Hyperphagia, Prader-Willi Syndrome
Conditions
Keywords
Prader-Willi Syndrome, PWS
Brief summary
This Phase 2b/3 double-blind, placebo-controlled study will evaluate the safety, tolerability, and effects of livoletide on food-related behaviors in patients with Prader-Willi Syndrome (PWS).
Detailed description
The protocol includes 2 consecutive parts: 1. The first part is a Phase 2b dose-response study consisting of a 3-month double-blind, placebo-controlled Core Period followed by a 9-month Extension Period. 2. The second part is a Phase 3 study consisting of a 6-month double-blind, placebo-controlled Core Period followed by a 6-month Extension Period. Phase 3 may be initiated following review of safety and efficacy results at the completion of the Phase 2b Core Period. A total of approximately 50 patients per group (8 to 65 years of age) will be randomized (approximately 150 patients in total). In addition to this cohort of 150 patients, a separate cohort of patients 4 to 7 years of age will also be randomized. Note: The 8-65 year old cohort has been fully enrolled. Enrollment into the 4-7 year age cohort remains ongoing.
Interventions
DRUGLivoletide
Daily subcutaneous injection
DRUGPlacebo
Daily subcutaneous injection
Sponsors
Millendo Therapeutics SAS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed genetic diagnosis of PWS * Evidence of increased appetite or hyperphagia * Patient must have a single primary caregiver who should be available for certain durations of the study * BMI ≤ 65 kg/m2 * Growth hormone treatment permitted if doses have been stable for at least 1 month prior to screening
Exclusion criteria
* History of chronic liver disease * Type 1 diabetes mellitus * HbA1c \> 10% * Body weight \<20 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT) | Baseline to month 3 | Change from baseline to the end of the 3-month Core Period for HQ-CT total score. The HQ-CT score range is 0 to 36 where the higher score represents more severe abnormal food related behaviors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese | Baseline to month 3 | Total body fat mass was assessed using dual energy X-ray absorptiometry (DXA) scan. DXAs were conducted at each local facility using standardized procedures and settings. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex |
| Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese | Baseline to month 3 | The waist circumference was measured in fasting condition at the superior border of iliac crest, according to recommendations from the Anthropometry Procedures Manual of the National Health and Nutrition Examination Survey, Revised 2007. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex |
| Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese | Baseline to month 3 | Patients were weighed in fasting condition, clothed (underwear, light gown or light clothing), without footwear or heavy jewelry, using a calibrated scale. The same scale should be used throughout the study if possible. The conditions under which patients are weighed should be kept consistent if possible. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex |
Countries
Australia, Belgium, France, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Original protocol: for Phase 2b, a total of 50 patients per group will need to be randomized. Amendment v1.2: for Phase 2b, a total of approximately 50 patients per group (8 to 65 years of age) will need to be randomized. In addition to this cohort of 150 patients, a separate cohort of patients 4 to 7 years of age will also be randomized.
Pre-assignment details
Screening Period was up to 4 weeks. After signing informed consent, patients with Prader-Willi Syndrome entered the Screening Period to assess preliminary eligibility for the study based on the inclusion and exclusion criteria. In addition, pertinent information was collected such as past medical history, demographic data, and prior and current medications
Participants by arm
| Arm | Count |
|---|---|
| Low-Dose Livoletide Daily subcutaneous injection of \
60 mcg/kg for 3 month double-blind core period and 9 month open label extension period.
Livoletide: Daily subcutaneous injection | 52 |
| High-Dose Livoletide Daily subcutaneous injection of \
120 mcg/kg for 3 month double-blind core period and 9 month open label extension period.
Livoletide: Daily subcutaneous injection | 52 |
| Placebo Daily subcutaneous injection of 0.9% NaCl for the 3 month double-blind core period and then low-dose or high-dose livoletide for 9 month open label extension period.
Placebo: Daily subcutaneous injection | 54 |
| Total | 158 |
Baseline characteristics
| Characteristic | Low-Dose Livoletide | High-Dose Livoletide | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 24 Participants | 26 Participants | 24 Participants | 74 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 26 Participants | 30 Participants | 84 Participants |
| Age, Continuous | 20.7 years STANDARD_DEVIATION 9.2 | 19.7 years STANDARD_DEVIATION 8.27 | 19.4 years STANDARD_DEVIATION 8.03 | 19.9 years STANDARD_DEVIATION 8.47 |
| Baseline HQ-CT | 20.4 units on a scale STANDARD_DEVIATION 6.37 | 19.5 units on a scale STANDARD_DEVIATION 6.34 | 20.5 units on a scale STANDARD_DEVIATION 5.87 | 20.2 units on a scale STANDARD_DEVIATION 6.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 5 Participants | 1 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 36 Participants | 37 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 11 Participants | 16 Participants | 37 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 12 Participants | 14 Participants | 35 Participants |
| Race (NIH/OMB) White | 38 Participants | 35 Participants | 36 Participants | 109 Participants |
| Region of Enrollment Australia | 3 Participants | 3 Participants | 1 Participants | 7 Participants |
| Region of Enrollment Belgium | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Region of Enrollment France | 9 Participants | 11 Participants | 14 Participants | 34 Participants |
| Region of Enrollment Italy | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Netherlands | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Spain | 12 Participants | 8 Participants | 10 Participants | 30 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 21 Participants | 24 Participants | 21 Participants | 66 Participants |
| Sex: Female, Male Female | 28 Participants | 28 Participants | 32 Participants | 88 Participants |
| Sex: Female, Male Male | 24 Participants | 24 Participants | 22 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 52 | 0 / 54 |
| other Total, other adverse events | 34 / 52 | 34 / 52 | 34 / 54 |
| serious Total, serious adverse events | 2 / 52 | 1 / 52 | 1 / 54 |
Outcome results
Primary
Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT)
Change from baseline to the end of the 3-month Core Period for HQ-CT total score. The HQ-CT score range is 0 to 36 where the higher score represents more severe abnormal food related behaviors.
Time frame: Baseline to month 3
Population: The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Livoletide | Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT) | -5.1 score on a scale | Standard Error 7.76 |
| High-Dose Livoletide | Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT) | -3.6 score on a scale | Standard Error 6.08 |
| Placebo | Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT) | -3.3 score on a scale | Standard Error 5.77 |
p-value: <0.025Mixed Models Analysis
Secondary
Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese
The waist circumference was measured in fasting condition at the superior border of iliac crest, according to recommendations from the Anthropometry Procedures Manual of the National Health and Nutrition Examination Survey, Revised 2007. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
Time frame: Baseline to month 3
Population: The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS.~For this endpoint, only patients considered overweight/obese at baseline were included in the analysis.~Overweight/obese patients were defined as follows:~* patients ≥18 years of age: BMI ≥27 kg/m2~* patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Livoletide | Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 0.92 cm | Standard Deviation 5.703 |
| High-Dose Livoletide | Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 0.11 cm | Standard Deviation 4.969 |
| Placebo | Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese | -0.45 cm | Standard Deviation 3.674 |
Secondary
Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese
Patients were weighed in fasting condition, clothed (underwear, light gown or light clothing), without footwear or heavy jewelry, using a calibrated scale. The same scale should be used throughout the study if possible. The conditions under which patients are weighed should be kept consistent if possible. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
Time frame: Baseline to month 3
Population: The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS.~For this endpoint, only patients considered overweight/obese at baseline were included in the analysis.~Overweight/obese patients were defined as follows:~* patients ≥18 years of age: BMI ≥27 kg/m2~* patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Livoletide | Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 1.39 percent change | Standard Deviation 3.313 |
| High-Dose Livoletide | Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 1.79 percent change | Standard Deviation 2.079 |
| Placebo | Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 1.06 percent change | Standard Deviation 2.589 |
Secondary
Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese
Total body fat mass was assessed using dual energy X-ray absorptiometry (DXA) scan. DXAs were conducted at each local facility using standardized procedures and settings. Overweight/obese patients were defined as follows: * patients ≥18 years of age: BMI ≥27 kg/m2 * patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
Time frame: Baseline to month 3
Population: The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS.~For this endpoint, only patients considered overweight/obese at baseline were included in the analysis.~Overweight/obese patients were defined as follows:~* patients ≥18 years of age: BMI ≥27 kg/m2~* patients 4-17 years of age: BMI ≥90th percentile for the same age and sex
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Livoletide | Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 0.33 percent change | Standard Deviation 3.806 |
| High-Dose Livoletide | Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese | 3.48 percent change | Standard Deviation 4.429 |
| Placebo | Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese | -0.36 percent change | Standard Deviation 4.302 |