This study will conduct a randomized controlled trial to compare the efficacy of ultra-low doses of rituximab (RTX) to the standard low dose in patients with rheumatoid arthritis (RA) who are being retreated with RTX. The trial will randomize 140 RA patients who have responded well previously to RTX to receive either an ultra-low dose of 1 x 200 mg or 1 x 500 mg RTX, or the standard low dose of 1 x 1000 mg RTX. The primary outcome is whether the ultra-low doses are non-inferior to the standard dose in reducing disease activity as measured by DAS28-CRP from baseline to 6 months, using a non-inferiority margin of 0
This randomized, double-blind, Phase 3 clinical trial compared the efficacy and safety of tofacitinib (5mg or 10mg twice daily) to methotrexate (MTX) for the treatment of rheumatoid arthritis in patients who had not previously received MTX. The study found that tofacitinib was associated with greater improvements in signs/symptoms of RA and less progression of structural damage compared to MTX. Tofacitinib also increased some lab abnormalities like cholesterol and reduced white blood cell counts. The results demonstrated that tofacitinib is an effective alternative treatment for RA patients who have failed or are intolerant to MTX.
The Phase I clinical trial combined pazopanib with gemcitabine and docetaxel chemotherapy in patients with high-risk soft tissue sarcomas. The trial was stopped after enrolling six patients due to unacceptable toxicity. Two patients experienced dose-limiting toxicities of diarrhea with neutropenic fever and diverticulitis during the first treatment cycle. Additional grade 2-3 adverse events led to dose modifications in most patients. There was one complete and one partial pathological response, but the combination showed no evidence of added benefit while toxicity was significant and not warranted for the neoadjuvant setting. Pazopanib should not be combined with chemotherapy based on this trial.
This study aims to compare rituximab to azathioprine as maintenance therapy for patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis who have relapsing disease. Patients will receive rituximab induction therapy and be randomized if in remission at 4 months to receive either rituximab every 4 months or daily azathioprine for 24 months. The primary outcome is time to disease relapse over a minimum 36-month follow up period. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized to determine if rituximab is superior to azathioprine at preventing relapses.
2007 Tmih Artekin Trial Malaria In Cambodiawvdamme
- The study aimed to compare the efficacy and tolerability of dihydroartemisinin–piperaquine (DHA–PQP) to a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia.
- 464 patients were randomly assigned to receive either DHA–PQP or MAS3. The PCR-adjusted cure rates on day 63 were 97.5% for both treatments, demonstrating non-inferiority.
- There were no serious adverse events reported. However, significantly more episodes of vomiting, dizziness, palpitations, and sleep disorders were reported in the MAS3
ADC- Creation of Cytotoxic Payload PosterZoe Vaughn
This document describes the synthesis of a novel linker, MC-val-cit-PAB-PNP, for an antibody-drug conjugate (ADC) using doxorubicin as the cytotoxic payload. Thin layer chromatography and LC/MS were used to analyze the purified conjugate product, which was identified in fraction 6 with an m/z value of 1146.2. The effectiveness of the linker-drug conjugate will be measured through conjugation to the antibody Trastuzumab and testing on cultured cancer cells. ADC's show potential for targeted cancer therapy by reducing side effects to normal tissue when the appropriate payload and linker combinations are identified.
Metronomic chemotherapy involves the chronic administration of low, minimally toxic doses of chemotherapy drugs on a frequent schedule with no prolonged breaks. This contrasts with conventional chemotherapy which uses maximum tolerated doses with breaks to allow for bone marrow recovery. Metronomic chemotherapy aims to target the tumor vasculature through its anti-angiogenic effects and has shown efficacy in palliative settings with less toxicity. Several drugs have been used in metronomic chemotherapy regimens with the most common being cyclophosphamide and methotrexate. Ongoing research is focused on optimizing dosing schedules and biomarkers to evaluate treatment response and resistance.
Metronomic chemotherapy involves administering lower doses of chemotherapy drugs more frequently to target tumor growth. This summary approach has three potential mechanisms of action - inhibiting angiogenesis, stimulating the immune system, and directly targeting tumor cells. It yields long-term improved outcomes despite slower initial decreases in tumor size compared to maximum tolerated dose regimens. Clinical trials have shown metronomic chemotherapy to be an effective treatment approach in several cancer types including breast, colon, ovarian and prostate cancer when used as a single agent or in combinations.
This randomized, double-blind, Phase 3 clinical trial compared the efficacy and safety of tofacitinib (5mg or 10mg twice daily) to methotrexate (MTX) for the treatment of rheumatoid arthritis in patients who had not previously received MTX. The study found that tofacitinib was associated with greater improvements in signs/symptoms of RA and less progression of structural damage compared to MTX. Tofacitinib also increased some lab abnormalities like cholesterol and reduced white blood cell counts. The results demonstrated that tofacitinib is an effective alternative treatment for RA patients who have failed or are intolerant to MTX.
The Phase I clinical trial combined pazopanib with gemcitabine and docetaxel chemotherapy in patients with high-risk soft tissue sarcomas. The trial was stopped after enrolling six patients due to unacceptable toxicity. Two patients experienced dose-limiting toxicities of diarrhea with neutropenic fever and diverticulitis during the first treatment cycle. Additional grade 2-3 adverse events led to dose modifications in most patients. There was one complete and one partial pathological response, but the combination showed no evidence of added benefit while toxicity was significant and not warranted for the neoadjuvant setting. Pazopanib should not be combined with chemotherapy based on this trial.
This study aims to compare rituximab to azathioprine as maintenance therapy for patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis who have relapsing disease. Patients will receive rituximab induction therapy and be randomized if in remission at 4 months to receive either rituximab every 4 months or daily azathioprine for 24 months. The primary outcome is time to disease relapse over a minimum 36-month follow up period. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized to determine if rituximab is superior to azathioprine at preventing relapses.
2007 Tmih Artekin Trial Malaria In Cambodiawvdamme
- The study aimed to compare the efficacy and tolerability of dihydroartemisinin–piperaquine (DHA–PQP) to a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia.
- 464 patients were randomly assigned to receive either DHA–PQP or MAS3. The PCR-adjusted cure rates on day 63 were 97.5% for both treatments, demonstrating non-inferiority.
- There were no serious adverse events reported. However, significantly more episodes of vomiting, dizziness, palpitations, and sleep disorders were reported in the MAS3
ADC- Creation of Cytotoxic Payload PosterZoe Vaughn
This document describes the synthesis of a novel linker, MC-val-cit-PAB-PNP, for an antibody-drug conjugate (ADC) using doxorubicin as the cytotoxic payload. Thin layer chromatography and LC/MS were used to analyze the purified conjugate product, which was identified in fraction 6 with an m/z value of 1146.2. The effectiveness of the linker-drug conjugate will be measured through conjugation to the antibody Trastuzumab and testing on cultured cancer cells. ADC's show potential for targeted cancer therapy by reducing side effects to normal tissue when the appropriate payload and linker combinations are identified.
Metronomic chemotherapy involves the chronic administration of low, minimally toxic doses of chemotherapy drugs on a frequent schedule with no prolonged breaks. This contrasts with conventional chemotherapy which uses maximum tolerated doses with breaks to allow for bone marrow recovery. Metronomic chemotherapy aims to target the tumor vasculature through its anti-angiogenic effects and has shown efficacy in palliative settings with less toxicity. Several drugs have been used in metronomic chemotherapy regimens with the most common being cyclophosphamide and methotrexate. Ongoing research is focused on optimizing dosing schedules and biomarkers to evaluate treatment response and resistance.
Metronomic chemotherapy involves administering lower doses of chemotherapy drugs more frequently to target tumor growth. This summary approach has three potential mechanisms of action - inhibiting angiogenesis, stimulating the immune system, and directly targeting tumor cells. It yields long-term improved outcomes despite slower initial decreases in tumor size compared to maximum tolerated dose regimens. Clinical trials have shown metronomic chemotherapy to be an effective treatment approach in several cancer types including breast, colon, ovarian and prostate cancer when used as a single agent or in combinations.
Comparing outcomes of meropenem administration strategies 2010eduardo de avila
This document systematically reviews evidence comparing traditional and alternative dosing strategies for meropenem. Sixteen studies were reviewed, including 13 pharmacokinetic/dynamic assessments, 5 clinical evaluations, and 3 economic appraisals. Studies suggest alternative dosing strategies like prolonged or continuous infusion may increase achieving pharmacodynamic targets compared to traditional dosing. However, evidence linking these strategies to improved clinical outcomes is lacking. Smaller, more frequent doses appear to provide similar clinical outcomes and pharmacodynamic target attainment as traditional dosing, with potential cost savings. Overall, alternative dosing strategies seem to provide comparable outcomes to traditional dosing, but evidence is limited and largely based on healthy subjects. Larger clinical trials are needed.
This document discusses the diagnosis and treatment of drugs five years after their approval, focusing on procarbazine. It provides the following key points:
1) Procarbazine has an established role in combination chemotherapy for Hodgkin's disease since its 1969 FDA approval, but its role has not expanded beyond this and a few other applications in the past 5 years.
2) It is most effective for Hodgkin's disease when used in combination with other drugs in the MOPP regimen, achieving around an 80% complete remission rate. However, relapse remains an issue.
3) For other cancers like non-Hodgkin's lymphomas and lung cancer, procarbazine has limited effectiveness as a single
Docetaxel injection 40 mg with solvent for docetaxel injection smpc taj ph...Taj Pharma
DOCETAXEL - Drug Information - Taj Pharma, DOCETAXEL dose Taj pharmaceuticals DOCETAXEL interactions, Taj Pharmaceutical DOCETAXEL contraindications, DOCETAXEL price, DOCETAXEL Taj Pharma Cancer, oncologyDocetaxel Injection 40mg with solvent for docetaxel injection SMPC- Taj Pharma . Stay connected to all updated on DOCETAXEL Taj Pharmaceuticals Taj pharmaceuticals Hyderabad.
While the incorporation of pertuzumab to a chemotherapy and trastuzumab backbone (dual HER2
blockade) yielded a robust improvement in the outcomes of HER2-positive metastatic patients in the
CLEOPATRA study, in the adjuvant setting the same magnitude of benefit was not reproduced with the
addition of pertuzumab in the overall population of the APHINITY study, being the reasons for this discrepancy unknown so far. In the present manuscript, we discuss biological and clinical differences between metastatic and early-stage HER2-positive breast cancer that may potentially explain the different magnitudes of benefit observed with pertuzumab in the different disease settings.
Recent Advances In The Development Of Innovative Therapies The Celgene Pipelinespa718
This document summarizes recent advances in Celgene's drug pipeline for cancer and inflammatory diseases. It discusses:
1) Celgene's focus on targeting unmet medical needs in hematologic and solid tumor malignancies as well as inflammatory disorders.
2) Recent accomplishments including approval and clinical trial results showing survival benefits for their drugs Lenalidomide (Revlimid), Pomalidomide (Pomalyst), and Abraxane in multiple myeloma, myelodysplastic syndromes, lymphomas, and cancers like pancreatic and lung.
3) Near-term milestones including data readouts for Phase 3 trials of Apremilast in psoriasis and psoriatic arthritis, which
AIM: To obtain confirmation of efficacy and safety of PXT3003 as a specific treatment for CMT1A
PRIMARY OBJECTIVE: To assess the efficacy of PXT3003 compared to placebo on the disability measured by the ONLS score in CMT1A patients treated for 15 months
SECONDARY OBJECTIVES:
To assess efficacy of PXT3003 compared to placebo
clinical scores (ONLS and CMTNS-v2)
functional tests ( 10mWT, 9-HPegT, QMT hand grip & dorsiflexion)
electrophysiological parameters ( CMAP, SNAP, NCV)
measures of quality of life (EQ-5D and VAS)
Safety and tolerability of PXT3003 compared to placebo
PXT3003 plasma sample (Cmax and through) for population
pharmacokinetics
Change over time of potential blood biomarkers
Molecular changes in skin biopsy (ancillary study)
Potential imaging changes through leg MRI (ancillary study).
L'efficacia clinica del trattamento con ixabepilone nel carcinoma mammario me...Merqurio
1) Approximately 30% of women diagnosed with early-stage breast cancer will progress to metastatic breast cancer, for which treatment options are limited after anthracycline and taxane chemotherapy.
2) Resistance to chemotherapy is a major challenge, as responses to subsequent treatments are typically low (20-30%) and last less than 6 months.
3) Ixabepilone is a potential treatment for taxane-resistant metastatic breast cancer due to its activity against microtubules and lack of cross-resistance with other chemotherapies. It may provide an option for patients with limited remaining treatment options.
Nick chen ppt presentation metronomic chemotherapy 2015CNPS, LLC
Metronomic chemotherapy provides several advantages over conventional chemotherapy:
- It is associated with lower toxicity due to more frequent lower doses, allowing better treatment consistency.
- It has enhanced anti-cancer effects through anti-angiogenesis and improved immune response against tumors.
- Targeting both the tumor and tumor microenvironment makes it less likely to encounter chemo-resistance.
Dasatinib is an effective first-line treatment for chronic myeloid leukemia (CML) based on results from the DASISION trial. The trial showed that dasatinib induced higher and faster rates of complete cytogenetic response and major molecular response compared to imatinib. At 5 years of follow-up, dasatinib maintained superior rates of molecular responses including deeper responses below 0.1% BCR-ABL1. Dasatinib therefore provides improved long-term outcomes for patients with newly diagnosed CML compared to standard imatinib treatment.
This protocol aims to test a gene therapy using an adeno-associated viral vector delivering a TNF receptor-Fc fusion protein for localized treatment of rheumatoid arthritis patients with partial responses to systemic therapies. Potential concerns discussed include immunological issues related to pre-existing antibodies to AAV or induced antibodies to the fusion protein, as well as determining whether the therapy has local or systemic effects. The reviewers provide feedback and the researchers respond addressing each point to refine the trial design and assessment of safety.
This study assessed the biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr-ibritumomab tiuxetan PET scans. Seven patients underwent PET scans after injection of 89Zr-ibritumomab tiuxetan alone and after co-injection with 90Y-ibritumomab tiuxetan. The highest absorbed radiation doses from 90Y were to the liver and spleen, followed by kidneys and lungs. Red marrow and effective doses were also calculated. Tumor doses ranged from 8.6 to 28.6 mGy
Cabazitaxel 60 mg concentrate and solvent for solution for infusion smpc taj...Taj Pharma
CABAZITAXEL - Drug Information - Taj Pharma, CABAZITAXEL dose Taj pharmaceuticals CABAZITAXEL interactions, Taj Pharmaceutical CABAZITAXEL contraindications, CABAZITAXEL price, CABAZITAXEL Taj Pharma Cancer, oncologyCABAZITAXEL 60 mg concentrate and solvent for solution for infusion. SMPC- Taj Pharma . Stay connected to all updated on CABAZITAXEL Taj Pharmaceuticals Taj pharmaceuticals Hyderabad.
CNS metastases in Her2+ mBC: does size matter?Mauricio Lema
Sponsored by Roche.
There is a debate In pretreated Her2+ mBC as to whether the indisputable benefit of T-DM1 (an antibody drug conjugate anti Her2) over lapatinib (a small anti Her2 TKI) seen in the EMILIA trial also translates to CNS disease. The subgroup analysis of the EMILIA clearly shows that patients with CNS disease do not appear to have worse outcomes when treated with the big (T-DM1) as opposed to the small (lapatinib) drug.
This document summarizes a case report of a 49-year-old woman with recurrent metastatic breast cancer who was treated with high daily doses of THC and CBD in lipid suspension. Imaging showed delayed progression of lung and lymph node tumors compared to expected outcomes without treatment. The patient was maintained on doses of 3mg/kg THC and CBD daily, with imaging in March showing no new metastases after 13 months of remission, the longest in her history. However, May imaging found new liver metastases, and she began chemotherapy. The report suggests cannabinoid treatment delayed tumor progression but additional treatment was ultimately needed.
The document summarizes several key studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting. It discusses results from the GALLIUM and ALCANZA studies showing improved outcomes for obinutuzumab and brentuximab vedotin, respectively, in follicular lymphoma and cutaneous T-cell lymphoma. It also summarizes positive results from maintenance rituximab in mantle cell lymphoma and lenalidomide in high-risk chronic lymphocytic leukemia. Finally, it discusses advances in CAR T-cell therapy and results from studies of pacritinib and transplant approaches in myeloma.
HER_Receptors_Quantif_BC_(Nuciforo,_Radosevic-Robin,_Ng,_Scaltriti,_BC_Resear...Nina Radosevic - Robin
The document discusses various methods for quantifying HER family receptors in breast cancer, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), VeraTag proximity-based assay, and fluorescence lifetime imaging microscopy (FLIM). It notes that while IHC and FISH are commonly used, they only partially predict response to anti-HER therapies. Better methods of quantifying HER receptors are needed to better categorize patients for individualized treatments.
This document describes key concepts related to dose-response relationships and drug interactions. It defines dose-response relationships and curves, and explains how drug potency, efficacy, selectivity, and therapeutic index are determined based on these curves. It also discusses how drugs can have synergistic or antagonistic effects when combined, including competitive and non-competitive receptor antagonism. The overall intent is to explain important pharmacological concepts for understanding how drug effects are produced at varying doses both alone and when administered together with other drugs.
Tofacitinib has been shown to significantly reduce signs and symptoms of RA as monotherapy and in combination with DMARDs. While treatments have improved, unmet needs remain like pain, fatigue, and psychological issues. ORAL Strategy showed tofacitinib + MTX was non-inferior to adalimumab + MTX. Tofacitinib provides an oral option for patients after inadequate response to csDMARDs and has an extensive safety profile from clinical trials and real-world use.
This study summarizes the results of long-term rituximab treatment (median of 60 months) in 30 patients with neuromyelitis optica spectrum disorder (NMOSD). Rituximab was administered based on the frequency of reemerging memory B cells. Over 5 years, 87% of patients had a significant reduction in annualized relapse rates. Disability was improved or stabilized in 93% of patients. No serious adverse events leading to discontinuation occurred with long-term rituximab treatment. This provides evidence that repeated rituximab treatment can produce sustained clinical responses in NMOSD with an acceptable safety profile over the long term.
Dr. Hager 2016 Presentation The Challenges of Achieving Early Efficacy in Cli...Dr. Martin Hager, MBA
This document summarizes information about the development of DS-6051, a ROS1/NTRK dual kinase inhibitor being developed by Daiichi-Sankyo for the treatment of cancers. It discusses challenges in early drug development including predicting phase II success. It provides details on DS-6051's mechanism of action, differentiation from other drugs, ongoing clinical trial design incorporating screening approaches, safety and efficacy results from the phase I trial, and plans for phase I expansion. The document covers multiple topics relating to DS-6051's development path and strategies to incorporate early efficacy data.
Comparing outcomes of meropenem administration strategies 2010eduardo de avila
This document systematically reviews evidence comparing traditional and alternative dosing strategies for meropenem. Sixteen studies were reviewed, including 13 pharmacokinetic/dynamic assessments, 5 clinical evaluations, and 3 economic appraisals. Studies suggest alternative dosing strategies like prolonged or continuous infusion may increase achieving pharmacodynamic targets compared to traditional dosing. However, evidence linking these strategies to improved clinical outcomes is lacking. Smaller, more frequent doses appear to provide similar clinical outcomes and pharmacodynamic target attainment as traditional dosing, with potential cost savings. Overall, alternative dosing strategies seem to provide comparable outcomes to traditional dosing, but evidence is limited and largely based on healthy subjects. Larger clinical trials are needed.
This document discusses the diagnosis and treatment of drugs five years after their approval, focusing on procarbazine. It provides the following key points:
1) Procarbazine has an established role in combination chemotherapy for Hodgkin's disease since its 1969 FDA approval, but its role has not expanded beyond this and a few other applications in the past 5 years.
2) It is most effective for Hodgkin's disease when used in combination with other drugs in the MOPP regimen, achieving around an 80% complete remission rate. However, relapse remains an issue.
3) For other cancers like non-Hodgkin's lymphomas and lung cancer, procarbazine has limited effectiveness as a single
Docetaxel injection 40 mg with solvent for docetaxel injection smpc taj ph...Taj Pharma
DOCETAXEL - Drug Information - Taj Pharma, DOCETAXEL dose Taj pharmaceuticals DOCETAXEL interactions, Taj Pharmaceutical DOCETAXEL contraindications, DOCETAXEL price, DOCETAXEL Taj Pharma Cancer, oncologyDocetaxel Injection 40mg with solvent for docetaxel injection SMPC- Taj Pharma . Stay connected to all updated on DOCETAXEL Taj Pharmaceuticals Taj pharmaceuticals Hyderabad.
While the incorporation of pertuzumab to a chemotherapy and trastuzumab backbone (dual HER2
blockade) yielded a robust improvement in the outcomes of HER2-positive metastatic patients in the
CLEOPATRA study, in the adjuvant setting the same magnitude of benefit was not reproduced with the
addition of pertuzumab in the overall population of the APHINITY study, being the reasons for this discrepancy unknown so far. In the present manuscript, we discuss biological and clinical differences between metastatic and early-stage HER2-positive breast cancer that may potentially explain the different magnitudes of benefit observed with pertuzumab in the different disease settings.
Recent Advances In The Development Of Innovative Therapies The Celgene Pipelinespa718
This document summarizes recent advances in Celgene's drug pipeline for cancer and inflammatory diseases. It discusses:
1) Celgene's focus on targeting unmet medical needs in hematologic and solid tumor malignancies as well as inflammatory disorders.
2) Recent accomplishments including approval and clinical trial results showing survival benefits for their drugs Lenalidomide (Revlimid), Pomalidomide (Pomalyst), and Abraxane in multiple myeloma, myelodysplastic syndromes, lymphomas, and cancers like pancreatic and lung.
3) Near-term milestones including data readouts for Phase 3 trials of Apremilast in psoriasis and psoriatic arthritis, which
AIM: To obtain confirmation of efficacy and safety of PXT3003 as a specific treatment for CMT1A
PRIMARY OBJECTIVE: To assess the efficacy of PXT3003 compared to placebo on the disability measured by the ONLS score in CMT1A patients treated for 15 months
SECONDARY OBJECTIVES:
To assess efficacy of PXT3003 compared to placebo
clinical scores (ONLS and CMTNS-v2)
functional tests ( 10mWT, 9-HPegT, QMT hand grip & dorsiflexion)
electrophysiological parameters ( CMAP, SNAP, NCV)
measures of quality of life (EQ-5D and VAS)
Safety and tolerability of PXT3003 compared to placebo
PXT3003 plasma sample (Cmax and through) for population
pharmacokinetics
Change over time of potential blood biomarkers
Molecular changes in skin biopsy (ancillary study)
Potential imaging changes through leg MRI (ancillary study).
L'efficacia clinica del trattamento con ixabepilone nel carcinoma mammario me...Merqurio
1) Approximately 30% of women diagnosed with early-stage breast cancer will progress to metastatic breast cancer, for which treatment options are limited after anthracycline and taxane chemotherapy.
2) Resistance to chemotherapy is a major challenge, as responses to subsequent treatments are typically low (20-30%) and last less than 6 months.
3) Ixabepilone is a potential treatment for taxane-resistant metastatic breast cancer due to its activity against microtubules and lack of cross-resistance with other chemotherapies. It may provide an option for patients with limited remaining treatment options.
Nick chen ppt presentation metronomic chemotherapy 2015CNPS, LLC
Metronomic chemotherapy provides several advantages over conventional chemotherapy:
- It is associated with lower toxicity due to more frequent lower doses, allowing better treatment consistency.
- It has enhanced anti-cancer effects through anti-angiogenesis and improved immune response against tumors.
- Targeting both the tumor and tumor microenvironment makes it less likely to encounter chemo-resistance.
Dasatinib is an effective first-line treatment for chronic myeloid leukemia (CML) based on results from the DASISION trial. The trial showed that dasatinib induced higher and faster rates of complete cytogenetic response and major molecular response compared to imatinib. At 5 years of follow-up, dasatinib maintained superior rates of molecular responses including deeper responses below 0.1% BCR-ABL1. Dasatinib therefore provides improved long-term outcomes for patients with newly diagnosed CML compared to standard imatinib treatment.
This protocol aims to test a gene therapy using an adeno-associated viral vector delivering a TNF receptor-Fc fusion protein for localized treatment of rheumatoid arthritis patients with partial responses to systemic therapies. Potential concerns discussed include immunological issues related to pre-existing antibodies to AAV or induced antibodies to the fusion protein, as well as determining whether the therapy has local or systemic effects. The reviewers provide feedback and the researchers respond addressing each point to refine the trial design and assessment of safety.
This study assessed the biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr-ibritumomab tiuxetan PET scans. Seven patients underwent PET scans after injection of 89Zr-ibritumomab tiuxetan alone and after co-injection with 90Y-ibritumomab tiuxetan. The highest absorbed radiation doses from 90Y were to the liver and spleen, followed by kidneys and lungs. Red marrow and effective doses were also calculated. Tumor doses ranged from 8.6 to 28.6 mGy
Cabazitaxel 60 mg concentrate and solvent for solution for infusion smpc taj...Taj Pharma
CABAZITAXEL - Drug Information - Taj Pharma, CABAZITAXEL dose Taj pharmaceuticals CABAZITAXEL interactions, Taj Pharmaceutical CABAZITAXEL contraindications, CABAZITAXEL price, CABAZITAXEL Taj Pharma Cancer, oncologyCABAZITAXEL 60 mg concentrate and solvent for solution for infusion. SMPC- Taj Pharma . Stay connected to all updated on CABAZITAXEL Taj Pharmaceuticals Taj pharmaceuticals Hyderabad.
CNS metastases in Her2+ mBC: does size matter?Mauricio Lema
Sponsored by Roche.
There is a debate In pretreated Her2+ mBC as to whether the indisputable benefit of T-DM1 (an antibody drug conjugate anti Her2) over lapatinib (a small anti Her2 TKI) seen in the EMILIA trial also translates to CNS disease. The subgroup analysis of the EMILIA clearly shows that patients with CNS disease do not appear to have worse outcomes when treated with the big (T-DM1) as opposed to the small (lapatinib) drug.
This document summarizes a case report of a 49-year-old woman with recurrent metastatic breast cancer who was treated with high daily doses of THC and CBD in lipid suspension. Imaging showed delayed progression of lung and lymph node tumors compared to expected outcomes without treatment. The patient was maintained on doses of 3mg/kg THC and CBD daily, with imaging in March showing no new metastases after 13 months of remission, the longest in her history. However, May imaging found new liver metastases, and she began chemotherapy. The report suggests cannabinoid treatment delayed tumor progression but additional treatment was ultimately needed.
The document summarizes several key studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting. It discusses results from the GALLIUM and ALCANZA studies showing improved outcomes for obinutuzumab and brentuximab vedotin, respectively, in follicular lymphoma and cutaneous T-cell lymphoma. It also summarizes positive results from maintenance rituximab in mantle cell lymphoma and lenalidomide in high-risk chronic lymphocytic leukemia. Finally, it discusses advances in CAR T-cell therapy and results from studies of pacritinib and transplant approaches in myeloma.
HER_Receptors_Quantif_BC_(Nuciforo,_Radosevic-Robin,_Ng,_Scaltriti,_BC_Resear...Nina Radosevic - Robin
The document discusses various methods for quantifying HER family receptors in breast cancer, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), VeraTag proximity-based assay, and fluorescence lifetime imaging microscopy (FLIM). It notes that while IHC and FISH are commonly used, they only partially predict response to anti-HER therapies. Better methods of quantifying HER receptors are needed to better categorize patients for individualized treatments.
This document describes key concepts related to dose-response relationships and drug interactions. It defines dose-response relationships and curves, and explains how drug potency, efficacy, selectivity, and therapeutic index are determined based on these curves. It also discusses how drugs can have synergistic or antagonistic effects when combined, including competitive and non-competitive receptor antagonism. The overall intent is to explain important pharmacological concepts for understanding how drug effects are produced at varying doses both alone and when administered together with other drugs.
Tofacitinib has been shown to significantly reduce signs and symptoms of RA as monotherapy and in combination with DMARDs. While treatments have improved, unmet needs remain like pain, fatigue, and psychological issues. ORAL Strategy showed tofacitinib + MTX was non-inferior to adalimumab + MTX. Tofacitinib provides an oral option for patients after inadequate response to csDMARDs and has an extensive safety profile from clinical trials and real-world use.
This study summarizes the results of long-term rituximab treatment (median of 60 months) in 30 patients with neuromyelitis optica spectrum disorder (NMOSD). Rituximab was administered based on the frequency of reemerging memory B cells. Over 5 years, 87% of patients had a significant reduction in annualized relapse rates. Disability was improved or stabilized in 93% of patients. No serious adverse events leading to discontinuation occurred with long-term rituximab treatment. This provides evidence that repeated rituximab treatment can produce sustained clinical responses in NMOSD with an acceptable safety profile over the long term.
Dr. Hager 2016 Presentation The Challenges of Achieving Early Efficacy in Cli...Dr. Martin Hager, MBA
This document summarizes information about the development of DS-6051, a ROS1/NTRK dual kinase inhibitor being developed by Daiichi-Sankyo for the treatment of cancers. It discusses challenges in early drug development including predicting phase II success. It provides details on DS-6051's mechanism of action, differentiation from other drugs, ongoing clinical trial design incorporating screening approaches, safety and efficacy results from the phase I trial, and plans for phase I expansion. The document covers multiple topics relating to DS-6051's development path and strategies to incorporate early efficacy data.
Rheumatoid arthritis is an inflammatory disease characterized by inflammation in the synovium that can lead to joint damage. The goals of treatment are to control inflammation and prevent further injury. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) is important to achieve remission and prevent long-term disability. Treatment involves DMARDs, glucocorticoids, exercise and lifestyle changes. Methotrexate is generally first-line for moderate-severe RA while hydroxychloroquine or sulfasalazine may be used for mild RA. Biologics that target cytokines like TNF may be added if initial treatment is ineffective. Prognosis is best when diagnosis and treatment occur early in the
The Efficacy of PARP Inhibitors According to Prior Taxanes Chemotherapy in Pr...semualkaira
No prospective data are available about the best treatment algorithm in mCRPC patients that had received intensified regimens in the castration-sensitive setting. We analyzed the efficacy of a PARPi for mCRPC patients according to prior taxanes treatment.
1) A study examined the clinical response to low-dose (500 mg twice) and conventional-dose (1 g twice) rituximab in over 2800 patients with rheumatoid arthritis. It found similar 6-month clinical results between the doses, though low-dose had lower disease activity and functional impairment at baseline.
2) While clinical results were similar at 6 months, radiographic data was lacking, and a prior trial found less control of structural progression with low-dose in the first 6 months.
3) The study highlights potential pharmacoeconomic benefits of low-dose rituximab, though long-term data is needed to determine if/when low-dose would require re-
The document discusses various aspects of radiation oncology and radiotherapy clinical trial design. It provides an overview of the evolution of radiation therapy techniques from the 1960s to present. It also covers important considerations for radiation oncology trials, including target volume delineation, dose schedules, quality assurance measures, and assessing toxicity. Multidisciplinary collaboration and factors influencing radiation sensitivity are also briefly discussed.
Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation...Wisit Cheungpasitporn
Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety. This study evaluated the efficacy and safety of rituximab (RTX) as induction therapy in renal transplant patients. The study randomized 280 patients to receive either a single dose of RTX or placebo before transplantation. The primary outcome was biopsy-proven acute rejection within 6 months. The results showed no difference in rejection rates between the overall RTX and placebo groups. However, among high-immunological risk patients, RTX showed a trend toward lower rejection rates compared to placebo. Patient and graft survival did not differ between groups after
This document describes a study protocol for a randomized phase III clinical trial comparing neoadjuvant chemoradiation followed by surgery versus surgery alone in patients with adenocarcinoma or squamous cell carcinoma of the esophagus. The trial aims to enroll 350 patients total with 175 patients in each arm. The primary objective is to compare median survival rates and quality of life between the two treatment groups. Secondary objectives include comparing pathological responses, progression-free survival, number of complete resections, treatment toxicity, and costs. The chemoradiation regimen involves weekly paclitaxel and carboplatin chemotherapy with concurrent radiation over 5 weeks. Patients will then undergo surgery and be followed up for survival and quality of life outcomes
Abstract—Colorectal cancer is leading cancer-related public health problem. This study was conducted to determine the effect of High-Dose-Rate intraluminal brachytherapy (HDR-BT) with or without interstitial brachytherapy during neoadjuvant chemoradiation for locally advanced rectal cancer. This randomized contrial was conducted on 28 patients attended with locally advanced rectal cancer (T3, T4 or N+) treated initially with concurrent capecitabine (800 mg/m2 twice daily for 5 days per week) and pelvic external beam radiation therapy (45Gy in 25 Fractions) after one week MRI for all patients; received intraluminal HDR-BT with 4Gy x 2 Fractions with one week interval for those had gross residual disease within 1cm of rectal wall and receiveed intraluminal and interstitial brachytherapy with 4Gy x 2 Fractions with one week interval for those had gross residual disease far from 1cm of rectal wall. All patients underwent surgery within 4-8 week after completion of neoadjuvant therapy. In the control group which were not randomized, twenty-eight patients underwent neoadjuvant chemoradiation (45Gy in 25 Fraction with concurrent capecitabine 800mg/m2 twice daily for 5 days per week) followed by surgery. It was found that in HDR-BT group pathologic complete response (pCR), pathologic partial response (pPR) and pathologic response rates (pCR+pPR) based on AJCC TNM staging for colorectal cancer were %35.7, %35.7, and %71.4 respectively. The pCR, pPR, and pRR were %25, %17, and %42 in the control group respectively. pCR, pPR, and pRR were improved with HDR-BT. However, only response rate improvement was statistically significant (p=0.031). There was no a statistically significant difference in the complications between the two groups (p > 0.05). So it can be concluded that HDR intraluminal with or without interstitial brachytherapy may be an effective method of dose escalation technique in neoadjuvant chemoradiation therapy of locally advanced rectal cancer with higher response rate and manageable side effects.
Methotrexate for optimizing its use in ra 2021 ( ff )SafwatElaraby
The document discusses optimizing the use of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). Some key points discussed include:
- Underdosing of MTX is common, so optimizing the dose is important.
- MTX should be the first-line therapy for most RA patients and be part of initial treatment for active disease.
- Monitoring is important to assess MTX efficacy and toxicity and determine if treatment modification is needed.
- Proper dosing, administration route, and use of folic acid supplementation can help maximize MTX efficacy and minimize toxicity.
This document summarizes potential uses of integrase inhibitors in clinical practice based on current guidelines and data. Some key points:
1. Integrase inhibitors are recommended as preferred treatment options for treatment-naive patients, especially those unable to tolerate NNRTIs or PIs. They have shown non-inferior efficacy to EFV in treatment-naive patients.
2. Integrase inhibitors can be used to simplify or reduce toxicity of regimens in virologically suppressed patients, though some studies like SWITCHMRK did not meet predefined criteria for non-inferiority.
3. For treatment-experienced patients, integrase inhibitors are generally used as part of
The document summarizes guidelines from the WHO on treating drug-resistant tuberculosis. It provides definitions for various drug-resistant TB types and recommendations for treatment regimens. For rifampicin-susceptible, isoniazid-resistant TB, it recommends a 6-month regimen containing rifampicin, ethambutol, pyrazinamide, and levofloxacin. For multidrug- or rifampicin-resistant TB, it recommends a 9-12 month all-oral regimen containing bedaquiline when resistance to fluoroquinolones has been excluded and the patient has not been exposed to the regimen's second-line drugs for over 1 month. The guidelines are based on evidence
Alan Garber: Value-Conscious Bio-Medical Innovation: Why? How? When?capstoneconference09
The document discusses value-conscious biomedical innovation and evaluating medical technologies based on their costs and benefits. It provides examples of how insurers and Medicare make coverage decisions based on whether a technology is medically necessary and cost-effective. The document also analyzes studies on different treatment options for prostate cancer and potential cost savings if lower-cost options were used. It examines cost-effectiveness analyses of COX-2 inhibitors compared to NSAIDs under various assumptions and for high-risk patients. Moving to a cost-effectiveness criterion could shift both health care expenditures and outcomes.
1) Combination DMARD therapy is superior to monotherapy in treating rheumatoid arthritis, with methotrexate as the cornerstone. Studies show combinations of traditional DMARDs can be as effective as combinations including biologics.
2) The COBRA trial demonstrated the benefits of initial intensive combination therapy including prednisolone, methotrexate, and sulfasalazine, followed by tapering medications. Benefits were seen even after medications were withdrawn.
3) Triple therapy with methotrexate, hydroxychloroquine and sulfasalazine is effective and durable for rheumatoid arthritis, shown in trials to be superior to double therapies and monotherapy.
This document describes a Markov model that estimates the incremental cost-utility of etanercept and infliximab compared to usual care over five years for patients with active ankylosing spondylitis. The model uses probabilities for treatment response, relapse, and toxicity derived from clinical trials to estimate quality-adjusted life years and costs for each treatment. The results suggest etanercept and infliximab provide significant clinical benefits but high drug costs limit their efficient use to all patients. The validity of the model is limited by uncertainties around the long-term course of ankylosing spondylitis and effects of TNF inhibitors.
The document discusses adjuvant and neoadjuvant treatment options for renal cell carcinoma (RCC), including targeted therapies. It notes that localized RCC may be treated with adjuvant therapy after nephrectomy or neoadjuvant therapy to downsize tumors before surgery. Several ongoing clinical trials are investigating adjuvant targeted therapies for RCC. Neoadjuvant targeted therapies aim to downsize or downstage primary tumors but may also accelerate metastasis, and there is no way to predict individual responses. Outcomes of cytoreductive nephrectomy combined with targeted therapy in metastatic RCC depend on prognostic risk factors.
This study compared different beam arrangements for stereotactic ablative radiation therapy (SABR) treatment planning for early stage lung cancer. Plans using three coplanar and three non-coplanar beam arrangements were created for 10 patients and evaluated based on dosimetric criteria from RTOG 1021. Non-coplanar plans had significantly better conformity for intermediate dose regions but similar target coverage and dose fall-off compared to coplanar plans. A 10-field plan with 6 or more non-coplanar beams best satisfied the RTOG criteria, with only one minor deviation for maximum rib dose. Further investigation is needed to determine if minor deviations should be accepted given increased treatment time for non-cop
John Tesser, MD, FACP, FACR, prepared useful Practice Aids pertaining to rheumatoid arthritis for this CME activity titled "Overcoming Challenges in the Management of Refractory Rheumatoid Arthritis: Expert Insight on the Clinical Potential of Novel Therapeutic Options." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2GoDoEt. CME credit will be available until April 28, 2020.
Letter to MREC - application to conduct studyAzreen Aj
Application to conduct study on research title 'Awareness and knowledge of oral cancer and precancer among dental outpatient in Klinik Pergigian Merlimau, Melaka'
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Hypotension, or low blood pressure, is when the pressure of blood circulating in the body is lower than normal or expected. It's only a problem if it negatively impacts the body and causes symptoms. Normal blood pressure is usually between 90/60 mmHg and 120/80 mmHg, but pressures below 90/60 are generally considered hypotensive.
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Hypertension and it's role of physiotherapy in it.Vishal kr Thakur
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Hypertension, also known as high blood pressure, is a serious medical condition that occurs when blood pressure in the body's arteries is consistently too high. Blood pressure is the force of blood pushing against the walls of blood vessels as the heart pumps it. Hypertension can increase the risk of heart disease, brain disease, kidney disease, and premature death.
LGBTQ+ Adults: Unique Opportunities and Inclusive Approaches to CareVITASAuthor
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Unlocking the Secrets to Safe Patient Handling.pdfLift Ability
Furthermore, the time constraints and workload in healthcare settings can make it challenging for caregivers to prioritise safe patient handling Australia practices, leading to shortcuts and increased risks.
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Can Allopathy and Homeopathy Be Used Together in India.pdfDharma Homoeopathy
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2. Background
Rituximab (RTX) is a chimeric anti-CD20 monoclonal
antibody authorised for use in patients with severe active
rheumatoid arthritis (RA) in combination with metho-
trexate (MTX) when patients have an inadequate
response or intolerance to other disease-modifying
antirheumatic drugs (DMARDs), including one or more
tumour necrosis factor inhibitors (TNFi). Two large sys-
tematic reviews confirmed the effectiveness of RTX in
patients with RA in combination with MTX compared
to MTX alone [1, 2]. In addition, long-term safety has
been confirmed up to 11 years, with infection risk com-
parable to other biological DMARDS (bDMARDs) [3, 4].
The dose-finding phase of RTX has some interesting
aspects. Since RTX was originally developed as a treat-
ment for non-Hodgkin’s lymphoma, its optimal dose was
initially determined for that indication [5]. The first two
studies of RTX in RA indeed used treatment protocols
based on experience in the treatment of lymphoma [6, 7].
Both studies were open-label and consisted of a lim-
ited number of patients. It was reasoned that RA
could be seen as a low-grade lymphoma of synovial
tissue, caused by an oligoclonal (instead of monoclo-
nal) proliferation of B cells exhibiting malignant be-
haviour by destroying local tissues. Using this
comparison, patients were treated with a single
remission-induction treatment course, identical to that
for non-Hodgkin’s lymphoma, combining four weekly
RTX infusions of 750 mg/m2
with prednisone and
cyclophosphamide. The treatment goal was to achieve
disease remission by eradication of pathogenic B cells.
Only adriamycin was omitted as co-medication to
decrease the chance on treatment-related side toxicity.
These two open-label case series showed that a single
RTX-based treatment course could induce disease remis-
sion in a proportion of patients with RA. Although no for-
mal dose-finding efforts were done, Leandro et al.
concluded in their uncontrolled study of 22 RA patients
that doses below 600 mg/m2
were less effective, but this
conclusion was based on only four patients. The first ran-
domised controlled trial (RCT) to examine the efficacy of
RTX in RA patients aimed at obtaining a treatment
regimen without cyclophosphamide instead of dose-
finding and used a simplified RTX dosing regimen of
1000 mg on treatment days 1 and 15 [8]. This dose is now
the registered dose for treatment of RA patients.
Thereafter, dosing schedules of 2 × 500 mg and 1 ×
1000 mg have been tested in several phase-three and
phase-four studies; a recent large systematic review
showed that these were non-inferior to regular-dose
RTX. Therefore, the current recommended RTX doses
are 2 × 500 mg or 1 × 1000 mg (standard low-dose RTX)
at least every six months. The second infusion is com-
monly given with an interval of two weeks (e.g. for 2 ×
1000 mg) [9]. Although there have been no high-quality
strategy studies to establish what is the best retreatment
strategy, either fixed six-month interval retreatment or
disease activity guided treat-to-target retreatment seem
the optimal strategy.
However, even lower doses of RTX may be effective
for treatment of RA. In three case studies, ultra-low
doses of RTX (1 × 50 to 2 × 100 mg) were surprisingly
associated with deep peripheral B-cell depletion and, in
general, adequate RA disease control [10–12]. Adding to
these observations, a recent small, prospective open
label study in 14 RA patients showed that a single dose
of 100 mg RTX led to peripheral B-cell depletion in 11
patients (79%) after two weeks [13]. In that study, mean
(± SEM) DAS28 score of all patients decreased from 6.2
± 0.8 at baseline to 2.9 ± 0.8 at 24 weeks after infusion,
although two patients needed additional RTX treatment.
The use of ultra-low-dose RTX for retreatment
could especially be effective. First, B-cell depletion by
RTX can persist during the entire interval between
infusions [8, 14]. It was shown that that lower base-
line B-cell counts were associated with complete B-
cell depletion following a first 500-mg dose of RTX
[15]. This suggests that the (partially) persisting B-cell
depletion induced by an earlier infusion could reduce
the dose of RTX needed for retreatment infusions.
A final argument for possible effectiveness of ultra-
low-dose RTX is the fact that similar monoclonal anti-
bodies have been shown to be effective well below the
authorised doses for RTX. For ocrelizumab and ofatu-
mumab, two humanized anti-CD20 monoclonal anti-
bodies, it was concluded that doses of 2 × 200 mg and
2 × 300 mg, respectively, provide optimal B-cell deple-
tion as well as the best clinical responses [16]. Although
these much lower doses compared to RTX might also be
possible due to higher affinity or cytotoxic efficacy of the
drug, it lends further credibility to study the efficacy of
similar ‘ultra-low’ doses of RTX.
The use of ultra-low RTX could present several advan-
tages over standard low-dose RTX. First, infection risk
should be lower, as RTX use is associated with a dose-
dependent – although still low – risk of serious infection
[17, 18]. Also, shorter infusion duration and less admin-
istered drug could lead to less patient burden and per-
haps lower risk for infusion reaction [19]. Further, RTX
treatment currently is relatively expensive, with costs for
low-dose 1 × 1000 mg every six months being in the
range of €4000–7000 per year. Although RTX was
proven to be cost-effective in patients with an inad-
equate response to TNFi [20], use of ultra-low doses will
further decrease costs and thereby improve cost-
effectiveness. A combination of a possible effective dose
of 200 mg every six months and expected price reduc-
tions due to upcoming availability of a rituximab
den Broeder et al. Trials (2017) 18:403 Page 2 of 9
3. biosimilar, could result in a bDMARD option availability
for under €1000 per patient per year.
The use of an ultra-low dose of RTX might, however,
also lead to increased disease activity in the subset of
patients whose minimal effective RTX dose is 1000 mg.
Therefore, prediction of response to ultra-low-dose RTX
would be key to prevent patients from flaring experien-
cing accelerated joint damage [21]. Interesting baseline
(at the moment of considering RTX retreatment) candi-
dates for predicting the chance of good response on an
ultra-low dose include higher RTX drug levels, absence
of anti-RTX-antibody levels and low peripheral B-cell
counts, as it might be hypothesised that these are all
indicators for lower RTX need [22].
In conclusion, although the use of ultra-low doses of
RTX seems promising, its effects have never been stud-
ied in a trial of proper design and size. We therefore aim
to perform a RCT to study whether retreatment with
one of two ultra-low RTX doses (1 × 200 mg or 1 ×
500 mg) is non-inferior to retreatment with the standard
low-dose RTX (1 × 1000 mg) for patients with RA who
were already successfully treated with standard low-dose
RTX. Also, we will analyse whether there are differences
between retreatment with ultra-low dose and standard
low dose in the occurrence of serious and non-serious
adverse events and cost-effectiveness, and we will ana-
lyse whether (non-)response to (ultra-)low dose of RTX
at six months can be predicted at the moment of initiat-
ing retreatment.
Methods
Design
The REDO study (REtreatment with Rituximab in RhE-
matoid arthritis: Disease Outcome after Dose Optimisa-
tion) is an investigator-driven, pragmatic, double-blind,
non-inferiority RCT of six months’ duration (Fig. 1,
SPIRIT checklist as Additional file 1). The trial is funded
by two healthcare insurance companies in the
Netherlands, Centraal Ziekenfonds (CZ) and Menzis,
and independent from the manufacturer of RTX
(Roche). The study is expected to be performed in at
least three departments of rheumatology of hospitals in
the Netherlands: the Sint Maartenskliniek, and Radboud
University Medical Centre (Radboudumc) in Nijmegen;
and Reade in Amsterdam. These centres together
have approximately 400 RA patients being treated
with RTX. Based on an earlier dose-tapering trial and
similar inclusion criteria, we expect an inclusion
percentage of 40%.
RA patients who are scheduled for RTX retreatment
with standard low-dose RTX will be randomised into
three groups: standard low dose (1 × 1000 mg) or one of
the two ultra-low dose intervention groups (1 × 500 mg
and 1 × 200 mg). Treatment response is assessed at three
Fig. 1 SPIRIT figure: trial visits and assessments
den Broeder et al. Trials (2017) 18:403 Page 3 of 9
4. and six months (study end); thereafter, the allocation of
patients will be revealed and treatment may be contin-
ued using any ultra-low or standard low dose of 1 ×
1000 mg, at the discretion of the physician and patient
in shared decision-making.
This report has been prepared in accordance to the
SPIRIT guideline. The final report will follow the
CONSORT criteria, including its extension to non-
inferiority trials. The full study protocol is available as
supplementary material. There are no publication
restrictions and publication of the final study results
will be performed in peer-reviewed journals as well as
to lay press and patient organisations.
Important protocol changes will be communicated
to the ethics committee and trial register. Privacy of
patients will be protected according to Dutch law,
WBP (‘wet bescherming persoonsgegevens’), by using
anonymised data and restricting access to patient
identification logs.
Objectives
The primary objective of the REDO trial is to compare
the difference in efficacy between two ultra-low doses
(1 × 200 mg and 1 × 500 mg) and standard low dose (1 ×
1000 mg) of RTX retreatment on the change in DAS28-
CRP, compared to a pre-specified non-inferiority margin
of 0.6 DAS28 points, at three and six months. Therefore,
the study has four primary endpoints. Although we are
aware that patients are sometimes treated with longer
intervals than six months, showing non-inferiority at six
months is relevant, for ultra-low RTX dose with at least
six-month intervals is still a lower cumulative dose as
standard low-dose 1000 mg every 9–12 months.
The main secondary objectives are: to assess the differ-
ence in efficacy between the two ultra-low dose inter-
ventions for the same outcomes; to compare the
proportion of patients with a DAS28-CRP < 2.9 (low
disease activity), DAS28-CRP < 2.4 (remission) and
remission according to Boolean ACR/EULAR criteria at
three-month and six-month follow-up; to assess the
between-group differences in the change in functioning
(HAQ-DI) and quality of life (EQ5D-5 L); and to com-
pare proportion (cumulative incidence and incidence
density) of patients developing (treatment-related)
adverse events in each study group over the duration of
the study, with special attention to infusion-related ad-
verse events and infections. Furthermore, the cost-
effectiveness of both ultra-low RTX doses and the con-
ventional low dose are compared for the six-month
study period. For prediction modelling, baseline factors
(including RF/ACPA status, CD19+ B-cell count, serum
RTX, serum anti-RTX) will be tested for associations
with the outcome of DAS28-CRP low disease activity
state at six months.
Non-inferiority margin
In non-inferiority trials, the choice for a specific non-
inferiority margin (NI margin) is critical for the inter-
pretability of the study. This choice can be based on
prior art (use of NI margin in comparable studies),
expert opinion or data-driven, based on association with
other (un)intended effects. We have found three non-
inferiority studies that have used the DAS28 as a
primary outcome measure. All three studies have chosen
to use a NI margin of 0.6. [23–25]. Although no clear
explanation is given by the authors regarding the ration-
ale for this NI margin, a non-inferiority margin of 0.6
points in DAS28 seems a reasonable choice, as the error
of measurement in DAS28 is 0.6 [26]. This error of
measurement is used in the EULAR response criteria to
denote the difference between a non-response and a
moderate response in DAS28 [27]. Regarding assay sen-
sitivity, the mean difference between placebo and RTX,
added to MTX, in DAS28, is 1.2 according to a recent
meta-analysis [1]. This means that the NI margin of 0.6
is sufficiently smaller than the treatment effect of RTX
against placebo. We have therefore chosen to use this
NI margin of 0.6, although it always remains debatable
what an acceptable small NI margin is. This is especially
important to prevent a situation where multiple non-
inferiority studies are performed after each other, each
using the non-inferior treatment from the last study as a
comparator for a new treatment. In this context,
although treatment B is non-inferior to A, and C is non-
inferior to B, treatment C can in fact be inferior to A,
the so called biocreep [28].
Assay sensitivity
Since this is a non-inferiority trial, assay sensitivity – the
ability to demonstrate inferiority with the chosen trial
design – is an important issue. Assay sensitivity could be
established by a placebo arm showing that not retreating
with RTX is inferior to retreating with RTX. Considering
it has been shown in earlier studies that the mean dis-
ease activity of patients will increase when not retreated
with RTX [29], it seems unnecessary and unethical to
include a placebo arm. Therefore, the comparator is a
standard low-dose of RTX, while the group sizes should
be large enough to gain a sufficient level of precision
(see sample size calculation).
Patients
Inclusion criteria for patients in this pragmatic study are
as non-restrictive as possible. This is based on the
underlying principle that the results of this trial should
be generalisable to all RA patients who are doing well
on their RTX treatment. We therefore include RA
patients fulfilling either 2010 EULAR/ACR RA [30] and/
or 1987 RA [31] criteria and/or having a clinical
den Broeder et al. Trials (2017) 18:403 Page 4 of 9
5. diagnosis of RA according to the treating rheumatolo-
gist, at any time point between start of the disease and
inclusion.
Patients are eligible if they were treated at least once
with regular low-dose RTX treatment in the last
18 months for RA, so in a dose of 1 × 1000 mg, 2 ×
1000 mg or 2 × 500 mg, and had received no other
bDMARDs after the last RTX dose. Patients treated with
innovator RTX (MabThera®) as well as authorised RTX
biosimilars in similar doses as conventional RTX will
also be included.
It is somewhat difficult to operationalise the criterion
that patients need to be doing well enough on RTX
because of the variety of retreatment strategies that are
used in clinical practice. We decided on at least six
months of stable, low-disease activity after the last RTX
infusion (operationalised by either DAS28-CRP < 2.9/
DAS28-ESR < 3.2 or judgement of low-disease activity by
a rheumatologist) and a current DAS28-CRP ≤ 3.5/
DAS28-ESR ≤ 3.8. The latter criterion is added, because
patients are often not retreated at fixed intervals, but are
retreated either based on treat-to-target or on demand
when disease activity increases. However, we do not
want to generalise to patients being treated only when
they flare severely, as it has been shown that the optimal
strategy for RTX retreatment (although not completely
clear yet) is either fixed interval or treat-to-target, but
not treated only on demand. Also, a high SD in disease
activity at study start would increase the required sample
size.
Further inclusion criteria are chosen to ensure that we
are able to study the participants and to measure the
outcomes: patient informed consent; age ≥ 18 years and
mentally competent; life expectancy > 6 months; no
planned relocation out of reach of study centre; and able
to read and communicate well in Dutch.
For generalisability reasons, exclusion criteria are kept
minimal and only exclude patients with known (non-)
response to ultra-low-dose RTX (below 1 × 1000 mg), to
prevent selection bias, and current corticosteroid dosing
above 10 mg per day prednisolone equivalent, because
these patients should preferably first taper their
corticosteroid.
Patient recruitment
All eligible patients will be selected and approached
based on information from the electronic health record
according to the abovementioned inclusion and exclu-
sion criteria. Patients will be asked to join this study by
their treating rheumatologist using a letter accompanied
with the patient information (including the informed
consent form). Informed consent is obtained before pa-
tients receive the study medication and baseline data are
collected.
Randomisation and blinding
Participants will be allocated to the treatment groups at
a ratio of 1:2:2 (1 × 1000 mg vs. 1 × 500 mg vs. 1 ×
200 mg). The experimental groups are larger than the
control group to increase experience with the lower dos-
ing and with the additional benefit that a larger number
of potential predictive factors for response can be studies
in multivariate prediction modelling in the ultra-low-
dose RTX groups.
Randomisation will be performed using a compu-
terised randomisation procedure and stratified to ensure
equal distributions of two possible effect modifiers for
response to ultra-low-dose RTX, concomitant conven-
tional DMARD use and RF/ACPA status. Patients will
be randomised using block randomisation in variable
block sizes (multiples of 5) to more closely achieve the
intended allocation ratio and to ensure that the alloca-
tion of participants will not be predictable. Patients, phy-
sicians, nurses, researchers and data analyst/statistician
will be blinded for treatment allocation. The allocation is
kept in opaque, sequentially numbered envelopes; enve-
lopes are sequentially assigned by the pharmacist to each
next patient. The infusions for the study will be prepared
by the hospital pharmacy based on the randomisation
number, the physical appearance of the three interven-
tions will be indiscriminate (see below). Unblinding is
expected to be rarely necessary (all patients receive RTX
and retreatment with 1000 mg is allowed when neces-
sary), but is possible after consulting the coordinating
centres pharmacist.
Interventions
Patients allocated to the standard low-dose group will
receive a (blinded) single 1000 mg RTX infusion accord-
ing to the standard protocol for infusion of rituximab.
Patients allocated to the ultra-low-dose groups will
receive 500 mg or 200 mg. This dose will be diluted to
the same volume as the standard low-dose infusion to
ensure the blinding of the study, all premedication and
procedures are identical to the standard low dose. Of
note, the possible advantage of shorter infusion times
cannot be assessed in our study, because this would lead
to patients and healthcare providers being unblinded.
It is aimed to leave all other rheumatic treatment un-
altered as much as possible during the study period.
However, all treatment decisions are left to the discre-
tion of the treating physician and (changes in) use of
paracetamol (acetaminophen), tramadol, non-steroidal
anti-inflammatory drugs (NSAIDs), oral corticosteroids
and DMARDs are all allowed during this study to ensure
good care. During each visit, patients are asked about
the use of these medications. Suggested treatment in
case of clear loss of response is escape treatment with an
extra dose of 1 × 1000 mg RTX. This can be done
den Broeder et al. Trials (2017) 18:403 Page 5 of 9
6. without unblinding, since the authorised dose of RTX is
2 × 1000 mg per six months and no patients will exceed
this dose as the maximum study dose is 1 × 1000 mg.
We have determined several medication changes that
are defined as ‘treatment failure’. These changes are: re-
ceiving an extra dose of RTX within the six-month study
period; receiving another bDMARD (thus switching to
another type of bDMARD); and using corticosteroids in
a dose > 10 mg/day. Starting a concomitant conventional
synthetic (cs)DMARD during the study period is not
considered a treatment failure. The reasoning behind
this is that all included patients will have received these
csDMARDs before, with little effect on their RA, and
the concomitant csDMARD is generally given as an ad-
juvant to increase the effectiveness of RTX.
In case of treatment failure, the patients will remain in
the study, but the last measure of disease activity and
other outcomes will be used as outcome employing a
‘last observation carried forward’ strategy.
Assessments
At baseline, several characteristics of the patients will be
measured, including demographics, disease and treatment
characteristics. Also, possible predictors for response to
ultra-low-dose RTX from peripheral blood will be
collected, including (anti-)RTX drug levels and peripheral
CD19 counts. Thereafter, visits will be performed at three
and six months and when necessary in between (Fig. 1).
Several measures on disease activity will be collected
during the study. The DAS28-CRP is a validated and
widely accepted measure for RA disease activity and will
be used as a primary outcome measure. It consists of
four components: 28 tender joint count; 28 swollen joint
count; CRP (mg/L); and patients VAS assessment of
global disease activity (0–100) [26]. Remission is defined
as DAS28-CRP < 2.4 and low disease activity by DAS28-
CRP < 2.9 [32]. In addition, patient VAS assessment of
pain, rheumatologist VAS assessment of global disease
activity, acute phase reactants (CRP and ESR) and the
OMERACT patient flare questionnaire are collected. To
measure functioning of patients, the HAQ-DI, a vali-
dated instrument that is widely used in rheumatology is
applied [33]. Quality of life is assessed using EQ5D-5 L,
which is a validated instrument and comprises five ques-
tions and a visual analogue self-rating scale [34].
Adverse events are assessed at every visit during the
study period and classified according to the Common
Toxicity Criteria (CTC) [35]. In addition, we focus expli-
citly on infusion reactions and infectious events. Patients
are asked to complete a short questionnaire after the
RTX infusion on the occurrence of infusion-related
adverse events. Medication use is charted using data
from the electronic patient records on the use of
DMARDs, corticosteroids and NSAIDs.
Costs will be calculated from a societal perspective.
We will include the cost of outpatients’ clinic visits and
telephone consultations, travel expenses for patients,
costs of hospitalisation due to RA, costs due to health-
related work absence and costs of medication during the
six-month study period.
Sample size considerations and statistical analyses
The study has four primary endpoints; multiplicity over
the primary endpoints will be protected by a fixed test-
ing procedure. First, the non-inferiority of the 500 mg
vs. 1000 mg at three months will be tested at p < 0.05
(two-sided). If this is statistically significant, then
500 mg vs. 1000 mg will be tested at p < 0.05 (two-sided)
at six months. If that is statistically significant, then
200 mg vs. 1000 mg will be tested at p < 0.05 (two-sided)
at three months and if that is statistically significant, the
last test will be 200 mg vs. 1000 mg at p < 0.05 (two-
sided) at six months. As we have four primary end-
points, we aim to have enough power for each at 95%
for an NI margin of δ = 0.6. Under the worst-case sce-
nario that these four are not correlated (the expectation
is that they are positively correlated, see Table 1) and
that the intervention is indeed non-inferior to the con-
trol condition, then the overall power for rejecting the
null hypothesis of inferiority on all four is at least 95% ×
95% × 95% × 95% = 81%. We calculated the sample size
for one endpoint (e.g. the comparison of 500 vs.
1000 mg at six months). For 2:1 randomisation and a
non-inferiority test assuming the true difference between
treatments is 0, the total sample size for a t-test having a
power 1-β when testing at significance level α (two-sided)
and a non-inferiority margin δ is Ntot = (4.5)2
× (z1-α/2 +
z1-β)2
× SD2
/δ2
, where z denotes the normal quantiles
which are correct for non-small sample sizes. When cor-
rection for baseline is incorporated, this sample size is re-
duced by (1-r2
) where r is the correlation in DAS28
between baseline and follow up (formula 7 with n = 1, π0
= 1/3, π1 = 2/3, and section 2.3 of Teerenstra S, et al. [36]).
Note that the two groups then have sizes Ntot/3 and 2 ×
Ntot/3. To determine the correlation r between baseline
and follow-up measurement of the DAS28, the following
assumptions were used. Baseline DAS28 has a SD = 0.7
Table 1 Total trial sample size at various correlations between
endpoints
SD change r Sample size
1000 mg arm
Total trial size
(5 x sample size
in 1000 mg arm)
0.9 0.17 26 130
0.8 0.35 24 120
0.7 0.5 20 100
0.6 0.63 16 80
den Broeder et al. Trials (2017) 18:403 Page 6 of 9
7. and the change from baseline to three (or six months) has
a standard deviation of SDchange = 0.6 based on data from
an earlier dose reduction trial [37]. As SD2
change =
2 × (1-r) × SD2
, it follows that r = 0.63. Then a total
trial size of 80 participants would be enough. Table 1
illustrates the total trial size when the correlation be-
tween endpoints is smaller than anticipated.
To protect for a too optimistic correlation, we there-
fore choose a total trial size of 130 and this is further in-
creased to 140 patients to account for patient drop-out.
Primary analyses will be done per protocol (PP), as this
is the most conservative approach for a non-inferiority
study. In addition, analyses will be performed on an
intention-to-treat basis (ITT). For PP analysis, we will
include patients who have received the study medication
and completed follow-up of six months or until treat-
ment failure (and last observation of disease activity
carried forward).
The primary endpoints will be tested using 95% confi-
dence intervals based on linear regression with the
change in DAS28-CRP as outcome, dose group as deter-
minant and baseline values of DAS28-CRP as covariate
(ANCOVA).
To find predictors (including age, sex, disease duration,
RF/ACPA status, CD19+ B-cell count, serum RTX, serum
anti-RTX), patients will be categorised into responders
(DAS28-CRP < 2.9 at six months and no treatment failure)
and non-responders (all other patients). The absolute
number (and thus also proportion) of responders will de-
termine the number of predictors that is admissible for
analysis, according to the rule of ten-events-per-variable
given that predictors are predetermined. Univariate logis-
tic regression analysis will be performed for the admissible
predictive factors, with a deliberately liberal p < 0.20 as se-
lection criterion. Univariately significant variables are en-
tered in a full multivariate logistic regression model, that
is step-wise reduced until all p < 0.20. Internal validation
and shrinkage will be performed using a bootstrapping
procedure with 1000 repetitions. Performance of the
multivariate predictive model will be evaluated using dis-
crimination (area under the receiver operator curve) and
calibration (calibration slope, calibration plot and
Hosmer-Lemeshow test).
Costs will be calculated and quality-adjusted life-years
(QALY) will be based on EuroQol-EQ5D-5 L utility
scores. Decremental cost-effectiveness analyses (CEA)
will be performed using bootstrap analyses; incremental
net monetary benefit (iNMB) will be used to express
cost-effectiveness at different willingness-to-pay (WTP)
values in the range of €20,000–80,000 per QALY.
Discussion
This study in summary is aimed at exploring the lower
bound of effective RTX doses in RA, as there seems at
least equipoise on whether ultra-low-dose RTX is effective
in RA. The development of the current study protocol has
some interesting aspects that should be discussed.
Because proper phase I/II dose-finding has not been
done in RA for RTX in the development phase, and be-
cause RTX is already widely used in RA treatment, our
study design shares some characteristics of both early
dose-finding trials (small-/medium-sized blinded trial,
medium follow-up, multiple dosing arms), as well as late
pragmatic clinical studies (non-inferiority design, wide
inclusion criteria, investigator driven, treat-to-target
strategy, embedded in clinical practice, cost-effectiveness
analyses). The lack of proper dose-finding may be caused
by the fact that RTX was first developed for use in
lymphoma. This means that the upper limit of toxicity
was already known. Also, there was presumably less in-
centive for the pharmaceutical company to actively look
for (much) lower effective RA dosing, as very different
dosing schedules for between different diseases presents
a problem when establishing drug prices. RTX was
therefore eventually authorised in the same high dose
for the treatment of RA. Indeed, due to the complex
field of anti-cell or cytokine treatment – which is more
pathophysiology than disease specific and might be very
different in dosing across diseases – we expect this hy-
brid approach of post marketing investigator driven dose
finding studies to be used more often in the near future.
Of note, our trial design precludes inference of the
value of long-term repeated treatment strategies with
ultra-low-dose RTX. For example, lower dosing might
lead to shorter infusion intervals or ultra-low dose
may not be effective enough after multiple retreat-
ments. However, we believe that showing non-
inferiority at six months would be a valuable step for-
ward to further study an ultra-low-dose RTX retreat-
ment strategy. Also, it will remain to be established
whether inhibition of radiographic progression is not
compromised using ultra-low-dose RTX.
In the specific case of ultra-low RTX dosing, some in-
teresting developments might make the results of this
study perhaps even more relevant. Recently, RTX – reg-
istered only after TNFi failure – has been shown to be
similar in efficacy to TNFi in bDMARD-naïve patients
[27]. Also, biosimilar RTX is expected to be available
starting early 2017, at least in Europe. These two devel-
opments might make RTX as a first bDMARD a very
realistic alternative. A promise of effective ultra-low-
dose retreatment would further support this more prom-
inent position of RTX in RA treatment.
Trial status
The trial started on 15 December 2016 and is currently
recruiting.
den Broeder et al. Trials (2017) 18:403 Page 7 of 9
8. Additional file
Additional file 1: SPIRIT checklist. (DOC 122 kb)
Abbreviations
(b/cs) DMARD: (biological/conventional synthetic) Disease modifying anti
rheumatic drug; ACPA: Anti-citrullinated peptide antibodies; ACR: American
College of Rheumatology; CRP: C-reactive protein; CTC: Common toxicity
criteria; DAS28: Disease Activity Score 28; ESR: Erythrocyte sedimentation rate;
EULAR: European League Against Rheumatism; EUROQOL: European Quality
of Life; HAQ DI: Health Assessment Questionnaire Disability Index; I/
DCER: Incremental/decremental cost-effectiveness ratio; INMB: Incremental
net monetary benefit; ITT: Intention to treat; MTX: Methotrexate; NSAID: Non-
steroidal anti-inflammatory drug; PP: Per protocol; QALY: Quality-adjusted
life-years; RA: Rheumatoid arthritis; RF: Rheumatoid factor; RTX: Rituximab;
SD: Standard deviation; TNFi: Tumor necrosis factor inhibitor;
WTP: Willingness to pay
Acknowledgements
Not applicable
Funding
The study is funded by CZ innovation fund (reference/project no.
201600033) and MENZIS (no reference number), two health insurance
providers in the Netherlands. There are no other financial or non-financial
conflicts of interest other than specified.
The Department of Rheumatology at Sint Maartenskliniek takes up the role
as sponsor and is the coordinating study centre. An independent data safety
and monitoring board will be installed.
Availability of data and materials
The datasets used and/or analysed during the current study available from
the corresponding author on reasonable request.
Authors’ contributions
AdB is rheumatologist and clinical epidemiologist, and principal investigator
and initiator of this RCT. He has designed and drafted the manuscript. LV is
MSc and the PhD student involved in design and execution of the study,
and has drafted the protocol and performed CMO admission and trial
registration. JF is an epidemiologist and has been involved in protocol
design and statistical considerations. RT is a rheumatologist specialised in
translational research and involved in study rationale, protocol design,
biomarker development and is the Radboudumc site investigator and
involved in patient recruitment. Bart JF van den Bemt is a PharmD,
pharmacist, and involved in PKPD modelling and prediction studies. NB is
also a BSc and epidemiology trainee, and has designed and drafted the
study protocol. NdB is a BSc and epidemiology trainee, and has designed
and drafted the study protocol. FvdH is a rheumatologist and director of the
rheumatology centre of Sint Maartenskliniek and Radboudumc and involved
as study sponsor, in trial rationale, drafting, patient inclusion and
organisation. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Dutch Trial Register, NTR 6117, date 15 November 2016. The study has
received ethical review board approval (number NL57520.091.16), dated 8
November 2016.
Ethics approval was obtained for all participating centres from the central
Commissie Mensgebonden Onderzoek (committee of human research) CMO
regio Arnhem Nijmegen, Radboud University Medical Center, PO Box 9101,
6500 HB, Nijmegen, The Netherlands. Patient informed consent will be
obtained from all participants in the study.
Consent to participate
The protocol as outlined here was approved by the central medical ethical
committee for all participating centres (CMO Arnhem-Nijmegen,
NL57520.091.16) in 2016. The Trial is registered at NTR6117.
Consent for publication
Not applicable
Competing interests
Alfons A den Broeder: congress invitations with Roche, Abbvie, Biogen,
Celltrion, expert witness for Amgen and BI. Rogier Thurlings: translational RTX
research sponsored by Roche, congress invitations from Abbvie, Roche. Bart
JF van den Bemt: Speakerfee from Abbvie, Pfizer, Mundipharma, Astra, MSD.
Research grant from Pfizer, Abbvie. Frank HJ van den Hoogen: advisory
board member mundipharma on RTX biosimilar, congress invitation
Cellgene, international advisory board Biogen etanercept biosimilar, speakers
fee biosimilars Celltrion and Egis and Janssen. The other authors declare
having no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Rheumatology, Sint Maartenskliniek, PO Box 9011, 6500 GM
Nijmegen, The Netherlands. 2
Department of Rheumatology, Radboudumc,
Nijmegen, The Netherlands. 3
Department of Pharmacy, Sint Maartenskliniek,
Nijmegen, The Netherlands. 4
Department of Pharmacy, Radboudumc,
Nijmegen, The Netherlands. 5
Department of for Health Evidence, Section of
biostatistics, Radboudumc, Nijmegen, The Netherlands.
Received: 6 February 2017 Accepted: 3 August 2017
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