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This study will evaluate whether conversion from cyclosporine, a calcineurin inhibitor (CI) to sirolimus (SRL) results in improved long-term renal function without a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of SRL to reduce the severity and/or progression of chronic allograft nephropathy (CAN).
This open-label, randomized, parallel-group, comparative, outpatient study will be conducted in multiple centers in Taiwan.
The study will randomize approximately 120 patients. 80 patients will be randomized to the SRL therapy group (conversion from CI- to SRL-based immunosuppression: group A) and 40 patients to the CI therapy group (continued CI therapy: group B).
Dosage and Administration
SRL Therapy: At the time of randomization on day 1, each patient will have been receiving:
SRL will be added to the immunosuppressive regimen for Group A. Group B will continue on this CI immunosuppressive regimen.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | Sirolimus therapy |
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| 2 | Active Comparator | Calcineurin Inhibitor therapy (either cyclosporine or tacrolimus) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus+MMF or MPS or AZA+Steroid | Drug | Corticosteroids will be administered according to local practice, within a daily maintenance dosage range of 2.5 to15 mg for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Glomerular Filtration Rate (GFR) Change From Baseline | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | 104 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Monitor | Wyeth is now a wholly owned subsidiary of Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Select Cities | Taiwan |
After consent and eligibility criteria patients needed to be receiving: triple therapy with a Calcineurin Inhibitor (CI) (tacrolimus or cyclosporine) that began at the time of transplantation or ≤2 weeks thereafter and corticosteroids plus either mycophenolate mofetil (MMF)/mycophenolate sodium (MPS) or azathioprine (AZA) for at least 12 weeks.
Patients were recruited in Taiwan from April 2007 to May 2008.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sirolimus (SRL) | SRL added to the immunosuppressive regimen at a daily maintenance dose of 2 mg, following a loading dose of 6 mg. The dose of SRL adjusted as necessary to maintain a whole blood trough concentration range of 10 to 15 ng/mL. CI dose was reduced by 50% and discontinued within 2 weeks if SRL at the target trough level. Once SRL trough level was at target range, MMF dose reduced to a maximum of 1500 mg/day or MPS dose reduced to a maximum of 1080 mg/day and AZA dose reduced to a maximum of 75 mg/day. Corticosteroids were administered according to local practice, within a daily maintenance dosage range (2.5 to 15 mg for prednisone or prednisolone; 2 to 12 mg/day for methylprednisolone) or the alternate day equivalent. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Calcineurin Inhibitors (either cyclosporine or tacrolimus)+MMF or MPS or AZA+Steroid | Drug | The maintenance dose of:
Thereafter, at the discretion of the investigator, MMF/MPS or AZA may be:
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| Baseline and Week 24 |
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Baseline and Week 52 |
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Baseline and Week 104 |
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 24 |
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 52 |
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 104 |
| Change From Baseline in Diastolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Baseline and Week 24 |
| Change From Baseline in Diastolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Baseline and Week 52 |
| Change From Baseline in Diastolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Baseline and Week 104 |
| Change From Baseline in Systolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Baseline and Week 24 |
| Change From Baseline in Systolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Baseline and Week 52 |
| Change From Baseline in Systolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Baseline and Week 104 |
| Change From Baseline in the Severity and Progression of Biopsy-Confirmed Chronic Allograft Nephropathy (CAN) at Week 104 | Baseline and Week 104 |
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 52 | Weeks 52 |
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 104 | Week 104 |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 24 | Week 24 |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 52 | Week 52 |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 104 | Week 104 |
| FG001 | Calcineurin Inhibitor (CI) | Patients will continue to receive a CI (tacrolimus or CsA). At the discretion of the investigator, patients will be permitted to: (a) change from MMF/MPS to AZA or vice versa, and from CsA to tacrolimus or vice versa; (b) continue MMF/MPS or AZA for the entire 104-week period of randomized therapy; or (c) discontinue MMF/MPS or AZA and subsequently restart either one after discontinuation. Whole blood CsA or tacrolimus trough concentrations will be monitored at designated intervals and the CI dose adjusted to maintain the following trough concentration ranges: CsA 50-250 ng/mL and Tacrolimus 4-10 ng/mL. |
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| ID | Title | Description |
|---|---|---|
| BG000 | Sirolimus (SRL) | SRL added to the immunosuppressive regimen at a daily maintenance dose of 2 mg, following a loading dose of 6 mg. The dose of SRL adjusted as necessary to maintain a whole blood trough concentration range of 10 to 15 ng/mL. CI dose was reduced by 50% and discontinued within 2 weeks if SRL at the target trough level. Once SRL trough level was at target range, MMF dose reduced to a maximum of 1500 mg/day or MPS dose reduced to a maximum of 1080 mg/day and AZA dose reduced to a maximum of 75 mg/day. Corticosteroids were administered according to local practice, within a daily maintenance dosage range (2.5 to 15 mg for prednisone or prednisolone; 2 to 12 mg/day for methylprednisolone) or the alternate day equivalent. |
| BG001 | Calcineurin Inhibitor (CI) | Patients will continue to receive a CI (tacrolimus or CsA). At the discretion of the investigator, patients will be permitted to: (a) change from MMF/MPS to AZA or vice versa, and from CsA to tacrolimus or vice versa; (b) continue MMF/MPS or AZA for the entire 104-week period of randomized therapy; or (c) discontinue MMF/MPS or AZA and subsequently restart either one after discontinuation. Whole blood CsA or tacrolimus trough concentrations will be monitored at designated intervals and the CI dose adjusted to maintain the following trough concentration ranges: CsA 50-250 ng/mL and Tacrolimus 4-10 ng/mL. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| 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 | Change in Glomerular Filtration Rate (GFR) Change From Baseline | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | No patients completed 104 weeks and therefore no data were available for efficacy analysis. | Posted | Sep 2009 | 104 weeks |
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| Secondary | Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Sep 2009 | Baseline and Week 24 |
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| Secondary | Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Sep 2009 | Baseline and Week 52 |
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| Secondary | Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Sep 2009 | Baseline and Week 104 |
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| Secondary | Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 24 |
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| Secondary | Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 52 |
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| Secondary | Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 104 |
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| Secondary | Change From Baseline in Diastolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 24 |
| |||||||||||||||||||||||
| Secondary | Change From Baseline in Diastolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 52 |
| |||||||||||||||||||||||
| Secondary | Change From Baseline in Diastolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 104 |
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| Secondary | Change From Baseline in Systolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 24 |
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| Secondary | Change From Baseline in Systolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 52 |
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| Secondary | Change From Baseline in Systolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 104 |
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| Secondary | Change From Baseline in the Severity and Progression of Biopsy-Confirmed Chronic Allograft Nephropathy (CAN) at Week 104 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Baseline and Week 104 |
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| Secondary | Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 52 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Weeks 52 |
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| Secondary | Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 104 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 104 |
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| Secondary | Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 24 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 24 |
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| Secondary | Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 52 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 52 |
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| Secondary | Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 104 | Insufficient or no data available for efficacy analyses because study was terminated early. | Posted | Week 104 |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sirolimus (SRL) | SRL added to the immunosuppressive regimen at a daily maintenance dose of 2 mg, following a loading dose of 6 mg. The dose of SRL adjusted as necessary to maintain a whole blood trough concentration range of 10 to 15 ng/mL. CI dose was reduced by 50% and discontinued within 2 weeks if SRL at the target trough level. Once SRL trough level was at target range, MMF dose reduced to a maximum of 1500 mg/day or MPS dose reduced to a maximum of 1080 mg/day and AZA dose reduced to a maximum of 75 mg/day. Corticosteroids were administered according to local practice, within a daily maintenance dosage range (2.5 to 15 mg for prednisone or prednisolone; 2 to 12 mg/day for methylprednisolone) or the alternate day equivalent. | 6 | 21 | 78 | 21 | ||
| EG001 | Calcineurin Inhibitor (CI) | Patients will continue to receive a CI (tacrolimus or CsA). At the discretion of the investigator, patients will be permitted to: (a) change from MMF/MPS to AZA or vice versa, and from CsA to tacrolimus or vice versa; (b) continue MMF/MPS or AZA for the entire 104-week period of randomized therapy; or (c) discontinue MMF/MPS or AZA and subsequently restart either one after discontinuation. Whole blood CsA or tacrolimus trough concentrations will be monitored at designated intervals and the CI dose adjusted to maintain the following trough concentration ranges: CsA 50-250 ng/mL and Tacrolimus 4-10 ng/mL. | 2 | 10 | 18 | 10 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mechanical ileus | Gastrointestinal disorders | Non-systematic Assessment |
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| Pyrexia | General disorders | Non-systematic Assessment |
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| Cellulitis | General disorders | Non-systematic Assessment |
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| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Pneumonitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Lens dislocation | Eye disorders | Non-systematic Assessment |
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| Appendicitis | Gastrointestinal disorders | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Eyelid oedema | Eye disorders | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | Non-systematic Assessment |
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| Haemorrhoids | Gastrointestinal disorders | Non-systematic Assessment |
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| Mouth ulceration | Gastrointestinal disorders | Non-systematic Assessment |
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| Tooth ache | Gastrointestinal disorders | Non-systematic Assessment |
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| Hepatic function abnormal | Hepatobiliary disorders | Non-systematic Assessment |
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| Herpes virus infection | General disorders | Non-systematic Assessment |
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| Upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | Non-systematic Assessment |
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| Hyperlipidaemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Hyperuricaemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | Non-systematic Assessment |
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| Insomina | Nervous system disorders | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Epistaxis | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Acne | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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Study terminated early due to difficulties in enrolling qualified patients. No patients completed 104 weeks (primary outcome); a few completed 60 weeks. Insufficient data were available for efficacy analyses.
The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| U. S. Contact Center | Wyeth | clintrialresults@wyeth.com |
| ID | Term |
|---|---|
| D065095 | Calcineurin Inhibitors |
| ID | Term |
|---|---|
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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