Acromegaly
Conditions
Keywords
Acromegaly, PATHFNDR, Paltusotine, CRN00808
Brief summary
A randomized, placebo-controlled study designed to evaluate the safety and efficacy of paltusotine (formerly CRN00808; an oral selective nonpeptide somatostatin receptor type 2 biased agonist) in subjects with non-pharmacologically treated acromegaly.
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 either medically naïve, not currently treated, or willing to washout during the study screening period. 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. Pituitary radiation therapy within 3 years of Screening 2. Prior treatment with paltusotine 3. History of ineffective or intolerance to octreotide or lanreotide 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 or previously using pegvisomant or cabergoline (within 16 weeks prior to Screening) or pasireotide LAR (within 24 weeks prior to Screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Biochemical Response in Insulin-like Growth Factor-1 (IGF-1) at the End of the Randomized Control Phase (EOR) | Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in IGF-1 From Baseline to EOT | Baseline to 24 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 Achieving IGF-1 <1.3×ULN at EOR | 24 weeks | A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Response is defined as an IGF-1 level \<1.3×ULN based on the average of last 2 measurements. |
| Percentage of Participants With Growth Hormone (GH) Concentration <1 ng/mL at Week 22 | Week 22 | The average from integrated GH sampling at week 22 was used to determine response. |
| Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOT | Baseline to 24 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, Brazil, Bulgaria, China, France, Germany, Greece, Hungary, India, Israel, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study where a total of 209 participants were screened, of which 111 participants were randomized (54 participants in the total paltusotine group and 57 participants in the placebo group) to the randomized control (RC) phase.
Pre-assignment details
Participants were randomized 1:1 to paltusotine or placebo in the RC phase, stratified by prior treatment (medically naive or previously treated versus washout). Those who completed RC or met rescue criteria entered the open-label extension (OLE). The RC phase is complete; the OLE is ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Paltusotine Participants were randomized in a 1:1 ratio and received a daily dose of paltusotine orally. | 54 |
| Placebo Participants were randomized to receive matching placebo tablets in a 1:1 ratio. | 57 |
| Direct to OLE: Paltusotine At the completion of study enrollment, participants who met eligibility criteria were directly enrolled in the OLE. The OLE is paltusotine only. | 11 |
| Total | 122 |
Baseline characteristics
| Characteristic | Paltusotine | Placebo | Direct to OLE: Paltusotine | Total |
|---|---|---|---|---|
| Age, Continuous | 47.5 years STANDARD_DEVIATION 13.59 | 45.9 years STANDARD_DEVIATION 12.3 | 58.4 years STANDARD_DEVIATION 8.59 | 50.6 years STANDARD_DEVIATION 11.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 18 Participants | 6 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 36 Participants | 5 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 19 Participants | 1 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 4 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) White | 28 Participants | 30 Participants | 4 Participants | 62 Participants |
| Sex: Female, Male Female | 26 Participants | 33 Participants | 4 Participants | 63 Participants |
| Sex: Female, Male Male | 28 Participants | 24 Participants | 7 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 57 | 0 / 11 |
| other Total, other adverse events | 49 / 54 | 49 / 57 | 6 / 11 |
| serious Total, serious adverse events | 0 / 54 | 1 / 57 | 0 / 11 |
Outcome results
Primary
Percentage of Participants With a Biochemical Response in Insulin-like Growth Factor-1 (IGF-1) 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.
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paltusotine | Percentage of Participants With a Biochemical Response in Insulin-like Growth Factor-1 (IGF-1) at the End of the Randomized Control Phase (EOR) | 55.6 percentage of participants |
| Placebo | Percentage of Participants With a Biochemical Response in Insulin-like Growth Factor-1 (IGF-1) at the End of the Randomized Control Phase (EOR) | 5.3 percentage of participants |
Comparison: Treatment comparison of all participants receiving paltusotine irrespective of dose levels with Placebo has been presented.p-value: <0.000195% CI: [8.444, 455.821]exact logistic regression model
Secondary
Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOT
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 24 weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paltusotine | Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOT | -2.669 units on a scale | Standard Error 1.4221 |
| Placebo | Change From Baseline in Total Acromegaly Symptoms Diary (ASD) Score to EOT | 2.754 units on a scale | Standard Error 1.3641 |
p-value: 0.003995% CI: [-9.07, -1.776]ANCOVA
Secondary
Change in IGF-1 From Baseline to EOT
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 24 weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paltusotine | Change in IGF-1 From Baseline to EOT | -0.819 nanograms per milliliter (ng/ml) | Standard Error 0.0789 |
| Placebo | Change in IGF-1 From Baseline to EOT | 0.087 nanograms per milliliter (ng/ml) | Standard Error 0.0751 |
p-value: <0.000195% CI: [-1.106, -0.706]ANCOVA
Secondary
Percentage of Participants Achieving IGF-1 <1.3×ULN at EOR
A value \>1.0 indicates IGF-1 levels above the age- and sex-adjusted ULN. Response is defined as an IGF-1 level \<1.3×ULN based on the average of last 2 measurements.
Time frame: 24 weeks
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paltusotine | Percentage of Participants Achieving IGF-1 <1.3×ULN at EOR | 66.7 percentage of participants |
| Placebo | Percentage of Participants Achieving IGF-1 <1.3×ULN at EOR | 14 percentage of participants |
Comparison: Treatment comparison of all participants receiving paltusotine irrespective of dose levels with Placebo has been presented.p-value: <0.000195% CI: [5.637, 79.156]exact logistic regression model
Secondary
Percentage of Participants With Growth Hormone (GH) Concentration <1 ng/mL at Week 22
The average from integrated GH sampling at week 22 was used to determine response.
Time frame: Week 22
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paltusotine | Percentage of Participants With Growth Hormone (GH) Concentration <1 ng/mL at Week 22 | 57.4 percentage of participants |
| Placebo | Percentage of Participants With Growth Hormone (GH) Concentration <1 ng/mL at Week 22 | 17.5 percentage of participants |
Comparison: Treatment comparison of all participants receiving paltusotine irrespective of dose levels with Placebo has been presented.p-value: <0.000195% CI: [2.776, 23.483]exact logistic regression model