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The purpose of this study is to follow and collect additional medical and developmental information on children after histrelin subcutaneous implant therapy is discontinued.
Thirty-two (32) patients will receive a histrelin subdermal implant under the anesthesia deemed appropriate by the administering physician. Ten-twelve (10-12) sites will enroll 2-3 patients per site. It is anticipated that half the patients will be receiving GnRH analog treatment and the other half will be treatment naïve. All patients will undergo selective PK sampling post-implantation to assess histrelin profile. At 12 months, provided that the patient continues to meet the safety and efficacy parameters, the original implant will be removed and the patient can receive a new implant. At 13 months, patients who receive new implants will be evaluated at the study site and administratively transferred to the initial extension study. At Month 24), the implants inserted at Month 12 will be removed. At this time, patients who have completed the initial extension study and who wish to continue therapy with the histrelin implant will be eligible to receive a new (ie, third) implant and to enter an additional 12-month extended access phase at the discretion of the investigator. At Month 36, the implants inserted at Month 24 for the Extended Access Phase will be removed. At this time, patients who have completed the Extended Access Phase and who wish to continue therapy with the histrelin implant will be eligible to receive a new (ie, fourth) implant and to enter the Long Term Extended Access Phase (referred to as the Implant Treatment Phase) at the discretion of the investigator. The purpose of this phase is to provide patients with the opportunity to continue to receive a new implant at the end of each 12-month period until the patient no longer requires hormone suppression. Once implant therapy is discontinued, all patients are eligible to enter the Long Term Follow Up Phase (Post Implant Phase) of the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Histrelin Subcutaneous Implant (50 mg) | Experimental | Subcutaneous implant designed to deliver histrelin continously for 12 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Histrelin Subcutaneous Implant | Drug | histrelin subcutaneous 50 mg implant |
|
| Measure | Description | Time Frame |
|---|---|---|
| Luteinizing Hormone (LH) | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog). | Baseline - 6 Months Post Last Implant |
| Measure | Description | Time Frame |
|---|---|---|
| Follicle Stimulating Hormone (FSH) | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog). | Baseline - 6 Month Post Last Implant |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Erica A Eugster, MD | Indiana University School of Medicine, 705 Riley Hosp Dr, Rm 5960 Indianapolis, IN 46202 | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25803268 | Derived | Silverman LA, Neely EK, Kletter GB, Lewis K, Chitra S, Terleckyj O, Eugster EA. Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial. J Clin Endocrinol Metab. 2015 Jun;100(6):2354-63. doi: 10.1210/jc.2014-3031. Epub 2015 Mar 24. | |
| 24295437 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Overall - Histrelin Subcutaneous Implant (50 mg) | Subcutaneous implant designed to deliver histrelin continously for 12 months. Histrelin Subcutaneous Implant: histrelin subcutaneous 50 mg implant |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Initial Extension Phase/Extended Access Phase (Second and Third Implant)
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| ID | Title | Description |
|---|---|---|
| BG000 | Histrelin Subcutaneous Implant (50 mg) | Subcutaneous implant designed to deliver histrelin continously for 12 months. Histrelin Subcutaneous Implant: histrelin subcutaneous 50 mg implant Extension Safety Population (Second & Third Implant) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Luteinizing Hormone (LH) | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog). | Extension Safety Population | Posted | Mean | Standard Deviation | MIU/ML | Baseline - 6 Months Post Last Implant |
|
|
From start of 2nd implant period through end of 6th implant period up to 48 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Overall - Histrelin Subcutaneous Implant (50 mg) | Subcutaneous implant designed to deliver histrelin continously for 12 months. Histrelin Subcutaneous Implant: histrelin subcutaneous 50 mg implant |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Aggression | Psychiatric disorders | MedDRA (12.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Implant Site Reaction | General disorders | MedDRA (12.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Saji Vijayan, MBBS | Endo Pharmaceuticals | 800-462-3636 | ClinicalTrials@Endo.com |
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| ID | Term |
|---|---|
| D011629 | Puberty, Precocious |
| ID | Term |
|---|---|
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| C029256 | histrelin |
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| Testosterone | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Testosterone suppression is defined as serum testosterone < 30.0 ng/dL (0.8 nmol/L) in boys following the induction of suppression. One black female participant age 8.9 years old had a testosterone value of 11ng/dL at visit 4 (month 6). | Baseline - 12 Months Post Last Implant |
| DHEA Sulfate | DHEA=Dehydroepiandrosterone | Baseline - 36 Months Post Last Implant |
| Estradiol (MS) | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range < 20 pg/mL (73 pmol/L) in girls following the induction of suppression. | Month 36 - 36 Months Post Last Implant |
| Estradiol (RIA) | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range < 20 pg/mL (73 pmol/L) in girls following the induction of suppression. | Baseline - Month 24 |
| Average Number of Implants Received | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. | 12 months |
| Average Mean Implant Duration by Subject | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. | 12 Months |
| Summary of EN3326 Implantation and Explantations | Once the female participants reached 11 years of age and the male participants reached 12 years of age or the investigator determined that subjects no longer required hormone suppression, participants underwent final explantation and were eligible to continue into an optional Long Term Follow Up Phase (Post Implant Treatment Phase) for up to 5 years. The purpose of the optional Long Term Follow Up Phase was to collect additional medical and developmental information, such as onset of menses and final adult height after hormone suppression was discontinued. | Day 1 - Month 60 |
| Neely EK, Silverman LA, Geffner ME, Danoff TM, Gould E, Thornton PS. Random unstimulated pediatric luteinizing hormone levels are not reliable in the assessment of pubertal suppression during histrelin implant therapy. Int J Pediatr Endocrinol. 2013 Dec 2;2013(1):20. doi: 10.1186/1687-9856-2013-20. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Height | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| Pretreatment with Prior GnRH Therapy | Count of Participants | Participants |
|
| Counts |
|---|
| Participants |
|
|
| Secondary | Follicle Stimulating Hormone (FSH) | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog). | Extension Safety Population | Posted | Mean | Standard Deviation | MIU/ML | Baseline - 6 Month Post Last Implant |
|
|
|
| Secondary | Testosterone | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Testosterone suppression is defined as serum testosterone < 30.0 ng/dL (0.8 nmol/L) in boys following the induction of suppression. One black female participant age 8.9 years old had a testosterone value of 11ng/dL at visit 4 (month 6). | Extension Safety Population | Posted | Mean | Standard Deviation | NG/DL | Baseline - 12 Months Post Last Implant |
|
|
|
| Secondary | DHEA Sulfate | DHEA=Dehydroepiandrosterone | Extension Safety Population | Posted | Mean | Standard Deviation | UG/DL | Baseline - 36 Months Post Last Implant |
|
|
|
| Secondary | Estradiol (MS) | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range < 20 pg/mL (73 pmol/L) in girls following the induction of suppression. | Extension Safety Population | Posted | Mean | Standard Deviation | NG/DL | Month 36 - 36 Months Post Last Implant |
|
|
|
| Secondary | Estradiol (RIA) | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range < 20 pg/mL (73 pmol/L) in girls following the induction of suppression. | Extension Safety Population | Posted | Mean | Standard Deviation | NG/DL | Baseline - Month 24 |
|
|
|
| Secondary | Average Number of Implants Received | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. | Extension Safety Population | Posted | Mean | Standard Deviation | Implants | 12 months |
|
|
|
| Secondary | Average Mean Implant Duration by Subject | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. | Extension Safety Population | Posted | Mean | Standard Deviation | Months | 12 Months |
|
|
|
| Secondary | Summary of EN3326 Implantation and Explantations | Once the female participants reached 11 years of age and the male participants reached 12 years of age or the investigator determined that subjects no longer required hormone suppression, participants underwent final explantation and were eligible to continue into an optional Long Term Follow Up Phase (Post Implant Treatment Phase) for up to 5 years. The purpose of the optional Long Term Follow Up Phase was to collect additional medical and developmental information, such as onset of menses and final adult height after hormone suppression was discontinued. | Extension Safety Population | Posted | Count of Participants | Participants | Day 1 - Month 60 |
|
|
|
| 1 |
| 31 |
| 3 |
| 31 |
| 31 |
| 31 |
| Depression | Psychiatric disorders | MedDRA (12.0) | Systematic Assessment |
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| Bronchopneumonia | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Apnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (12.0) | Systematic Assessment |
|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Pharyngitis Streptococcal | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (12.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
|
| Weight Increased | Investigations | MedDRA (12.0) | Systematic Assessment |
|
| Agression | Psychiatric disorders | MedDRA (12.0) | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (12.0) | Systematic Assessment |
|
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| Day 1, Visit 1 |
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| Month 1, Visit 2 |
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| Month 3, Visit 3 |
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| Month 6, Visit 4 |
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| Month 9, Visit 5 |
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| Month 12, Visit 6 |
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| Month 13, Visit 7 |
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| Month 18, Visit 9 |
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| Month 24, Visit 11 |
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| Month 36, Visit 13 |
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| Month 42, Visit 14 |
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| Month 48, Visit 15 |
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| Month 54, Visit 16 |
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| Month 60, Visit 17 |
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| Month 66, Visit 18 |
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| Month 72, Visit 19 |
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| 1 Month Post Last Implant |
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| 6 Month Post Last Implant |
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| Month 1, Visit 2 |
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| Month 3, Visit 3 |
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| Month 6, Visit 4 |
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| Month 9, Visit 5 |
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| Month 12, Visit 6 |
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| Month 13, Visit 7 |
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| Month 18, Visit 9 |
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| Month 24, Visit 11 |
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| Month 36, Visit 13 |
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| Month 42, Visit 14 |
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| Month 48, Visit 15 |
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| Month 54, Visit 16 |
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| Month 60, Visit 17 |
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| 6 Months Post Last Implant |
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| 12 Months Post Last Implant |
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| Month 3, Visit 3 |
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| Month 6, Visit 4 |
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| Month 9, Visit 5 |
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| Month 12, Visit 6 |
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| Month 13, Visit 7 |
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| Month 18, Visit 9 |
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| Month 24, Visit 11 |
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| Month 36, Visit 13 |
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| Month 42, Visit 14 |
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| Month 48, Visit 15 |
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| Month 54, Visit 16 |
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| Month 60, Visit 17 |
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| Month 66, Visit 18 |
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| Month 72, Visit 19 |
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| 6 Months Post Last Implant |
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| 12 Months Post Last Implant |
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| 24 Months Post Last Implant |
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| 36 Months Post Last Implant |
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| Month 48, Visit 15 |
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| Month 54, Visit 16 |
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| Month 60, Visit 17 |
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| Month 66, Visit 18 |
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| Month 72, Visit 19 |
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| 6 Months Post Last Implant |
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| 12 Months Post Last Implant |
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| 24 Months Post Last Implant |
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| 36 Months Post Last Implant |
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| Day 1, Visit 1 |
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| Month 1, Visit 2 |
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| Month 3, Visit 3 |
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| Month 6, Visit 4 |
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| Month 9, Visit 5 |
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| Month 12, Visit 6 |
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| Month 13, Visit 7 |
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| Month 18, Visit 9 |
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| Month 24, Visit 11 |
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| Third Implant (Month 24, Visit 11) |
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| Fourth Implant (Month 36, Visit 13) |
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| Fifth Implant (Month 48, Visit 15) |
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| Sixth Implant (Month 60, Visit 17) |
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