Efficacy and Safety of Two Treatment Algorithms in Adults With Moderate to Severe Crohn's Disease

Study Overview
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Brief Summary
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The primary objective of this study was to demonstrate that tight control of disease activity, using stringent criteria based on Crohn's disease activity Index (CDAI), biomarkers (high sensitivity C-reactive protein [hs-CRP] and fecal calprotectin), and corticosteroid use, improves the rate of mucosal healing 48 weeks after randomization compared with management using less stringent criteria based only on CDAI and corticosteroid use.

Detailed Description
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The study included a 1- to 3-week screening period, up to 8 weeks of prednisone run-in treatment, a 48-week post-randomization treatment period, and a 70 day follow-up phone call or clinic visit, for a total duration of up to 69 weeks. Participants who met entry criteria were enrolled and initiated an oral prednisone regimen at Baseline (Week 0). At the first key visit, participants were randomized into 1 of 2 groups (Tight Control group or Clinically Driven group), with stratification according to screening smoking status, weight, and disease duration. The first key visit was the randomization visit; subsequent key visits occurred every 12 weeks following the first key visit. Randomization normally took place 9 weeks after Baseline. However, participants who fulfilled the early randomization criteria may have been randomized as early as the Baseline (Week 0) visit. Therapeutic option changes, if appropriate, occurred at key visits based on results from previous success criteria visits.

Official Title
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An Open-Label, Multicenter, Efficacy and Safety Study to Evaluate Two Treatment Algorithms in Subjects With Moderate to Severe Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Biological: Adalimumab
* Drug: Prednisone
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ileal, colonic (including rectal), or ileocolonic Crohn's disease (CD) confirmed using imaging technology or endoscopy not more than 6 years prior to Baseline. CDAI score of greater than or equal to 220 and less than or equal to 450 at the Baseline visit in participants not receiving prednisone or equivalent at Baseline. CDAI score of greater than or equal to 200 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone less than or equal to 20 mg or equivalent for at least 7 days before Baseline. CDAI score of greater than 150 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone higher than 20 mg or equivalent for greater than or equal to 7 days before Baseline Participant or his/her legal representative have voluntarily signed and dated an informed consent approved by and compliant with the requirements of this study protocol which has been approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC). Adequate cardiac, renal and hepatic function as determined by the Principal Investigator and demonstrated by Screening laboratory evaluations, questionnaires and physical examination results that do not indicate an abnormal clinical condition which would place the participant at undue risk and thus preclude participation in the study. Participant must be able to self-inject and orally administer study medication or have a designee or Healthcare Professional who can assist Exclusion Criteria: Previous or current biologic use for Crohn's disease or participation in a biologic study Previous or current use of immunomodulators (e.g., methotrexate, azathioprine, 6-mercaptopurine, JAK inhibitor, alpha-integrin) for Crohn's disease or participation in a Crohn's disease study with immunomodulator(s). Current use of immunomodulators for non-Crohn's disease at Baseline. Greater than two previous courses of corticosteroid (systemic corticosteroid) or budesonide) for Crohn's Disease. A course is defined as 1) total duration for burst and taper ≥ 4 weeks and 2) prednisone or equivalent ≥ 40 mg (or budesonide ≥ 9 mg) for at least 2 weeks. Participants with a poorly controlled medical condition such as: uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association [NYHA] class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator or the sponsor, would put the participant at risk by participation in the protocol Participants with positive C. difficile stool assay at Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tight Control Management<br>Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week. | Biological: Adalimumab<br>* If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.<br>* Other names: Humira;Drug: Prednisone<br>* The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.<br>Drug: Azathioprine<br>* Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.<br>|
| Active Comparator: Clinically Driven Management<br>Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified failure criteria using less stringent criteria: At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week. | Biological: Adalimumab<br>* If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.<br>* Other names: Humira;Drug: Prednisone<br>* The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.<br>Drug: Azathioprine<br>* Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Mucosal Healing and No Deep Ulcerations | Percentage of participants with mucosal healing (defined as Crohn's disease endoscopy Index of severity [CDEIS] < 4) and no deep ulcerations on ileocolonoscopy (defined as the absence of all deep ulcerations in all segments explored in CDEIS) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after Randomization were counted as non-responders. | 48 weeks after Randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Deep Remission 48 Weeks After Randomization | Deep remission was defined as CDAI < 150, discontinuation from steroids for at least 8 weeks, absence of draining fistula, CDEIS < 4 and no deep ulcerations. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after randomization were counted as non-responders. | 48 weeks after Randomization | 
| Percentage of Participants in Biologic Remission 48 Weeks After Randomization | Biologic remission was defined as high sensitivity C-reactive protein (hs-CRP) < 5 mg/L, fecal Calprotectin < 250 μg/g, and CDEIS < 4 at 48 weeks after randomization. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. | 48 weeks after Randomization | 
| Percentage of Participants With Mucosal Healing 48 Weeks After Randomization | Percentage of participants with mucosal healing (defined as a CDEIS < 4) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. | 48 weeks after Randomization | 
| Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization | Percentage of participants with mucosal healing (defined as CDEIS < 4) and CDEIS < 4 in every segment on ileocolonoscopy at 48 weeks after randomization. The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders. | 48 weeks after Randomization | 
| Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization | Complete mucosal healing was defined as CDEIS = 0. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders. | 48 weeks after Randomization | 
| Percentage of Participants With Endoscopic Response 48 Weeks After Randomization | Endoscopic response was defined as a decrease CDEIS > 5 points. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. | 48 weeks after Randomization | 
| Change From Baseline in CDEIS at 48 Weeks After Randomization | CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. A negative change from Baseline indicates improvement. | Baseline and 48 weeks after Randomization | 
| Change From Baseline in CDAI Over Time | The Crohn's Disease Activity Index (CDAI) is a research tool used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where remission of Crohn's disease is defined as CDAI < 150, and severe disease is defined as CDAI > 450. A negative change from Baseline indicates improvement. | Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | 
| Time to Crohn's Disease Flare | Time to Crohn's disease flare, where flare is defined as an increase in CDAI ≥ 70 points compared to Week 8 or Early Randomization CDAI, and a CDAI > 220. | From Randomization to 48 weeks after Randomization | 
| Time to Clinical Remission | Clinical remission was defined as CDAI < 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI scores generally range from 0 to 600 where higher scores indicate more severe disease. | From Randomization through 48 weeks after Randomization | 
| Time to Steroid-free Remission | Steroid-free remission was defined as CDAI < 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. | From Randomization through 48 weeks after Randomization | 
| Percentage of Participants in Clinical Remission Over Time | Clinical remission was defined as CDAI < 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. | Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | 
| Percentage of Participants in Steroid-free Remission Over Time | Steroid-free remission was defined as CDAI < 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. | 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | 
| Time to All-cause Hospitalization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. | From Randomization through 48 weeks after Randomization | 
| Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication | Crohn's disease-related hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic for reasons related to Crohn's disease (CD). Hospitalization for adverse events relating to study medication, i.e., prednisone, azathioprine or adalimumab, were according to Investigator's clinical judgment. | From Randomization through 48 weeks after Randomization | 
| Number of Major Crohn's Disease-related Surgeries After Randomization | Major Crohn's disease-related intra-abdominal surgery included: bowel resection ostomy by-pass strictureplasty drainage of abdominal or pelvic abscess (surgical drainage or percutaneous drainage by interventional radiology). The following were excluded: debridement exploration laparotomy abdominal surgery for other reason perineal related surgery abscess drainage placement of setons fistulotomy Total parental nutrition (TPN) use | From Randomization through 48 weeks after Randomization | 
| Number of Crohn's Disease-related Hospitalizations After Randomization | Any hospitalization with an overnight stay in hospital/clinic related to Crohn's disease. | From Randomization through 48 weeks after Randomization | 
| Number of All-cause Hospitalizations After Randomization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. | From Randomization through 48 weeks after Randomization | 
| Total Length of Stay in Hospital for All-cause Hospitalizations |  | From Randomization through 48 weeks after Randomization | 
| Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations |  | From Randomization through 48 weeks after Randomization | 
| Number of Crohn's Disease-related Surgical Procedures After Randomization | The total number of CD-related surgical procedures included major CD-related surgery, debridement, perineal related surgery - abscess drainage, seton placement, fistulotomy, and TPN. | From Randomization through 48 weeks after Randomization | 
| Time to Crohn's Disease-related Hospitalization Due to Emergency | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. | From Randomization through 48 weeks after Randomization | 
| Number of Crohn's Disease-related Hospitalizations Due to Emergency | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. | From Randomization through 48 weeks after Randomization | 
| Change in Crohn's Disease Behavior According to Montreal Classification | Participants' Crohn's Disease was classified according to the Montreal Classification which classifies CD according to its predominant phenotypic elements (age at diagnosis, location, and disease behavior) based on the results of clinical examination and endoscopy. Disease behavior was classified according to the following: B1 = non-stricturing, non-penetrating; B2 = structuring; B3 = penetrating; P = perianal disease modifier. The change in Montreal Classification is presented in three categories: no change, deterioration, and improvement. Deterioration was defined as an increase in behavior index between 1 and 3, or development of perianal disease. Participants with missing data at Week 48 were classified as deterioration. | From Baseline to 48 weeks after Randomization | 
| Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | High sensitivity C-reactive protein was analyzed by a central laboratory. | Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization. | 
| Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Stool samples were analyzed by a central laboratory for fecal calprotectin qualitative measurement (< 250 or ≥ 250 μg/g). Results are reported for participants in each category at Baseline and 48 weeks after Randomization. Participants with missing data 48 weeks after Randomization were counted as having fecal calprotectin ≥ 250µg/g. | Baseline and 48 weeks after Randomization | 
| Total Dose of Prednisone | The total dose of prednisone each participant received during both the run-in phase and post-randomization treatment phase. | From Baseline through 48 weeks after Randomization | 
| Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | The IBDQ measures the effects of inflammatory bowel disease on daily function and quality of life. The IBDQ consists of 32 questions which address symptoms as a result of Crohn's disease, feeling in general, and mood. Each question is answered on a scale from 1 (all of the time) to 7 ( none of the time); the total score ranges from 7 (worst) to 224 (best). A positive change from baseline indicates improvement. | Baseline and 48 weeks after Randomization | 
| Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | The WPAI:CD questionnaire was used to assess impairments in both paid work and unpaid work due to symptoms of Crohn's Disease. The self-administered questionnaire consisted of 6 questions. Work time missed was defined as the percentage of time absent from work due to Crohn's disease in the past week. Impairment while working is the participant's assessment of the degree to which Crohn's disease affected productivity while working in the past 7 days. Total work productivity impairment takes into account both hours missed due to Crohn's disease symptoms and the patient's assessment of the degree to which Crohn's disease affected their productivity while working. Total activity impairment is the percent impairment of non-work related activities due to Crohn's disease. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement. | Baseline and 48 weeks after Randomization | 
| Change From Baseline in Patient Health Questionnaire - 9 (PHQ9) | The PHQ-9 is a 9-item questionnaire for assessing the severity of depression. Each question is answered on a scale from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, where higher scores indicate more severe depression. A negative change from Baseline score indicates improvement. | Baseline and 48 weeks after Randomization | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score | The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, from 0 (not at all) to 4 (very much). The FACIT-Fatigue score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from Baseline score indicates an improvement. . | Baseline and 48 weeks after Randomization | 
| Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2 is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary (PCS) score summarizes the subscales physical functioning, role-physical, bodily pain, and general health. The mental component summary (MCS) score summarizes the subscales vitality, social functioning, role-emotional, and mental health. Each score ranges from 0 to 100 where higher scores indicate a better quality of life. A positive change from Baseline score indicates an improvement. | Baseline and 48 weeks after Randomization |