A Study to Evaluate Injection Pain and Local Tolerability Following Subcutaneous (SC) Administration of TV-46046

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03700658
• Collaborator: FHI 360 (Other)
• Enrollment: 27
• Location: 1
• Arms: 4
• Actual Duration (Months): 20.6
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the local tolerability associated with the SC administration of TV-46046, and inform next steps of the TV-46046 development program.

Condition or Disease	Intervention/Treatment	Phase
Contraception	Drug: TV-46046; Drug: Depo-subQ 104; Drug: TV-46046 Placebo	Phase 1

Detailed Description

Eligible participants will be enrolled and receive 1 of each of the 4 SC study injections in each abdominal quadrant approximately 1 hour apart: 120 milligrams (mg)/0.3 milliliter (mL) of TV-46046, 60 mg/0.3 mL of 1:1 saline diluted TV-46046, 0.3 mL of TV-46046 Placebo and 104 mg/0.65 mL Depo-subQ 104 per the assigned sequence.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Masking Description: The study will be partially blinded due to differences in appearance and volume of the treatments. Designated unblinded study staff will conduct randomization procedures. The staff preparing and administering injections will also be unblinded to treatment sequence but will be trained to shield the syringe prior to and at the time of injection from view of the participant and study staff assessing injection site reactions (ISRs).
• Primary Purpose: Other
• Official Title: A Randomized Cross-Over Study to Evaluate Local Tolerability Following Subcutaneous Administration of TV-46046
• Actual Study Start Date: Jan 15, 2019
• Actual Primary Completion Date: Oct 2, 2020
• Actual Study Completion Date: Oct 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TV-46046 Undiluted Participants will receive TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) SC injection as a test formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart.	Drug: TV-46046; TV-46046 will be administered per dose and schedule specified in the arm.
Experimental: TV-46046 Diluted Participants will receive TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart.	Drug: TV-46046; TV-46046 will be administered per dose and schedule specified in the arm.
Placebo Comparator: TV-46046 Placebo Participants will receive TV-46046 placebo (0.3 mL) SC injection in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart.	Drug: TV-46046 Placebo; TV-46046 Placebo will be administered per schedule specified in the arm.
Active Comparator: Depo-subQ 104 Participants will receive Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart.	Drug: Depo-subQ 104; Depo-subQ 104 will be administered per dose and schedule specified in the arm.; Other Names: Medroxyprogesterone acetate injectable suspension Depo-subQ Provera 104®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Injection Site Reactions (ISRs) (Excluding Injection Site Pain) [Day 0 (immediately after and 1 hour after the injection) up to Month 18]

   ISRs were assessed by self-reports and direct observation for each injection at least twice on the day of injection. ISRs included erythema (redness), swelling, pruritus (itching), bleeding, bruising, injection site discoloration (for example, hypopigmentation), or atrophy (that is, dimple).

Secondary Outcome Measures

1. Injection Site Pain Score, as Assessed by Numerical Rating Scale (NRS) [Day 0 (Immediately after and 1 hour after injection)]

   Participants assessed their injection site pain using an 11-point NRS (0 = no pain at all; 10 = worst pain). Higher scores denote worse outcome.

2. Participant's Perception of Pain, as Assessed by an Overall Ranking of the 4 Study Injections From Least to Most Painful [Day 0 (1 hour after injection)]

   Each participant was asked to rank the injections according to overall pain from least (score = 1) to most (score = 4) painful. If a participant could not rank all of her injections from least to most painful or could not uniquely identify which injection was the most painful, then her responses were appropriately weighted across groups (for example, if a participant ranked all 4 treatments as equally most painful, then that participant contributed a score of 0.25 to each group when assessing the distribution of the most painful injection and in the event of a tie between 2 rankings, 0.5 was assigned to each tied ranking).

3. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Day 0 up to Month 18]

   An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were considered treatment emergent if (a) the onset occurred on or after the time of first injection or (b) an event had an onset prior to the first injection but increased in severity after administration of the injection. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Participant has a low risk of pregnancy (that is, sterilized, in exclusively same-sex partnership, in menopause and/or post-menopausal, abstinent, in a monogamous relationship with vasectomized partner, using nonhormonal intrauterine device [IUD], or consistent use of condoms)

• Participant is not pregnant and does not have desire to become pregnant in the subsequent 18 months

• Participant had a normal mammogram within the last year, if 40 years or older

• Participant has no skin disorders or skin allergies

• Additional criteria apply, please contact the investigator for more information

Exclusion Criteria:

• Participant has hypertension

• Participant has ischemic heart disease or a history of ischemic heart disease

• Participant has a history of stroke

• Participant has a history of thromboembolic event(s)

• Participant has systemic lupus erythematosus

• Participant has rheumatoid arthritis and is undergoing immunosuppressive therapy

• Participant has migraine with aura

• Participant has unexplained vaginal bleeding

• Participant has diabetes

• Participant has a strong family history of breast cancer

• Participant has cervical cancer or a history of cervical cancer

• Participant has severe cirrhosis (decompensated) or liver tumors

• Participant has known significant renal disease

• Participant has a history of diagnosed clinical depression or bipolar disorder, with or without suicidal ideation, and/or history of suicide attempt

• Participant is currently using hormonal contraception

• Participant had an injection of DMPA (Depo-Provera CI or Depo-subQ 104) in the past 12 months; or combined injectable in the last 3 months

• Participant is chronically using pain medication

• Participant has a plan to move to another location in the next 18 months

• Additional criteria apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 1	Santo Domingo		Dominican Republic

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.
• FHI 360

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

• Study Protocol - May 18, 2020
• Statistical Analysis Plan - May 3, 2019

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT03700658
• Other Study ID Numbers: TV46046-WH-10147
• First Posted: Oct 9, 2018
• Last Update Posted: Jan 26, 2022
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Medroxyprogesterone Acetate; Medroxyprogesterone

Study Results

Participant Flow

Arm/Group Title	Overall Study
Arm/Group Description	Participants received TV-46046 undiluted (120 milligrams [mg]/0.3 milliliters [mL] of 400 mg/mL) and TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) subcutaneous (SC) injection as a test formulation, Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation, and TV-46046 placebo SC injection in a crossover design. The 4 study drug injections were administered approximately 1 hour apart.
Period Title: Overall Study
STARTED	27
Received at Least 1 Dose of Study Drug	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Participants received TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) and TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation, Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation, and TV-46046 placebo SC injection in a crossover design. The 4 study drug injections were administered approximately 1 hour apart.
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.7 (6.20)
Sex: Female, Male (Count of Participants)
Female	27 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
Biracial	26 96.3%
Black or African American	1 3.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Injection Site Reactions (ISRs) (Excluding Injection Site Pain)
Description	ISRs were assessed by self-reports and direct observation for each injection at least twice on the day of injection. ISRs included erythema (redness), swelling, pruritus (itching), bleeding, bruising, injection site discoloration (for example, hypopigmentation), or atrophy (that is, dimple).
Time Frame	Day 0 (immediately after and 1 hour after the injection) up to Month 18

Outcome Measure Data

Analysis Population Description

The treated analysis set included all participants who received at least 1 of the 4 study drug injections excluding 3 participants who had partial injections.

Arm/Group Title	TV-46046 Undiluted	TV-46046 Diluted	TV-46046 Placebo	Depo-subQ 104
Arm/Group Description	Participants received TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) subcutaneous (SC) injection as a test formulation.	Participants received TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation.	Participants received TV-46046 placebo (0.3 mL) SC injection.	Participants received Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation.
Measure Participants	25	27	27	26
Count of Participants [Participants]	12 44.4%	6 NaN	0 NaN	8 NaN

2. Secondary Outcome

Title	Injection Site Pain Score, as Assessed by Numerical Rating Scale (NRS)
Description	Participants assessed their injection site pain using an 11-point NRS (0 = no pain at all; 10 = worst pain). Higher scores denote worse outcome.
Time Frame	Day 0 (Immediately after and 1 hour after injection)

Outcome Measure Data

Analysis Population Description

The treated analysis set included all participants who received at least 1 of the 4 study drug injections excluding 5 participants with needle blockage/manipulation.

Arm/Group Title	TV-46046 Undiluted	TV-46046 Diluted	TV-46046 Placebo	Depo-subQ 104
Arm/Group Description	Participants received TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) SC injection as a test formulation.	Participants received TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation.	Participants received TV-46046 placebo (0.3 mL) SC injection.	Participants received Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation.
Measure Participants	22	22	22	22
Immediately after injection	2.1 (1.72)	1.9 (1.46)	3.3 (2.15)	1.2 (1.40)
1 hour after injection	0.2 (0.50)	0.2 (0.50)	0.6 (1.00)	0.1 (0.29)

3. Secondary Outcome

Title	Participant's Perception of Pain, as Assessed by an Overall Ranking of the 4 Study Injections From Least to Most Painful
Description	Each participant was asked to rank the injections according to overall pain from least (score = 1) to most (score = 4) painful. If a participant could not rank all of her injections from least to most painful or could not uniquely identify which injection was the most painful, then her responses were appropriately weighted across groups (for example, if a participant ranked all 4 treatments as equally most painful, then that participant contributed a score of 0.25 to each group when assessing the distribution of the most painful injection and in the event of a tie between 2 rankings, 0.5 was assigned to each tied ranking).
Time Frame	Day 0 (1 hour after injection)

Outcome Measure Data

Analysis Population Description

The treated analysis set included all participants who received at least 1 of the 4 study drug injections excluding 5 participants with needle blockage/manipulation.

Arm/Group Title	TV-46046 Undiluted	TV-46046 Diluted	TV-46046 Placebo	Depo-subQ 104
Arm/Group Description	Participants received TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) SC injection as a test formulation.	Participants received TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation.	Participants received TV-46046 placebo (0.3 mL) SC injection.	Participants received Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation.
Measure Participants	22	22	22	22
Pain Rank 1	4	5	4	9
Pain Rank 2	8.5	8.5	0	5
Pain Rank 3	4.5	4.5	6	7
Pain Rank 4	5	4	12	1

4. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were considered treatment emergent if (a) the onset occurred on or after the time of first injection or (b) an event had an onset prior to the first injection but increased in severity after administration of the injection. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Day 0 up to Month 18

Outcome Measure Data

Analysis Population Description

The treated analysis set included all participants who received at least 1 of the 4 study drug injections.

Arm/Group Title	Overall Study
Arm/Group Description	Participants received TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) and TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation, Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation, and TV-46046 placebo SC injection in a crossover design. The 4 study drug injections were administered approximately 1 hour apart.
Measure Participants	27
Count of Participants [Participants]	23 85.2%

Adverse Events

Time Frame	Day 0 up to Month 18
Adverse Event Reporting Description	The treated analysis set included all participants who received at least 1 of the 4 study injections. The adverse events which occurred during the follow-up are reported in a separate arm "Follow-up After Treatment".
Arm/Group Title	Follow-up After Treatment		TV-46046 Undiluted		TV-46046 Diluted		TV-46046 Placebo		Depo-subQ 104
Arm/Group Description	All Participants were followed for at least 6 months after receiving their injections. Participants with unresolved injection site reactions (ISRs) were followed monthly through the resolution of ISRs or Month 18, whichever came first.		Participants received TV-46046 undiluted (120mg/0.3 mL of 400 mg/mL) SC injection as a test formulation.		Participants received TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation.		Participants received TV-46046 placebo SC injection.		Participants received Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation.
All Cause Mortality
	Follow-up After Treatment		TV-46046 Undiluted		TV-46046 Diluted		TV-46046 Placebo		Depo-subQ 104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	Follow-up After Treatment		TV-46046 Undiluted		TV-46046 Diluted		TV-46046 Placebo		Depo-subQ 104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/27 (3.7%)		0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)
Hepatobiliary disorders
Cholelithiasis	1/27 (3.7%)	1	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Other (Not Including Serious) Adverse Events
	Follow-up After Treatment		TV-46046 Undiluted		TV-46046 Diluted		TV-46046 Placebo		Depo-subQ 104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/27 (66.7%)		0/27 (0%)		1/27 (3.7%)		2/27 (7.4%)		0/27 (0%)
Gastrointestinal disorders
Abdominal pain lower	2/27 (7.4%)	2	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
General disorders
Injection site pain	0/27 (0%)	0	0/27 (0%)	0	1/27 (3.7%)	1	2/27 (7.4%)	2	0/27 (0%)	0
Infections and infestations
Acarodermatitis	3/27 (11.1%)	3	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Influenza	3/27 (11.1%)	3	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Urinary tract infection	3/27 (11.1%)	3	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Vulvitis	2/27 (7.4%)	2	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Nervous system disorders
Dizziness	3/27 (11.1%)	3	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Headache	8/27 (29.6%)	13	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Reproductive system and breast disorders
Breast pain	3/27 (11.1%)	3	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Dysmenorrhoea	2/27 (7.4%)	2	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.