Acromegaly
Conditions
Keywords
Acromegaly, ACROBAT, EDGE, Paltusotine
Brief summary
An open label exploratory study designed to evaluate the safety, efficacy, and pharmacokinetics of paltusotine (formerly CRN00808) in subjects with acromegaly that are treated with somatostatin analogue (SSA) based treatment regimens.
Interventions
DRUGPaltusotine
Paltusotine, capsules, once daily by mouth
Sponsors
Crinetics Pharmaceuticals 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
1. Male and female subjects 18 to 75 years of age 2. Confirmed diagnosis of acromegaly with either a partial or complete response to protocol defined somatostatin analogue therapy regimens 3. Females must be non-pregnant and non-lactating, and either surgically sterile, post-menopausal, or using effective method(s) of birth control 4. Willing to provide signed informed consent
Exclusion criteria
1. Treatment naïve acromegaly subjects 2. Prior treatment with paltusotine 3. Pituitary surgery within 6 months prior to Screening. Subjects receiving radiation therapy may be eligible with some restrictions. 4. History or presence of malignancy except adequately treated basal cell and squamous cell carcinomas of the skin within the past 5 years 5. Use of any investigational drug within the past 30 days or 5 half-lives, whichever is longer 6. Positive test at Screening for HIV, hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV-Ab) or has a history of a positive result 7. History of alcohol or substance abuse in the past 12 months 8. Any condition that in the opinion of the investigator would jeopardize the subject's appropriate participation in this study 9. Cardiovascular conditions or medications associated with prolonged QT or those which predispose subjects to heart rhythm abnormalities 10. Subjects with symptomatic cholelithiasis 11. Subjects with clinically significant abnormal findings during the Screening Period, and any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardize the subject's safety or ability to complete the study 12. Subjects taking octreotide LAR at a dose higher than 40 mg, or lanreotide depot at a dose higher than 120 mg, or pasireotide LAR at a dose higher than 60 mg 13. Subjects who usually take octreotide LAR or lanreotide depot less frequently than every 4 weeks (e.g. every 6 weeks or 8 weeks)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level | 13 Weeks | Change from baseline in IGF-1 level at Week 13/End of Treatment (W13/EoT) in Group 1 subjects Efficacy Analysis Set (EAS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | 13 Weeks | The secondary endpoint was the proportion of participants who maintained IGF-1 response, defined as the last assessment before the EoT with IGF-1 ≤1.0× ULN meet responder criteria, in Group 3, 4, and 5 subjects only at W13/EoT |
| Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | 13 Weeks | Proportion of participants with IGF-1 ≤1.5× ULN at W13/EoT. |
Countries
Brazil, Germany, Greece, Hungary, Italy, New Zealand, Poland, Romania, Serbia, Slovakia, United Kingdom, United States
Participant flow
Recruitment details
A total of 45 subjects were planned to be enrolled in the study. 47 subjects participated in the study.
Pre-assignment details
A total of 45 subjects were planned to be enrolled in the study. 47 subjects participated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Efficacy Analysis Set - Primary Analysis Population for all efficacy analyses. Only includes participants from Group 1.
Eligibility to enter this group was specified as: Partial responders on a stable treatment of octreotide long-acting release (LAR) or lanreotide depot (at least 1 Screening IGF-1 value was greater than upper limit of normal (ULN), and the V2 value was ≤2.5× ULN) | 25 |
| Group 2 Eligibility to enter this group was specified as: Partial responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 1 Screening IGF-1 value was \>ULN, and the V2 value was ≤2.5 × ULN) | 10 |
| Group 3 Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN) | 5 |
| Group 4 Eligibility to enter this group was specified as: Complete responders on a stable dose of pasireotide LAR (mean of Screening IGF-1 values were ≤ULN) | 4 |
| Group 5 Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were
≤ULN). | 3 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Follow-up Period: up to 4 Weeks | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
| Treatment Period: up to 13 Weeks | COVID-19 Lockdown | 0 | 0 | 1 | 0 | 0 |
| Treatment Period: up to 13 Weeks | Prohibited Medication | 1 | 0 | 0 | 1 | 0 |
| Treatment Period: up to 13 Weeks | Unable to Travel | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 8 Participants | 4 Participants | 3 Participants | 2 Participants | 39 Participants |
| Age, Customized Age, y, median (range) | 52.0 years | 52.5 years | 51.0 years | 56.0 years | 38.0 years | 51.0 years |
| BMI | 29.25 kilogram(s)/square meter | 30.30 kilogram(s)/square meter | 28.50 kilogram(s)/square meter | 34.85 kilogram(s)/square meter | 31.20 kilogram(s)/square meter | 29.95 kilogram(s)/square meter |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants | 0 Participants | 1 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 4 Participants | 3 Participants | 4 Participants | 2 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 173.95 centimeter | 167.75 centimeter | 173.00 centimeter | 169.45 centimeter | 157.50 centimeter | 170.25 centimeter |
| IGF-1 (x ULN) at Baseline | 1.335 ng/mL x ULN | 1.400 ng/mL x ULN | 0.922 ng/mL x ULN | 0.659 ng/mL x ULN | 0.909 ng/mL x ULN | 1.214 ng/mL x ULN |
| IGFBP-3 | 0.803 ng/mL | 0.789 ng/mL | 0.684 ng/mL | 0.716 ng/mL | 0.585 ng/mL | 0.786 ng/mL |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 5 Participants | 5 Participants | 4 Participants | 3 Participants | 42 Participants |
| Region of Enrollment Brazil | 4 participants | 6 participants | 3 participants | 0 participants | 0 participants | 13 participants |
| Region of Enrollment Germany | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Greece | 5 participants | 0 participants | 0 participants | 1 participants | 0 participants | 6 participants |
| Region of Enrollment Hungary | 5 participants | 1 participants | 0 participants | 0 participants | 0 participants | 6 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment New Zealand | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 2 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Romania | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Serbia | 3 participants | 0 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Slovakia | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment United Kingdom | 2 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 3 participants | 1 participants | 0 participants | 2 participants | 2 participants | 8 participants |
| Ring Size | 12.5 Scores on a Scale | 12.0 Scores on a Scale | 11.0 Scores on a Scale | 12.5 Scores on a Scale | 8.0 Scores on a Scale | 12.0 Scores on a Scale |
| Serum Growth Hormone Levels | 0.6907 nanogram(s)/milliliter | 1.0490 nanogram(s)/milliliter | 0.8733 nanogram(s)/milliliter | 0.1976 nanogram(s)/milliliter | 2.8763 nanogram(s)/milliliter | 0.8733 nanogram(s)/milliliter |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 3 Participants | 3 Participants | 3 Participants | 27 Participants |
| Sex: Female, Male Male | 14 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 20 Participants |
| Weight | 90.95 kilogram(s) | 84.95 kilogram(s) | 87.30 kilogram(s) | 107 kilogram(s) | 77.50 kilogram(s) | 87.15 kilogram(s) |
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 / 2 | 0 / 47 | 0 / 43 | 0 / 37 | 0 / 32 |
| other Total, other adverse events | 0 / 2 | 23 / 47 | 24 / 43 | 15 / 37 | 19 / 32 |
| serious Total, serious adverse events | 0 / 2 | 0 / 47 | 1 / 43 | 0 / 37 | 0 / 32 |
Outcome results
Primary
Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level
Change from baseline in IGF-1 level at Week 13/End of Treatment (W13/EoT) in Group 1 subjects Efficacy Analysis Set (EAS).
Time frame: 13 Weeks
Population: Efficacy Analysis Set includes all subjects in Group 1 who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 | Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level | -0.034 ng/mL x ULN |
Comparison: The primary efficacy endpoint was completed with the Efficacy Analysis Set (EAS), which included all treated subjects in Group 1. The median (Interquartile range) for change from baseline in IGF-1xULN to Week 13/EoT and p-value from the Wilcoxon signed rank test were presented. Baseline was defined as the mean of all IGF-1xULN values prior to first dose. Last on treatment assessment was used for EoT if subject discontinued before Week 13.p-value: 0.6285Wilcoxon Signed Rank test
Primary
Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level
Change from baseline in IGF-1 level at Week 13/End of Treatment (W13/EoT) in Group 1 subjects Efficacy Analysis Set (EAS).
Time frame: 13 Weeks
Population: Efficacy Analysis Set includes all subjects in Group 1 who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 | Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level | Baseline | 1.335 ng/mL x ULN |
| Group 1 | Change From Baseline (Median of Screening Values) in Insulin-like Growth Factor-1 (IGF-1) Level | Week 13 (Visit 14)/ End of Treatment | 1.343 ng/mL x ULN |
Secondary
Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN
Proportion of participants with IGF-1 ≤1.5× ULN at W13/EoT.
Time frame: 13 Weeks
Population: This endpoint was estimated for all the subjects in the Full Analysis Set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | Baseline (Response) | 19 Participants |
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (Response) | 20 Participants |
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (No Response) | 5 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | Baseline (Response) | 6 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (No Response) | 6 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (Response) | 4 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (Response) | 4 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (No Response) | 1 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | Baseline (Response) | 5 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (No Response) | 1 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (Response) | 3 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | Baseline (Response) | 4 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | Baseline (Response) | 2 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (Response) | 1 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurements ≤1.5×ULN | W13/EoT (No Response) | 2 Participants |
Secondary
Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN)
The secondary endpoint was the proportion of participants who maintained IGF-1 response, defined as the last assessment before the EoT with IGF-1 ≤1.0× ULN meet responder criteria, in Group 3, 4, and 5 subjects only at W13/EoT
Time frame: 13 Weeks
Population: This endpoint was limited to only subjects in Groups 3, 4 and 5 who started the study with IGF-1 ≤ULN.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (Response) | 2 Participants |
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | Baseline | 5 Participants |
| Group 1 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (No Response) | 3 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (Response) | 1 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | Baseline | 4 Participants |
| Group 4 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (No Response) | 3 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | Baseline | 3 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (No Response) | 2 Participants |
| Group 5 | Proportion of Subjects With Their Last IGF-1 Measurement ≤ Upper Limit of Normal (ULN) | W13/EoT (Response) | 1 Participants |
p-value: 0.3877exact binomial test assuming the null pr