Trial Outcomes & Findings for Safety and Efficacy of EN3835 in Participants With Frozen Shoulder (NCT NCT04496167)

NCT ID: NCT04496167

Last Updated: 2023-09-13

Results Overview

Adapted ASES is a self-administered participant reported outcome measure, divided into 2 sections: pain and function. Pain subscale is a single item, 11-point numeric rating scale, ranging from 0 (no pain at all) to 10 (worst pain), calculated as 10 - pain raw score and multiplying by 5, score ranging from 0 (worst pain) to 50 (no pain). Function subscale consists of 10 activities, 4-point ordinal scale about their ability to do the activity with the affected arm, ranging from 0 (unable to do) to 3 (not difficult), calculated by multiplying total score for 10 items by 5 and then dividing it by 3, score range of 0 (no function) to 50 (full function). Adapted ASES composite score is the sum of the pain subscale score (50% of the composite score) and function subscale score (50% of the composite score), score range of 0 (worst pain) to 100 (least pain). Positive change from Baseline score means an improvement in pain and/or shoulder function.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 198 participants
• Primary outcome timeframe: Baseline, Day 95
• Results posted on: 2023-09-13

Participant Flow

Participant milestones

Measure	EN3835 Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Overall Study STARTED	102	96
Overall Study Received at Least 1 Dose of Study Drug	101	94
Overall Study COMPLETED	84	80
Overall Study NOT COMPLETED	18	16

Reasons for withdrawal

Measure	EN3835 Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Overall Study Adverse Event	6	2
Overall Study Withdrawal by Subject	7	6
Overall Study Lost to Follow-up	3	5
Overall Study Not Treated	1	2
Overall Study Other Than Specified	1	1

Baseline Characteristics

Safety and Efficacy of EN3835 in Participants With Frozen Shoulder

Baseline characteristics by cohort

Measure	EN3835 n=101 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=94 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Total n=195 Participants Total of all reporting groups
Age, Continuous	53.76 years STANDARD_DEVIATION 7.565 • n=5 Participants	55.50 years STANDARD_DEVIATION 7.806 • n=7 Participants	54.59 years STANDARD_DEVIATION 7.712 • n=5 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	66 Participants n=7 Participants	131 Participants n=5 Participants
Sex: Female, Male Male	36 Participants n=5 Participants	28 Participants n=7 Participants	64 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized Black	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Race/Ethnicity, Customized White	82 Participants n=5 Participants	72 Participants n=7 Participants	154 Participants n=5 Participants
Race/Ethnicity, Customized Other Race	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Multiple Race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	87 Participants n=5 Participants	78 Participants n=7 Participants	165 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Day 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment and had both Baseline and Day 95 measurements. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Adapted ASES is a self-administered participant reported outcome measure, divided into 2 sections: pain and function. Pain subscale is a single item, 11-point numeric rating scale, ranging from 0 (no pain at all) to 10 (worst pain), calculated as 10 - pain raw score and multiplying by 5, score ranging from 0 (worst pain) to 50 (no pain). Function subscale consists of 10 activities, 4-point ordinal scale about their ability to do the activity with the affected arm, ranging from 0 (unable to do) to 3 (not difficult), calculated by multiplying total score for 10 items by 5 and then dividing it by 3, score range of 0 (no function) to 50 (full function).

Adapted ASES composite score is the sum of the pain subscale score (50% of the composite score) and function subscale score (50% of the composite score), score range of 0 (worst pain) to 100 (least pain). Positive change from Baseline score means an improvement in pain and/or shoulder function.

Outcome measures

Measure	EN3835 n=84 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=82 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in the Adapted American Shoulder and Elbow Surgeons Shoulder Assessment Form (ASES) Composite Score for the Affected Shoulder at Day 95	41.35 score on a scale Standard Deviation 22.432	41.16 score on a scale Standard Deviation 21.942

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for forward flexion was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in Passive Range of Motion (PROM) for Forward Flexion in the Affected Shoulder Day 22	19.1 degrees Standard Deviation 24.88	13.9 degrees Standard Deviation 22.40
Change From Baseline in Passive Range of Motion (PROM) for Forward Flexion in the Affected Shoulder Day 43	25.6 degrees Standard Deviation 26.89	21.4 degrees Standard Deviation 20.14
Change From Baseline in Passive Range of Motion (PROM) for Forward Flexion in the Affected Shoulder Day 64	31.4 degrees Standard Deviation 26.31	27.3 degrees Standard Deviation 23.68
Change From Baseline in Passive Range of Motion (PROM) for Forward Flexion in the Affected Shoulder Day 95	32.8 degrees Standard Deviation 25.59	29.7 degrees Standard Deviation 27.08

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for internal rotation was measured using a goniometer and a spinal level. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=83 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Day 22	6.9 degrees Standard Deviation 23.95	7.0 degrees Standard Deviation 17.94
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Day 43	11.0 degrees Standard Deviation 25.97	12.4 degrees Standard Deviation 19.92
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Day 64	18.0 degrees Standard Deviation 24.65	18.3 degrees Standard Deviation 21.95
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Day 95	19.9 degrees Standard Deviation 22.59	21.6 degrees Standard Deviation 23.11

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for external rotation was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for External Rotation in the Affected Shoulder Day 22	7.3 degrees Standard Deviation 19.39	8.8 degrees Standard Deviation 15.61
Change From Baseline in PROM for External Rotation in the Affected Shoulder Day 43	11.2 degrees Standard Deviation 20.98	14.5 degrees Standard Deviation 18.87
Change From Baseline in PROM for External Rotation in the Affected Shoulder Day 64	17.4 degrees Standard Deviation 24.87	17.8 degrees Standard Deviation 17.87
Change From Baseline in PROM for External Rotation in the Affected Shoulder Day 95	19.1 degrees Standard Deviation 21.24	19.2 degrees Standard Deviation 18.20

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for abduction was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Abduction in the Affected Shoulder Day 22	15.6 degrees Standard Deviation 28.47	13.1 degrees Standard Deviation 23.89
Change From Baseline in PROM for Abduction in the Affected Shoulder Day 43	29.6 degrees Standard Deviation 30.19	18.9 degrees Standard Deviation 27.13
Change From Baseline in PROM for Abduction in the Affected Shoulder Day 64	35.6 degrees Standard Deviation 36.76	31.1 degrees Standard Deviation 29.27
Change From Baseline in PROM for Abduction in the Affected Shoulder Day 95	42.1 degrees Standard Deviation 38.17	36.0 degrees Standard Deviation 33.35

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for shoulder extension was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Day 43	8.0 degrees Standard Deviation 18.34	9.2 degrees Standard Deviation 16.93
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Day 22	3.9 degrees Standard Deviation 16.51	5.7 degrees Standard Deviation 13.54
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Day 64	15.2 degrees Standard Deviation 18.44	12.0 degrees Standard Deviation 17.23
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Day 95	20.3 degrees Standard Deviation 18.30	14.7 degrees Standard Deviation 17.15

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for forward flexion was measured using a goniometer. PROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. PROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-34.48 degrees Standard Deviation 29.067	-37.33 degrees Standard Deviation 27.179
Change From Baseline in PROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-28.34 degrees Standard Deviation 27.939	-30.24 degrees Standard Deviation 26.369
Change From Baseline in PROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-22.14 degrees Standard Deviation 27.983	-23.01 degrees Standard Deviation 24.200
Change From Baseline in PROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-20.82 degrees Standard Deviation 26.245	-21.06 degrees Standard Deviation 25.198

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for internal rotation was measured using a goniometer and a spinal level. PROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. PROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=83 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-30.76 degrees Standard Deviation 24.692	-28.51 degrees Standard Deviation 24.930
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-26.81 degrees Standard Deviation 24.950	-22.03 degrees Standard Deviation 24.311
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-20.50 degrees Standard Deviation 21.561	-16.88 degrees Standard Deviation 24.096
Change From Baseline in PROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-18.22 degrees Standard Deviation 21.444	-13.49 degrees Standard Deviation 26.037

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for external rotation was measured using a goniometer PROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. PROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-35.12 degrees Standard Deviation 22.928	-35.49 degrees Standard Deviation 23.027
Change From Baseline in PROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-31.30 degrees Standard Deviation 25.102	-29.40 degrees Standard Deviation 25.727
Change From Baseline in PROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-24.46 degrees Standard Deviation 26.063	-26.08 degrees Standard Deviation 24.494
Change From Baseline in PROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-22.94 degrees Standard Deviation 22.153	-25.06 degrees Standard Deviation 23.844

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for abduction was measured using a goniometer. PROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. PROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-54.90 degrees Standard Deviation 40.162	-57.56 degrees Standard Deviation 35.565
Change From Baseline in PROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-41.37 degrees Standard Deviation 39.918	-53.17 degrees Standard Deviation 36.106
Change From Baseline in PROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-34.87 degrees Standard Deviation 39.860	-41.48 degrees Standard Deviation 37.136
Change From Baseline in PROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-28.91 degrees Standard Deviation 41.483	-36.54 degrees Standard Deviation 41.288

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

PROM for shoulder extension was measured using a goniometer. PROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. PROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-18.82 degrees Standard Deviation 21.558	-17.11 degrees Standard Deviation 19.106
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-14.99 degrees Standard Deviation 22.313	-14.01 degrees Standard Deviation 20.363
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-7.97 degrees Standard Deviation 22.633	-9.91 degrees Standard Deviation 18.869
Change From Baseline in PROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-2.87 degrees Standard Deviation 20.756	-7.33 degrees Standard Deviation 17.676

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for forward flexion was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in Active Range of Motion (AROM) for Forward Flexion in the Affected Shoulder Day 22	13.6 degrees Standard Deviation 26.28	13.0 degrees Standard Deviation 26.55
Change From Baseline in Active Range of Motion (AROM) for Forward Flexion in the Affected Shoulder Day 43	21.9 degrees Standard Deviation 30.00	22.3 degrees Standard Deviation 26.17
Change From Baseline in Active Range of Motion (AROM) for Forward Flexion in the Affected Shoulder Day 64	27.7 degrees Standard Deviation 25.47	29.6 degrees Standard Deviation 28.85
Change From Baseline in Active Range of Motion (AROM) for Forward Flexion in the Affected Shoulder Day 95	31.7 degrees Standard Deviation 25.31	30.1 degrees Standard Deviation 31.20

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for internal rotation was measured using a goniometer and a spinal level. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=83 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Day 22	7.5 degrees Standard Deviation 20.45	5.8 degrees Standard Deviation 19.12
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Day 43	9.1 degrees Standard Deviation 22.13	10.2 degrees Standard Deviation 20.40
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Day 64	18.4 degrees Standard Deviation 22.44	17.5 degrees Standard Deviation 21.55
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Day 95	19.6 degrees Standard Deviation 21.99	21.6 degrees Standard Deviation 23.87

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: All randomized participants who received at least 1 injection of study treatment who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment and had both Baseline and measurements at specified timepoints.

AROM for external rotation was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for External Rotation in the Affected Shoulder Day 22	5.3 degrees Standard Deviation 16.85	5.6 degrees Standard Deviation 14.79
Change From Baseline in AROM for External Rotation in the Affected Shoulder Day 43	8.7 degrees Standard Deviation 19.59	10.0 degrees Standard Deviation 19.12
Change From Baseline in AROM for External Rotation in the Affected Shoulder Day 64	13.9 degrees Standard Deviation 22.18	15.4 degrees Standard Deviation 21.65
Change From Baseline in AROM for External Rotation in the Affected Shoulder Day 95	16.8 degrees Standard Deviation 21.67	16.1 degrees Standard Deviation 21.00

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for abduction was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Abduction in the Affected Shoulder Day 22	14.2 degrees Standard Deviation 30.75	13.7 degrees Standard Deviation 23.17
Change From Baseline in AROM for Abduction in the Affected Shoulder Day 43	26.6 degrees Standard Deviation 37.79	22.2 degrees Standard Deviation 27.93
Change From Baseline in AROM for Abduction in the Affected Shoulder Day 64	37.2 degrees Standard Deviation 35.60	33.3 degrees Standard Deviation 30.53
Change From Baseline in AROM for Abduction in the Affected Shoulder Day 95	42.0 degrees Standard Deviation 37.71	39.8 degrees Standard Deviation 31.79

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for shoulder extension was measured using a goniometer. Positive change from Baseline means an improvement.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=83 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Day 22	7.0 degrees Standard Deviation 17.37	8.5 degrees Standard Deviation 15.84
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Day 43	13.7 degrees Standard Deviation 21.63	12.0 degrees Standard Deviation 16.72
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Day 64	16.2 degrees Standard Deviation 19.29	15.3 degrees Standard Deviation 16.70
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Day 95	19.7 degrees Standard Deviation 19.91	17.3 degrees Standard Deviation 17.17

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for forward flexion was measured using a goniometer. AROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. AROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-38.34 degrees Standard Deviation 30.007	-40.72 degrees Standard Deviation 24.602
Change From Baseline in AROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-31.00 degrees Standard Deviation 29.397	-32.17 degrees Standard Deviation 24.879
Change From Baseline in AROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-23.62 degrees Standard Deviation 29.115	-23.82 degrees Standard Deviation 23.083
Change From Baseline in AROM for Forward Flexion in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-19.83 degrees Standard Deviation 26.729	-23.39 degrees Standard Deviation 24.774

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for internal rotation was measured using a goniometer and a spinal level. AROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. AROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=86 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-30.53 degrees Standard Deviation 24.699	-27.94 degrees Standard Deviation 24.757
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-29.78 degrees Standard Deviation 24.728	-23.45 degrees Standard Deviation 24.923
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-20.57 degrees Standard Deviation 23.335	-16.99 degrees Standard Deviation 24.708
Change From Baseline in AROM for Internal Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-19.27 degrees Standard Deviation 23.646	-12.66 degrees Standard Deviation 27.685

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for external rotation was measured using a goniometer. AROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. AROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-34.78 degrees Standard Deviation 25.743	-35.82 degrees Standard Deviation 22.666
Change From Baseline in AROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-31.07 degrees Standard Deviation 29.543	-31.23 degrees Standard Deviation 23.379
Change From Baseline in AROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-25.31 degrees Standard Deviation 28.454	-25.84 degrees Standard Deviation 26.291
Change From Baseline in AROM for External Rotation in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-22.52 degrees Standard Deviation 26.313	-25.42 degrees Standard Deviation 26.075

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for abduction was measured using a goniometer. AROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. AROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-58.41 degrees Standard Deviation 38.888	-57.28 degrees Standard Deviation 36.353
Change From Baseline in AROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-46.14 degrees Standard Deviation 41.198	-49.32 degrees Standard Deviation 34.988
Change From Baseline in AROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-35.08 degrees Standard Deviation 36.868	-39.82 degrees Standard Deviation 38.397
Change From Baseline in AROM for Abduction in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-30.74 degrees Standard Deviation 38.227	-33.01 degrees Standard Deviation 39.718

SECONDARY outcome

Timeframe: Baseline, Days 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

AROM for shoulder extension was measured using a goniometer. AROM measurements for the contralateral (unaffected) shoulder were taken at Baseline. AROM measurements of the affected shoulder were take at Baseline, Days 22, 43, 64, and 95.

Baseline Value = Measurement at Baseline in Affected Shoulder- Measurement at Baseline Contralateral Unaffected Shoulder

Change from baseline was calculated as:

(Measurement at Visit in Affected Shoulder - Measurement at Baseline Contralateral Shoulder) - Baseline Value

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=84 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 22	-13.65 degrees Standard Deviation 19.893	-15.25 degrees Standard Deviation 21.385
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 43	-7.55 degrees Standard Deviation 20.771	-11.65 degrees Standard Deviation 20.674
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 64	-4.29 degrees Standard Deviation 20.214	-6.94 degrees Standard Deviation 20.775
Change From Baseline in AROM for Shoulder Extension in the Affected Shoulder Compared to the Contralateral (Unaffected) Shoulder at Baseline Day 95	-1.00 degrees Standard Deviation 18.904	-5.34 degrees Standard Deviation 20.922

SECONDARY outcome

Timeframe: Baseline, Day 22, 43, and 64

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

The adapted ASES is a self-administered participant reported outcome measure, divided into 2 sections: pain and function. Pain subscale is a single item, 11-point numeric rating scale, ranging from (no pain at all) to 10 (worst pain), calculated as 10 - pain raw score and multiplying by 5, score ranging from 0 (worst pain) to 50 (no pain). Function subscale consists of 10 activities, 4-point ordinal scale about their ability to do the activity with the affected arm, ranging from 0 (unable to do) to 3 (not difficult), calculated by multiplying the total score for 10 items by 5 and then dividing it by 3, score ranging from 0 (no function) to 50 (full function).

The adapted ASES composite score is the sum of the pain subscale score (50% of the composite score) and function subscale score (50% of the composite score). The range for composite score is 0 (worst pain) to 100 (least pain). Positive change from Baseline score means an improvement in pain and/or shoulder function.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in the Adapted ASES Composite Score Day 22	14.87 score on a scale Standard Deviation 15.684	15.96 score on a scale Standard Deviation 14.269
Change From Baseline in the Adapted ASES Composite Score Day 43	25.15 score on a scale Standard Deviation 21.532	21.77 score on a scale Standard Deviation 18.199
Change From Baseline in the Adapted ASES Composite Score Day 64	38.21 score on a scale Standard Deviation 22.837	34.98 score on a scale Standard Deviation 21.222

SECONDARY outcome

Timeframe: Baseline, Day 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

The adapted ASES function subscale consists of 10 activities, 4-point ordinal scale about their ability to do the activity with the affected arm, ranging from 0 (unable to do) to 3 (not difficult), calculated by multiplying the total score for 10 items by 5 and then dividing it by 3, score ranging from 0 (worst no function) to 50 (full function).

Positive change from Baseline score means an improvement in shoulder function.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in the Adapted ASES Function Subscale Score Day 64	19.60 score on a scale Standard Deviation 12.127	17.98 score on a scale Standard Deviation 11.337
Change From Baseline in the Adapted ASES Function Subscale Score Day 95	21.05 score on a scale Standard Deviation 11.538	20.73 score on a scale Standard Deviation 11.823
Change From Baseline in the Adapted ASES Function Subscale Score Day 22	7.56 score on a scale Standard Deviation 8.245	7.96 score on a scale Standard Deviation 7.388
Change From Baseline in the Adapted ASES Function Subscale Score Day 43	12.82 score on a scale Standard Deviation 10.365	11.77 score on a scale Standard Deviation 9.964

SECONDARY outcome

Timeframe: Baseline, Day 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

The adapted ASES pain subscale is a single item, 11-point numeric rating scale, ranging from (no pain at all) to 10 (worst pain), calculated as 10 - pain raw score and multiplying by 5, score ranging from 0 (worst pain) to 50 (no pain). Positive change from Baseline score means an improvement in shoulder pain.

Outcome measures

Measure	EN3835 n=91 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=85 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in the Adapted ASES Pain Subscale Score Day 22	7.3 score on a scale Standard Deviation 9.61	8.0 score on a scale Standard Deviation 9.49
Change From Baseline in the Adapted ASES Pain Subscale Score Day 43	12.3 score on a scale Standard Deviation 12.73	10.0 score on a scale Standard Deviation 11.87
Change From Baseline in the Adapted ASES Pain Subscale Score Day 64	18.6 score on a scale Standard Deviation 12.67	17.0 score on a scale Standard Deviation 12.29
Change From Baseline in the Adapted ASES Pain Subscale Score Day 95	20.3 score on a scale Standard Deviation 13.11	20.4 score on a scale Standard Deviation 12.28

SECONDARY outcome

Timeframe: Baseline, Days 64 and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

The PUM scale is a single item 11-point numerical rating scale of pain in the affected shoulder after AROM forward flexion, internal rotation, external rotation, abduction, and shoulder extension on a scale from 0 (no pain at all) to 10 (pain as bad as it can be). A decrease from Baseline indicates improvement.

Outcome measures

Measure	EN3835 n=88 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=82 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in the Pain Upon Movement (PUM) Scale Score for the Affected Shoulder Day 64	-3.6 score on a scale Standard Deviation 2.60	-3.0 score on a scale Standard Deviation 2.72
Change From Baseline in the Pain Upon Movement (PUM) Scale Score for the Affected Shoulder Day 95	-4.1 score on a scale Standard Deviation 2.59	-3.8 score on a scale Standard Deviation 2.96

SECONDARY outcome

Timeframe: Baseline, Day 22, 43, 64, and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had both Baseline and measurements at specified timepoints).

The Patient-reported Global Severity of Adhesive Capsulitis is a single item, 11-point numerical rating scale that asks participants to rate the overall severity of their adhesive capsulitis symptoms on a scale from 0 (no severity) to 10 (severe as can be). A decrease from Baseline indicates improvement.

Outcome measures

Measure	EN3835 n=90 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=84 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Change From Baseline in Patient-reported Global Severity of Adhesive Capsulitis Scale Day 22	-1.8 score on a scale Standard Deviation 1.84	-1.5 score on a scale Standard Deviation 1.87
Change From Baseline in Patient-reported Global Severity of Adhesive Capsulitis Scale Day 43	-3.0 score on a scale Standard Deviation 2.21	-2.3 score on a scale Standard Deviation 2.16
Change From Baseline in Patient-reported Global Severity of Adhesive Capsulitis Scale Day 64	-4.0 score on a scale Standard Deviation 2.41	-3.6 score on a scale Standard Deviation 2.61
Change From Baseline in Patient-reported Global Severity of Adhesive Capsulitis Scale Day 95	-4.4 score on a scale Standard Deviation 2.48	-4.0 score on a scale Standard Deviation 2.87

SECONDARY outcome

Timeframe: Days 22, 43, 64 and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had measurement at specified timepoint).

The Patient-reported Change in Severity of Adhesive Capsulitis is a questionnaire that asks participants if their adhesive capsulitis symptoms are "Better, About the Same, or Worse" since the last time the questionnaire was administered. Participants who reported that their symptoms are better or worse are then asked to rate the change in their symptoms on a 7-point ordinal scale for worse and better severity. An overall severity of worse was rated from 0 (almost the same, hardly worse at all) to -6 (a very great deal worse). An overall severity of better was rated from 0 (almost the same, hardly better at all) to 6 (a very great deal better).

Only participants with a response of 'Worse' or 'Better' were analyzed. Participants with an overall severity response of 'About the same' were excluded from the summary table below. For overall worse severity, a lower score indicated a worse outcome. For overall better severity, a higher score indicated a better outcome.

Outcome measures

Measure	EN3835 n=72 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=69 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 22: Worse Severity	-3.4 score on a scale Standard Deviation 1.52	-3.2 score on a scale Standard Deviation 2.23
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 64: Better Severity	4.5 score on a scale Standard Deviation 1.29	4.2 score on a scale Standard Deviation 1.40
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 95: Better Severity	4.7 score on a scale Standard Deviation 1.27	4.7 score on a scale Standard Deviation 1.09
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 22: Better Severity	2.4 score on a scale Standard Deviation 1.40	2.5 score on a scale Standard Deviation 1.29
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 43: Worse Severity	-3.3 score on a scale Standard Deviation 1.53	-4.0 score on a scale Standard Deviation 2.16
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 43: Better Severity	3.4 score on a scale Standard Deviation 1.46	3.6 score on a scale Standard Deviation 1.44
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 64: Worse Severity	—	-4.8 score on a scale Standard Deviation 0.50
Patient-reported Change in Severity of Adhesive Capsulitis Scale Day 95: Worse Severity	—	-3.5 score on a scale Standard Deviation 1.91

SECONDARY outcome

Timeframe: Days 64 and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had measurement at specified timepoint).

Investigator assessment of improvement with treatment in the severity of the participant's treated shoulder using a 7-point Likert scale from very much worse (-3) to very much improved (3). A responder was defined as a response of "very much improved", "much improved" or "minimally improved" in the investigator assessment of improvement with treatment.

Outcome measures

Measure	EN3835 n=82 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=73 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Number of Responders Assessed With Investigator Assessment of Improvement Day 95	80 Participants	65 Participants
Number of Responders Assessed With Investigator Assessment of Improvement Day 64	71 Participants	59 Participants

SECONDARY outcome

Timeframe: Days 64 and 95

Population: Modified intent-to-treat population included all randomized participants who received at least 1 injection of study treatment and who had a valid baseline adapted ASES composite score in the affected shoulder and at least 1 valid adapted ASES composite score after the injection of the study treatment. Here, number analyzed = participants evaluable at specified time-point (had measurement at specified timepoint).

Participants rated their satisfaction with treatment on a 7-point Likert scale from very dissatisfied (-3) to very satisfied (3) at specified times for relief of pain in treated shoulder, relief of stiffness in treated shoulder, relief of pain in treated shoulder compared to better shoulder, and relief of stiffness in treated shoulder compared to better shoulder. A responder was defined as a participant with a response of "very satisfied", "satisfied" or "somewhat satisfied" in the satisfaction with treatment.

Outcome measures

Measure	EN3835 n=88 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=82 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 64: Pain relief in treated shoulder compared to better shoulder	74 Participants	57 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 64: Pain relief in treated shoulder	80 Participants	60 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 64: Stiffness relief in treated shoulder	74 Participants	59 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 95: Stiffness relief in treated shoulder	71 Participants	69 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 64: Stiffness relief in treated shoulder compared to better shoulder	73 Participants	54 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 95: Pain relief in treated shoulder	73 Participants	69 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 95: Pain relief in treated shoulder compared to better shoulder	71 Participants	68 Participants
Number of Responders Assessed by the Subject Satisfaction With Treatment Assessment Day 95: Stiffness relief in treated shoulder compared to better shoulder	68 Participants	65 Participants

SECONDARY outcome

Timeframe: Day 95

Population: Safety population included all participants who received at least 1 dose of study drug and had an assessment at the specified timepoint. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Serum samples were collected and tested for the presence of anti-AUX-I and anti-AUX-II antibodies.

Outcome measures

Measure	EN3835 n=83 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=72 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Number of Participants Positive for Anti-AUX-I and Anti-AUX-II Antibodies Anti-AUX-I Antibodies	83 Participants	3 Participants
Number of Participants Positive for Anti-AUX-I and Anti-AUX-II Antibodies Anti-AUX-II Antibodies	81 Participants	3 Participants

SECONDARY outcome

Timeframe: Day 95

Population: All participants who received at least 1 dose of study drug, were positive for anti-AUX-I and anti-AUX-II antibodies and had an assessment at the specified timepoint. Here, overall number of participants analyzed = participants evaluable for this outcome measure. Only samples positive for anti-AUX-I and anti-AUX-II antibodies were analyzed for neutralizing antibodies.

Serum samples were collected and tested for the presence of anti-AUX-I and anti-AUX-II antibodies. Only samples positive for anti-AUX-I and anti-AUX-II antibodies were analyzed for neutralizing antibodies.

Outcome measures

Measure	EN3835 n=83 Participants Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=3 Participants Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Number of Participants Positive for Neutralizing Antibodies Neutralizing AUX-II Antibodies	4 Participants	0 Participants
Number of Participants Positive for Neutralizing Antibodies Neutralizing AUX-I Antibodies	31 Participants	0 Participants

Adverse Events

EN3835

Serious events: 1 serious events

Other events: 69 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Measure	EN3835 n=101 participants at risk Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=94 participants at risk Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
Psychiatric disorders Depression	0.99% 1/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	0.00% 0/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.
Injury, poisoning and procedural complications Fall	0.00% 0/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	1.1% 1/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.

Other adverse events

Measure	EN3835 n=101 participants at risk Participants received EN3835 (up to 1.74 mg total) by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.	Placebo n=94 participants at risk Participants received placebo by pericapsular (periarticular) injection in up to 3 treatment sessions at least 21 days apart.
General disorders Injection site bruising	46.5% 47/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	4.3% 4/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.
General disorders Injection site pain	22.8% 23/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	10.6% 10/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	22.8% 23/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	12.8% 12/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.
General disorders Injection site swelling	13.9% 14/101 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.	2.1% 2/94 • Day 1 (after dosing) through Day 95 Safety population included all participants who received at least 1 dose of study treatment.

Additional Information

Clinical Operations

Endo Pharmaceuticals

Phone: 800-462-3636

Email: clinicaltrials@endo.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place