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

Phase 3

Completed

• Conditions: Crohn's Disease
• Interventions: Biological: Adalimumab; Drug: Prednisone; Drug: Azathioprine

• Registration Number: NCT01235689
• Lead Sponsor: AbbVie (prior sponsor, Abbott)

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2010-11-04
• Study First Submitted QC: 2010-11-04
• Study First Posted: 2010-11-05
• Study Start: 2011-02-11
• Primary Completion: 2016-11-03
• Study Completion: 2017-01-03
• Results First Submitted: 2017-10-30
• Status Verified: 2017-12
• Results First Submitted QC: 2017-12-05
• Results First Posted: 2017-12-07
• Last Update Submitted: 2017-12-15
• Last Update Posted: 2018-01-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 252

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tight Control Management	Adalimumab	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.
Clinically Driven Management	Adalimumab	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.
Tight Control Management	Prednisone	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.
Tight Control Management	Azathioprine	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.
Clinically Driven Management	Prednisone	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.
Clinically Driven Management	Azathioprine	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Mucosal Healing and No Deep Ulcerations	48 weeks after Randomization	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants in Deep Remission 48 Weeks After Randomization	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.
Percentage of Participants With Endoscopic Response 48 Weeks After Randomization	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.
Percentage of Participants in Biologic Remission 48 Weeks After Randomization	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.
Percentage of Participants With Mucosal Healing 48 Weeks After Randomization	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.
Change From Baseline in CDEIS at 48 Weeks After Randomization	Baseline and 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.
Change From Baseline in CDAI Over Time	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.	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.
Time to Crohn's Disease Flare	From Randomization to 48 weeks after Randomization	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.
Time to Clinical Remission	From Randomization through 48 weeks after Randomization	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.
Time to All-cause Hospitalization	From Randomization through 48 weeks after Randomization	Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic.
Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication	From Randomization through 48 weeks after Randomization	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.
Number of Major Crohn's Disease-related Surgeries After Randomization	From Randomization through 48 weeks 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
Number of Crohn's Disease-related Hospitalizations After Randomization	From Randomization through 48 weeks after Randomization	Any hospitalization with an overnight stay in hospital/clinic related to Crohn's disease.
Number of All-cause Hospitalizations After Randomization	From Randomization through 48 weeks after Randomization	Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic.
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
Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization	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.
Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization	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.
Percentage of Participants in Steroid-free Remission Over Time	11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.	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.
Time to Steroid-free Remission	From Randomization through 48 weeks after Randomization	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.
Percentage of Participants in Clinical Remission Over Time	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.	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.
Number of Crohn's Disease-related Surgical Procedures After Randomization	From Randomization through 48 weeks 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.
Number of Crohn's Disease-related Hospitalizations Due to Emergency	From Randomization through 48 weeks after Randomization	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.
Change in Crohn's Disease Behavior According to Montreal Classification	From Baseline to 48 weeks after Randomization	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.
Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time	Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization.	High sensitivity C-reactive protein was analyzed by a central laboratory.
Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization	Baseline and 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.
Total Dose of Prednisone	From Baseline through 48 weeks after Randomization	The total dose of prednisone each participant received during both the run-in phase and post-randomization treatment phase.
Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score	Baseline and 48 weeks after Randomization	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.
Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD)	Baseline and 48 weeks after Randomization	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.
Time to Crohn's Disease-related Hospitalization Due to Emergency	From Randomization through 48 weeks after Randomization	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.
Change From Baseline in Patient Health Questionnaire - 9 (PHQ9)	Baseline and 48 weeks after Randomization	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.
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score	Baseline and 48 weeks after Randomization	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.; .
Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores	Baseline and 48 weeks after Randomization	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.