We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The...We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.展开更多
Objective： The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor（PEG rhG-CSF） is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy.However, ...Objective： The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor（PEG rhG-CSF） is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy.However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy.Methods：Eligible patients received 3-cycle chemotherapy every 3 weeks.No PEG rhG-CSF was given in the first cycle.Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3.In cycle 2,patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3,and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5,respectively.Escalating doses（30,60,100 and 200μg/kg）of PEG rhG-CSF were investigated.Results：A total of 26 patients were enrolled and received chemotherapy,in which 24 and 18 patients entered cycle 2 and cycle 3 treatment,respectively.In cycle 2,the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30,60,100 and 200 μg/kg was 66.67%,33.33%,22.22% and 0,respectively,with a median duration less than 1（0–2）d.No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts.Conclusions：The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported,as well as the safety.Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above.The single dose of 60 μg/kg,100 μg/kg and double half dose of 30 μg/kg were recommended to the phase Ⅱ study,hoping to find a preferable method for neutropenia treatment.展开更多
A dose-finding study was performed with respect to the clinical applicability and tolerability of three different concentrations of propolis special extract GH 2002 in a lip balm (0.1%, 0.5% and 1%). The trial was des...A dose-finding study was performed with respect to the clinical applicability and tolerability of three different concentrations of propolis special extract GH 2002 in a lip balm (0.1%, 0.5% and 1%). The trial was designed as a double-blind, randomized dermatological study in 150 outpatients with Herpes labialis. The primary parameter was the duration in days until painless incrustation in 50% or 90% of the patients (observable in 121 patients). Secondary parameters were local pain (assessed on a visual analogue scale), itching, burning and tension/ swelling on a verbal rating scale, and tolerability. Visits were performed on days 2/3, 5/6 and 8/9. Best efficacy results with shortest healing time (3.4 and 5.4 days in the 50th and 90th percentile, respectively;p = 0.008 vs. 1% and 0.09 vs. 0.1%) and good tolerability were observed with the 0.5% concentration. All three concentrations achieved highly significant therapeutic results in comparison with baseline values (p < 0.0005) for all secondary parameters as early as day 2/3. Analgesia was the most prominent effect for the patients. Conclusion: The 0.5 % concentration of propolis special extract GH 2002 in a lip balm was found to have the best risk-benefit ratio for the treatment of Herpes labialis.展开更多
文摘We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.
基金supported by Hangzhou Jiuyuan Gene Engineering Co., Ltdpartly funded by the Chinese National Science and Technology Major Project on Key New Drug Creation (2012ZX09303-012)Beijing Municipal Science & Technology Commission Major Project for New Drug Innovation (Z111102071011001), China
文摘Objective： The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor（PEG rhG-CSF） is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy.However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy.Methods：Eligible patients received 3-cycle chemotherapy every 3 weeks.No PEG rhG-CSF was given in the first cycle.Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3.In cycle 2,patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3,and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5,respectively.Escalating doses（30,60,100 and 200μg/kg）of PEG rhG-CSF were investigated.Results：A total of 26 patients were enrolled and received chemotherapy,in which 24 and 18 patients entered cycle 2 and cycle 3 treatment,respectively.In cycle 2,the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30,60,100 and 200 μg/kg was 66.67%,33.33%,22.22% and 0,respectively,with a median duration less than 1（0–2）d.No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts.Conclusions：The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported,as well as the safety.Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above.The single dose of 60 μg/kg,100 μg/kg and double half dose of 30 μg/kg were recommended to the phase Ⅱ study,hoping to find a preferable method for neutropenia treatment.
文摘A dose-finding study was performed with respect to the clinical applicability and tolerability of three different concentrations of propolis special extract GH 2002 in a lip balm (0.1%, 0.5% and 1%). The trial was designed as a double-blind, randomized dermatological study in 150 outpatients with Herpes labialis. The primary parameter was the duration in days until painless incrustation in 50% or 90% of the patients (observable in 121 patients). Secondary parameters were local pain (assessed on a visual analogue scale), itching, burning and tension/ swelling on a verbal rating scale, and tolerability. Visits were performed on days 2/3, 5/6 and 8/9. Best efficacy results with shortest healing time (3.4 and 5.4 days in the 50th and 90th percentile, respectively;p = 0.008 vs. 1% and 0.09 vs. 0.1%) and good tolerability were observed with the 0.5% concentration. All three concentrations achieved highly significant therapeutic results in comparison with baseline values (p < 0.0005) for all secondary parameters as early as day 2/3. Analgesia was the most prominent effect for the patients. Conclusion: The 0.5 % concentration of propolis special extract GH 2002 in a lip balm was found to have the best risk-benefit ratio for the treatment of Herpes labialis.
