Trial Outcomes & Findings for Efficacy and Safety Study of ARC-4558 for Management of Pain Associated With Painful Diabetic Neuropathy (NCT NCT00695565)

NCT ID: NCT00695565

Last Updated: 2016-11-08

Results Overview

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS) through Day 84. Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain". The change in pain is represented as Week 12 minus Baseline, so greater negative numbers represent more improvement (more pain relief).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 180 participants
• Primary outcome timeframe: Baseline (average of Days -7 to -1) and Week 12 (Average of Days 78 to 84)
• Results posted on: 2016-11-08

Participant Flow

Subjects were recruited from May 2008 until September 2009. All study sites were medical clinics.

Subjects were required to meet all eligibility criteria at both the Screening and Baseline visits. If a subject met the Screening criteria but not the Baseline criteria, the subject was not eligible for enrollment. Two subjects were randomized but were not treated because they were found ineligible. They are not counted in the 180 enrolled.

Participant milestones

Measure	Placebo Gel Placebo Gel is vehicle without clonidine	Clonidine Topical Gel (ARC-4558) Clonidine Topical Gel contains 0.1% clonidine hydrochloride
Overall Study STARTED	90	90
Overall Study COMPLETED	77	81
Overall Study NOT COMPLETED	13	9

Reasons for withdrawal

Measure	Placebo Gel Placebo Gel is vehicle without clonidine	Clonidine Topical Gel (ARC-4558) Clonidine Topical Gel contains 0.1% clonidine hydrochloride
Overall Study Lost to Follow-up	4	4
Overall Study Adverse Event	3	1
Overall Study Protocol Violation	3	1
Overall Study Withdrawal by Subject	1	1
Overall Study Lack of Efficacy	1	1
Overall Study Subject did not follow instructions	1	1

Baseline Characteristics

Efficacy and Safety Study of ARC-4558 for Management of Pain Associated With Painful Diabetic Neuropathy

Baseline characteristics by cohort

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine	Clonidine Topical Gel (ARC-4558) n=90 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride	Total n=180 Participants Total of all reporting groups
Age, Continuous	57.6 years STANDARD_DEVIATION 9.5 • n=93 Participants	59.4 years STANDARD_DEVIATION 9.9 • n=4 Participants	58.5 years STANDARD_DEVIATION 9.7 • n=27 Participants
Sex: Female, Male Female	48 Participants n=93 Participants	46 Participants n=4 Participants	94 Participants n=27 Participants
Sex: Female, Male Male	42 Participants n=93 Participants	44 Participants n=4 Participants	86 Participants n=27 Participants
Region of Enrollment United States	90 participants n=93 Participants	90 participants n=4 Participants	180 participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline (average of Days -7 to -1) and Week 12 (Average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was mLOCF (modified Last Observation Carried Forward): LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication (in which case Baseline Observation Carried Forward (BOCF) was used).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS) through Day 84. Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain".

The change in pain is represented as Week 12 minus Baseline, so greater negative numbers represent more improvement (more pain relief).

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in the Average Daily Pain NPRS (Numeric Pain Rating Scale) Score; mLOCF Imputation All subjects	-1.9 units on a scale Standard Deviation 1.9	-2.4 units on a scale Standard Deviation 2.1
Change From Baseline to Week 12 in the Average Daily Pain NPRS (Numeric Pain Rating Scale) Score; mLOCF Imputation Capsaicin response ≥ 2	-1.5 units on a scale Standard Deviation 1.8	-2.7 units on a scale Standard Deviation 1.9

SECONDARY outcome

Timeframe: Baseline (average of Days -7 to -1) and Weeks 1 through 12 (weekly averages)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation)

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain". A weekly average was calculated from the daily scores for each week. The change in pain is represented as the average weekly score minus Baseline, so greater negative numbers represent more improvement (more pain relief).

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 1	-0.6 units on a scale Standard Deviation 1.01	-0.7 units on a scale Standard Deviation 1.34
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 2	-1.0 units on a scale Standard Deviation 1.30	-1.0 units on a scale Standard Deviation 1.45
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 3	-1.2 units on a scale Standard Deviation 1.47	-1.5 units on a scale Standard Deviation 1.58
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 4	-1.5 units on a scale Standard Deviation 1.63	-1.6 units on a scale Standard Deviation 1.71
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 5	-1.7 units on a scale Standard Deviation 1.77	-1.7 units on a scale Standard Deviation 1.65
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 6	-1.8 units on a scale Standard Deviation 1.84	-1.8 units on a scale Standard Deviation 1.74
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 7	-1.8 units on a scale Standard Deviation 1.83	-2.1 units on a scale Standard Deviation 1.86
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 8	-1.9 units on a scale Standard Deviation 1.93	-2.2 units on a scale Standard Deviation 1.92
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 9	-1.9 units on a scale Standard Deviation 1.96	-2.3 units on a scale Standard Deviation 1.95
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 10	-1.9 units on a scale Standard Deviation 1.98	-2.4 units on a scale Standard Deviation 2.06
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 11	-1.9 units on a scale Standard Deviation 1.93	-2.3 units on a scale Standard Deviation 2.12
Change From Baseline in Average Daily Pain NPRS Score for Each Week of Treatment; mLOCF Imputation Week 12	-1.9 units on a scale Standard Deviation 1.91	-2.4 units on a scale Standard Deviation 2.12

SECONDARY outcome

Timeframe: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale. Subjects were asked to record the worst pain in their feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain". The change in pain is represented as Week 12 minus Baseline, so greater negative numbers represent greater improvement (greater pain relief).

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in the Worst Daily Pain NPRS Score; mLOCF Imputation	-2.1 units on a scale Standard Deviation 2.1	-2.5 units on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain".

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Percentage of Subjects Who Experience at Least 30% Reduction in Average Daily Pain From Baseline; mLOCF Imputation	47 percentage of subjects	52 percentage of subjects

SECONDARY outcome

Timeframe: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated "no pain" and a score of 10 was "worst possible pain".

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Percentage of Subjects Who Experience at Least 50% Reduction in Average Daily Pain From Baseline; mLOCF Imputation	32 percentage of subjects	37 percentage of subjects

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The Brief Pain Inventory was completed by the subject at clinic visits. The Severity Scale (of 0 to 40) is a composite score, which is the sum of the individual ratings for worst pain, least pain, average pain, and current pain. Each individual question is rated on a scale of 0 to 10, where 0 indicates "No Pain" and 10 indicates "Pain as bad as you can imagine". The change in pain severity is represented as Week 12 minus Baseline, so greater negative numbers represent greater improvement (pain relief).

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline in the Brief Pain Inventory (BPI) Severity Scale at Week 12; mLOCF Imputation	-7.9 units on a scale Standard Deviation 8.5	-9.6 units on a scale Standard Deviation 8.7

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The Brief Pain Inventory was completed by the subject at clinic visits. The Functional Interference Scale (of 0 to 70) is a composite score that measures the degree to which pain interferes with mood, walking, work, relationships, sleep, general activity, and enjoyment of life. The composite score is a sum of the seven individual question scores. Each individual question is rated in reference to pain over the past 24 hours on a scale of 0 to 10, where 0 indicates that pain "does not interfere" and 10 indicates that pain "completely interferes" with that function, so lower scores represent better outcomes on this scale.

The change in functional interference is represented as Week 12 minus Baseline, so greater negative numbers represent more improvement.

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline in the Brief Pain Inventory Functional Interference Scale at Week 12; mLOCF Imputation	-15.1 units on a scale Standard Deviation 14.9	-17.3 units on a scale Standard Deviation 17.5

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

Subjects rated overall quality of sleep over the past week using a 100 mm Visual Analog Scale (VAS) where 100=Excellent and 0=Very Poor. This scale was completed during clinic visits. Change from Baseline is a positive value where quality of sleep improved.

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in Overall Quality of Sleep (Chronic Pain Sleep Inventory)	17.7 units on a scale Standard Deviation 33.4	19.2 units on a scale Standard Deviation 31.3

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The HADS was completed at the Baseline and Week 12 clinic visits. The Depression Score component of the HADS includes 7 questions, each with 4 possible answer choices (rated 0 to 3). The composite score is created by adding the scores of the 7 individual questions. A score of 0 to 7 is Normal, 8-10 indicates Mild Depression, 11-14 indicates Moderate Depression, and 15-21 indicates Severe Depression. The change from Baseline is calculated as the Week 12 composite score minus the Baseline composite score.

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in the Depression Score of the Hospital Anxiety and Depression Scale (HADS)	-0.4 units on a scale Standard Deviation 2.6	-0.9 units on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The HADS was completed at the Baseline and Week 12 clinic visits. The Anxiety Score component of the HADS includes 7 questions, each with 4 possible answer choices (rated 0 to 3). The composite score is created by adding the scores of the 7 individual questions. A score of 0 to 7 is Normal, 8-10 indicates Mild Anxiety, 11-14 indicates Moderate Anxiety, and 15-21 indicates Severe Anxiety. The change from Baseline is calculated as the Week 12 composite score minus the Baseline composite score.

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in the Anxiety Score of the Hospital Anxiety and Depression Scale (HADS)	-0.6 units on a scale Standard Deviation 2.67	-1.1 units on a scale Standard Deviation 3.14

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The McGill Pain Questionnaire asks subjects to rate 15 different kinds of pain, each on a scale of 0 to 3 (0=None, 1=Mild, 2=Moderate, 3=Severe). The total score is a sum of the individual ratings and has a range from 0 to 45, where higher numbers indicate more pain. The 15 types of pain assessed are throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, splitting, tiring-exhausting, sickening, fearful, and punishing-cruel. This scale was completed at the Baseline and Week 12 clinic visits. The change from Baseline is calculated as the Week 12 total score minus the Baseline total score, so greater negative numbers indicate more improvement (pain relief).

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=89 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change From Baseline to Week 12 in the McGill Pain Questionnaire (Short Form) Total Score	-7.3 units on a scale Standard Deviation 8.3	-8.7 units on a scale Standard Deviation 9.8

SECONDARY outcome

Timeframe: Week 12

Population: All subjects with a PGIC score were analyzed.

At Week 12 the subject was asked to rate their total improvement relative to Baseline, whether or not, in their judgement, it was due entirely to study drug treatment or not. Answer choices were: (+3) very much improved, (+2) much improved, (+1) minimally improved, (0) no change, (-1) minimally worse, (-2) much worse, (-3) very much worse.

Outcome measures

Measure	Placebo Gel n=85 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=85 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Patient Global Impression of Change (PGIC) at Week 12 Very Much Improved	11.8 percentage of subjects	21.2 percentage of subjects
Patient Global Impression of Change (PGIC) at Week 12 Much Improved	32.9 percentage of subjects	27.1 percentage of subjects
Patient Global Impression of Change (PGIC) at Week 12 Very Much Worse	1.2 percentage of subjects	0 percentage of subjects
Patient Global Impression of Change (PGIC) at Week 12 Minimally Improved	31.8 percentage of subjects	28.2 percentage of subjects
Patient Global Impression of Change (PGIC) at Week 12 No Change	21.2 percentage of subjects	22.4 percentage of subjects
Patient Global Impression of Change (PGIC) at Week 12 Minimally Worse	1.2 percentage of subjects	1.2 percentage of subjects

SECONDARY outcome

Timeframe: Week 12

Population: All subjects with a CGIC score were analyzed.

At Week 12, the Investigator was asked to independently rate the subject's total improvement relative to Baseline, whether or not, in their judgement, it was due entirely to study drug treatment or not. Answer choices were: (+3) very much improved, (+2) much improved, (+1) minimally improved, (0) no change, (-1) minimally worse, (-2) much worse, (-3) very much worse.

Outcome measures

Measure	Placebo Gel n=85 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=86 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Clinician Global Impression of Change (CGIC) at Week 12 Very Much Improved	5.8 percentage of subjects	16.5 percentage of subjects
Clinician Global Impression of Change (CGIC) at Week 12 Much Improved	38.4 percentage of subjects	30.6 percentage of subjects
Clinician Global Impression of Change (CGIC) at Week 12 Minimally Improved	27.9 percentage of subjects	24.7 percentage of subjects
Clinician Global Impression of Change (CGIC) at Week 12 No Change	25.6 percentage of subjects	27.1 percentage of subjects
Clinician Global Impression of Change (CGIC) at Week 12 Minimally Worse	2.3 percentage of subjects	1.2 percentage of subjects
Clinician Global Impression of Change (CGIC) at Week 12 Very Much Worse	0 percentage of subjects	0 percentage of subjects

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: ITT (Intent-to-Treat)

Systolic and Diastolic Blood Pressure were measured at clinic visits. This outcome assesses the change in blood pressure from Baseline to Week 12 of treatment.

Outcome measures

Measure	Placebo Gel n=90 Participants Placebo Gel is vehicle without clonidine; Subjects applied the gel to their feet 3 times daily starting on Day 1.	Clonidine Topical Gel (ARC-4558) n=90 Participants Clonidine Topical Gel contains 0.1% clonidine hydrochloride; Subjects applied the gel to their feet 3 times daily starting on Day 1.
Change in Blood Pressure From Baseline to Week 12 Change in Systolic BP	-0.4 mmHg Standard Deviation 20.6	1.0 mmHg Standard Deviation 13.9
Change in Blood Pressure From Baseline to Week 12 Change in Diastolic BP	-0.2 mmHg Standard Deviation 9.4	1.0 mmHg Standard Deviation 8.8

Adverse Events

Placebo Gel

Serious events: 3 serious events

Other events: 28 other events

Deaths: 0 deaths

Clonidine Topical Gel (ARC-4558)

Serious events: 3 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Gel n=90 participants at risk Placebo Gel is vehicle without clonidine	Clonidine Topical Gel (ARC-4558) n=90 participants at risk Clonidine Topical Gel contains 0.1% clonidine hydrochloride
Cardiac disorders Acute Coronary Syndrome	0.00% 0/90	1.1% 1/90 • Number of events 1
Cardiac disorders Atrial Fibrillation	0.00% 0/90	1.1% 1/90 • Number of events 1
Gastrointestinal disorders Abdominal Pain Upper	1.1% 1/90 • Number of events 1	0.00% 0/90
Gastrointestinal disorders Pancreatitis Acute	1.1% 1/90 • Number of events 1	0.00% 0/90
General disorders Chest Pain	1.1% 1/90 • Number of events 1	0.00% 0/90
Infections and infestations Abscess Neck	0.00% 0/90	1.1% 1/90 • Number of events 1
Infections and infestations Pneumonia	0.00% 0/90	1.1% 1/90 • Number of events 1

Other adverse events

Measure	Placebo Gel n=90 participants at risk Placebo Gel is vehicle without clonidine	Clonidine Topical Gel (ARC-4558) n=90 participants at risk Clonidine Topical Gel contains 0.1% clonidine hydrochloride
Nervous system disorders Headache	11.1% 10/90	6.7% 6/90
Musculoskeletal and connective tissue disorders Pain in Extremity	7.8% 7/90	3.3% 3/90
General disorders Pain	6.7% 6/90	0.00% 0/90
Infections and infestations Nasopharyngitis	4.4% 4/90	5.6% 5/90
Gastrointestinal disorders Toothache	1.1% 1/90	5.6% 5/90

Additional Information

Dr. James Campbell

Arcion Therapeutics, Inc.

Phone: (410) 522-8701

Email: jcampbell@arciontherapeutics.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Investigator may not publish or present any study information without the express written approval of the Sponsor. The Sponsor may withhold approval for publication or presentation.
• Publication restrictions are in place

Restriction type: OTHER