A Study of Pharmacokinetic/Pharmacodynamic Profile of Orally Administered Leuprolide in Healthy Female Volunteers

• ClinicalTrials.gov Identifier: NCT02807363
• Recruitment Status: Completed
• First Posted: June 21, 2016
• Results First Posted: February 11, 2022
• Last Update Posted: February 11, 2022
• Sponsor: Enteris BioPharma Inc.
• Collaborator: Syneos Health
• Information provided by (Responsible Party): Enteris BioPharma Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Endometriosis
• Interventions: Drug: Leuprolide Oral Tablet 4-mg QD; Drug: Leuprolide Oral Tablet 4-mg BID; Drug: Leuprolide Depot; Drug: Leuprolide Oral Tablet 10-mg BID
• Enrollment: 35

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Period Title: Dosing Period
Started	9	9	5	12
Completed	9	8	5	12
Not Completed	0	1	0	0
Reason Not Completed
Adverse Event	0	1	0	0
Period Title: Post- Dosing Period
Started	9	8	5	12
Completed	9	8	5	12
Not Completed	0	0	0	0

Baseline Characteristics

Arm/Group Title		Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)	Total
Arm/Group Description		Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.	Total of all reporting groups
Overall Number of Baseline Participants		9	9	5	12	35
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
		38.4 (6.1)	38.4 (5.9)	37.8 (6.6)	37.2 (4.9)	37.9 (5.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
	Female	9	9	5	12	35
	Male	0	0	0	0	0
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
	Hispanic or Latino	3 33.3%	0 0.0%	1 20.0%	1 8.3%	5 14.3%
	Not Hispanic or Latino	6 66.7%	9 100.0%	4 80.0%	11 91.7%	30 85.7%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 11.1%	0 0.0%	0 0.0%	2 16.7%	3 8.6%
	White	8 88.9%	9 100.0%	5 100.0%	10 83.3%	32 91.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Height; Mean (Standard Deviation); Unit of measure: Inches
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
		63.93 (2.14)	63.60 (1.10)	65.28 (2.69)	64.05 (2.15)	64.1 (2.0)
Body Mass Index; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
		25.734 (3.292)	26.054 (3.262)	24.242 (3.255)	24.988 (3.235)	25.3 (3.2)
Weight; Mean (Standard Deviation); Unit of measure: Lbs
	Number Analyzed	9 participants	9 participants	5 participants	12 participants	35 participants
		149.41 (22.36)	149.63 (20.63)	147.40 (17.47)	146.64 (22.38)	148.15 (20.4)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adequacy of Suppression of Estradiol (E2) as Assessed by Estradiol Level Below 40 pg/mL
Description	Criterion: E2 level is considered suppressed during the evaluation period if a value below pre-specified threshold was reported at least once during that period. The days in the row title indicate the evaluation interval.
Time Frame	Dosing Period: Day 8 to 28, Post-dosing: Day 1 to day 28 of post dosing period; Day 29 is the post dosing day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description:	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Overall Number of Participants Analyzed	9	8	5	12
Measure Type: Count of Participants; Unit of Measure: Participants
Days 8,15, 22, 28 and 29	6 66.7%	7 87.5%	5 100.0%	12 100.0%
Days 15, 22, 28 and 29	5 55.6%	7 87.5%	5 100.0%	12 100.0%
Days 22, 28 and 29	4 44.4%	6 75.0%	5 100.0%	9 75.0%
Days 22 and 29	4 44.4%	6 75.0%	5 100.0%	9 75.0%
Entire 28-day Dosing Period	7 77.8%	8 100.0%	5 100.0%	12 100.0%
28-day Post-dosing Period	7 77.8%	6 75.0%	5 100.0%	9 75.0%

2. Primary Outcome

Title	Ovulation Rate - Measured by Number of Subjects With Progesterone Levels Not Less Than 3000 pg/mL
Description	Progesterone level is considered suppressed during the evaluation period if a value below pre-specified threshold (3000 pg/mL) was reported at least once during that period. The days in row title indicate the evaluation interval.
Time Frame	Dosing period: Day 1 to Day 28 and 28 day Post-Dosing Period; 29 day is post dosing day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description:	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month (28 day cycle) of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Overall Number of Participants Analyzed	9	8	5	12
Measure Type: Count of Participants; Unit of Measure: Participants
Days 8, 15, 22, 28 and 29	4 44.4%	3 37.5%	3 60.0%	10 83.3%
Days 15, 22, 28 and 29	2 22.2%	2 25.0%	0 0.0%	0 0.0%
Days 22, 28 and 29	2 22.2%	2 25.0%	0 0.0%	0 0.0%
Days 22 and 29	2 22.2%	1 12.5%	0 0.0%	0 0.0%
Entire 28-day Dosing Period	8 88.9%	5 62.5%	4 80.0%	12 100.0%
28-day Post-dosing Period	9 100.0%	7 87.5%	2 40.0%	12 100.0%

3. Primary Outcome

Title	Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAE) Excluding Menstrual Disorders
Description	The participant incidence of TEAEs was generally comparable during the dosing period across the treatment groups. Treatment C is a depot formulation established to release the drug over a period of 1 month. The data for adverse event was collected for day 1 to 28 of the dosing period.
Time Frame	Dosing Period: Day 1 to day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description:	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Overall Number of Participants Analyzed	9	9	5	12
Measure Type: Count of Participants; Unit of Measure: Participants
Number of subjects with at least one TEAE	7 77.8%	9 100.0%	4 80.0%	8 66.7%
Number of subjects who discontinued due to TEAE	0 0.0%	1 11.1%	0 0.0%	0 0.0%

4. Primary Outcome

Title	Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs), Excluding Menstrual Disorders
Description	Treatment C is a depot formulation established to release the drug over a period of 1 month. The data for post dosing adverse event was collected starting from day 1 to 28 post the 28th day of dosing.
Time Frame	Post dosing period (starting day 1 to day 28 post dosing period)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot(Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description:	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Overall Number of Participants Analyzed	9	8	5	12
Measure Type: Count of Participants; Unit of Measure: Participants
Number of subjects with at least one TEAE	1 11.1%	2 25.0%	1 20.0%	3 25.0%
Number of subject who discontinued due to TEAEs	0 0.0%	0 0.0%	0 0.0%	0 0.0%

5. Primary Outcome

Title	Steady State Concentration Level, (Css) of Leuprolide
Description	Treatment A and B: Steady state concentration level calculated for oral tablets at the end of the fourth treatment week (Treatment Day 28) as the 24-hour AUCs divided by the duration of the dosing interval i.e. 24 hours. Treatment C: Steady state concentration level calculated for IM injection at the fourth treatment week (a mean of leuprolide levels on Days 22 and 29).
Time Frame	Treatment Day 28 for oral groups; Treatment Days 22-29 for Lupron Depot group

Outcome Measure Data

Analysis Population Description

Treatment D: Css determination along with most other pharmacokinetic parameters was not done for this treatment arm as fewer blood samples were planned for this treatment arm.

Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)	Leuprolide Oral Tablet, 4 mg BID (Treatment B)	Leuprolide 1 Month Depot (Treatment C)	Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description:	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.	Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.	Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection	Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
Overall Number of Participants Analyzed	8	8	5	0
Mean (Standard Deviation); Unit of Measure: pg/mL
	357.80 (367.37)	688.27 (258.01)	180.95 (101.04)

Adverse Events

Time Frame	Dosing period (day 1 to day 28) and post dosing period (day 1 to day 28)
Adverse Event Reporting Description	Treatment C being a 1 month (28 day cycle) depot formulation is mentioned as a 1 month therapy but the adverse event monitoring was done for the same time frame as treatment A, B and D.
Arm/Group Title	Leuprolide Oral Tablet, 4 mg QD (Treatment A)		Leuprolide Oral Tablet, 4 mg BID (Treatment B)		Leuprolide 1 Month Depot (Treatment C)		Leuprolide Oral Tablet, 10 mg BID (Treatment D)
Arm/Group Description	Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. Leuprolide Oral Tablet 4-mg QD: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.		Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. Leuprolide Oral Tablet 4-mg BID: 4-mg oral tablet twice daily for 28 consecutive days.		Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy Leuprolide Depot: 3.75 mg intramuscular depot injection		Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days Leuprolide Oral Tablet 10-mg BID: 10-mg oral tablet twice daily for 28 consecutive days.
All-Cause Mortality
	Leuprolide Oral Tablet, 4 mg QD (Treatment A)		Leuprolide Oral Tablet, 4 mg BID (Treatment B)		Leuprolide 1 Month Depot (Treatment C)		Leuprolide Oral Tablet, 10 mg BID (Treatment D)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/9 (0.00%)		0/9 (0.00%)		0/5 (0.00%)		0/12 (0.00%)
Serious Adverse Events
	Leuprolide Oral Tablet, 4 mg QD (Treatment A)		Leuprolide Oral Tablet, 4 mg BID (Treatment B)		Leuprolide 1 Month Depot (Treatment C)		Leuprolide Oral Tablet, 10 mg BID (Treatment D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0.00%)		0/9 (0.00%)		0/5 (0.00%)		0/12 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Leuprolide Oral Tablet, 4 mg QD (Treatment A)		Leuprolide Oral Tablet, 4 mg BID (Treatment B)		Leuprolide 1 Month Depot (Treatment C)		Leuprolide Oral Tablet, 10 mg BID (Treatment D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/9 (77.78%)		9/9 (100.00%)		4/5 (80.00%)		8/12 (66.67%)
Gastrointestinal disorders
Nausea, Vomiting, Abdominal pain, abdominal pain upper, dry mouth, faeces soft * 1	0/9 (0.00%)	0	5/9 (55.56%)	6	1/5 (20.00%)	2	2/12 (16.67%)	5
General disorders
Axillary pain * 1	0/9 (0.00%)	0	0/9 (0.00%)	0	0/5 (0.00%)	0	1/12 (8.33%)	1
Infections and infestations
Nasopharyngitis, gastroenteritis, vaginitis gardnerella * 1	0/9 (0.00%)	0	1/9 (11.11%)	1	1/5 (20.00%)	1	2/12 (16.67%)	2
Injury, poisoning and procedural complications
Procedural dizziness * 1	0/9 (0.00%)	0	1/9 (11.11%)	1	0/5 (0.00%)	0	0/12 (0.00%)	0
Musculoskeletal and connective tissue disorders
Myalgia * 1	1/9 (11.11%)	1	0/9 (0.00%)	0	0/5 (0.00%)	0	0/12 (0.00%)	0
Nervous system disorders
Headache, disturbance in attention, dizziness, presyncope * 1	4/9 (44.44%)	6	8/9 (88.89%)	10	3/5 (60.00%)	3	4/12 (33.33%)	4
Psychiatric disorders
Depressed mood, Insomnia * 1	1/9 (11.11%)	1	0/9 (0.00%)	0	1/5 (20.00%)	1	0/12 (0.00%)	0
Reproductive system and breast disorders
Breast tenderness. Metrorrhagia, † 1	1/9 (11.11%)	1	3/9 (33.33%)	3	0/5 (0.00%)	0	4/12 (33.33%)	4
Respiratory, thoracic and mediastinal disorders
Cough, Oropharyngeal pain * 1	1/9 (11.11%)	1	1/9 (11.11%)	1	0/5 (0.00%)	0	1/12 (8.33%)	1
Skin and subcutaneous tissue disorders
Acne, erythema * 1	1/9 (11.11%)	1	1/9 (11.11%)	1	1/5 (20.00%)	1	1/12 (8.33%)	2
Vascular disorders
hot flush * 1	1/9 (11.11%)	1	3/9 (33.33%)	3	1/5 (20.00%)	1	3/12 (25.00%)	4
1 Term from vocabulary, MedDRA 20.1; * Indicates events were collected by non-systematic assessment; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Paul Shields, Ph.D
• Organization: Enteris Biopharma Inc.
• Phone: 9734533520
• EMail: pshields@enterisbiopharma.com

• Responsible Party: Enteris BioPharma Inc.
• ClinicalTrials.gov Identifier: NCT02807363
• Other Study ID Numbers: LOPDT-ENDO-01
• First Submitted: June 14, 2016
• First Posted: June 21, 2016
• Results First Submitted: October 27, 2021
• Results First Posted: February 11, 2022
• Last Update Posted: February 11, 2022