Adult Growth Hormone Deficiency (AGHD)
Conditions
Keywords
VRS-317, Long Acting Growth Hormone, Versartis, somavaratan, Growth Hormone Deficiency, Adult Growth Hormone Deficiency, AGHD, Growth Hormone Replacement, Growth Hormone Replacement Therapy, XTEN
Brief summary
Open-label extension study to evaluate the safety of long-term twice-monthly administration of somavaratan in adults with Growth Hormone Deficiency (GHD).
Detailed description
An open-label extension study to evaluate the safety of long-term twice-monthly administration of somavaratan in adults with GHD. This multicenter study is open to participants completing a Versartis adult GHD study as well as approximately 40 new somavaratan naïve participants (either recombinant human growth hormone \[rhGH\] treatment naïve or currently receiving daily rhGH therapy). All participants will receive twice-monthly (every 15 days ± 2 days) subcutaneous (SC) somavaratan. Doses will be titrated to each participant's individual insulin-like growth factor-I (IGF-I) responses based on the IGF-I level 7 days post-dose until a maintenance dose is achieved. Participants receiving somavaratan in a previous somavaratan study will have their dose decreased by half (minimum dose of 20 milligrams \[mg\], 40 mg for women on estrogen, rounded down to the nearest even number) and will be titrated per the Dose Titration Plan. New participants enrolling in this study will be assigned to one of two cohorts based on sensitivity to rhGH and titrated per the Dose Titration Plan.
Interventions
DRUGsomavaratan
Long-acting recombinant human growth hormone therapy administered subcutaneously twice-monthly
Sponsors
Versartis Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Female participants of childbearing potential must have negative pregnancy test and use appropriate contraceptive methods * Documented GHD during adulthood * Participants naive to somavaratan must have an IGF-1 SDS value ≤ 0 at Screening * Participants taking other hormone replacement therapy must have been on a stable course of treatment for at least 3 months * Underlying disorders responsible for the participant's GHD must have been clinically stable for at least 6 months * Participants receiving daily rhGH injections must washout for ≥ 14 days * Body mass index (BMI) (kilograms \[kg\]/meter square \[m\^2\]) between 18.0 and 40.0
Exclusion criteria
* Untreated adrenal insufficiency * Recently diagnosed thyroid dysfunction which is not being treated or has not been stable on therapy for at least 3 months * Currently taking anti-inflammatory dose of glucocorticoids that could potentially compromise safety or efficacy assessments * Currently taking a GHRH or IGF-I product * Current significant cardiovascular disease, heart insufficiency of New York Heart Association (NYHA) class \> 2 * Current significant disease thought to increase risk of receiving growth hormone or confound assessment of study outcomes * History of diabetes mellitus or inadequate glucose control * Current drug or alcohol abuse * Current human immunodeficiency virus (HIV) wasting syndrome (HIV testing not required) * History of malignancy in adulthood (participants with a history of childhood malignancy that were subsequently treated with rhGH in childhood and remain GHD in adulthood may be enrolled) * Women who are pregnant or breastfeeding * Treatment with an investigational drug other than somavaratan within 30 days prior to Screening * A significant abnormality in Screening laboratory results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | From first dose of study drug up to approximately 2 years | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Adjustments | Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | The number of participants with a dose adjustment (titrated up/down) at each month are summarized. |
| Number of Participants Who Were Anti-drug Antibody (ADA) Positive | Up to approximately 2 years | — |
| Average Dose Level During Titration/Maintenance | Up to Month 12 | Total average dose received by a participant during titration/maintenance has been reported. |
| Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Baseline, Month 2 Day 1, Month 2 Day 8, Month 3 Day 1, Month 3 Day 8, Month 4 Day 1, Month 4 Day 8, Month 5 Day 1, Month 5 Day 8, Month 6 Day 1, Month 6 Day 8, Month 7 Day 1, Month 7 Day 8, Month 8 Day 1, Month 8 Day 8, Month 10 Day 1, and Month 10 Day 8 | Changes in the IGF-I levels were assessed as Standard Deviation Scores (SDS). The SDS was calculated as the actual value of IGF-I minus mean reference value of IGF-1 divided by reference standard deviation of IGF-I. The mean and the standard deviation (SD) vary depending on the age and sex of the participant. Change in IGF-I level (SDS) at specified timepoints from baseline was assessed. A higher score reflects a better outcome. |
| Mean Insulin-like Growth Factor-binding Protein 3 (IGFBP-3) SDS During Maintenance Period | Baseline up to Month 12 | — |
| Number of Participants With Positive Neutralizing Antibodies (NABs) | Up to approximately 2 years | — |
Participant flow
Pre-assignment details
The study was open to participants completing a Versartis adult growth hormone deficiency (GHD) study (15VR7 \[NCT02526420\]) as well as new somavaratan naïve participants (either recombinant human growth hormone \[rhGH\] treatment naïve or receiving daily rhGH therapy).
Participants by arm
| Arm | Count |
|---|---|
| Somavaratan Participants received once-monthly SC somavaratan per Protocol Version 1.0. The dosing regimen was then modified in Protocol Version 2.0 to twice-monthly SC somavaratan. Doses were titrated to each participant's individual IGF-I responses based on the IGF-I level 7 days postdose until a maintenance dose was achieved. Maintenance dose was defined as an IGF-I value between 0 and 2.0 SDS for two consecutive 7-day postdose time points (Day 8, peak level). Participants who received somavaratan once-monthly in this study or in a previous somavaratan study (15VR7), had their dose decreased by half (minimum dose of 20 mg, 40 mg for women on estrogen, rounded down to the nearest even number) and were titrated based on IGF-I level at Day 8. New participants enrolling in this study received a starting dose of 20 mg twice-monthly (40 mg for women on estrogen) and were titrated based on IGF-I level at Day 8. Maintenance doses were adjusted further based on PD data at the discretion of the Investigator or Medical Monitor. The maximum allowable dose of somavaratan was 250.0 mg. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
| Overall Study | Study Terminated By Sponsor | 32 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Somavaratan |
|---|---|
| Age, Continuous | 50.1 years STANDARD_DEVIATION 10.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 36 |
| other Total, other adverse events | 30 / 36 |
| serious Total, serious adverse events | 5 / 36 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.
Time frame: From first dose of study drug up to approximately 2 years
Population: Safety population included all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Somavaratan | Number of Participants With Adverse Events (AEs) | 30 Participants |
Secondary
Average Dose Level During Titration/Maintenance
Total average dose received by a participant during titration/maintenance has been reported.
Time frame: Up to Month 12
Population: Safety population included all participants who received any amount of study drug. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Somavaratan | Average Dose Level During Titration/Maintenance | 41.60 mg | Standard Deviation 47.398 |
Secondary
Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period
Changes in the IGF-I levels were assessed as Standard Deviation Scores (SDS). The SDS was calculated as the actual value of IGF-I minus mean reference value of IGF-1 divided by reference standard deviation of IGF-I. The mean and the standard deviation (SD) vary depending on the age and sex of the participant. Change in IGF-I level (SDS) at specified timepoints from baseline was assessed. A higher score reflects a better outcome.
Time frame: Baseline, Month 2 Day 1, Month 2 Day 8, Month 3 Day 1, Month 3 Day 8, Month 4 Day 1, Month 4 Day 8, Month 5 Day 1, Month 5 Day 8, Month 6 Day 1, Month 6 Day 8, Month 7 Day 1, Month 7 Day 8, Month 8 Day 1, Month 8 Day 8, Month 10 Day 1, and Month 10 Day 8
Population: Safety population included all participants who received any amount of study drug. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants analyzed at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 2 Day 1 | 0.76 SDS | Standard Deviation 0.639 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 2 Day 8 | 1.83 SDS | Standard Deviation 0.899 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 3 Day 1 | 0.45 SDS | Standard Deviation 0.457 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 3 Day 8 | 1.44 SDS | Standard Deviation 0.915 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 4 Day 1 | 0.49 SDS | Standard Deviation 0.751 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 4 Day 8 | 1.73 SDS | Standard Deviation 1.221 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 5 Day 1 | 0.18 SDS | Standard Deviation 0.738 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 5 Day 8 | 1.68 SDS | Standard Deviation 0.691 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 6 Day 1 | 0.74 SDS | Standard Deviation 0.5 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 6 Day 8 | 1.38 SDS | Standard Deviation 0.777 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 7 Day 1 | 0.74 SDS | Standard Deviation 0.541 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 7 Day 8 | 1.82 SDS | Standard Deviation 1.414 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 8 Day 1 | 0.30 SDS | — |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 8 Day 8 | 4.30 SDS | — |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 10 Day 1 | 0.91 SDS | Standard Deviation 0.845 |
| Somavaratan | Change From Baseline in Mean Insulin-like Growth Factor 1 (IGF-I) Standard Deviation Score (SDS) at Specified Timepoints During Maintenance Period | Month 10 Day 8 | 1.76 SDS | Standard Deviation 1.539 |
Secondary
Mean Insulin-like Growth Factor-binding Protein 3 (IGFBP-3) SDS During Maintenance Period
Time frame: Baseline up to Month 12
Population: Due to early termination of study, no data were collected for this outcome measure.
Secondary
Number of Participants Who Were Anti-drug Antibody (ADA) Positive
Time frame: Up to approximately 2 years
Population: Safety population included all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Somavaratan | Number of Participants Who Were Anti-drug Antibody (ADA) Positive | 22 Participants |
Secondary
Number of Participants With Dose Adjustments
The number of participants with a dose adjustment (titrated up/down) at each month are summarized.
Time frame: Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Population: Safety population included all participants who received any amount of study drug. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants analyzed at specified timepoint.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Somavaratan | Number of Participants With Dose Adjustments | Month 2 | Titrated Up | 11 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 2 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 3 | Titrated Up | 7 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 3 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 4 | Titrated Up | 6 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 4 | Titrated Down | 2 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 5 | Titrated Up | 3 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 5 | Titrated Down | 2 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 6 | Titrated Up | 3 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 6 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 7 | Titrated Up | 3 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 7 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 8 | Titrated Up | 3 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 8 | Titrated Down | 1 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 9 | Titrated Up | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 9 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 10 | Titrated Up | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 10 | Titrated Down | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 11 | Titrated Up | 1 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 11 | Titrated Down | 2 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 12 | Titrated Up | 0 Participants |
| Somavaratan | Number of Participants With Dose Adjustments | Month 12 | Titrated Down | 1 Participants |
Secondary
Number of Participants With Positive Neutralizing Antibodies (NABs)
Time frame: Up to approximately 2 years
Population: Safety population included all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Somavaratan | Number of Participants With Positive Neutralizing Antibodies (NABs) | 15 Participants |