CAH - Congenital Adrenal Hyperplasia, Congenital Adrenal Hyperplasia
Conditions
Keywords
17-hydroxyprogesterone
Brief summary
This is a multicenter Phase 2, multiple dose, dose escalation study to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SPR001 in adult patients with classic congenital adrenal hyperplasia (CAH).
Detailed description
This is a 6-week, multiple-dose, dose escalation study of SPR001 for the treatment of adults with classic CAH. After screening, eligible patients will be enrolled into a 6-week treatment period followed by a 4-week washout/safety follow-up period. It is initially planned that up to approximately 18 patients in 2 dose cohorts will be enrolled. Additional patients or dose groups may be considered based upon specific safety, PK/PD, and/or efficacy findings, or if an active dose has not yet been reached. SPR001 will be administered as an oral daily dose. Patients will undergo titration of SPR001 through three escalating dosage strengths at 2-week intervals. Patients will have overnight PK/PD assessments performed at baseline, which include an pre-dose overnight assessment and a post-dose overnight assessment for PK/PD following administration of the first dose. At the end of each 2-week dosing period, patients will return for single overnight visits for steady-state PK/PD assessments. A follow-up outpatient visit will occur 30 days after their last dose.
Interventions
DRUGSPR001
SPR001 Capsules
Sponsors
Spruce Biosciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients age 18 or older. * Documented diagnosis of classic CAH due to 21-hydroxylase deficiency * Elevated 17-OHP at screening * On a stable glucocorticoid replacement regimen for a minimum of 30 days
Exclusion criteria
* Clinically significant unstable medical condition, illness, or chronic disease * Clinically significant psychiatric disorder. * Clinically significant abnormal laboratory finding or assessment * History of bilateral adrenalectomy or hypopituitarism * Pregnant or nursing females * Use of any other investigational drug within 30 days * Unable to understand and comply with the study procedures, understand the risks, and/or unwilling to provide written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of SPR001 in Patients With CAH | 6 weeks | Incidence of treatment-emergent adverse events, changes from Baseline to End-of-study in clinical laboratory parameters, physical examination findings, vital signs, ECG parameters |
| Change in 17-hydroxyprogesterone | Cohort A: Baseline/2a (Day -1-0), First dose/2b (Day 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41-42). Cohort B and Cohort C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 14-15), Visit 5 (Last dose +30d) | Change in 17-hydroxyprogesterone from Baseline to End-of-study. Results are expressed as mean percent change from baseline. Reductions in 17-OHP are indicators of better disease control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Pharmacodynamic (PD) Markers | Cohort A: Visit 2a (Day -1 to 0), Visit 2b (Days 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41 to 42). Cohorts B+C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 27-28), Visit 5 (+30 days after last dose) | Changes in adrenocorticotropic hormone (ACTH) and androstenedione (A4) from Baseline to End-of-study are measured in patient serum. Results are expressed as a mean percentage change from baseline. A negative change indicates improvement. |
| Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | Serial PK sampling was performed at the end of the 2 weeks for all cohorts and dose levels | To evaluate the pharmacokinetic (PK) parameter of maximum plasma concentration (Cmax) of SPR001 in patients with CAH. |
| Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | For Cohort A, serial blood collections were made for PK measurements on Day 1 for 200 mg SD and at Week 2 for all QD dose levels. In Cohorts B and C, serial blood samples were drawn for PK measurements at the end of the 2-week treatment period. | To evaluate the PK parameter of area under the concentration-time curve (AUC) of SPR001 in patients with CAH |
Countries
United States
Participant flow
Recruitment details
No participants enrolled in Period 4: Cohort D
Pre-assignment details
A total of 24 subjects were enrolled into the study and 24 ICFs were signed. Two subjects were enrolled in more than one cohort: one subject was enrolled in both Cohorts A and C and one subject was enrolled in both in Cohorts A and B. Therefore, the total when adding Cohorts A+B+C = 26; however, 2 subject were the same, thus a total of 24 unique subjects participated and signed the ICFs.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A The first cohort of 9 patients underwent dose escalation through 3 dose levels of tildacerfont capsules, beginning with 200 mg QD for 2 weeks, then escalating to 600 mg QD/day for 2 weeks, then escalating to 1000 mg QD for 2 weeks with no washout between dose levels. | 10 |
| Cohort B Cohort B will begin enrollment after Cohort A has been fully enrolled. Cohorts B, C, and D underwent a 2-week run-in period, a 2-week treatment period, and a 30-day washout and safety follow-up period. Cohort B was administered tildacerfont 200 mg BID during the treatment period. | 8 |
| Cohort C Cohort C will begin enrollment after Cohort B has been fully enrolled. Cohorts B, C, and D underwent a 2-week run-in period, a 2-week treatment period, and a 30-day washout and safety follow-up period. Cohort C was administered tildacerfont 100 mg BID during the treatment period. | 6 |
| Cohort D Cohort D will begin enrollment after Cohort C has been fully enrolled. Cohorts B, C, and D underwent a 2-week run-in period, a 2-week treatment period, and a 30-day washout and safety follow-up period. For Cohort D, the dose level and the frequency and timing of dosing were to be determined based on interim data from the previous cohorts, but the dose level of Cohort D was to be capped at 800 mg/day. Based on PK/PD results from Cohorts B and C, this cohort was not enrolled. | 0 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Cohort A | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Cohort B | Discontinued due to Sponsor decision | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort B | Cohort C | Cohort A | Cohort D | Total |
|---|---|---|---|---|---|
| Age, Categorical Cohort A <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Cohort A >=65 years | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Cohort A Between 18 and 65 years | 0 Participants | 0 Participants | 9 Participants | 0 Participants | 9 Participants |
| Age, Categorical Cohort B <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Cohort B >=65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Cohort B Between 18 and 65 years | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Age, Categorical Cohort C <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Cohort C >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Cohort C Between 18 and 65 years | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Body Mass Index (kg/m^2) | 30.4 kg/m^2 STANDARD_DEVIATION 6.31 | 32.3 kg/m^2 STANDARD_DEVIATION 5.67 | 31.7 kg/m^2 STANDARD_DEVIATION 11.8 | — | 31.4 kg/m^2 STANDARD_DEVIATION 8.44 |
| Ethnicity (NIH/OMB) Cohort A Hispanic or Latino | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Cohort A Not Hispanic or Latino | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Cohort A Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Cohort B Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | — | 2 Participants |
| Ethnicity (NIH/OMB) Cohort B Not Hispanic or Latino | 6 Participants | 0 Participants | 0 Participants | — | 6 Participants |
| Ethnicity (NIH/OMB) Cohort B Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Ethnicity (NIH/OMB) Cohort C Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | — | 1 Participants |
| Ethnicity (NIH/OMB) Cohort C Not Hispanic or Latino | 0 Participants | 5 Participants | 0 Participants | — | 5 Participants |
| Ethnicity (NIH/OMB) Cohort C Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Cohort A American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort A White | 0 Participants | 0 Participants | 10 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) Cohort B American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort B White | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) Cohort C American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort C Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort C Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort C More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Cohort C Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort C Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort C White | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment United States | 8 participants | 6 participants | 10 participants | — | 24 participants |
| Sex: Female, Male Cohort A Female | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Cohort A Male | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Cohort B Female | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Cohort B Male | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Cohort C Female | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Cohort C Male | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 9 | 0 / 9 | 0 / 7 |
| other Total, other adverse events | 6 / 10 | 3 / 10 | 3 / 9 | 5 / 9 | 4 / 7 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 9 | 0 / 7 |
Outcome results
Primary
Change in 17-hydroxyprogesterone
Change in 17-hydroxyprogesterone from Baseline to End-of-study. Results are expressed as mean percent change from baseline. Reductions in 17-OHP are indicators of better disease control.
Time frame: Cohort A: Baseline/2a (Day -1-0), First dose/2b (Day 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41-42). Cohort B and Cohort C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 14-15), Visit 5 (Last dose +30d)
Population: Only subjects with both baseline and post baseline (week 2) assessments were summarized. Baseline values were collected at 8am on Visit 2a (Day -1) and post-baseline Week 2 values were collected at 8a on Visit 3, Visit 4, or Visit 5. A negative change indicates improvement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change in 17-hydroxyprogesterone | -47.79 percentage of mean change from baseline | Standard Deviation 63.3 |
| Cohort B | Change in 17-hydroxyprogesterone | -33.19 percentage of mean change from baseline | Standard Deviation 41.604 |
| Cohort C | Change in 17-hydroxyprogesterone | 22.16 percentage of mean change from baseline | Standard Deviation 172.298 |
| Cohort A - Dose B | Change in 17-hydroxyprogesterone | -23.71 percentage of mean change from baseline | Standard Deviation 64.146 |
| Cohort A - Dose C | Change in 17-hydroxyprogesterone | -13.79 percentage of mean change from baseline | Standard Deviation 74.742 |
Primary
Safety of SPR001 in Patients With CAH
Incidence of treatment-emergent adverse events, changes from Baseline to End-of-study in clinical laboratory parameters, physical examination findings, vital signs, ECG parameters
Time frame: 6 weeks
Population: This full analysis set includes all subjects who received at least 1 dose of study drug. The FAS was used to analyze all safety data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Safety of SPR001 in Patients With CAH | 6 Participants |
| Cohort B | Safety of SPR001 in Patients With CAH | 5 Participants |
| Cohort C | Safety of SPR001 in Patients With CAH | 4 Participants |
Secondary
Changes in Pharmacodynamic (PD) Markers
Changes in adrenocorticotropic hormone (ACTH) and androstenedione (A4) from Baseline to End-of-study are measured in patient serum. Results are expressed as a mean percentage change from baseline. A negative change indicates improvement.
Time frame: Cohort A: Visit 2a (Day -1 to 0), Visit 2b (Days 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41 to 42). Cohorts B+C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 27-28), Visit 5 (+30 days after last dose)
Population: Only subjects with both baseline and post baseline (week 2) assessments were summarized. Baseline values were collected at 8am on Visit 2a (Day -1) and post-baseline Week 2 values were collected at 8a on Visit 3, Visit 4, or Visit 5.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Changes in Pharmacodynamic (PD) Markers | Adrenocorticotropic hormone (ACTH) | -26.05 percentage of mean change from baseline | Standard Error 54.807 |
| Cohort A | Changes in Pharmacodynamic (PD) Markers | Androstenedione (A4) | -1.58 percentage of mean change from baseline | Standard Error 101.458 |
| Cohort B | Changes in Pharmacodynamic (PD) Markers | Adrenocorticotropic hormone (ACTH) | 16.66 percentage of mean change from baseline | Standard Error 120.211 |
| Cohort B | Changes in Pharmacodynamic (PD) Markers | Androstenedione (A4) | -30.17 percentage of mean change from baseline | Standard Error 35.055 |
| Cohort C | Changes in Pharmacodynamic (PD) Markers | Adrenocorticotropic hormone (ACTH) | -28.53 percentage of mean change from baseline | Standard Error 53.834 |
| Cohort C | Changes in Pharmacodynamic (PD) Markers | Androstenedione (A4) | -12.12 percentage of mean change from baseline | Standard Error 47.381 |
| Cohort A - Dose B | Changes in Pharmacodynamic (PD) Markers | Androstenedione (A4) | -33.18 percentage of mean change from baseline | Standard Error 36.465 |
| Cohort A - Dose B | Changes in Pharmacodynamic (PD) Markers | Adrenocorticotropic hormone (ACTH) | -67.60 percentage of mean change from baseline | Standard Error 32.1 |
| Cohort A - Dose C | Changes in Pharmacodynamic (PD) Markers | Adrenocorticotropic hormone (ACTH) | -36.83 percentage of mean change from baseline | Standard Error 48.51 |
| Cohort A - Dose C | Changes in Pharmacodynamic (PD) Markers | Androstenedione (A4) | -28.93 percentage of mean change from baseline | Standard Error 45.167 |
Secondary
Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC)
To evaluate the PK parameter of area under the concentration-time curve (AUC) of SPR001 in patients with CAH
Time frame: For Cohort A, serial blood collections were made for PK measurements on Day 1 for 200 mg SD and at Week 2 for all QD dose levels. In Cohorts B and C, serial blood samples were drawn for PK measurements at the end of the 2-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 2975.968 ng*hr/dL | Standard Deviation 970.6 |
| Cohort B | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 1425.582 ng*hr/dL | Standard Deviation 941.9188 |
| Cohort C | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 1474.162 ng*hr/dL | Standard Deviation 642.6 |
| Cohort A - Dose B | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 4449.263 ng*hr/dL | Standard Deviation 1826.4801 |
| Cohort A - Dose C | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 6212.983 ng*hr/dL | Standard Deviation 2051.9077 |
| PK Population Cohort A - Dose A (After single dose) | Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) | 421.539 ng*hr/dL | Standard Deviation 331.54 |
Secondary
Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax)
To evaluate the pharmacokinetic (PK) parameter of maximum plasma concentration (Cmax) of SPR001 in patients with CAH.
Time frame: Serial PK sampling was performed at the end of the 2 weeks for all cohorts and dose levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 411.25 ng/dL | Standard Deviation 130.107 |
| Cohort B | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 200.96 ng/dL | Standard Deviation 132.262 |
| Cohort C | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 283.69 ng/dL | Standard Deviation 150.116 |
| Cohort A - Dose B | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 719.30 ng/dL | Standard Deviation 325.056 |
| Cohort A - Dose C | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 892.56 ng/dL | Standard Deviation 289.272 |
| PK Population Cohort A - Dose A (After single dose) | Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) | 96.35 ng/dL | Standard Deviation 86.1 |