Not provided
Not provided
Not provided
Not provided
Due to the coronavirus disease 2019 (COVID-19) pandemic and the deleterious impact of rituximab on vaccination efficacy, the trial was concluded before reaching the target enrollment of 200.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The purpose of this study is to determine the best management strategy to maintain remission in patients with ANCA vasculitis who have been treated with rituximab induced B cell depletion for at least two years. This study will compare intermittent B Cell depletion upon B cell return or intermittent B cell depletion upon serologic relapse.
Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease characterized by small vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO). Immunosuppressive therapy can result in remission; however, many patients relapse, which results in additional injury.
Rituximab, a humanized murine monoclonal antibody directed against CD20 located on the surface of B-lymphocytes (B cells), is effective in depleting B cells. The RAVE and RITUXVAS trials have shown efficacy of rituximab with steroids for induction of remission in ANCA vasculitis, similar to cyclophosphamide and steroids. Rituximab is now FDA-approved for induction of remission therapy in ANCA vasculitis. The utility of anti-B-cell therapy for early induction of remission in ANCA vasculitis is not surprising given that ANCA are pathogenic in vitro and in vivo. It is clear that remission in many patients is not sustained with a single induction course of rituximab, and relapses often occur after B cell re-population suggesting that scheduled, serial dosing of rituximab could result in sustained remissions.
Despite yielding promising outcomes, rituximab is also associated with a number of adverse events including infectious complications and late onset of neutropenia5, 15. Furthermore, the complications of continuous B cell depletion for extended durations are unknown. One of the major goals in the field is to utilize prolonged B cell depletion only in the subpopulation of patients where the risk of disease relapse outweighs the risk of treatment-related adverse events.
A rise in ANCA titers and reconstitution of B cells are promising biomarkers of impending disease relapse following treatment with rituximab4-6
A prospective and longitudinal clinical trial is needed to determine the ideal treatment strategy for long-term maintenance of remission. We propose to compare intermittent rituximab dosing based on B cell return and a serologic ANCA flare
The study design is an open-label, single center, randomized and two-arm controlled trial to evaluate the optimal maintenance of remission strategy that provides the best relapse-free survival in patients with ANCA vasculitis as determined by relapse-free remission at 18, 24 and 36 months from enrollment. The investigators are looking to enroll and randomize 200 subjects with ANCA vasculitis on rituximab-induced continuous B cell depletion for a minimum of two years to one of two arms as follows:
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| B cell reconstitution | Active Comparator | Subjects will not receive their regularly-scheduled every-six-month dose of rituximab and will instead receive rituximab 1000 mg IV x 1 dose once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. |
|
| Serologic ANCA flare | Active Comparator | Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | re-dosing dependent on interventional arm parameter. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Disease Relapse(s) as Defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 | Relapses recording period was from 6/1/2016 to 12/31/2021. The outcome was reported as the number of participants with disease relapse who had either positive ANCA titers specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients Affected by Serious Adverse Events | Number of patients with serious adverse events (SAEs), including all episodes of late onset neutropenia (LON). SAE are defined in the Serious adverse event section. Serious adverse events were reported over the entire study period (5.5 years) | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| John L Niles, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21422922 | Background | Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis. Curr Opin Nephrol Hypertens. 2011 May;20(3):263-70. doi: 10.1097/MNH.0b013e3283456731. | |
| 20647198 | Background | Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | B Cell Reconstitution | Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab (1 dose of 1000mg IV) each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. Rituximab: re-dosing dependent on interventional arm parameter. |
| FG001 | Serologic ANCA Flare | Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise as described above. Baseline ANCA titer will be recalculated to an average of the two highest of the last four values if all four are less than the original baseline. Patients in the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (>90 cells/uL). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | B Cell Reconstitution | Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab (1 dose of 1000mg IV) each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. Rituximab: re-dosing dependent on interventional arm parameter. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Age reported is the age of each participant at the time of enrollment. Only subjects aged 18-82 years old were enrolled in the study (inclusion criteria). |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Patients With Disease Relapse(s) as Defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 | Relapses recording period was from 6/1/2016 to 12/31/2021. The outcome was reported as the number of participants with disease relapse who had either positive ANCA titers specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Posted | Count of Participants | Participants | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021
All adverse events will be reported per PHRC guidelines which includes unanticipated problems involving risks to subjects/others, including adverse events, within 5 working days/7 calendar days of the date that the investigator first became aware of the problem.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | B Cell Reconstitution | Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab (1 dose of 1000mg IV) each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. Rituximab: re-dosing dependent on interventional arm parameter. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bronchitis | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper Respiratory Infection (Cold) | Infections and infestations | Non-systematic Assessment | Cold, pharyngitis and other URI. Sinusitis are not included if isolated and specified in the description of event. |
The trial has several limitations:
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John L Niles | Massachusetts General Hospital- Vasculitis and Glomerulonephritis Center | 617-726-4132 | JLNILES@mgh.harvard.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 21, 2020 | Jan 26, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 20, 2021 | Jan 26, 2023 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D056648 | Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis |
| ID | Term |
|---|---|
| D056647 | Systemic Vasculitis |
| D014657 | Vasculitis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069283 | Rituximab |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Composite of Disease Relapse (Defined a BVAS/WG ≥ 2) and Serious Adverse Events | Number of disease relapse added with the number of SAE in each group | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| Number of Patients With Hypogammaglobulinemia | Hypogammaglobulinemia defined as an IgG < 250mg/dL | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| Patient Survival | number of deaths throughout the study. | 5.5 years |
| Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores | The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status and is commonly used in health economics as a variable in the quality-adjusted life year calculation to determine the cost-effectiveness of a health treatment. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | Assessed throughout the study period, every 6 months unless such time point was not reached or was missed by the patient. Median follow-up period is of 4.1 years (IQR, 2.5 - 5.0) |
| Mean Number of Rituximab Infusions Per Subject | The rituximab utilization was measured in how many times a subject received Rituximab throughout the study which was then averaged for all subjects in each treatment arm, including those who did not receive any infusion. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| Organ Damage as Assessed by the Vasculitis Damage Index (VDI). | The Vasculitis Damage Index (VDI) is a validated formal assessment tool in ANCA-associated vasculitis clinical trials. The VDI distinguishes vasculitis-induced chronic damage from active inflammation or persistent disease. Each item represents a disease manifestation and is given a score (of 1) if present for at least 3 months. Neither the cause of damage (vasculitis vs treatment) nor an ongoing activity are taken into consideration. The VDI includes 64 items categorized into 11 groups (by organ system) and the scored items are summed to give a total score ranging from 0 to 64. A higher score means more accrued damage. | 3 years starting at inclusion |
| Number of Major Relapses Defined as a BVAS/WG ≥ 3 | The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| Number of Infections | Number of infections mild and severe, whether they were treated or not with antibiotics | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
| 20647199 | Background | Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. |
| 12840090 | Background | Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286. |
| 23902481 | Background | Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Fessler BJ, Ding L, Viviano L, Tchao NK, Phippard DJ, Asare AL, Lim N, Ikle D, Jepson B, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Mueller M, Sejismundo LP, Mieras K, Stone JH; RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug 1;369(5):417-27. doi: 10.1056/NEJMoa1213277. |
| 24626432 | Background | Pendergraft WF 3rd, Cortazar FB, Wenger J, Murphy AP, Rhee EP, Laliberte KA, Niles JL. Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clin J Am Soc Nephrol. 2014 Apr;9(4):736-44. doi: 10.2215/CJN.07340713. Epub 2014 Mar 13. |
| 25372085 | Background | Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quemeneur T, Blanchard-Delaunay C, Godmer P, Puechal X, Carron PL, Hatron PY, Limal N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231. |
| 12631091 | Background | Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis. Kidney Int. 2003 Mar;63(3):1079-85. doi: 10.1046/j.1523-1755.2003.00821.x. |
| 25477054 | Background | Alberici F, Smith RM, Jones RB, Roberts DM, Willcocks LC, Chaudhry A, Smith KG, Jayne DR. Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis. Rheumatology (Oxford). 2015 Jul;54(7):1153-60. doi: 10.1093/rheumatology/keu452. Epub 2014 Dec 3. |
| 38123922 | Derived | Zonozi R, Cortazar FB, Jeyabalan A, Sauvage G, Nithagon P, Huizenga NR, Rosenthal JM, Sipilief A, Cosgrove K, Laliberte KA, Rhee EP, Pendergraft WF 3rd, Niles JL. Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial. Ann Rheum Dis. 2024 Feb 15;83(3):351-359. doi: 10.1136/ard-2023-224489. |
| Minor relapse, BVAS-WG = 2 |
|
| Major relapse without ILD, BVAS-WG ≥ 3 |
|
| Major relapse with ILD, BVAS-WG ≥ 3 |
|
| Adverse Event |
|
| Serious Adverse Event, Related, infection, COVID-19, with death |
|
| Serious Adverse Event, Related, infection, COVID-19, without death |
|
| Requiring glucocorticoids |
|
| Cancer |
|
| BG001 | Serologic ANCA Flare | Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise as described above. Baseline ANCA titer will be recalculated to an average of the two highest of the last four values if all four are less than the original baseline. Patients in the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (>90 cells/uL). |
| BG002 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Age reported are based on age of subjects at time of enrollment. Means reported are the arithmetic means and each of the standard deviations was calculated based on the sample/ group for which it was calculated. | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Race was self-reported by the participants at the time of enrollment, two participants indicated no to each choice of race available. One other participant put "Other" as their race and so the three participants were counted as "Unknown or not Reported" in this report. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ANCA serotype | Count of Participants | Participants |
|
| Continuous Rituximab prior to entry | Count of Participants | Participants |
|
| Induction Regimen- Rituximab and Cyclophosphamide | Count of Participants | Participants |
|
| Induction Regimen- Plasma Exchange | Count of Participants | Participants |
|
| Clinical manifestations at diagnosis | Number of participants presenting with a specific clinical manifestation of ANCA-associated vasculitis at the time of diagnosis. Clinical manifestations are non-exclusive | Count of Participants | Participants |
|
| BVAS/WG at entry | The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Median | Standard Deviation | units on a scale |
|
| VDI at entry | The Vasculitis Damage Index (VDI) is a validated formal assessment tool in ANCA-associated vasculitis clinical trials. The VDI distinguishes vasculitis-induced chronic damage from active inflammation or persistent disease. Each item (disease manifestation) is given a score (of 1) if present for at least 3 months. Neither the cause of damage nor an ongoing activity are taken into consideration. The VDI includes 64 items categorized into 11 groups (by organ system) and the scored items are summed to give a total score ranging from 0 to 64. A higher score means more accrued damage. | Median | Standard Deviation | units on a scale |
|
| Creatinine at entry | Median | Inter-Quartile Range | mg/dL |
|
| Ig levels at entry | Median | Inter-Quartile Range | mg/dL |
|
| eGFR at entry | Median | Inter-Quartile Range | cc/min/1.73m^2 |
|
| Disease status | Count of Participants | Participants |
|
| B Cell Reconstitution |
Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab (1 dose of 1000mg IV) each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. Rituximab: re-dosing dependent on interventional arm parameter. |
| OG001 | Serologic ANCA Flare | Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise as described above. Baseline ANCA titer will be recalculated to an average of the two highest of the last four values if all four are less than the original baseline. Patients in the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (>90 cells/uL). |
|
|
|
| Secondary | Number of Patients Affected by Serious Adverse Events | Number of patients with serious adverse events (SAEs), including all episodes of late onset neutropenia (LON). SAE are defined in the Serious adverse event section. Serious adverse events were reported over the entire study period (5.5 years) | Posted | Count of Participants | Participants | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
|
| Secondary | Composite of Disease Relapse (Defined a BVAS/WG ≥ 2) and Serious Adverse Events | Number of disease relapse added with the number of SAE in each group | Posted | Number | Number of events | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
| Secondary | Number of Patients With Hypogammaglobulinemia | Hypogammaglobulinemia defined as an IgG < 250mg/dL | Posted | Count of Participants | Participants | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
| Secondary | Patient Survival | number of deaths throughout the study. | Posted | Number | number of deaths | 5.5 years |
|
|
|
| Secondary | Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores | The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status and is commonly used in health economics as a variable in the quality-adjusted life year calculation to determine the cost-effectiveness of a health treatment. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | We collected data using the SF-36 on the quality of life due to its importance in the long-term treatment of ANCA vasculitis. Questionnaires were given to patients every 6 months throughout the study period. Some participants do not have scores at certain time points due to either a missed visit or not being enrolled anymore in the study. | Posted | Mean | Standard Deviation | score on a scale | Assessed throughout the study period, every 6 months unless such time point was not reached or was missed by the patient. Median follow-up period is of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
| Secondary | Mean Number of Rituximab Infusions Per Subject | The rituximab utilization was measured in how many times a subject received Rituximab throughout the study which was then averaged for all subjects in each treatment arm, including those who did not receive any infusion. | Posted | Mean | Standard Deviation | Infusions per subject | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
|
| Secondary | Organ Damage as Assessed by the Vasculitis Damage Index (VDI). | The Vasculitis Damage Index (VDI) is a validated formal assessment tool in ANCA-associated vasculitis clinical trials. The VDI distinguishes vasculitis-induced chronic damage from active inflammation or persistent disease. Each item represents a disease manifestation and is given a score (of 1) if present for at least 3 months. Neither the cause of damage (vasculitis vs treatment) nor an ongoing activity are taken into consideration. The VDI includes 64 items categorized into 11 groups (by organ system) and the scored items are summed to give a total score ranging from 0 to 64. A higher score means more accrued damage. | Posted | Mean | Standard Deviation | score on a scale | 3 years starting at inclusion |
|
|
|
|
| Secondary | Number of Major Relapses Defined as a BVAS/WG ≥ 3 | The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Posted | Number | number of events | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
|
| Secondary | Number of Infections | Number of infections mild and severe, whether they were treated or not with antibiotics | Posted | Number | number of events | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) |
|
|
|
| 2 |
| 58 |
| 15 |
| 58 |
| 46 |
| 58 |
| EG001 | Serologic ANCA Flare | Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise as described above. Baseline ANCA titer will be recalculated to an average of the two highest of the last four values if all four are less than the original baseline. Patients in the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (>90 cells/uL). | 0 | 57 | 14 | 57 | 44 | 57 |
| Pneumonia | Infections and infestations | Non-systematic Assessment |
|
| Urinary Track Infection | Infections and infestations | Non-systematic Assessment |
|
| Appendicitis | Infections and infestations | Non-systematic Assessment |
|
| Skin infection | Infections and infestations | Non-systematic Assessment |
|
| COVID-19 | Infections and infestations | Non-systematic Assessment |
|
| Cancer | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Squamous cell carcinoma |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Thromboembolic disease |
|
| Neutropenia | Immune system disorders | Non-systematic Assessment |
|
| Death | Infections and infestations | Non-systematic Assessment | all were due to COVID-19 |
|
| Psychiatric Disorder | Psychiatric disorders | Non-systematic Assessment |
|
| Cholecystitis | Hepatobiliary disorders | Non-systematic Assessment |
|
| Small intestinal obstruction | Gastrointestinal disorders | Non-systematic Assessment |
|
| Gastric hemorrhage | Gastrointestinal disorders | Non-systematic Assessment |
|
| Transient ischemic attacks | Vascular disorders | Non-systematic Assessment |
|
| Urinary retention and elevated creatinine | Renal and urinary disorders | Non-systematic Assessment |
|
| Rectal bleeding status post colonoscopy | Gastrointestinal disorders | Non-systematic Assessment |
|
| bleeding gastric nodule | Gastrointestinal disorders | Non-systematic Assessment |
|
| Asymptomatic AKI | Renal and urinary disorders | Non-systematic Assessment | Cr to 1.9 from baseline 1.5. Kidney biopsy 10/22/19 showed chronic active interstitial nephritis |
|
| Gallstone pancreatitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Pancreatitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Pulmonary edema in setting of fluid resuscitation | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Gallbladder pain | Hepatobiliary disorders | Non-systematic Assessment |
|
| Lumbar disc herniation, cervical and lumbar stenosis | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Renal Calculi | Renal and urinary disorders | Non-systematic Assessment |
|
| New elevated IgM in setting of longstanding pancytopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Atrial fibrillation with rapid ventricular response | Cardiac disorders | Non-systematic Assessment |
|
| Chest pain, LAD stenosis and RAD stenosis | Cardiac disorders | Non-systematic Assessment | Admitted with chest pain - arteriogram at cath lab found LAD: 99% mid LAD stenosis; RCA: 95% stenosis with an early branching acute marginal. |
|
| Myocardial infarction | Cardiac disorders | Non-systematic Assessment |
|
| Coronary artery disease- Three-vessel disease | Cardiac disorders | Non-systematic Assessment |
|
| Myocarditis and Heart failure with preserved ejection fraction | Cardiac disorders | Non-systematic Assessment | Myocarditis was the first diagnosis. New diagnosis of HFpEF later on. |
|
| Atrial fibrillation | Cardiac disorders | Non-systematic Assessment |
|
|
| Urinary Track Infection | Renal and urinary disorders | Non-systematic Assessment |
|
| Gout flare | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | Non-systematic Assessment |
|
| COVID-19 Positive | Infections and infestations | Non-systematic Assessment |
|
| Allergic Reaction to Rituximab Infusion | Immune system disorders | Non-systematic Assessment |
|
| Allergic reaction unrelated to Rituximab | Immune system disorders | Non-systematic Assessment |
|
| Vaginitis | Infections and infestations | Non-systematic Assessment | One due to yeasts, for the two other the cause is unknown |
|
| Asymptomatic Sinus tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Right thigh pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Mild, not injury related, for 2 days and resolved. |
|
| Bronchitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Heart murmurs | Cardiac disorders | Non-systematic Assessment |
|
| Hematuria | Renal and urinary disorders | Non-systematic Assessment |
|
| pleural infection | Infections and infestations | Non-systematic Assessment |
|
| Myalgias and arthralgias. Severe pains and frank arthritis in knees. | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Pleuritic chest pain | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | CTA scan negative for PE but positive for pleural inflammatory process |
|
| Mild fatty replacement of the liver | Hepatobiliary disorders | Non-systematic Assessment |
|
| Metacarpophalangeal tenderness | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Right 1st MCP |
|
| Headache/ Migraine | Nervous system disorders | Non-systematic Assessment |
|
| Influenza | Infections and infestations | Non-systematic Assessment |
|
| Cellulitis | Infections and infestations | Non-systematic Assessment |
|
| Conduction disorder (LBBB) | Cardiac disorders | Non-systematic Assessment |
|
| Fall injury | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
|
| colonoscopy finding:tubulovillous adenomatous colon poplyp | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Renal calculi | Renal and urinary disorders | Non-systematic Assessment |
|
| Rash in distribution of trigeminal nerve - consistent with zoster | Infections and infestations | Non-systematic Assessment |
|
| Hypotension, fatigue, cough, HA, fever, malaise, volume depletion from high dose valtrex reaction | General disorders | Non-systematic Assessment |
|
| Urine cx positive for E.coli | Infections and infestations | Non-systematic Assessment |
|
| Conjunctivitis | Infections and infestations | Non-systematic Assessment |
|
| Paronychia | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Elevated Liver Function Tests | Hepatobiliary disorders | Non-systematic Assessment | LFTs for each patients:
|
|
| Mandibular pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Neutropenia | Immune system disorders | Non-systematic Assessment |
|
| Epistaxis | Vascular disorders | Non-systematic Assessment |
|
| Jaw swelling, | Immune system disorders | Non-systematic Assessment | internal swelling and sensation of fullness in jaw. Related AE, led to stop cephalexin. |
|
| Distal Ventricular Tachycardia | Cardiac disorders | Non-systematic Assessment | New edema and clot in lower leg near ankle |
|
| Stomach discomfort | Gastrointestinal disorders | Non-systematic Assessment | Stomach discomfort. Mild ache and cramping pain over last month. Patient noted start coincided with switch to amlodipine |
|
| Sore throat | Infections and infestations | Non-systematic Assessment | sore throat; symptoms consistent of swollen lymph node, likely secondary viral or bacterial infection. |
|
| Pneumonia | Infections and infestations | Non-systematic Assessment | Non serious and moderate |
|
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | Non-systematic Assessment |
|
| RLL possibe airspace disease and/or atelectasis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Degenerative disk disease of c-spine | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Vertigo | General disorders | Non-systematic Assessment |
|
| Diarrhea | Infections and infestations | Non-systematic Assessment |
|
| Colitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Lung opacity and nodule | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Dizziness | Investigations | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hypertension | Cardiac disorders | Non-systematic Assessment |
|
| Leg Edema | Cardiac disorders | Non-systematic Assessment |
|
| Ear pain | Infections and infestations | Non-systematic Assessment | Possibly due to infection |
|
| Surgical procedure | Surgical and medical procedures | Non-systematic Assessment |
|
| Tooth infection | Infections and infestations | Non-systematic Assessment |
|
| Skin rash on arms and legs | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Raised red rash on bilateral arms and legs. Not itchy or painful. Lesions come and go |
|
| Atrial flutter | Cardiac disorders | Non-systematic Assessment | Annual ECG with new atrial flutter. Patient asymptomatic |
|
| Achilles tendon pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Bilateral Achilles tendon pain. Patient had taken levaquin ~1 month prior |
|
| Shoulder cyst | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment | Shoulder cyst. Now large and tense |
|
| Atrial fibrillation | Cardiac disorders | Non-systematic Assessment | Atrial fibrillation Mild |
|
| Muscle weakness lower limb | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Exertional dyspnea | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Exertional dyspnea. Requires break after 1-2 blocks; a/w diaphoresis. DDx includes poorly controlled asthma vs deconditioning vs coronary disease |
|
| Prostatic Obstruction | Reproductive system and breast disorders | Non-systematic Assessment |
|
| Herpes simplex virus rash | Infections and infestations | Non-systematic Assessment | Herpes simplex virus. Vesicular rash on lower lip and chin. Mostly on left and on midline |
|
| Heart palpitations | Cardiac disorders | Non-systematic Assessment | 3x/week for 3 weeks lasting less than 1 min. No pain, SOB or numbness. |
|
| Adrenal incidentaloma | Endocrine disorders | Non-systematic Assessment |
|
| Conduction disorder- Non-specific intraventricular block | Cardiac disorders | Non-systematic Assessment | Non-specific intraventricular block (conduction disorder). QRS 128ms. |
|
| Bilateral impacted cerumen | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Herpes simplex cold sore | Infections and infestations | Non-systematic Assessment | Cold sore on lip, treated with valtrex |
|
| Balanitis | Infections and infestations | Non-systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Ankle soreness and swelling post exercize | Injury, poisoning and procedural complications | Non-systematic Assessment | Left ankle soreness with severe swelling after walking a lot in France |
|
| Bilateral swelling in the ankle and high blood pressure | Immune system disorders | Non-systematic Assessment |
|
| Knee arthritis | Immune system disorders | Non-systematic Assessment | New left acute knee arthritis. Initially thought consistent with gout, but patient on uloric for past 2 years. Uric acid 5.5 |
|
| Esophageal narrowing | Gastrointestinal disorders | Non-systematic Assessment |
|
| Recurrent Lightheadedness | Vascular disorders | Non-systematic Assessment | Patient experienced recurrent lightheadedness after increasing Losartan HCT from 50/12.5 to 100/25. |
|
| Cardiac arrythmia | Cardiac disorders | Non-systematic Assessment |
|
| Sores in mouth | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Sores in mouth attributed to Invisalign |
|
| Infection lower eye lid | Infections and infestations | Non-systematic Assessment | Treated with polymyxin drops |
|
| Polyarticular arthritis | Immune system disorders | Non-systematic Assessment | Developed large toe arthritis then wrist, finger, ankle swelling. |
|
| Infection on left side of the face | Infections and infestations | Non-systematic Assessment | Non serious, related and treated with 5 days of antibiotics. |
|
| Epigastric pain | Gastrointestinal disorders | Non-systematic Assessment | epigastric pain radiating to back and RUQ. Associated with nausea and 3 episodes emesis |
|
| Eye and face swelling | Infections and infestations | Non-systematic Assessment | Present to the ED with right eye swelling and pain. Right chin swelling and pain. Subject was prescribed doxycycline cyclate 100mg tablet |
|
| Arm, shoulder and neck pains | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | On and off, for 10 minutes. Not associated with exertion. |
|
| Shingles | Infections and infestations | Non-systematic Assessment | Shingles. C4 distribution. Right |
|
| Syncopal episode | Cardiac disorders | Non-systematic Assessment |
|
| Rash on chest - Allergy | Immune system disorders | Non-systematic Assessment | Rash on chest for 5 days. Pt believes caused by perfume or lotion |
|
| Scleritis | Infections and infestations | Non-systematic Assessment | Medial right eye scleritis treated emergently with prednisolone x 2 weeks, with improvement over 24 hours and no return of symptoms after drops stopped. Presented with gritty feeling whe blinking. Attributed to foreign body in eye |
|
Not provided
Not provided
| D017445 |
| Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Role functioning/physical at 6 months |
|
|
| Role functioning/emotional at 6 months |
|
|
| Energy/fatigue at 6 months |
|
|
| Emotional well-being at 6 months |
|
|
| Social functioning at 6 months |
|
|
| Pain at 6 months |
|
|
| General health at 6 months |
|
|
| Physical functioning at 36 months |
|
|
| Role functioning/physical at 36 months |
|
|
| Role functioning/emotional at 36 months |
|
|
| Energy/fatigue at 36 months |
|
|
| Emotional well-being at 36 months |
|
|
| Social functioning at 36 months |
|
|
| Pain at 36 months |
|
|
| General health at 36 months |
|
|
| Physical functioning at 12 months |
|
|
| Role functioning/physical at 12 months |
|
|
| Role functioning/emotional at 12 months |
|
|
| Energy/ fatigue at 12 months |
|
|
| Emotional well-being at 12 months |
|
|
| Social functioning at 12 months |
|
|
| Pain at 12 months |
|
|
| General health at 12 months |
|
|
| Physical functioning at 18 months |
|
|
| Role functioning/physical at 18 months |
|
|
| Role functioning/emotional at 18 months |
|
|
| Energy/fatigue at 18 months |
|
|
| Emotional well-being at 18 months |
|
|
| Social functioning at 18 months |
|
|
| Pain at 18 months |
|
|
| General health at 18 months |
|
|
| Physical functioning at 24 months |
|
|
| Role functioning/physical at 24 months |
|
|
| Role functioning/emotional at 24 months |
|
|
| Energy/fatigue at 24 months |
|
|
| Emotional well-being at 24 months |
|
|
| Social functioning at 24 months |
|
|
| Pain at 24 months |
|
|
| General health at 24 months |
|
|
| Physical functioning at 30 months |
|
|
| Role functioning/physical at 30 months |
|
|
| Role functioning/emotional at 30 months |
|
|
| Energy/fatigue at 30 months |
|
|
| Emotional well-being at 30 months |
|
|
| Social functioning at 30 months |
|
|
| Pain at 30 months |
|
|
| General health at 30 months |
|
|
| Physical functioning at 42 months |
|
|
| Role functioning/physical at 42 months |
|
|
| Role functioning/emotional at 42 months |
|
|
| Energy/fatigue at 42 months |
|
|
| Emotional well-being at 42 months |
|
|
| Social functioning at 42 months |
|
|
| Pain at 42 months |
|
|
| General health at 42 months |
|
|
| Physical functioning at 48 months |
|
|
| Role functioning/physical at 48 months |
|
|
| Role functioning/emotional at 48 months |
|
|
| Energy/fatigue at 48 months |
|
|
| Emotional well-being at 48 months |
|
|
| Social functioning at 48 months |
|
|
| Pain at 48 months |
|
|
| General health at 48 months |
|
|
| Physical functioning at 54 months |
|
|
| Role functioning/physical at 54 months |
|
|
| Role functioning/emotional at 54 months |
|
|
| Energy/fatigue at 54 months |
|
|
| Emotional well-being at 54 months |
|
|
| Social functioning at 54 months |
|
|
| Pain at 54 months |
|
|
| General health at 54 months |
|
|
| Physical functioning at 60 months |
|
|
| Role functioning/physical at 60 months |
|
|
| Role functioning/emotional at 60 months |
|
|
| Energy/fatigue at 60 months |
|
|
| Emotional well-being at 60 months |
|
|
| Social functioning at 60 months |
|
|
| Pain at 60 months |
|
|
| General health at 60 months |
|
|