Diabetic Neuropathy
Conditions
Keywords
Diabetes, Pain, Neuropathy
Brief summary
To evaluate the effectiveness of DA-9801 at 300mg, 600mg, 900mg and placebo, in reducing pain in subjects with diabetic neuropathic pain compared to their baseline values.
Detailed description
This is a double-blind, randomized, parallel group, dose ranging, placebo-controlled study where eligible subjects (age 18 to 75 years) will have an average pain score ≥ 4 on an 11-point Likert numerical rating scale (NRS) for at least four days each week prior to randomization as assessed by daily pain diaries. Eligible subjects will be randomized to a 1:1:1:1 ratio to receive 300mg, 600mg, 900mg of DA-9801, or placebo three times a day for 12 weeks. During and at the end of the 12-week treatment period subjects will be evaluated for safety and efficacy parameters. A follow-up visit for safety will occur two weeks after the last treatment visit (TV). The Screening Phase (2 weeks) is designed to determine whether subjects are eligible to proceed to the Treatment Phase of the study and consists of a series of screening assessments designed to determine eligibility. Eligible subjects will undergo a two-week washout period for medications and therapies administered for pain management. At or up to 21 days before the Screening Visit, written informed consent from (ICF) the subject will be obtained by the Investigator or a suitably qualified designee before the performance of any protocol specific procedure. At the Screening Visit, the subject will be issued a daily diary in order to record daily pain level during the screening phase. The Treatment Phase (TV0 to TV12) begins with a series of assessments designed to confirm the subjects' continued eligibility. The site will collect the daily diary and the subject's pain score will be determined. Only subjects whose average pain score is ≥ 4 for at least four days each week will be randomized to any of the four treatment groups. DA-9801 administration schedule is three times per day, starting from TV0 to TV12. During this study phase subjects will be evaluated on a weekly basis. Efficacy evaluations each week will include the subject's global impression of improvement and CGI of pain. Safety evaluations during the Treatment Phase will consist of adverse event assessments at each visit. The Follow-up Visit (two weeks after last TV) The Follow-up Visit is designed to assess safety and will occur 14 days after the last TV. If the subject is withdrawn from the study prior to TV12, the subject should be exited from the study AFTER completing the specified assessments for that visit.
Interventions
DRUGDA-9801 300mg
300 mg of DA-9801 in tablet form, 100 mg to be taken 3 times daily for 12 weeks.
DRUGDA-9801 600mg
600 mg of DA-9801 in tablet form, 200 mg to be taken 3 times daily for 12 weeks.
DRUGDA-9801 900mg
900 mg of DA-9801 in tablet form, to be taken 300 mg to be taken 3 times daily for 12 weeks.
DRUGPlacebo
Placebo, in tablet form, to be taken 3 times daily for 12 weeks. The placebo is the same formulation as DA-9801 except that it does not contain the active pharmaceutical ingredient.
Sponsors
Dong-A ST Co., Ltd.
NeuroBo Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Must be 18 to 75 years of age * Diagnosed with Type I or Type II diabetes * HbA1c ≤ 12% at the time of screening * Has diabetic neuropathic pain (numbness, soreness, shooting or poking pain) in the lower extremities for more than 3 months prior to screening and with no adequate relief from other treatments * Has an average pain score of ≥ 4 for 24 hours at least 4 days out of the week prior to randomization as assessed by the 11-point Likert NRS. * If female of childbearing potential, subject must have a negative serum pregnancy test at screening * Understands and is willing to participate in the clinical study and can comply with study procedures and visits. * Normal cognitive and communicative ability as judged by clinical assessment and ability to complete self-reported questionnaires * Subject is willing and able to give informed consent
Exclusion criteria
* Evidence of another type of neuropathic pain caused by a condition other than diabetes * Pain from another source as severe or greater than the pain under study * BMI (Body Mass Index) \> 37 kg/m2 * Clinical signs of infection related to sores of any type on the legs * Subjects on any investigational drug(s) or therapeutic device(s) within 30 days preceding screening; or subject or physician anticipates use of any of these therapies by the subject during the course of the study * Previous participation in the Treatment Phase of this Protocol * History of drug or alcohol abuse, within the past 6 months * Malignant disease not in remission for 5 years or more that has been medically or surgically treated without evidence of metastases * Presence of one or more medical conditions, as determined by medical history, which seriously compromises the subject's ability to complete the study, including history of poor adherence with medical treatment, renal, hepatic, hematologic, active auto-immune or immune diseases that, in the opinion of the Investigator, would make the subject an inappropriate candidate for this study: c) One or more abnormal blood biochemistry analyte result that is ≥ 3 times that of the upper limit of the normal range; d) For laboratory results that are significantly lower than the normal range, specific criteria will be used to judge subject eligibility for randomization for Total protein, Albumin, and Hemoglobin or Platelets. * Known history of having Acquired Immunodeficiency Syndrome (AIDS) or with a history known to be infected with Human Immunodeficiency Virus (HIV) * New York Heart Association (NYHA) Class III and IV congestive heart failure (CHF), as defined by the following criteria: a)Class III: Symptoms with moderate exertion b)Class IV: Symptoms at rest * Pregnant or breast feeding * Women of child-bearing potential not using an effective birth control method. Women of child-bearing potential are defined as women physiologically capable of becoming pregnant, UNLESS they meet the following criteria: d) Post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels \> 40mIU/m, OR; e) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy, OR; f) Are using one or more of the following acceptable methods of contraception: surgical sterilization, hormonal contraception, and double-barrier methods. Reliable contraception should be maintained throughout the study and for 7 days after study discontinuation. * Subjects with a diagnosis of psychiatric disorders such as major depressive disorder, bipolar disorder, obsessive compulsive disorder, generalized anxiety, dysthymia or suicidality/suicide ideation * Administration of local anesthetic shot or systemic steroids within two months of screening * Subjects not willing to undergo a two-week washout period for pharmacologic and non-pharmacologic pain management techniques
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | Baseline to 12 weeks of treatment | Pain score was assessed by the subject using the 11-point Likert rating scale for pain (0=no pain to 10=worst possible pain) prior to conduct of any other study assessment. The change in clinic visit pain score at the 12-week visit was compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit | Baseline to 12 week treatment period | Pain intensity was assessed by the subject before any other protocol procedures at baseline and week 12 based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). The number of participants who had achieved ≥ a 30% reduction in pain from the baseline was to be compared between the treatment groups and placebo. |
| Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary | Baseline to 12 week treatment period | Average 24-hour pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum pain score for a week would be 0 and the maximum would be 70. Difference in the average weekly pain score at Week 12 is the score for each week minus the baseline . |
| Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary | Baseline to 12 week treatment period | Most severe 24-hour pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly most severe pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly pain score at Week 12 is the score at each week minus baseline . |
| Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary | Baseline to 12 week treatment period | Overnight pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly overnight pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly overnight pain score at Week 12 is the score at each week minus baseline |
| Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | Baseline and over 12 week treatment period | Pain intensity was assessed by the subject before any other protocol procedures at baseline and at the 12- week visit using an 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain) (Negative values indicate percentage reductions). |
| Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline to 12 week treatment period | Overnight pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly overnight pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly overnight pain score at Week 12 is the score at each week minus baseline |
| Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12 | Week 12 | PGI measures the subject's overall improvement in pain. The assessment was to be completed each week during the Treatment Phase. Global impression of improvement was assessed by the subject based on a 7 point scale (1-very much improved, 2-much improved, 3-minimally improved, 4-no change, 5-minimally worse, 6-much worse, 7-very much worse. Responders are defined as subjects with response of very much improved, much improved or minimally improved |
| Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12 | Week 12 | CGI measures global severity of illness at a given point of time and the improvement from baseline. The assessment was to be completed by the Investigator at baseline and each week during the treatment phase. CGI responders were defined as subjects achieving a score of: (1): Very much improved or (2): Much improved or (3): Minimally improved on the clinician-rated CGI global improvement item. |
| Average Weekly Rescue Medication Use | Week 1 to Week 12 | During the Treatment Periods, subjects taking 500 mg acetaminophen or Tylenol® for severe pain recorded the frequency and dosage in the daily diary. The use of 500 mg acetaminophen or Tylenol® was recorded for Morning, Afternoon or Evening time. For each subject, the total weekly rescue medication was calculated, and it was used to assess average weekly rescue medication use. |
| Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline to 12 week treatment period | Average weekly pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly pain score at Week 12 is the score at each week minus baseline. |
Countries
United States
Participant flow
Recruitment details
A total of 185 subjects were screened in this study from which, 128 subjects were randomized to the treatment groups, and 57 subjects were categorized as screen failure. Thirty-two (32) subjects were randomized to each of the four (4) study treatment groups: 900 mg DA-9801, 600 mg DA9801, 300 mg DA-9801 and placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo oral tablets three (3) times per day. | 32 |
| 300 mg DA-9801 Oral tablets three (3) times per day for total daily doses of 300 mg | 32 |
| 600 mg DA-9801 Oral tablets three (3) times per day for total daily doses of 600 mg | 32 |
| 900 mg DA-9801 Oral tablets three (3) times per day for total daily doses of 900 mg | 32 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
| Overall Study | Taking prohibited medication | 2 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | 600 mg DA-9801 | 900 mg DA-9801 | Total | Placebo | 300 mg DA-9801 |
|---|---|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 10.6 | 61.6 years STANDARD_DEVIATION 9.2 | 60.8 years STANDARD_DEVIATION 9.8 | 61.8 years STANDARD_DEVIATION 8.8 | 59.7 years STANDARD_DEVIATION 10.6 |
| Body Mass Index (BMI) | 31.8 kg/m^2 STANDARD_DEVIATION 3.5 | 31.2 kg/m^2 STANDARD_DEVIATION 3.9 | 31 kg/m^2 STANDARD_DEVIATION 3.9 | 30.2 kg/m^2 STANDARD_DEVIATION 3.9 | 30.8 kg/m^2 STANDARD_DEVIATION 4.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 7 Participants | 21 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 25 Participants | 107 Participants | 29 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 68.9 Inches STANDARD_DEVIATION 4 | 69.4 Inches STANDARD_DEVIATION 4.5 | 69 Inches STANDARD_DEVIATION 4.4 | 68.9 Inches STANDARD_DEVIATION 4.6 | 69 Inches STANDARD_DEVIATION 4.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 4 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 4 Participants | 22 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 24 Participants | 28 Participants | 101 Participants | 24 Participants | 25 Participants |
| Region of Enrollment United States | 32 participants | 32 participants | 128 participants | 32 participants | 32 participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 37 Participants | 10 Participants | 9 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 91 Participants | 22 Participants | 23 Participants |
| Weight | 217 lbs STANDARD_DEVIATION 31.3 | 215 lbs STANDARD_DEVIATION 41.2 | 211 lbs STANDARD_DEVIATION 37.6 | 205 lbs STANDARD_DEVIATION 41.9 | 207 lbs STANDARD_DEVIATION 35.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 32 | 21 / 32 | 16 / 32 | 8 / 32 |
| serious Total, serious adverse events | 3 / 32 | 0 / 32 | 2 / 32 | 0 / 32 |
Outcome results
Primary
Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS)
Pain score was assessed by the subject using the 11-point Likert rating scale for pain (0=no pain to 10=worst possible pain) prior to conduct of any other study assessment. The change in clinic visit pain score at the 12-week visit was compared to baseline.
Time frame: Baseline to 12 weeks of treatment
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 12 | 4 Scores on a scale | Standard Deviation 2.58 |
| Placebo | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 0 (Baseline) | 6.2 Scores on a scale | Standard Deviation 1.93 |
| 300 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 0 (Baseline) | 6.6 Scores on a scale | Standard Deviation 1.43 |
| 300 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 12 | 3.4 Scores on a scale | Standard Deviation 2.49 |
| 600 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 12 | 3.5 Scores on a scale | Standard Deviation 2.63 |
| 600 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 0 (Baseline) | 6.6 Scores on a scale | Standard Deviation 1.54 |
| 900 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 0 (Baseline) | 6.5 Scores on a scale | Standard Deviation 1.54 |
| 900 mg DA-9801 | Change in Clinic Visit Pain Score at the 12 Week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | TV 12 | 3.8 Scores on a scale | Standard Deviation 2.69 |
Secondary
Average Weekly Rescue Medication Use
During the Treatment Periods, subjects taking 500 mg acetaminophen or Tylenol® for severe pain recorded the frequency and dosage in the daily diary. The use of 500 mg acetaminophen or Tylenol® was recorded for Morning, Afternoon or Evening time. For each subject, the total weekly rescue medication was calculated, and it was used to assess average weekly rescue medication use.
Time frame: Week 1 to Week 12
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Average Weekly Rescue Medication Use | Week 5 | 1047 mg | Standard Deviation 3817 |
| Placebo | Average Weekly Rescue Medication Use | Week 7 | 1156 mg | Standard Deviation 3775 |
| Placebo | Average Weekly Rescue Medication Use | Week 9 | 1297 mg | Standard Deviation 4275 |
| Placebo | Average Weekly Rescue Medication Use | Week 11 | 1266 mg | Standard Deviation 4076 |
| Placebo | Average Weekly Rescue Medication Use | Week 3 | 1438 mg | Standard Deviation 3656 |
| Placebo | Average Weekly Rescue Medication Use | Week 8 | 1156 mg | Standard Deviation 3971 |
| Placebo | Average Weekly Rescue Medication Use | Week 4 | 1313 mg | Standard Deviation 4484 |
| Placebo | Average Weekly Rescue Medication Use | Week 6 | 1078 mg | Standard Deviation 3612 |
| Placebo | Average Weekly Rescue Medication Use | Week 2 | 1844 mg | Standard Deviation 4683 |
| Placebo | Average Weekly Rescue Medication Use | Week 12 | 1641 mg | Standard Deviation 5448 |
| Placebo | Average Weekly Rescue Medication Use | Week 1 | 1688 mg | Standard Deviation 3941 |
| Placebo | Average Weekly Rescue Medication Use | Week 10 | 1438 mg | Standard Deviation 4499 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 5 | 844 mg | Standard Deviation 2807 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 3 | 1391 mg | Standard Deviation 4666 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 4 | 563 mg | Standard Deviation 1384 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 7 | 906 mg | Standard Deviation 3254 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 10 | 1281 mg | Standard Deviation 4447 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 11 | 891 mg | Standard Deviation 3184 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 8 | 719 mg | Standard Deviation 3976 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 1 | 1469 mg | Standard Deviation 3617 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 2 | 1547 mg | Standard Deviation 3927 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 6 | 859 mg | Standard Deviation 3114 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 9 | 625 mg | Standard Deviation 2362 |
| 300 mg DA-9801 | Average Weekly Rescue Medication Use | Week 12 | 1109 mg | Standard Deviation 3638 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 10 | 93.8 mg | Standard Deviation 530 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 7 | 78.1 mg | Standard Deviation 314 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 9 | 125 mg | Standard Deviation 707 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 1 | 1625 mg | Standard Deviation 4849 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 4 | 531 mg | Standard Deviation 1905 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 3 | 1188 mg | Standard Deviation 3963 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 8 | 93.8 mg | Standard Deviation 390 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 5 | 375 mg | Standard Deviation 1621 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 2 | 2156 mg | Standard Deviation 5566 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 6 | 172 mg | Standard Deviation 577 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 12 | 93.8 mg | Standard Deviation 390 |
| 600 mg DA-9801 | Average Weekly Rescue Medication Use | Week 11 | 109 mg | Standard Deviation 619 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 12 | 344 mg | Standard Deviation 1125 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 5 | 578 mg | Standard Deviation 2703 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 7 | 891 mg | Standard Deviation 2999 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 11 | 516 mg | Standard Deviation 2256 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 1 | 2141 mg | Standard Deviation 5008 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 10 | 531 mg | Standard Deviation 2359 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 9 | 500 mg | Standard Deviation 1827 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 2 | 2375 mg | Standard Deviation 5414 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 3 | 1063 mg | Standard Deviation 2602 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 4 | 625 mg | Standard Deviation 1535 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 6 | 578 mg | Standard Deviation 2254 |
| 900 mg DA-9801 | Average Weekly Rescue Medication Use | Week 8 | 578 mg | Standard Deviation 1627 |
Secondary
Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary
Overnight pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly overnight pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly overnight pain score at Week 12 is the score at each week minus baseline
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 43.7 average weekly overnight pain score | Standard Deviation 11 |
| Placebo | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 29.4 average weekly overnight pain score | Standard Deviation 17 |
| Placebo | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 14.3 average weekly overnight pain score | Standard Deviation 14 |
| 300 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 19.9 average weekly overnight pain score | Standard Deviation 16.4 |
| 300 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 24.5 average weekly overnight pain score | Standard Deviation 15.6 |
| 300 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 44.4 average weekly overnight pain score | Standard Deviation 11.8 |
| 600 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 27.5 average weekly overnight pain score | Standard Deviation 19 |
| 600 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 46.5 average weekly overnight pain score | Standard Deviation 9.38 |
| 600 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 19 average weekly overnight pain score | Standard Deviation 18.1 |
| 900 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 16.9 average weekly overnight pain score | Standard Deviation 15.5 |
| 900 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 29.5 average weekly overnight pain score | Standard Deviation 19.4 |
| 900 mg DA-9801 | Change From Baseline Within Group-Difference in Average Weekly Overnight Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 46.4 average weekly overnight pain score | Standard Deviation 12.6 |
Secondary
Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary
Average weekly pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly pain score at Week 12 is the score at each week minus baseline.
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 28.3 average weekly pain score | Standard Deviation 16.8 |
| Placebo | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 14.3 average weekly pain score | Standard Deviation 13 |
| Placebo | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 42.7 average weekly pain score | Standard Deviation 10.7 |
| 300 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 19.8 average weekly pain score | Standard Deviation 16.3 |
| 300 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 45.9 average weekly pain score | Standard Deviation 9.1 |
| 300 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 26.1 average weekly pain score | Standard Deviation 17.1 |
| 600 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 17.9 average weekly pain score | Standard Deviation 18.1 |
| 600 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 46.3 average weekly pain score | Standard Deviation 10 |
| 600 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 28.4 average weekly pain score | Standard Deviation 18.1 |
| 900 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Change | 15.9 average weekly pain score | Standard Deviation 14.4 |
| 900 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Baseline | 44.2 average weekly pain score | Standard Deviation 11.3 |
| 900 mg DA-9801 | Change From Baseline Within Group- Difference in Average Weekly Pain Score Compared to Baseline as Assessed by Daily Diary | Week 12 | 28.3 average weekly pain score | Standard Deviation 18.5 |
Secondary
Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary
Most severe 24-hour pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly most severe pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly pain score at Week 12 is the score at each week minus baseline .
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary | 16 weekly most severe pain score | Standard Deviation 14.7 |
| 300 mg DA-9801 | Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary | 23.2 weekly most severe pain score | Standard Deviation 17.3 |
| 600 mg DA-9801 | Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary | 19.7 weekly most severe pain score | Standard Deviation 19.6 |
| 900 mg DA-9801 | Difference in Average Weekly Most Severe Pain Score Between Dose Groups as Assessed by Daily Diary | 18.9 weekly most severe pain score | Standard Deviation 15.9 |
Secondary
Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary
Overnight pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly overnight pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum possible pain score for a week would be 0 and the maximum possible would be 70. Difference in the average weekly overnight pain score at Week 12 is the score at each week minus baseline
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary | 14.3 average weekly overnight pain score | Standard Deviation 14 |
| 300 mg DA-9801 | Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary | 19.9 average weekly overnight pain score | Standard Deviation 16.4 |
| 600 mg DA-9801 | Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary | 19 average weekly overnight pain score | Standard Deviation 18.1 |
| 900 mg DA-9801 | Difference in Average Weekly Overnight Pain Score Between Dose Groups as Assessed by Daily Diary | 16.9 average weekly overnight pain score | Standard Deviation 15.5 |
Secondary
Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary
Average 24-hour pain intensity was assessed daily based on the 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Average weekly pain scores are defined as 7\* \[(Pain Day 1 + Pain Day 2 + …+ Pain Day n)\]/n where n is the number of available diary entries for the week. The minimum pain score for a week would be 0 and the maximum would be 70. Difference in the average weekly pain score at Week 12 is the score for each week minus the baseline .
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary | 14.3 Average weekly group pain score | Standard Deviation 13 |
| 300 mg DA-9801 | Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary | 19.8 Average weekly group pain score | Standard Deviation 16.3 |
| 600 mg DA-9801 | Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary | 17.9 Average weekly group pain score | Standard Deviation 18.1 |
| 900 mg DA-9801 | Difference in Average Weekly Pain Score Between Dose Groups as Assessed by Daily Diary | 15.9 Average weekly group pain score | Standard Deviation 14.4 |
Secondary
Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12
PGI measures the subject's overall improvement in pain. The assessment was to be completed each week during the Treatment Phase. Global impression of improvement was assessed by the subject based on a 7 point scale (1-very much improved, 2-much improved, 3-minimally improved, 4-no change, 5-minimally worse, 6-much worse, 7-very much worse. Responders are defined as subjects with response of very much improved, much improved or minimally improved
Time frame: Week 12
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12 | 18 Participants |
| 300 mg DA-9801 | Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12 | 20 Participants |
| 600 mg DA-9801 | Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12 | 22 Participants |
| 900 mg DA-9801 | Number of Participants Considered to be Responders on Global Impression of Improvement (PGI-I) at Week 12 | 16 Participants |
Secondary
Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12
CGI measures global severity of illness at a given point of time and the improvement from baseline. The assessment was to be completed by the Investigator at baseline and each week during the treatment phase. CGI responders were defined as subjects achieving a score of: (1): Very much improved or (2): Much improved or (3): Minimally improved on the clinician-rated CGI global improvement item.
Time frame: Week 12
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12 | 19 Participants |
| 300 mg DA-9801 | Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12 | 24 Participants |
| 600 mg DA-9801 | Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12 | 24 Participants |
| 900 mg DA-9801 | Number of Participants Number of Participants Considered to be Responders in Clinical Global Impression (CGI) at Week 12 | 21 Participants |
Secondary
Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit
Pain intensity was assessed by the subject before any other protocol procedures at baseline and week 12 based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). The number of participants who had achieved ≥ a 30% reduction in pain from the baseline was to be compared between the treatment groups and placebo.
Time frame: Baseline to 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit | 16 Participants |
| 300 mg DA-9801 | Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit | 20 Participants |
| 600 mg DA-9801 | Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit | 21 Participants |
| 900 mg DA-9801 | Number of Participants With at Least 30% Improvement Compared to Baseline as Assessed by the 11- Point Likert Numerical Rating Scale (NRS) at the Week 12 Clinic Visit | 17 Participants |
Secondary
Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS)
Pain intensity was assessed by the subject before any other protocol procedures at baseline and at the 12- week visit using an 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain) (Negative values indicate percentage reductions).
Time frame: Baseline and over 12 week treatment period
Population: Intent-to-Treat (ITT) population - defined as all subjects who were randomized and had an ICF. The ITT population was the primary population for the analysis of primary and secondary endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | -35.6 Percentage change | Standard Deviation 35.3 |
| 300 mg DA-9801 | Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | -45 Percentage change | Standard Deviation 42 |
| 600 mg DA-9801 | Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | -47 Percentage change | Standard Deviation 36.5 |
| 900 mg DA-9801 | Percentage Change in Clinic Visit Pain Score at the 12-week Visit Compared to Baseline as Assessed by the 11-point Likert Numerical Rating Scale (NRS) | -41.4 Percentage change | Standard Deviation 41.2 |