafting, or any other surgery in the cheek area, had received collagen in the cheek area within the past 6 months, had received over-the-counter wrinkle products (e.g., alphahydroxy acids) or prescription treatments (e.g., Renova, Retin-A, microdermabrasion, chemical peels) within 4 weeks prior to study or intended to receive these products and/or treatments during the study, had facial hair that would preclude ability to assess facial lipoatrophy, had a history of keloid formation, was pregnant or lactating or not using a reliable form of birth control, if female of child bearing potential and was enrolled in an interfering study.

Study Results

Demographics / Injection Information

The study enrolled a population of predominantly multi-ethnic, non-smoking males (94% male) with a mean age of 48 years. Forty-four (44) percent of patients were Black, Hispanic or Asian. Fifty-six (56) percent were Caucasian. Fifty-one (51) percent of patients had a Fitzpatrick Skin score of IV, V or VI. All treatments were performed with a 25 gauge, 1½ inch needle. Mean initial treatment volumes were 4.8mL for the initial treatment and 1.8mL at 1 month if necessary (85% of patients were treated at 1 month). At 6 months, the mean touch up volume was 2.4mL (89% of patients). Four (4) percent of patients received only one treatment, 18% of patients received a total of two treatments and 78% of patients received a total of three treatments. No patient received more than three treatments.

Effectiveness Results

A live GAIS rating was determined at 3, 6 and 12 months (see Table 28).

Table 28: GAIS RATINGS

% OF PATIENTS 3 MONTH
N = 100
6 MONTH
N = 98
12 MONTHS
N = 98
Very Much Improved 26% 7% 31%
Much Improved 72% 86% 53%
Improved 2% 7% 16%
No Change 0% 0% 0%
Worse 0% 0% 0%
TOTAL 100% 100% 100%

Cheek thickness measurements of patients left and right cheeks were performed at baseline, 3, 6 and 12 months (see Table 29).

Table 29: CHEEK THICKNESS MEASUREMENTS

  BASELIN E 3 MONTH 6 MONTH 12 MONTH
Mean
(N=100)
Mean
(N=100)
Δ From Baseline P-Value Mean
(N=97)
Δ From Baseline P-Value Mean
(N=98)
Δ From Baseline P-Value
Left Cheek 4.7mm 7.3mm 2.6mm < 0.0001 7.1mm 2.4mm < 0.0001 6.9mm 2.2mm < 0.0001
Right Cheek 4.9mm 8.0mm 2.1mm < 0.0001 7.5mm 2.7mm < 0.0001 7.3mm 2.5mm < 0.0001

Patients provided responses to a 5-question patient satisfaction questionnaire at 3, 6 and 12 months (see Table 30).

Table 30: PATIENT SATISFACTION ASSESSMENT

  3 MONTH
N=100
6 MONTH
N=98
12 MONTH
N = 98
YES YES YES
Would you recommend RADIESSE® treatment? 99% 99% 99%
Has the RADIESSE® treatment been beneficial to you? 100% 100% 100%
Do you feel more attractive since receiving RADIESSE® treatment? 98% 98% 99%
Is your emotional wellbeing better since receiving RADIESSE®? 91% 96% 97%
Do you have more confidence in your appearance since receiving RADIESSE®? 98% 98% 99%

Data For Hiv-Associated Facial Lipoatrophy Long-Term Safety Study

Study Objective

A post-approval study was performed to evaluate adverse events after repeat injections of RADIESSE injectable implant for the treatment of facial lipoatrophy in patients with human immunodeficiency virus.

Study Design

The safety and effectiveness of RADIESSE injectable implant for the treatment of facial lipoatrophy was evaluated in a premarket prospective, open-label, multi-center study of 100 patients with facial lipoatrophy with human immunodeficiency virus. As a condition of approval, a post-approval study was undertaken to provide long term data on the patients enrolled in the premarket study to evaluate any adverse events after repeat injections. Effectiveness was assessed as part of the post-approval study at 18 and 30 months from initial treatment by means of a Global Aesthetic Improvement Scale (GAIS) rating, cheek skin thickness measurements, and patient satisfaction assessment. Safety was assessed by the recording of adverse events through 30 months. Touch-up injections were performed as needed at 18 and 30 months. Therefore, the 18-month and 30-month effectiveness results are one year from last touch-up injection.

Study Endpoints

The primary endpoint of the post-approval study was to evaluate the correction of lipoatrophy 18 and 30 months after treatment by comparing changes from baseline on the GAIS. The GAIS is a 5-category scale (Very much improved, much improved, improved, no change and worse). The secondary endpoint of the post-approval study was to evaluate the correction of facial lipoatrophy 18 and 30 months after treatment by comparing changes from baseline in cheek skin thickness measurements.

Study Population

The patient cohort in this post approval study was the continued follow-up of the pre-market cohort. The inclusion criterion for the post-approval study was participation in the pre-market clinical study (Section I in HIV-Associated Facial Lipoatrophy CLINICAL STUDIES section) through 12 months, signed a written informed consent, understood and accepted the obligation not to receive any other facial procedures or treatment affecting facial lipoatrophy through 30 month follow-up and understood and accepted the obligation and was logistically able to present for 18 and 30 month follow-up visits.

The exclusion criteria for the clinical study were patients that had a known bleeding disorder (e.g., thrombocytopenia, thrombasthenia, or von Willebrand's disease), had received or was anticipated to receive antiplatelets, anticoagulants, thrombolytics, vitamin E, anti-inflammatories, interferon, or prednisone from 1 week pre- to 1 month post-injection, was receiving systemic or topical corticosteroids or anabolic steroids at any time through 30 month visit, had another medical condition that would preclude continued study participation or suggested an AIDS diagnosis (e.g., Kaposi sarcoma, recurrent infection, recurrent pneumonia), intended to receive over-the-counter wrinkle products (e.g., alpha-hydroxy acids) or prescription treatments (e.g., Renova, Retin-A, microdermabrasion, chemical peels) any time through 30 month visit, had a history of keloid formation, was pregnant or lactating or not using a reliable form of birth control, if female of child bearing potential.

Follow-up Assessments

Patients enrolled in the post-approval study returned for two (2) follow-up assessments after completion of the pre-market study. The first post-approval assessment was 540 ± 45 days from initial treatment if not treated at 1 month and 570 ± 45 days from initial treatment if treated at 1 month (18/19 month visit). The second post-approval assessment was 900 ± 45 days from initial treatment if not treated at 1 month and 930 ± 45 days from initial treatment if treated at 1 month (30/31 month visit). The assessment consisted of a live GAIS rating, facial photographs, skin thickness measurements, patient satisfaction assessment, recording of CD4 counts antiviral loads, recording of relevant medications, and an assessment for adverse events.

Study Results

The study enrolled a population of predominantly multi-ethnic, non-smoking males (94% male) with a mean age of 48 years (age range of 34 – 69). Forty-four (44) percent of patients were Black, Hispanic or Asian. Fifty-six (56) percent were Caucasian. Fifty-one (51) percent of patients had a Fitzpatrick Skin score of IV, V or VI. All treatments were performed with a 25 gauge, 1½ inch needle. At 18 months, 92% of patients received a mean touch-up volume of 4.4mL. At 30 months, 90% of patients received a mean touch-up volume of 2.8mL. Over the course of both the premarket and post-approval studies, two (2) percent of patients received only one treatment, 3% - two treatments, 5% - 3 treatments, 12% - 4 treatments, and 78% - 5 treatments. No patient received more than five treatments.

A live GAIS rating was determined at 18 and 30 months (see Table 31). The last pre-market study touch up injection was allowed at 6 months. Post-market study touch-up injections were allowed at 18 and 30 months. Therefore, the 18-month and 30-month response rates of 91.0% and 90.1%, respectively, are one year from last touch-up injection.

Table 31: GAIS RATINGS

RATING 18 MONTHS
N = 94
30 MONTHS
N = 91
Very Much Improved 9.6% 3.3%
Much Improved 43.6% 28.6%
Improved 38.3% 58.2%
No Change 8.5% 8.8%
Worse 0.0% 1.1%
TOTAL IMPROVED 91.0% 90.1%

Cheek thickness measurements of patients left and right cheeks were performed at 18 and 30 months and are one year from last touch up injection (see Table 32).

Table 32: CHEEK THICKNESS MEASUREMENTS

  MEAN
BASELINE
N=100
18 MONTHS
N = 93
30 MONTHS
N = 91
mm mm ΔFrom Baseline p-value mm Δ From Baseline p-value
Left Side 4.7 6.2 1.45 < 0.0001 6.8 2.1 < 0.0001
Right Side 4.9 6.5 1.71 < 0.0001 7.2 2.3 < 0.0001

Patients provided responses to a 5-question patient satisfaction questionnaire at 18 and 30 months, one year from last touch up injection (see Table 33).

Table 33: PATIENT SATISFACTION ASSESSMENT

QUESTIONS % ANSWERING “YES”
18 MONTHS
N=94
30 MONTHS
N=91
Would you recommend RADIESSE® treatment? 98.9% 100%
Has the RADIESSE® treatment been beneficial to you? 98.9% 100%
Do you feel more attractive since receiving RADIESSE® treatment? 97.9% 100%
Is your emotional wellbeing better since receiving RADIESSE®? 94.7% 95.6%
Do you have more confidence in your appearance since receiving RADIESSE®? 98.9% 100%

Study Limitations

RADIESSE injectable implant was studied in a limited number of predominately male HIV positive patients. The safety of RADIESSE injectable implant following treatment of HIV associated Lipoatrophy beyond 30 months was not studied.

Other

Short Term And Long Term Radiographic Evaluation

RADIESSE injectable implant contains calcium hydroxylapatite particles (25-45 microns) that are radiopaque and suspended in a water based gel. Therefore a radiographic study was conducted to assess the radiographic appearance of RADIESSE injectable implant in patients with both short-term and long-term follow-up after injection for HIV-associated facial lipoatrophy and treatment of nasolabial folds. The radiographic assessment consisted of standard, plain radiography and CT scanning. X-rays and CT Scans were assessed by two blinded, licensed radiologists. The inclusion of these patients allowed assessment of patients immediately after initial injection, at least 12 months after initial injection, and patients with varying volumes implanted.

A total of 58 patients in three patients groups were enrolled into the study. RADIESSE injectable implant was determined to be visualizable in the X-ray radiographs by both evaluators, but the X-ray readings were not conclusive for the presence of the implant, when in fact it was present. This may be due to the fact that the volume of RADIESSE injectable implant in some patients was small and the sensitivity of X-ray imaging may not be sufficient to detect small volumes of implant. RADIESSE injectable implant was more readily visualizable by CT Scan when compared to X-ray and the CT Scan results were read more consistently between two evaluators. RADIESSE injectable implant was easily seen when imaging was done soon after an injection and was also seen when imaging was done several months after injection (minimum of 12 months). As expected, the results for the CT Scan provided a superior image capability as compared to X-ray when visualizing RADIESSE injectable implant.

Last reviewed on RxList: 7/8/2013
This monograph has been modified to include the generic and brand name in many instances.

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