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Phase II Study of Minocycline for Reducing Symptom Burden in Colorectal Patients

ABSTRACT: The goal of this clinical research study is to learn if minocycline can reduce numbness, pain, and/or loss of motor function in patients with colorectal cancer. In this study, minocycline will be compared to a placebo. The study doctor can explain how the study drug is designed to work. A placebo is not a drug. It looks like the study drug, but it is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

DISEASE(S): Pain,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2148815 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:These experiments are designed to discover genes that are expressed selectively by synaptic nuclei in skeletal muscle with the particular goal of identifying genes that regulate motor axon growth and differentiation. We plan to isolate RNA from the dissected synaptic region of skeletal muscle and from the non-synaptic region of skeletal muscle and to identify the genes that are expressed at higher levels in the synaptic than non-synaptic region. Previously, we showed that motor axons fail to stop and differentiate in mice lacking MuSK, a receptor tyrosine kinase that is activated by motor neuron-derived Agrin. We hypothesize that MuSK activation normally leads to the production of a retrograde stop/differentiation signal that is encoded by a gene that is expressed preferentially in synaptic nuclei. In the absence of MuSK signaling, the retrograde signaling is not produced by synaptic nuclei, and consequently motor axons wander aimlessly over the muscle. We obtain 6 to 8 micrograms of total RNA from the dissected synaptic or non-synaptic region from a single P21 mouse diaphragm muscle. This is a standard procedure in the lab, and we have used these methods to analzye gene expression and to generate high-quality cDNA libraries. Because the synaptic zone is narrower in the left hemi-diaphragm, we will isolate RNA from this half of the diaphragm. In order to isolate sufficient RNA (5 micrograms from each sample), we will pool the synaptic and non-synaptic regions from two hemi-diaphragms. In order to reduce experimental variability, we wish to analzye expression in six samples: three samples of synaptic RNA and three samples of non-synaptic RNA. We will ship the isolated RNA samples to the Consortium in order to generate labeled cDNA, to screen Affymetrix mouse oligo arrays and to assist in the analysis. Several genes, including the subunits of the acetylcholine receptor, MuSK, acetylcholinesterase, and utrophin are known to be expressed preferentially in synaptic nuclei; thus, these genes serve as internal controls for the reliability and effectiveness of the screen. Most other genes, several of which we have analyzed in previous studies, including actin, GAPDH, runx1, nogoC, creatine kinase, etc. are expressed uniformly in skeletal muscle; thus, expression of these genes should be equally represented in synaptic and non-synaptic regions. Keywords: other

Project description:Lockwood2006 - AlzheimersDisease PBPK model A mathematical model to predict the effectiveness of CI-1017 (muscarinic agonist) for Alzheimer's disease by evaluating changes in ADAS-cog score. This model is described in the article: Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease. Lockwood P, Ewy W, Hermann D, Holford N. Pharm. Res. 2006 Sep; 23(9): 2050-2059 Abstract: OBJECTIVE: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials. MATERIALS AND METHODS: A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability. CONCLUSION: CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial. This model is hosted on BioModels Database and identified by: BIOMD0000000673. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Phase II Study of Minocycline for Reducing Symptom Burden in Colorectal Patients

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