Acromegaly
Conditions
Keywords
Acromegaly, ACROBAT, EVOLVE, Paltusotine
Brief summary
A Phase 2 double-blind, placebo-controlled, randomized withdrawal study is designed to evaluate the safety, efficacy, and pharmacokinetics of paltusotine (formerly CRN00808) in subjects with acromegaly that are responders to octreotide LAR or lanreotide depot.
Interventions
DRUGPaltusotine
Paltusotine, capsules, once daily by mouth
DRUGPlacebo
Placebo, capsules, once daily by mouth
Sponsors
Crinetics Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
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 that is controlled on stable doses of octreotide LAR or lanreotide depot 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 or radiation therapy at any time prior to the study entry. Pituitary radiation therapy (within 3 to 4 years or more than 4 years prior to study entry) with recently documented elevated IGF-1 may be eligible. 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 who have been taking the following prior medications: pegvisomant (within the last 3 months), dopamine agonists (within the last 3 months) and pasireotide LAR (within the last 6 months) 13. Subjects taking octreotide LAR at a dose higher than 40 mg or lanreotide depot at a dose higher than 120 mg 14. 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 |
|---|---|---|
| Responder Criteria Was Based on the Mean of Two Consecutive Insulin-like Growth Factor-1 [IGF-1] Measurements ≤ULN at Week 13 | 13 Weeks | Proportion of subjects who meet responder criteria (based on the mean of two consecutive IGF-1 measurements ≤ upper limit of normal \[ULN\]) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in IGF-1 Levels | From Week 10 to Week 13 | Change in IGF-1 levels between RWP Baseline/Week 10 and Week 13 |
| Change in Growth Hormone (GH) Levels | From Week 8 to Week 13 | Change in growth hormone levels between RWP Baseline/Week 8 and Week 13 |
| Change in Total ASD Score Between RWP Baseline/Week 10 and Week 13 | From Week 10 to Week 13 | Measured by total Acromegaly symptom diary (ASD) score from W10-W13. ASD is a sponsor-developed daily diary to assess important acromegaly symptoms from the patient perspective. It covers 7 symptoms (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling). Patients rate the severity of each experience in the past 24 hours on an 11-point numeric scale that ranges from 0 (no symptom) to 10 (worst symptom). A weekly average ASD score is calculated for each item as the sum of the item responses for a specific item over the course of the study week divided by the number of days on which the item was completed. The weekly average ASD total score is calculated by computing the sum of the weekly average item scores for the 7 items (total range from 0 to 70), where higher score = higher symptom severity. |
Countries
Brazil, Greece, Hungary, New Zealand, Poland, Serbia, Slovakia, United States
Participant flow
Recruitment details
Medically stable male and female subjects 18 to 75 years of age, inclusive, with a confirmed acromegaly diagnosis that was controlled on a stable approved dose of octreotide LAR or lanreotide depot. At a minimum, there had to be documentation available of a pituitary tumour and elevated IGF-1 in the past.
Pre-assignment details
Medically stable male and female participants 18 to 75 years of age, with a confirmed acromegaly diagnosis that was controlled on a stable approved dose of octreotide LAR or lanreotide depot. There had to be documentation available of a pituitary tumour and elevated IGF-1 in the past.
Participants by arm
| Arm | Count |
|---|---|
| Titration Period: Paltusotine, Then Randomized Withdrawal Period: Paltusotine During the titration period, the study drug dose was titrated up in a blinded fashion. At randomization for the randomized withdrawal period, these subjects continued to receive paltusotine at the same level as end of the titration period. | 3 |
| Titration Period: Paltusotine, Then Randomized Withdrawal Period: Placebo During the titration period, the study drug dose was titrated up in a blinded fashion. At randomization for the randomized withdrawal period, these subjects were switched to placebo. | 4 |
| Titration Period: Paltusotine, Then Not Randomized Titration period proceeded for these subjects in the same manner as other groups.
To be eligible for randomization, the subject had to have IGF-1 value ≤ULN at V10/W8 and an Investigator determination at V11/W10 that the subject tolerated the study drug. Subjects who did not meet both criteria were not to be randomized but were to be allowed to stay in the study and continue on a study drug dose that was tolerated until completion of all study visits or until criteria to resume standard acromegaly therapy and discontinuation from the study were met. The dose of study drug used at V9/W7 remained stable through V11/W10 if tolerated. | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period: up to 4 Weeks | COVID-19 | 0 | 1 | 0 |
| Randomized Withdrawal: up to 4 Weeks | Participants who did not meet randomization criteria did not enter the Randomized Withdrawal Period. | 0 | 0 | 5 |
| Titration Period: up to 9 Weeks | COVID-19 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Titration Period: Paltusotine, Then Randomized Withdrawal Period: Paltusotine | Titration Period: Paltusotine, Then Randomized Withdrawal Period: Placebo | Titration Period: Paltusotine, Then Not Randomized | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 4 Participants | 4 Participants | 9 Participants |
| Age, Continuous | 65.0 years STANDARD_DEVIATION 3 | 38.8 years STANDARD_DEVIATION 8.66 | 57.7 years STANDARD_DEVIATION 11.48 | 53.5 years STANDARD_DEVIATION 13.76 |
| BMI | 26.37 kg/m2 STANDARD_DEVIATION 3.371 | 26.95 kg/m2 STANDARD_DEVIATION 1.76 | 28.48 kg/m2 STANDARD_DEVIATION 7.008 | 27.52 kg/m2 STANDARD_DEVIATION 4.903 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 163.07 cm STANDARD_DEVIATION 8.1 | 181.90 cm STANDARD_DEVIATION 14.461 | 167.73 cm STANDARD_DEVIATION 12.502 | 171.02 cm STANDARD_DEVIATION 13.748 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 4 Participants | 5 Participants | 12 Participants |
| Ring Size | 13.7 Scores on a Scale STANDARD_DEVIATION 3.51 | 14.5 Scores on a Scale STANDARD_DEVIATION 5.45 | 11.3 Scores on a Scale STANDARD_DEVIATION 1.86 | 12.8 Scores on a Scale STANDARD_DEVIATION 3.63 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 3 Participants | 7 Participants |
| UGT1A1 Genotype *1/*1 | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| UGT1A1 Genotype *1/*80 | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| UGT1A1 Genotype *80/*80 | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| UGT1A1 Genotype Not reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| UGT1A1 Phenotype Intermediate Metabolizer | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| UGT1A1 Phenotype Normal Metabolizer | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| UGT1A1 Phenotype Not reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| UGT1A1 Phenotype Poor Metabolizer | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Weight | 70.83 kg STANDARD_DEVIATION 15.942 | 89.05 kg STANDARD_DEVIATION 10.12 | 80.65 kg STANDARD_DEVIATION 22.542 | 80.97 kg STANDARD_DEVIATION 18.088 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 3 | 0 / 4 | 0 / 13 |
| other Total, other adverse events | 8 / 13 | 3 / 3 | 4 / 4 | 10 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 3 | 0 / 4 | 0 / 13 |
Outcome results
Primary
Responder Criteria Was Based on the Mean of Two Consecutive Insulin-like Growth Factor-1 [IGF-1] Measurements ≤ULN at Week 13
Proportion of subjects who meet responder criteria (based on the mean of two consecutive IGF-1 measurements ≤ upper limit of normal \[ULN\])
Time frame: 13 Weeks
Population: The Analysis Population includes all subjects who received treatment in the titration period. This includes subjects who were randomized in the randomized withdrawal period to receive placebo or continue receiving paltusotine and subjects who were not randomized and continued receiving paltusotine. The primary endpoint of the proportion of subjects who met responder criteria (based on the mean of two consecutive IGF-1 measurements ≤ULN) at Week 13 is presented for all subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Withdrawal Period: Paltusotine | Responder Criteria Was Based on the Mean of Two Consecutive Insulin-like Growth Factor-1 [IGF-1] Measurements ≤ULN at Week 13 | 66.7 percentage of responders |
| Randomized Withdrawal Period: Placebo | Responder Criteria Was Based on the Mean of Two Consecutive Insulin-like Growth Factor-1 [IGF-1] Measurements ≤ULN at Week 13 | 25.0 percentage of responders |
| Randomized Withdrawal Period: Not Randomized | Responder Criteria Was Based on the Mean of Two Consecutive Insulin-like Growth Factor-1 [IGF-1] Measurements ≤ULN at Week 13 | 16.7 percentage of responders |
Secondary
Change in Growth Hormone (GH) Levels
Change in growth hormone levels between RWP Baseline/Week 8 and Week 13
Time frame: From Week 8 to Week 13
Population: Analysis Population includes all subjects who met protocol pre-specified criteria for randomization into paltusotine/placebo. Per the study design, Randomized Withdrawal Period (RWP) baseline only applies to those subjects who met criteria for randomization. RWP baseline is undefined for non-randomized subjects. Demographics and Baseline Characteristics were reported for all subjects at Titration Period Baseline, but not RWP baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: Paltusotine | Change in Growth Hormone (GH) Levels | 71.96 percent change in GH | Standard Deviation 48.865 |
| Randomized Withdrawal Period: Placebo | Change in Growth Hormone (GH) Levels | 108.30 percent change in GH | Standard Deviation 179.977 |
Secondary
Change in IGF-1 Levels
Change in IGF-1 levels between RWP Baseline/Week 10 and Week 13
Time frame: From Week 10 to Week 13
Population: Analysis Population includes all subjects who met protocol pre-specified criteria for randomization into paltusotine/placebo. Per the study design, Randomized Withdrawal Period (RWP) baseline only applies to those subjects who met criteria for randomization. RWP baseline is undefined for non-randomized subjects. Demographics and Baseline Characteristics were reported for all subjects at Titration Period Baseline, but not RWP baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: Paltusotine | Change in IGF-1 Levels | 4.04 percent change in IGF1 | Standard Deviation 5.064 |
| Randomized Withdrawal Period: Placebo | Change in IGF-1 Levels | 48.17 percent change in IGF1 | Standard Deviation 41.408 |
Secondary
Change in Total ASD Score Between RWP Baseline/Week 10 and Week 13
Measured by total Acromegaly symptom diary (ASD) score from W10-W13. ASD is a sponsor-developed daily diary to assess important acromegaly symptoms from the patient perspective. It covers 7 symptoms (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling). Patients rate the severity of each experience in the past 24 hours on an 11-point numeric scale that ranges from 0 (no symptom) to 10 (worst symptom). A weekly average ASD score is calculated for each item as the sum of the item responses for a specific item over the course of the study week divided by the number of days on which the item was completed. The weekly average ASD total score is calculated by computing the sum of the weekly average item scores for the 7 items (total range from 0 to 70), where higher score = higher symptom severity.
Time frame: From Week 10 to Week 13
Population: Analysis Population includes all subjects who met protocol pre-specified criteria for randomization into paltusotine/placebo. Per the study design, Randomized Withdrawal Period (RWP) baseline only applies to those subjects who met criteria for randomization. RWP baseline is undefined for non-randomized subjects. Demographics and Baseline Characteristics were reported for all subjects at Titration Period Baseline, but not RWP baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: Paltusotine | Change in Total ASD Score Between RWP Baseline/Week 10 and Week 13 | 1.571 Total ASD score change -units on a scale | Standard Deviation 3.1004 |
| Randomized Withdrawal Period: Placebo | Change in Total ASD Score Between RWP Baseline/Week 10 and Week 13 | 7.962 Total ASD score change -units on a scale | Standard Deviation 7.1591 |