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Livoletide did not result in a statistically significant improvement in hyperphagia and food-related behaviors
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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).
The protocol includes 2 consecutive parts:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low-Dose Livoletide | Experimental | Daily subcutaneous injection of ~ 60 mcg/kg for 3 month double-blind core period and 9 month open label extension period. |
|
| High-Dose Livoletide | Experimental | Daily subcutaneous injection of ~120 mcg/kg for 3 month double-blind core period and 9 month open label extension period. |
|
| Placebo | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Livoletide | Drug | Daily subcutaneous injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline to month 3 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
|
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35233 | United States | ||
| University of California - Irvine Medical Center |
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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
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | High-Dose Livoletide |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 23, 2020 | Jan 21, 2021 |
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| Placebo | Drug | Daily subcutaneous injection |
|
| Baseline to month 3 |
| 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:
| Baseline to month 3 |
| 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:
| Baseline to month 3 |
| Orange |
| California |
| 92868 |
| United States |
| Rady Children's Hospital - San Diego | San Diego | California | 92123 | United States |
| Children's Hospital Colorado | Denver | Colorado | 80045 | United States |
| University of Kansas Medical Center | Kansas City | Kansas | 66160 | United States |
| Johns Hopkins University | Baltimore | Maryland | 21287 | United States |
| Boston Children's Hospital | Boston | Massachusetts | 02215 | United States |
| University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| Children's Hospitals and Clinics of Minnesota-Minneapolis | Saint Paul | Minnesota | 55102 | United States |
| Winthrop University Hospital | Mineola | New York | 11501 | United States |
| New York Presbyterian Morgan Stanley Children's Hospital | New York | New York | 10032 | United States |
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| University of Texas Southwestern Medical Center | Dallas | Texas | 75390 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
| Seattle Children's Hospital | Seattle | Washington | 98105 | United States |
| Royal Prince Alfred Hospital | Camperdown | 2050 | Australia |
| Austin Health | Melbourne | 3084 | Australia |
| Perth Children's Hospital | Nedlands | 6009 | Australia |
| The Childrens Hospital at Westmead | Westmead | 2145 | Australia |
| Cliniques Universitaires Saint-Luc | Brussels | 1200 | Belgium |
| Centre Hospitalier Universitaire d'Angers | Angers | 49100 | France |
| CHU Lyon - Hopital Femmes Mere Enfant | Bron | 69677 | France |
| Hospital Pitie Salpetriere | Paris | 75013 | France |
| Hopital Necker-Enfants Malades | Paris | 75015 | France |
| CHU de Toulouse - Hospital Rangueil | Toulouse | 31059 | France |
| CHU de Toulouse - Hopital des Enfants | Toulouse | France |
| Azienda Ospedaliera Universitaria Federico II | Naples | 80131 | Italy |
| Ospedale Pediatrico Bambino Gesù | Roma | 00165 | Italy |
| Erasmus University Medical Center | Rotterdam | 3015 | Netherlands |
| Stichting Kind en Groei | Rotterdam | 3016 | Netherlands |
| Hospital General Universitario de Alicante | Alicante | 03010 | Spain |
| Hospital de Cruces | Barakaldo | 48903 | Spain |
| Hospital Sant Joan de Deu | Barcelona | 08950 | Spain |
| Corporacio Sanitaria Parc Tauli - Hospital de Sabadell | Sabadell | 08208 | Spain |
| NHS Tayside | Dundee | DD1 9SY | United Kingdom |
| Chelsea and Westminster Hospital | London | SW109NH | United Kingdom |
| Imperial College London | London | W12 0NN | United Kingdom |
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
| FG002 | Placebo | Daily subcutaneous injection of 0.9% sodium chloride 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 |
| COMPLETED |
|
| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
| ||||||||||||||||
| Baseline HQ-CT | The hyperphagia questionnaire for clinical trials (HQ-CT) total score range is 0 to 36 where the higher score represents more severe abnormal food related behaviors. | Mean | Standard Deviation | units on a scale |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS. | Posted | Mean | Standard Error | score on a scale | Baseline to month 3 |
|
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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:
| 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:
| Posted | Mean | Standard Deviation | percent change | Baseline to month 3 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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:
| 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:
| Posted | Mean | Standard Deviation | cm | Baseline to month 3 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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:
| 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:
| Posted | Mean | Standard Deviation | percent change | Baseline to month 3 |
|
The analysis of treatment-emergent adverse events (TEAEs) was done starting first dose of study drug and through 30 days after the end of the treatment period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 52 | 2 | 52 | 34 | 52 |
| EG001 | 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 | 0 | 52 | 1 | 52 | 34 | 52 |
| EG002 | 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 | 0 | 54 | 1 | 54 | 34 | 54 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lower respiratory tract infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Impulse control disorder | Psychiatric disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Abdominal Pain | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Injection site pain | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Injection site bruising | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Injection site erythma | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Injection site hematoma | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Injection site mass | General disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Upper respiration infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Ear infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Paronychia | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA version 22.0 | Systematic Assessment |
| |
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA version 22.0 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA version 22.0 | Systematic Assessment |
| |
| Blood pressure systolic increased | Investigations | MedDRA version 22.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Dermatillomania | Psychiatric disorders | MedDRA version 22.0 | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.0 | Systematic Assessment |
|
The double-blind, placebo-controlled phase 2b study did not meet the primary endpoint or any of the secondary endpoints. Therefore, the Sponsor has decided to discontinue further development of livoletide.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Information | Millendo Therapeutics | +1 734-845-9000 | millendo@millendo.com |
| SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Jul 31, 2019 | Jan 21, 2021 | Prot_001.pdf |
Not provided
| ID | Term |
|---|---|
| D011218 | Prader-Willi Syndrome |
| D006963 | Hyperphagia |
| ID | Term |
|---|---|
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |
| D000096803 | Imprinting Disorders |
| D009765 | Obesity |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| C581708 | cyclic des-acyl ghrelin (6-13) |
Not provided
Not provided
Not provided
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Belgium |
|
| United States |
|
| United Kingdom |
|
| Italy |
|
| France |
|
| Australia |
|
| Spain |
|
| OG002 |
| 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 |
|
|
| OG002 | 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 |
|
|
| OG002 | 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 |
|
|