Epidermal Nevus Syndrome (ENS) Clinical Trial
Official title:
A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia
| Verified date | May 2024 |
| Source | Kyowa Kirin Co., Ltd. |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
The primary objectives of this study are to evaluate the effect of burosumab treatment on: - Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia - Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).
| Status | Completed |
| Enrollment | 17 |
| Est. completion date | January 21, 2021 |
| Est. primary completion date | July 27, 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: 1. Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of excessive fibroblast growth factor 23 (FGF23) that was not amenable to cure by surgical excision of the underlying tumor/lesion (documented by Investigator). 2. Be = 18 years of age 3. Have a fasting serum phosphorus level < 2.5 mg/dL 4. Have an FGF23 level = 100 pg/mL by Kainos assay 5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5 mg/dL 6. Have an estimated glomerular filtration rate (eGFR) = 60 mL/min (using Cockcroft-Gault formula). Subjects with eGFR = 30 but < 60 mL/min will be considered eligible as long as in the opinion of the investigator the decline in renal function is not related to nephrocalcinosis. 7. Have a corrected serum calcium level < 10.8 mg/dL 8. Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 9. Be willing to use 2 forms of effective methods of contraception while participating in the study (sexually active subjects) and for 12 weeks after last dose of study drug. 10. Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data 11. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures 12. Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments (in the opinion of the investigator) Exclusion Criteria: 1. Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C 2. Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency 3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study 4. Have participated in an investigational drug or device trial within 30 days prior to Screening or are currently enrolled in another study of an investigational product or device 5. Have used a therapeutic monoclonal antibody (mAb), including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb 6. Have or a have a history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects 7. Have used a pharmacologic vitamin D metabolite or its analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study 8. Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening 9. Have a history of malignancy within 5 years of study entry with the exception of phosphaturic mesenchymal tumors (PMTs) of the mixed connective tissue type or non-melanoma skin cancers such as basal cell skin cancer 10. Have donated blood or blood products within 60 days prior to Screening 11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline hydrochloride [HCl] and demeclocycline), benzodiazepines, fentanyl or lidocaine 12. Have any condition, which in the opinion of the investigator and sponsor, could present a concern for either subject safety or difficulty with data interpretation |
| Country | Name | City | State |
|---|---|---|---|
| United States | Johns Hopkins University | Baltimore | Maryland |
| United States | Duke University | Durham | North Carolina |
| United States | Colorado Center for Bone Research at Panorama Orthopedics and Spine Center | Golden | Colorado |
| United States | Houston Methodist Research Institute | Houston | Texas |
| United States | Indiana University Hospital | Indianapolis | Indiana |
| United States | Yale University School of Medicine | New Haven | Connecticut |
| United States | Mayo Clinic | Rochester | Minnesota |
| Lead Sponsor | Collaborator |
|---|---|
| Kyowa Kirin, Inc. |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). | From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days. | |
| Other | Number of Participants With Anti-burosumab Antibodies | From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days. | ||
| Primary | Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24 | The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL [0.81 mmol/L]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). | Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18]) | |
| Primary | Change From Baseline to Week 48 in Osteoid Thickness | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader.
Osteoid thickness is the mean thickness of osteoid seams. |
Baseline, Week 48 | |
| Primary | Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS) | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader.
Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid. |
Baseline, Week 48 | |
| Primary | Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV) | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid). | Baseline, Week 48 | |
| Primary | Change From Baseline to Week 48 in Mineralization Lag Time (MLt) | Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling.
Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR*MS/OS), where O.Th = osteoid thickness, MAR is imputed as 0.3 µm/day, MS/OS=mineralizing surface/osteoid surface, each measured at the same visit. |
Baseline, Week 48 | |
| Secondary | Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24 | The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (2.5 mg/dL [0.81 mmol/L]) at the end of the dose interval (4 weeks post-dose, prior to the next dose), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). | End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24) | |
| Secondary | Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | Mean change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). | Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22) | |
| Secondary | Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | Mean percent change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). | Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22) | |
| Secondary | Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | Mean change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). | Baseline and Weeks 4, 8, 12, 16, 20, and 24 | |
| Secondary | Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | Mean percent change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). | Baseline and Weeks 4, 8, 12, 16, 20, and 24 | |
| Secondary | Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24 | Serum phosphorus level versus time AUC was calculated using the trapezoidal rule. Time-adjusted AUC was calculated by dividing the AUC by duration of time included in AUC calculation. | Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24 | |
| Secondary | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Least squares (LS) means and standard errors (SE) were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 1,25(OH)2D, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Total FGF23 included free FGF23 and FGF23 bound to burosumab. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline total FGF23, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline free FGF23, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 24-hour urinary phosphorus, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Tubular reabsorption of phosphate (TRP) is the fraction of filtered phosphorus that is reabsorbed by renal tubules.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TRP, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | TmP/GFR measures renal phosphate reabsorption (the primary mechanism by which FGF23 regulates phosphate homeostasis) by comparing the fractional absorption of phosphate relative to the estimated rate of glomerular filtration.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TmP/GFR, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | FEP is the percentage of phosphorus filtered by the kidney that is excreted into urine, calculated as 100% * (2-hour urine phosphorus*serum creatinine)/(2-hour urine creatinine * serum phosphorus).
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline FEP, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline ALP, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Percent Change From Baseline Over Time in BALP | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Percent Change From Baseline Over Time in CTx | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Percent Change From Baseline Over Time in P1NP | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Osteocalcin | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Percent Change From Baseline Over Time in Osteocalcin | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure. | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the elbow flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure. |
Baseline and Weeks 24 and 48 | |
| Secondary | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the knee flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure. |
Baseline and Weeks 24 and 48 | |
| Secondary | Change From Baseline Over Time in Sit-to-Stand (STS) Test | The STS test measures lower extremity strength and mobility as a participant moves repeatedly from a seated position to standing. This study used a modified STS test that allowed participants to use the arms of the chair to help them stand and sit if necessary. The number of sit-to-stand repetitions performed in a 30-second period was recorded.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24 and 48 | |
| Secondary | Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | The Weighted arm lift (WAL) test assesses upper extremity strength, mobility and reaching ability. The test was administered bilaterally to determine the number of times the participant could raise a 1 kg weight above the head in a 30-second period. The number of repetitions completed with each arm was recorded.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline WAL measurements, with compound symmetry covariance structure. |
Baseline and Weeks 24 and 48 | |
| Secondary | Change From Baseline Over Time in Six-Minute Walk Test (6MWT) | The 6MWT is a commonly used measure of mobility and was conducted in accordance with general principles set forth in the American Thoracic Society guidelines (ATS 2002). Participants were instructed to walk the length of a pre-measured course for 6 consecutive minutes (assistive devices could be used). The total distance walked at the end of 6 minutes was recorded in meters.
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 6MWT measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24 and 48 | |
| Secondary | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Worst pain is defined as the answer to Question 3, in which participants rated their pain at its worst in the last 24 hours on a scale from 0 (no pain) to 10 (pain as bad as you can imagine).
A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours.
Pain severity is defined as the average of 4 questions (Questions 3 through 6) assessing worst pain, least pain, average pain, and pain right now, rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). Mild pain is defined as a score of 1 to 4, moderate pain is defined as a score of 5 to 6, and severe pain is defined as a score of 7 to 10. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours.
Pain interference is defined as the average of 7 questions (9A through 9G) regarding the extent to which pain interfered with daily activities, including general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours.
Worst fatigue is defined as the answer to Question 3 in which participants rated their fatigue at its worst in the last 24 hours on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours.
Fatigue severity is defined as the average of 3 questions (Questions 1 through 3) assessing fatigue right now, usual level of fatigue, and worst fatigue, rated on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours.
The fatigue interference score is defined as the average of 6 questions (Questions 4A through 4F) regarding the extent to which fatigue interfered with daily activities, including general activity, mood, walking ability, work, relations with others, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. The first 3 questions measure fatigue severity and the next 6 questions assess the impact of fatigue on daily activities.
The global fatigue score is defined as the average of all 9 questions on the BFI including severity and interference, and ranges from from 0 to 10, where higher scores correspond to greater levels of fatigue. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 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 score (PCS) is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance struct |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The physical functioning (PF) domain includes 10 questions that assess limitations in physical activities because of health problems. The PF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The role-physical (RP) domain includes 4 questions that assess limitations in usual role activities because of physical health problems. The RP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The bodily pain (BP) domain includes 2 questions that assess pain level and impact of pain on normal work. The BP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The general health perceptions (GH) domain includes 5 questions that assess participants' perception of their own general health. The GH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The mental component summary score (MCS) is a weighted combination of the 8 subscales with positive weighting for vitality, social function, role limitations due to emotional problems, and mental health. The MCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The vitality (VT) domain includes 4 questions that assess energy levels and fatigue. The VT domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The social functioning (SF) domain includes 2 questions that assess limitations in social activities because of physical health or emotional problems. The SF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The role-emotional (RE) domain includes 3 questions that assess limitations in usual role activities because of emotional problems. The RE domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | |
| Secondary | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).
The mental health (MH) domain includes 5 questions that assess general mental health (psychological distress and well-being). The MH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 |