Prader-Willi Syndrome
Conditions
Keywords
PWS, Prader-Willi syndrome, carbetocin
Brief summary
This Phase 3 study is designed to test the effectiveness of intranasal carbetocin (LV-101) in participants with Prader-Willi syndrome (PWS). Carbetocin is an oxytocin analog (a man-made chemical that is like oxytocin). This study will also evaluate the safety and tolerability of LV-101.
Detailed description
This is a Phase 3 randomized, double-blind study with an 8-week, placebo-controlled period designed to test the effectiveness, safety, and tolerability of LV-101 in participants with PWS. Effectiveness will be measured using both caregiver-reported and clinician-reported measures of hyperphagia (extreme hunger), obsessive and compulsive behaviors, and anxiety. Safety and tolerability will be measured by adverse events, laboratory tests, and physical exams. After the 8-week placebo-controlled period, there will be a long-term follow-up period of 56 weeks and an optional extension period after study week 64 during which all participants will receive active treatment with LV-101. At Week 8, participants who were randomized to placebo in the placebo-controlled period will be randomized to one of the two LV-101 doses, administered three times per day before meals.
Interventions
DRUG3.2 mg intranasal carbetocin
three times per day with meals
DRUG9.6 mg intranasal carbetocin
three times per day with meals
DRUGplacebo
three times per day with meals
Sponsors
Levo Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Three parallel groups (two different doses of carbetocin and placebo) for the first 8 weeks; two parallel groups (two different doses of carbetocin) during 56 weeks of follow-up and the optional extension period
Eligibility
Sex/Gender
ALL
Age
7 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Genetically-confirmed Prader-Willi syndrome * Provide voluntary, written informed consent (parent(s) / legal guardian(s) of participant); provide voluntary, written assent (participants, as appropriate) * PWS Nutritional Phase 3 (hyperphagic, rarely feels full)
Exclusion criteria
* Living in a group home * Genetically diagnosed Schaaf-Yang syndrome or other genetic, hormonal, or chromosomal cognitive impairment * New food-related interventions, including environment or dietary restrictions, within 1 month of screening * Dose of any allowed chronic concomitant medications or supplements that have not been stable for ≥3 months prior to the study or is not expected to remain stable while participating in the study; adjustments in growth hormone dose ≤10% are not exclusionary * Presence of cardiovascular disorders, epilepsy, frequent migraines, or severe asthma * More than 3 episodes of sinusitis in the 12 months prior to Screening Visit or presence of nasal diseases that may affect deposition of intranasal medication * Unwilling to abstain from nasal saline, other nasal irrigation, or other intranasal medications for 2 weeks prior to the Baseline visit and during the 8-week, placebo-controlled period of the study * Use of weight loss medication, oxytocin, carbetocin, or vasopressin in the 6 months prior to screening * Participation in an interventional research study involving another investigational medication or device in the 6 months prior to screening or during the study * Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to unstable medical condition, inability to comply with the protocol, or other risk to subject or to the integrity of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hyperphagia Behavior | Baseline to Week 8 | Change in hyperphagia (extreme hunger) as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score versus placebo. Score range: 0-36; higher scores mean a worse outcome. Reduction in score indicates improvement. |
| Obsessive and Compulsive Behaviors | baseline to Week 8 | Change in obsessive and compulsive behaviors as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Total Score versus placebo. Score range: 0-40; higher scores mean a worse outcome. Reduction in score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anxiety | Baseline to Week 8 | Change in participant anxiety as measured by the PWS Anxiety and Distress Questionnaire (PADQ) Total Score versus placebo. Score range: 0-56; higher scores mean a worse outcome. Reduction in score indicates improvement. |
| Global Impression | Week 8 | Clinical Global Impression of Change (CGI-C) score versus placebo. Score range: 1-7; higher scores mean a worse outcome. Reduction in score indicates improvement. |
| Hyperphagia Behavior (Subset) | Baseline to Week 8 | Change in hyperphagia as measured by the change in specified subsets of HQ-CT questions versus placebo. Score range: 0-24; higher scores mean a worse outcome. Reduction in score indicates improvement. |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
Participants were enrolled in three countries, the United States, Canada and Australia. The first participant was screened in November 2018, the first participant was enrolled in December 2018, and the last participant was enrolled in March 2020.
Pre-assignment details
Subjects were randomized 1:1:1 at Baseline to receive the 9.6 mg/dose, 3.2 mg/dose, or placebo during the 8-week placebo-controlled period. A total of 130 subjects were evaluated (44 subjects in the 9.6 mg/dose arm, and 43 subjects each in the 3.2 mg/dose and placebo arms). Of these 130 subjects, 128 subjects (98.5%) completed the Week 8 visit and entered into the long-term follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| 9.6 mg of LV-101 9.6 mg of LV-101 during the 8-week placebo-controlled period
9.6 mg intranasal carbetocin: three times per day with meals | 44 |
| 3.2 mg of LV-101 3.2 mg of LV-101 during the 8-week placebo controlled period
3.2 mg intranasal carbetocin: three times per day with meals | 43 |
| Placebo Matched intranasal placebo during the 8-week placebo controlled period
placebo: three times per day with meals | 43 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | 9.6 mg of LV-101 | 3.2 mg of LV-101 | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 42 Participants | 43 Participants | 43 Participants | 128 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 5 Participants | 4 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 38 Participants | 39 Participants | 117 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 4 Participants | 9 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 37 Participants | 37 Participants | 111 Participants |
| Sex: Female, Male Female | 21 Participants | 27 Participants | 24 Participants | 72 Participants |
| Sex: Female, Male Male | 23 Participants | 16 Participants | 19 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 43 | 0 / 43 |
| other Total, other adverse events | 20 / 44 | 19 / 43 | 10 / 43 |
| serious Total, serious adverse events | 0 / 44 | 0 / 43 | 0 / 43 |
Outcome results
Primary
Hyperphagia Behavior
Change in hyperphagia (extreme hunger) as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score versus placebo. Score range: 0-36; higher scores mean a worse outcome. Reduction in score indicates improvement.
Time frame: Baseline to Week 8
Population: Primary Analysis Set: A subset of the Full Analysis Set that included all subjects with at least one post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 01, 2020 and excluded all efficacy data collected on or after March 01, 2020.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 9.6 mg of LV-101 | Hyperphagia Behavior | -3.439 score on a scale |
| 3.2 mg of LV-101 | Hyperphagia Behavior | -5.372 score on a scale |
| Placebo | Hyperphagia Behavior | -2.237 score on a scale |
p-value: 0.349395% CI: [-3.729, 1.324]Mixed Models Analysis
p-value: 0.016295% CI: [-5.685, -0.586]Mixed Models Analysis
Primary
Obsessive and Compulsive Behaviors
Change in obsessive and compulsive behaviors as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Total Score versus placebo. Score range: 0-40; higher scores mean a worse outcome. Reduction in score indicates improvement.
Time frame: baseline to Week 8
Population: Primary Analysis Set: A subset of the Full Analysis Set that included all subjects with at least one post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 01, 2020 and excluded all efficacy data collected on or after March 01, 2020.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 9.6 mg of LV-101 | Obsessive and Compulsive Behaviors | -2.968 score on a scale |
| 3.2 mg of LV-101 | Obsessive and Compulsive Behaviors | -3.123 score on a scale |
| Placebo | Obsessive and Compulsive Behaviors | -2.360 score on a scale |
p-value: 0.600195% CI: [-2.89, 1.674]Mixed Models Analysis
p-value: 0.514395% CI: [-3.068, 1.541]Mixed Models Analysis
Secondary
Anxiety
Change in participant anxiety as measured by the PWS Anxiety and Distress Questionnaire (PADQ) Total Score versus placebo. Score range: 0-56; higher scores mean a worse outcome. Reduction in score indicates improvement.
Time frame: Baseline to Week 8
Population: Primary Analysis Set: A subset of the Full Analysis Set that included all subjects with at least one post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 01, 2020 and excluded all efficacy data collected on or after March 01, 2020.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 9.6 mg of LV-101 | Anxiety | -4.306 score on a scale |
| 3.2 mg of LV-101 | Anxiety | -8.301 score on a scale |
| Placebo | Anxiety | -4.489 score on a scale |
p-value: 0.914495% CI: [-3.175, 3.541]Mixed Models Analysis
p-value: 0.026695% CI: [-7.177, -0.446]Mixed Models Analysis
Secondary
Global Impression
Clinical Global Impression of Change (CGI-C) score versus placebo. Score range: 1-7; higher scores mean a worse outcome. Reduction in score indicates improvement.
Time frame: Week 8
Population: Primary Analysis Set: A subset of the Full Analysis Set that included all subjects with at least one post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 01, 2020 and excluded all efficacy data collected on or after March 01, 2020.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 9.6 mg of LV-101 | Global Impression | 3.582 score on a scale |
| 3.2 mg of LV-101 | Global Impression | 3.395 score on a scale |
| Placebo | Global Impression | 3.893 score on a scale |
p-value: 0.159895% CI: [-0.748, 0.125]Mixed Models Analysis
p-value: 0.026695% CI: [-0.937, -0.059]Mixed Models Analysis
Secondary
Hyperphagia Behavior (Subset)
Change in hyperphagia as measured by the change in specified subsets of HQ-CT questions versus placebo. Score range: 0-24; higher scores mean a worse outcome. Reduction in score indicates improvement.
Time frame: Baseline to Week 8
Population: Primary Analysis Set: A subset of the Full Analysis Set that included all subjects with at least one post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 01, 2020 and excluded all efficacy data collected on or after March 01, 2020.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 9.6 mg of LV-101 | Hyperphagia Behavior (Subset) | -3.295 score on a scale |
| 3.2 mg of LV-101 | Hyperphagia Behavior (Subset) | -4.621 score on a scale |
| Placebo | Hyperphagia Behavior (Subset) | -2.209 score on a scale |
p-value: 0.247995% CI: [-2.932, 0.761]Mixed Models Analysis
p-value: 0.011495% CI: [-4.276, -0.548]Mixed Models Analysis