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Effects of Livoletide (AZP-531) on Food-related Behaviors in Patients With Prader-Willi Syndrome (ZEPHYR)

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ClinicalTrials.gov Identifier: NCT03790865
Recruitment Status : Terminated (Livoletide did not result in a statistically significant improvement in hyperphagia and food-related behaviors)
First Posted : January 2, 2019
Results First Posted : February 17, 2021
Last Update Posted : February 17, 2021
Sponsor:
Information provided by (Responsible Party):
Millendo Therapeutics, Inc. ( Millendo Therapeutics SAS )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Prader-Willi Syndrome
Hyperphagia
Interventions Drug: Livoletide
Drug: Placebo
Enrollment 158
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
Arm/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description

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

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

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

Period Title: Overall Study
Started 52 52 54
Completed 52 50 54
Not Completed 0 2 0
Arm/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo Total
Hide Arm/Group Description

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

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

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

Total of all reporting groups
Overall Number of Baseline Participants 52 52 54 158
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 52 participants 54 participants 158 participants
<=18 years
24
  46.2%
26
  50.0%
24
  44.4%
74
  46.8%
Between 18 and 65 years
28
  53.8%
26
  50.0%
30
  55.6%
84
  53.2%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 52 participants 52 participants 54 participants 158 participants
20.7  (9.20) 19.7  (8.27) 19.4  (8.03) 19.9  (8.47)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 52 participants 54 participants 158 participants
Female
28
  53.8%
28
  53.8%
32
  59.3%
88
  55.7%
Male
24
  46.2%
24
  46.2%
22
  40.7%
70
  44.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 52 participants 54 participants 158 participants
Hispanic or Latino
5
   9.6%
5
   9.6%
1
   1.9%
11
   7.0%
Not Hispanic or Latino
37
  71.2%
36
  69.2%
37
  68.5%
110
  69.6%
Unknown or Not Reported
10
  19.2%
11
  21.2%
16
  29.6%
37
  23.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 52 participants 54 participants 158 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
3
   5.8%
3
   5.6%
6
   3.8%
Native Hawaiian or Other Pacific Islander
1
   1.9%
0
   0.0%
0
   0.0%
1
   0.6%
Black or African American
4
   7.7%
2
   3.8%
1
   1.9%
7
   4.4%
White
38
  73.1%
35
  67.3%
36
  66.7%
109
  69.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
9
  17.3%
12
  23.1%
14
  25.9%
35
  22.2%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 52 participants 54 participants 158 participants
Netherlands
3
   5.8%
1
   1.9%
4
   7.4%
8
   5.1%
Belgium
1
   1.9%
2
   3.8%
2
   3.7%
5
   3.2%
United States
21
  40.4%
24
  46.2%
21
  38.9%
66
  41.8%
United Kingdom
2
   3.8%
1
   1.9%
0
   0.0%
3
   1.9%
Italy
1
   1.9%
2
   3.8%
2
   3.7%
5
   3.2%
France
9
  17.3%
11
  21.2%
14
  25.9%
34
  21.5%
Australia
3
   5.8%
3
   5.8%
1
   1.9%
7
   4.4%
Spain
12
  23.1%
8
  15.4%
10
  18.5%
30
  19.0%
Baseline HQ-CT   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 52 participants 52 participants 54 participants 158 participants
20.4  (6.37) 19.5  (6.34) 20.5  (5.87) 20.2  (6.15)
[1]
Measure Description: 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.
1.Primary Outcome
Title Change in Hyperphagia and Food-related Behaviors (Hyperphagia Questionnaire for Clinical Trials; HQ-CT)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all randomized patients. Efficacy analyses for the Phase 2b Core Period were performed on the FAS.
Arm/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description:

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

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

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

Overall Number of Participants Analyzed 52 52 54
Mean (Standard Error)
Unit of Measure: score on a scale
-5.1  (7.76) -3.6  (6.08) -3.3  (5.77)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-Dose Livoletide, High-Dose Livoletide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.025
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 4
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage Change From Baseline to Month 3 in Total Body Fat Mass in Patients Eight to 65 Years of Age Defined as Overweight/Obese
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description

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/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description:

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

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

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

Overall Number of Participants Analyzed 40 39 40
Mean (Standard Deviation)
Unit of Measure: percent change
0.33  (3.806) 3.48  (4.429) -0.36  (4.302)
3.Secondary Outcome
Title Change From Baseline to Month 3 in Waist Circumference in Patients Eight to 65 Years of Age Defined as Overweight/Obese
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description

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/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description:

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

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

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

Overall Number of Participants Analyzed 40 39 40
Mean (Standard Deviation)
Unit of Measure: cm
0.92  (5.703) 0.11  (4.969) -0.45  (3.674)
4.Secondary Outcome
Title Percentage Change From Baseline to Month 3 in Body Weight in Patients Eight to 65 Years of Age Defined as Overweight/Obese
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description

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/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description:

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

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

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

Overall Number of Participants Analyzed 40 39 40
Mean (Standard Deviation)
Unit of Measure: percent change
1.39  (3.313) 1.79  (2.079) 1.06  (2.589)
Time Frame 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
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Low-Dose Livoletide High-Dose Livoletide Placebo
Hide Arm/Group Description

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

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

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

All-Cause Mortality
Low-Dose Livoletide High-Dose Livoletide Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/52 (0.00%)      0/52 (0.00%)      0/54 (0.00%)    
Hide Serious Adverse Events
Low-Dose Livoletide High-Dose Livoletide Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/52 (3.85%)      1/52 (1.92%)      1/54 (1.85%)    
Infections and infestations       
Lower respiratory tract infection  1  1/52 (1.92%)  1 0/52 (0.00%)  0 0/54 (0.00%)  0
Nervous system disorders       
Syncope  1  0/52 (0.00%)  0 1/52 (1.92%)  1 0/54 (0.00%)  0
Psychiatric disorders       
Impulse control disorder  1  1/52 (1.92%)  1 0/52 (0.00%)  0 1/54 (1.85%)  1
1
Term from vocabulary, MedDRA version 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Low-Dose Livoletide High-Dose Livoletide Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   34/52 (65.38%)      34/52 (65.38%)      34/54 (62.96%)    
Gastrointestinal disorders       
Diarrhea  1  8/52 (15.38%)  10 4/52 (7.69%)  4 5/54 (9.26%)  5
Abdominal Pain  1  1/52 (1.92%)  2 0/52 (0.00%)  0 2/54 (3.70%)  3
Constipation  1  2/52 (3.85%)  2 0/52 (0.00%)  0 1/54 (1.85%)  1
Nausea  1  1/52 (1.92%)  1 0/52 (0.00%)  0 2/54 (3.70%)  2
General disorders       
Injection site pain  1  8/52 (15.38%)  11 6/52 (11.54%)  6 2/54 (3.70%)  2
Injection site bruising  1  3/52 (5.77%)  3 5/52 (9.62%)  5 3/54 (5.56%)  3
Injection site erythma  1  5/52 (9.62%)  5 2/52 (3.85%)  2 0/54 (0.00%)  0
Pyrexia  1  4/52 (7.69%)  4 2/52 (3.85%)  2 1/54 (1.85%)  2
Fatigue  1  1/52 (1.92%)  1 2/52 (3.85%)  2 1/54 (1.85%)  1
Injection site hematoma  1  3/52 (5.77%)  6 1/52 (1.92%)  1 0/54 (0.00%)  0
Injection site mass  1  2/52 (3.85%)  2 1/52 (1.92%)  1 1/54 (1.85%)  1
Infections and infestations       
Nasopharyngitis  1  2/52 (3.85%)  2 2/52 (3.85%)  2 6/54 (11.11%)  6
Influenza  1  0/52 (0.00%)  0 1/52 (1.92%)  1 4/54 (7.41%)  4
Gastroenteritis  1  1/52 (1.92%)  1 2/52 (3.85%)  2 1/54 (1.85%)  1
Upper respiration infection  1  0/52 (0.00%)  0 2/52 (3.85%)  2 1/54 (1.85%)  2
Ear infection  1  2/52 (3.85%)  2 0/52 (0.00%)  0 0/54 (0.00%)  0
Paronychia  1  2/52 (3.85%)  3 0/52 (0.00%)  0 0/54 (0.00%)  0
Sinusitis  1  0/52 (0.00%)  0 0/52 (0.00%)  0 2/54 (3.70%)  2
Injury, poisoning and procedural complications       
Ligament sprain  1  1/52 (1.92%)  1 2/52 (3.85%)  2 0/54 (0.00%)  0
Contusion  1  0/52 (0.00%)  0 0/52 (0.00%)  0 2/54 (3.70%)  2
Investigations       
Blood pressure systolic increased  1  2/52 (3.85%)  2 0/52 (0.00%)  0 0/54 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Pain in extremity  1  1/52 (1.92%)  1 0/52 (0.00%)  0 2/54 (3.70%)  2
Myalgia  1  0/52 (0.00%)  0 0/52 (0.00%)  0 2/54 (3.70%)  2
Nervous system disorders       
Headache  1  3/52 (5.77%)  6 2/52 (3.85%)  2 3/54 (5.56%)  3
Psychiatric disorders       
Dermatillomania  1  0/52 (0.00%)  0 2/52 (3.85%)  2 0/54 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Oropharyngeal pain  1  4/52 (7.69%)  4 2/52 (3.85%)  2 0/54 (0.00%)  0
1
Term from vocabulary, MedDRA version 22.0
Indicates events were collected by 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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trial Information
Organization: Millendo Therapeutics
Phone: +1 734-845-9000
EMail: millendo@millendo.com
Layout table for additonal information
Responsible Party: Millendo Therapeutics, Inc. ( Millendo Therapeutics SAS )
ClinicalTrials.gov Identifier: NCT03790865    
Other Study ID Numbers: AZP01-CLI-003
First Submitted: December 28, 2018
First Posted: January 2, 2019
Results First Submitted: January 21, 2021
Results First Posted: February 17, 2021
Last Update Posted: February 17, 2021