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Renal artery stenosis is a chronic disease reported in 1-5% of hypertensive cases and 5-15% of end-stage renal disease cases. The prevalence of RAS (renal arterial stenosis) is <5% in genera population and in peripheral artery disease found to be 45%. Current treatment namely medical therapy, surgery, and precutaneous transluminal renal angioplasty have needed to further emphasize for the accurate detecting of stenosis. Intra -arterial digital substraction angiography (IA DSA) is the gold standard technique for the diagnosing of RAS but more invading. Now CE MRA is finding the preferred application for the diagnosis of RAS which is non-invasive and provides good quality images. A contrast agent 3d gadolinium enhanced MRA which compared with IA DSA. Diagnostic quality of technique depends on the relay of the gadodiamide, the finding of transit time, the technique of agent administration, and pulse modulation designing (1).
Description of published study
In this phase 2, prospective, randomized, double blind, parallel group study conducted at 27 centers in Europe and US. From 1 to 35 patients were included in this study at each center and received four different concentrations of gadodiamide (0.5mmol/ml) were 0.01mmol/kg, 0.05mmol/kg, 0.1mmol/kg, and 0.2mmol/kg. Study protocol was approved by Institutional Review Board or Ethical Committees at each participating centers. Study was conducted according to GCP guidelines and Declaration of Helsinki, local laws and regulations. Written informed consent was obtained from all patients who were enrolled in the study. From January 2001 to October 2002, patients were enrolled that were the clinical suspicion of RAS referred to IA DSA, obtained written informed consent, conscious and cooperative and above 18 years of age. Patients were excluded that were already attached to this study, pregnant and lactating women and also who had not taking suitable contraception. Any suspected contradiction for MRA as per as the clinical guidelines and any severe drug reaction associated with gadodiamide. In this study, total 273 patients were recruited whom 7 patients were disengaged before the trial start. In remaining 266 patients, 158 were men and 108 were women, assess for safety analysis. 12 patients were withdrawn from the study during dosing due to technical impairment by IA DSA and CE MRA.
The 3D TOF MRA was applied before the 3D CE MRA. The drug gadodiamide was given intravenously by a power injector system at a rate of 3ml/s. Then given a saline bolus (20-30ml) via intravenous root. Subjects took CE MRA among two weeks earlier or later IA DSA. Detailed data were not collected by IA DSA technique. Investigator was monitored the images at site while in offsite mages were by three independent blinded MRA readers and one dependent DSA reader. An independent reader checked the stenosis location across the modalities. For primary endpoints analysis of the images just concentrated on the site and assortment of main RAS. To avoid bias, evaluated images of IA DSA were not expelled from the statistical analysis. If non evaluability associated to imaging modalities with TOF MRA or concentration of gadodiamide with CE MRA, the images remained in the statistical analysis but addressed as a mismatch for respected readers if equated to IA DSA.
Primary endpoint of the study was to assess the sensitivity of four different concentrations of gadodiamide in detecting main RAS by CE MRA. Secondary endpoint was to assess the accuracy and specificity detection of hemodynamically relevant stenosis by 3D CE MRA and TOF MRA versus IA DSA. Safety of gadodiamide was monitored by equating the data of 12 lead-ECG, vital signs, serum biochemistry, and physical examination accumulated before and after 24 hours gadodiamide given. 2.3% (6patients) experienced the adverse events. One patient got allergic reactions at a dose of gadodiamide 0.1mmol/kg. Three events of mild intensity were accumulated and three serious life threatening effect (pulmonic edemas, heart failure, and intense nephritic failure) detected in one subject who finally die.
The result for two higher doses (0.1 and 0.2mmol/kg) for CE MRA was in good correlation with the standard IA DSA. Sensitivity, specificity, and accuracy of the lower doses manifested slightly different results as compared to the other doses by all three readers. All readers were achieved significantly better results for accuracy with CE MRA images. We conclude that gadodiamide was the well tolerated and safe drug with 3D CE MRA and this technique provides better insight about its sensitivity, specificity, and accuracy in diagnosis of RAS. We obtained significant result with CE MRA, sensitivity ranges from 85-99% and specificity from 80-97% in hemodynamically relevant subjects. It is a better technique than TOF MRA and could show concentration pendant correspondence to IA DSA. The study demonstrates gadodiamide to be safe and reliable drug. Based on the primary and secondary endpoints 0.1mmol/kg was the most appropriate gadodiamide dose. In this study severe adverse events were found that were pulmonic edemas, heart failure, and intense nephritic failure. Study duration did not mention in this study. The limitation of this technology the patients should have been cooperative (1).
It was confirmed the published study was robust. I have taken the decision to move study in to the next phase-3. We have taken four different doses of gadodiamide are 0.1mmol/kg, 0.2mmol/kg, 0.4mmol/kg, and 0.5mmol/kg followed by saline bolus will have been given about 20-30ml. The doses and saline was administered by a power injector via intravenous root at a rate of 3ml/s. Study design is prospective, randomized, double blind, multicentric and parallel group phase-3 study in United State, Australia and Europe. Recruitment duration of study is 1 year and recruits 2000 patients (both women and men). 60-100 patients are at each centre. All the patients include in the study after achieving the eligibility criteria. Study conducted according to GCP (good clinical practice) and SOP (standard operating process), and under the guidelines of Declaration of Helsinki. To make trial successful investigator and site staff should be well trained. We will give gadodiamide before CE MRA to the detection of RAS and compared with TOF MRA. Both 3D TOF MRA and 3D CE MRA techniques are performing according to clinical practice, and hard and software capacities. Comparison between TOF MRA and CE MRA doses group arm in case of sensitivity, specificity, and accuracy on the bases of Chi square test. Decrease the voxel size 1.0 x 1.0 x 0.3 for the better resolution of gadodiamide to CE MRA. Detailed data were not collected on machine by IA DSA technique. This technique was to be performed with standard institutional practice at every centre. Images were monitored by investigator and by three independent blinded MRA readers and one dependent DSA reader. An independent reader checked the stenosis location across the modalities.
Rationale for Strategy
The strategy will be following rationale:
To reduce bias-Block randomized will be do by sponsor to sustain double blind nature of the trial; doses will provide in non-discriminating test vials. The injections will be giving by some other staff members to reduce bias. Images will evaluate by three independent MRA readers and one IADSA reader. This is parallel group design taking single intervention by all study's subjects.
To better resolution-There we are taking voxel size 1.0 x 1.0 x 0.3 little bit smaller as compare to published study. Smaller is the voxel size larger will be the resolution of drug.
Ethics Committee or Institutional Review Board protects the right of the human subjects.
Study will be conducted after the approval of protocol by IRB of every centre.
Power injector uses because with the hands it is not possible to inject the drug at a rate of 3ml/s.
3D CE MRA is non-invasive and provides good quality images.
Contrast agent gadodiamide is non-nephrotoxic. It is a paramagnet which increases the magnetic field next to the gadolinium molecule. This contracts the T1 relaxation time and raises the MR signal intensity of blood (2).
Purpose- To determine the most effective and safe concentration of gadodiamide for 3D CE MRA in detecting of RAS, keeping IA DSA as gold standard and TOF MRA as a comparator.
Condition- Renal artery stenosis.
Study Type- Interventional (gadodiamide and saline bolus 30ml)
Device-3D TOF MRA and 3D CE MRA
Arm-1 Given .01mmol/kg gadodiamide.
Arm-2 Given .01mmol/kg gadodiamide.
Arm-3 Given .01mmol/kg gadodiamide.
Arm-4 Given .01mmol/kg gadodiamide.
Phase- Phase 3 study
Study design- Prospective, randomized, multicentric, double blinded, parallel group.
Study title- Safety and efficacy of gadodiamide in assessing RAS for 3DCE MRA: Phase 3 study.
Primary endpoint- Assess the most sensitive concentration of gadodiamide by 3D CE MRA for detection of main RAS (occlusion) and compare with IA DSA.
Secondary endpoint- Detect Accuracy and specificity by 3D CE MRA and TOF MRA versus IA DSA in hemodynamically relevant stenosis.
Estimated enrollment- 2000 patients.
Study location- United State,
Study starts date- March 30, 2010.
Gender eligible for the study both men and women and healthy volunteers not enrolled.
Patients were included in the studies that were the clinical suspicion of RAS referred to IA DSA.
Obtained written informed consent.
Enrolled aware and helpful subjects only.
Enrolled patients above 20 years of age.
Pregnant and lactating women and also who had not taking suitable contraception.
If subject got X-ray contrast medium within 14 hours earlier to or less than 28hours after trial product given.
The subject has got trial product within 30 days earlier to or will get a trial product less than 24 hours after trial product given.
Subject has severe life-threatening disease with a life expectancy of less than 6 months.
The subject has had a percutaneous transluminal angioplasty (PTA) in the renal region performed within 4 weeks earlier to trial product administration.
Subject who had a tube in renal arterial blood vessel.
Subject who had excretory organ transplantation.
The subject who was earlier admitted in the same study.
A contra-indication for MRI and gadodiamide stated by clinical guidelines (3).