Acromegaly
Conditions
Keywords
Acromegaly, PATHFNDR, Paltusotine, CRN00808
Brief summary
A randomized, placebo-controlled study designed to evaluate the safety and efficacy of paltusotine (also known as CRN00808; an orally administered nonpeptide somatostatin agonist) in subjects with acromegaly previously treated with somatostatin receptor ligand (SRL) based treatment regimens.
Interventions
DRUGPaltusotine
Paltusotine, tablets, once daily by mouth
DRUGPlacebo
Placebo, tablets, once daily by mouth
Sponsors
Crinetics Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects ≥18 years of age 2. Confirmed diagnosis of acromegaly and controlled (as measured by IGF-1 ≤1.0×ULN) via stable dose of protocol defined somatostatin receptor ligand therapy 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 Treatment naïve or treatment-withdrawn acromegaly subjects 2. Prior treatment with paltusotine 3. Pituitary surgery within 24 weeks prior to Screening or history of pituitary radiation therapy 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. Known history of HIV, hepatitis B, or active hepatitis C 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, or 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 currently taking pasireotide LAR (within 24 weeks prior to Screening) or pegvisomant, dopamine agonists (within 12 weeks prior to Screening), or short acting somatostatin analogs (within 12 weeks prior to first dose of study drug)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Maintain Biochemical Response in IGF-1 (≤1.0× the Upper Limit of Normal [ULN]) at the End of the Randomized Control Phase (EOR) | 36 Weeks | A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Response is defined as an IGF-1 level ≤1.0×ULN based on the average of last 2 measurements (weeks 34 and 36). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in IGF-1 to EOR | Baseline to 36 Weeks | A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Baseline was defined as the last non-missing assessment prior to first dose of study drug for all assessments except IGF-1, growth hormone (GH), and acromegaly symptoms diary (ASD). Change from Baseline was determined by calculating (post-Baseline value - Baseline value). |
| Percentage of Participants With GH <1.0 ng/mL at Week 34 | Week 34 | GH maintenance of response was analyzed in participants with GH\<1.0 ng/mL at week 34, out of those who had GH\<1.0 ng/mL at Baseline, using the same methodology as the primary endpoint. |
| Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOR | Baseline to 36 Weeks | The ASD is a sponsor-developed daily diary to assess important acromegaly symptoms from the patient perspective. The weekly average ASD total score is calculated from 7 items associated with acromegaly (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling). The ASD total score ranges from 0 to 70 with each symptom contributing up to 10 points. A higher score = higher symptom severity. Change from baseline in total ASD was defined as the postbaseline total ASD score (the average of the available scores seven days on or prior to the scheduled visit date) minus the baseline total ASD score. |
Countries
Argentina, Belgium, Brazil, Bulgaria, France, Hungary, Israel, Italy, Peru, Poland, Russia, Serbia, United Kingdom, United States
Participant flow
Recruitment details
This is a Phase 3, multicenter, randomized, placebo-controlled study where a total of 115 participants were screened, of which 58 participants were randomized (30 participants in the total paltusotine group and 28 participants in the placebo group) to the randomized control (RC) Phase.
Pre-assignment details
Participants were randomized to treatment or placebo in a 1:1 ratio. Participants who completed the RC phase or who met rescue criteria could enter the open-label extension (OLE) phase. The RC Phase is completed. The OLE Phase is ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Paltusotine Participants were randomized in a 1:1 ratio and received a daily dose paltusotine orally. | 30 |
| Placebo Participants were randomized to receive matching placebo tablets in a 1:1 ratio. | 28 |
| Total | 58 |
Baseline characteristics
| Characteristic | Placebo | Total | Paltusotine |
|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 12.89 | 54.9 years STANDARD_DEVIATION 13.7 | 55.9 years STANDARD_DEVIATION 14.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 19 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 35 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 19 Participants | 42 Participants | 23 Participants |
| Sex: Female, Male Female | 17 Participants | 32 Participants | 15 Participants |
| Sex: Female, Male Male | 11 Participants | 26 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 28 |
| other Total, other adverse events | 24 / 30 | 28 / 28 |
| serious Total, serious adverse events | 0 / 30 | 1 / 28 |
Outcome results
Primary
Percentage of Participants Who Maintain Biochemical Response in IGF-1 (≤1.0× the Upper Limit of Normal [ULN]) at the End of the Randomized Control Phase (EOR)
A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Response is defined as an IGF-1 level ≤1.0×ULN based on the average of last 2 measurements (weeks 34 and 36).
Time frame: 36 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paltusotine | Percentage of Participants Who Maintain Biochemical Response in IGF-1 (≤1.0× the Upper Limit of Normal [ULN]) at the End of the Randomized Control Phase (EOR) | 83.3 percentage of participants |
| Placebo | Percentage of Participants Who Maintain Biochemical Response in IGF-1 (≤1.0× the Upper Limit of Normal [ULN]) at the End of the Randomized Control Phase (EOR) | 3.6 percentage of participants |
Comparison: Treatment comparison of all participants receiving paltusotine versus placebo has been presented.p-value: <0.000195% CI: [13.733, 999.999]exact logistic regression model
Secondary
Change From Baseline in IGF-1 to EOR
A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Baseline was defined as the last non-missing assessment prior to first dose of study drug for all assessments except IGF-1, growth hormone (GH), and acromegaly symptoms diary (ASD). Change from Baseline was determined by calculating (post-Baseline value - Baseline value).
Time frame: Baseline to 36 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paltusotine | Change From Baseline in IGF-1 to EOR | 0.042 nanograms per milliliter (ng/ml) | Standard Error 0.0932 |
| Placebo | Change From Baseline in IGF-1 to EOR | 0.833 nanograms per milliliter (ng/ml) | Standard Error 0.0962 |
p-value: <0.000195% CI: [-1.057, -0.525]ANCOVA
Secondary
Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOR
The ASD is a sponsor-developed daily diary to assess important acromegaly symptoms from the patient perspective. The weekly average ASD total score is calculated from 7 items associated with acromegaly (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling). The ASD total score ranges from 0 to 70 with each symptom contributing up to 10 points. A higher score = higher symptom severity. Change from baseline in total ASD was defined as the postbaseline total ASD score (the average of the available scores seven days on or prior to the scheduled visit date) minus the baseline total ASD score.
Time frame: Baseline to 36 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paltusotine | Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOR | -0.606 units on a scale | Standard Error 1.5044 |
| Placebo | Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOR | 4.558 units on a scale | Standard Error 1.5926 |
p-value: 0.021695% CI: [-9.536, -0.792]ANCOVA
Secondary
Percentage of Participants With GH <1.0 ng/mL at Week 34
GH maintenance of response was analyzed in participants with GH\<1.0 ng/mL at week 34, out of those who had GH\<1.0 ng/mL at Baseline, using the same methodology as the primary endpoint.
Time frame: Week 34
Population: Full Analysis Set. Only those participants with data available at specified timepoints have been presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paltusotine | Percentage of Participants With GH <1.0 ng/mL at Week 34 | 87.0 percentage of participants |
| Placebo | Percentage of Participants With GH <1.0 ng/mL at Week 34 | 27.8 percentage of participants |
Comparison: Treatment comparison of all participants receiving paltusotine versus placebo has been presented.p-value: 0.000395% CI: [2.864, 181.355]exact logistic regression model