Outpatient Intravenous Insulin Treatment (Therapy)

I appreciate the effort by CMS to make their review. This is a very complex subject, a new area of medical therapeutics, and the procedures within the category of OIVIT are not all clearly defined. I also appreciated the opportunity to present the scientific aspects of the therapy I developed, metabolic activation therapy (MAT®), in person to staff from CMS and the FDA. Unfortunately my brief presentation must not have answered all of the questions on the subject since there were many deficiencies of facts and understanding in the Proposed Decision. I would like to address some of them now.

First, regarding the laboratory tests discussed in the Proposed Decision. In MAT® treatment, the respiratory quotient (RQ) is measured at baseline and at hourly intervals to provide evidence (an increase in value from .75 to .90 or higher) that hepatic glucose oxidation which was “turned off” due to a lack of high portal insulin concentrations is being “turned on” by the MAT insulin pulses. This non-invasive measurement in turn indicates that all the biochemical steps (including insulin dependent enzymes such as hepatic glucokinase) from glucose to glucose-6-phosphate to the Citric Acid cycle are in place. The RQ has been used for decades to accurately measure total body fuel oxidation at rest and during exercise. The use of the RQ to measure hepatic glucose oxidation is based on extensive biochemical studies of liver homogenates, liver slices, and perfused liver studies (diabetic and non-diabetic animals) conducted in the late 1950s and early 1960s. During a MAT® treatment, the RQ may not rise if the patient has an infection or is pain, i.e. is insulin resistant. This fact may not become obvious until the start of the 2nd and 3rd treatments at which time appropriate adjustments in the number of insulin pulses or pulse duration must be made. In short, the RQ provides a real time, non-invasive index of therapeutic efficacy.

I am puzzled as to why CMS refers to the need to measure the urinary urea nitrogen excretion (UUN). The contribution to the RQ of protein oxidation alone is modest during MAT® treatment and does not significantly affect the direction of the change in RQ. The non-protein RQ was measured in the earliest studies (see Foss et al) for completeness; however, it quickly became obvious that the uncorrected RQ value was all that was needed to indicate that the patient was or was not “activating”. Eliminating the urine collection and UUN measurement, dramatically simplified and dramatically lowered the costs of MAT® treatments.

I would like to comment on CMS''s focus on potassium levels. It is true that the potassium level does fall during a prolonged insulin infusion. However, in MAT® treatment, the infusion is for only an hour and the fall in potassium is on the order of .5 mEq/liter. Once the infusion is stopped, the potassium levels promptly return to their baseline levels. We do monitor potassium levels in patients known to have somewhat low potassium levels. However, clinically significant hypokalemia has not occurred during MAT® treatment. We know of no patients who have developed cardiac arrhythmias during a MAT® treatment.

Second, with regard to the long term safety record of MAT® treatment at ADRI, the main adverse event has been hypoglycemia (50 mg/dl or less). Hypoglycemia occurred during 59 of 23,431 MAT® treatments (0.025%) at ADRI.

Third with regard to the literature review in the Proposed Decision, I have never conducted any MAT® studies using the glucose clamp technique. MAT® is not a glucose clamp. Glucose clamp studies/procedures are not needed to measure the biochemical changes accompanying MAT® treatment. The cited glucose clamp studies are not relevant to any discussion of MAT®.

Fourth, the Proposed Decision quoted the Blue Shield Technology Assessment. I have arranged to place, on the ADRI website, the response I wrote in 2001 to that Blue Shield TA. In it, I address the scientific and statistical issues raised in the CMS recent Proposed Decision. In addition, I would like to call your attention to the comments below by the Administrative Law Judge, the Honorable Stephen Smith, regarding the timing of the Blue Shield TA meeting in question. "8. The Blue Shield of California''s Medical Policy on Quality and Technology is not enforceable in this action. The policy was not enacted until February 2001, almost three years after the denial actions that compose this action, and was enacted under circumstances that raise at least an inference that it was enacted as a tactic to assist in this litigation."

Fifth, CMS should reread the CalPERS decision. The CalPERS decision provides a very comprehensive, focused, and thoughtful look at MAT® treatment (aka PIVIT) that is lacking in the CMS Proposed Decision.

Sixth, the CMS Proposed Decision incorrectly identified groups as being legitimately licensed to use MAT® treatment, the therapy I developed which has also been called CIIIT, PIVIT, hepatic activation, etc. Of the groups mentioned by CMS as having a license for this unique therapy -see below - only ADRI and MI have been licensed to use MAT® treatment. The other groups have never had a license for my therapy and since the earlier NCA Public Comment period have been notified to “cease and desist.”

“(ADRI, MI, Strategic Partners-Bionica, VitalCare, Pulse Medix, Normedex, Diabetes.net.)"

I believe it is very important for CMS to distinguish between all the therapies that come under the category of Outpatient Intravenous Insulin Therapy and to judge each of them on their individual protocols, published outcomes, and safety record. CMS has added to the confusion by discussing separate elements of such therapies in their Proposed Decision without making it clear exactly which of several therapies they are discussing.

CMS also added confusion when they stated in the first few paragraphs of the Proposed Decision, a list of elements that might appear in an OIVIT procedure, including opposites such as a continuous infusion of insulin vs pulses of insulin, and various lab tests and then in the next paragraph stated OIVIT was only a single regimen that has been called by many names. The names CMS listed included both those used in the past to refer to MAT® treatment and trade names used by companies which have no rights to MAT® treatment. Companies apparently used these other designations as trade names in advertisements of various procedures and devices and made many questionable claims including an "FDA approved therapy" using outpatient IV insulin.

In the section titled "Outpatient Intravenous Insulin Therapy (OIVIT)" CMS again makes the claim that Aoki''s therapy is available at various corporations other than ADRI and MI. This claim is false. These institutions have no license for my therapy and patients and investors may be deceived by the CMS statements

"Dr. Aoki holds patents for metabolic activation therapy for a variety of diabetic and non-diabetic indications. (Aoki Patent Series) Respiratory quotient measurements are integral to his proprietary treatment regimen, which is available at ADRI and other authorized institutions. (ADRI, ADRI Injunction, MI, Strategic Partners-Bionica, VitalCare, Pulse Medix, Nomedex, CA Cases ) A variety of other clinics provide similar therapy. (ADRI, MI, Strategic Partners-Bionica, VitalCare, Pulse Medix, Nomedex, Diabetes.net)"

CMS has a legal obligation to provide an accurate and more careful Final Decision.

Seventh, CMS has yet to consult experts on OIVIT, but promises to do so prior to their Final Decision. I believe that "experts" who have no experience using the therapy, are not experts on the therapy. I would be happy to suggest nationally known physicians who do have experience using MAT® treatment. This field is small because most clinical researchers (and funding) have been devoted to trying to control blood glucose levels rather than looking beyond that for ways to provide enough insulin to the tissues to normalize metabolism.

Finally, the Proposed Decision acknowledged that a large number of patients have progression of diabetic complications despite vigorous therapy directed at blood glucose control and also noted the current lack of effective therapy for those patients. MAT® is not directed at blood glucose control. MAT® is directed against the complications of diabetes, and its comparative effectiveness should be judged against other therapies directed against diabetic complications. In medicine, where no effective therapy is available, new therapies that show improvement, in even a small number of patients, are usually called "promising" rather than "no evidence of benefit". CMS must be careful to avoid bias against a new procedure because of expense, or time required. The alternatives for these patients are hospitalizations, disability, dialysis, etc. which are very expensive. MAT® patients gladly give up the weekly 6 hours to get relief and results not otherwise attainable.

Less

Thank you for again letting me respond to this NCA.I think it is important to keep in mind the stated reasons for this internally initiated NCA.From the Medicare NCA:“Diabetes is an important disease in the Medicare beneficiary population. Diabetes in this population is primarily type 2 diabetes, reflecting the older age of most beneficiaries. Diabetic beneficiaries younger than 65 years of age frequently have either type 1 disease and disability from diabetic complications or type 2 disease in the setting of another disabling co-morbidity that impacts diabetes management. Glycemic control itself has not been demonstrated to reverse end-stage microvascular diabetic complications in either type 1 or type 2 patients. Glycemic control does not appear to confer major protection against cardiovascular or renal disease, which is the primary cause of death in older type 2 patients. Nor does it confer protection against an increasing cause of morbidity in type 2 diabetes beneficiaries, renal disease due to hypertension and/or macrovascular disease.”This Medicare NCA internally initiated on September 25, 2009 was purportedly for the purpose of seeing if pulsatile insulin therapy addressed the complications of diabetes and to see what further studies might be needed if more evidence was needed.

First, CMS makes an erroneous assumption in calling Metabolic Activation therapy (MAT) a broad class of therapies. The therapy has been called various names by investigators in different peer reviewed papers but the technique in all those papers is the same.MAT consists of:Intravenous administration of insulin in a series of boluses (pulses) in a specific time interval, pulse number and insulin amount.The regular insulin used is always diluted.At the initiation of the series of pulses, an amount of oral glucose is given.Additional glucose is given orally, if blood glucose drops too low.That is MAT, PIVIT, CIIIT, or Hepatic Activation.

Respiratory Quotient (R.Q.) and blood glucose measurement are performed as a means of monitoring the therapy for adequate insulin dosage and also to prevent the possibility of hypoglycemia.Potassium and Urea Nitrogen are not measured routinely for MAT.There is no computer input of data or dosing algorithm.

The NCA lists various other entities claiming to offer MAT or presumably something similar (Normedex and Vitalcare). It appears this information was copied from websites with no verification of the companies’ validity or legitimacy. For an NCA to be meaningful it must use information that has been validated. Many of the links given in the appendix of this NCA are non-functional.MAT, as has been stated, is a patented treatment and unless entities are licensed and trained to use the therapy one cannot legally use it let alone sell stock in a company. Cease and desist orders have been sent to identified violators, the SEC has been notified, and in fact, referenced websites have disappeared such as Normedex and Vitalcare (which was removed before this NCA was initiated).Fraudulent individuals or companies should not be allowed to confuse the issue at hand.From the NCA:Exploratory animal studiesThere have been three important animal studies in which IV insulin therapy was employed. We include them as background as they illustrate the preliminary research in this field. One study was a short-term physiology study. Two studies employed IV insulin as a chronic treatment. In the latter two studies, the IV insulin therapy replaced standard therapy; it was not used as intermittent adjunctive therapy. These may be important animal studies but they really have no relevance to MAT.Grubert et al. studied 15 fasted non-diabetic mongrel dogs with the 3.5 hour glucose clamp. (Grubert 2005) Endogenous insulin was suppressed with somatostatin. Glucagon was kept constant. Sampling catheters were placed in the portal and hepatic veins as well as the aorta. Infusion catheters were placed in the splenic and jejunal veins (a physiologic location). The dogs underwent three infusion procedures: constant insulin infusion (1 µU/kg/min, pulsatile insulin (12 µU/kg/min over 1 minute q 12 minutes), and pulsatile insulin (3 µU/kg/min over 4 minutes every 12 minutes). The results indicated that hepatic glucose uptake did not differ by the infusion mode or by the amplitude and duration of the insulin pulse when the pulses were given at 12 minute intervals (physiologic for canines).A short duration euglycemic clamp study in no way resembles MAT therapy. Perhaps CMS could also provide a description of the Clamp technique for the lay person also listing its difficulties and draw backs.Weigle et al. studied five streptozoticin-induced diabetic baboons over three ~ 1-month long treatment periods (pulsatile insulin continuous insulin pulsatile insulin). (Weigle 1991) Insulin needs throughout the day were determined and then delivered either continuously or as pulses every 10 minutes. (N.B. This differs from the use of intravenous insulin as adjunctive therapy.) Endpoints included four-times daily glucose values, HbA1c, fasting hepatic glucose production (via titrated glucose dilution) and beta-cell function (via response to glucose and arginine loads). Counter-regulatory hormones and other metabolic parameters were also measured. There were no differences by treatment group. Of note, glucagon secretion, which is postulated to contribute to the putative glycemic control associated with pulsatile insulin, was not entrained by insulin. (Matthews 1983, Paolisso 1987, 1988)As clearly stated, this differs from MAT, so no comparisons or conclusions can be inferred.Koopmans et al. studied 25 streptozoticin-induced diabetic rats in parallel treatment groups (pulsatile insulin, continuous insulin, control) for ~ 18 days. (Koopmans 1996) Endpoints included fasting glucose levels, fasting insulin levels, diurnal glucose areas-under-the-curve, diurnal insulin areas-under-the-curve and urinary glucose levels. Counter-regulatory hormones, insulin binding, glucose uptake by adipocytes and glycerol production by adipocytes were also measured. Glycemic control was markedly improved as was the anti-lipolytic action of insulin (as measured by glycerol production) in the setting of pulsatile insulin.Again, this was not MAT therapy and in fact contradicts the Weigle paper.The NCA states:Results from animal studies assessing pulsatile IV insulin have been contradictory. The reasons for the disparate animal results are not well understood. The baboons had a higher level of endogenous insulin reserve (comparable to some patients with Type 2 diabetes) whereas the dogs had endogenous insulin suppressed by somatostatin and the rats had a lower insulin level (comparable to Type 1 diabetes). It is possible that higher levels of endogenous insulin obscure small insulin pulses or that longer periods of infusion are required or that the biologic benefit conferred by pulsatility is relatively small in comparison to other environmental factors. (Grubert 2005This begs the question; why was this section even written? It has no bearing on MAT.The NCA further states:No animal studies have demonstrated that exogenous IV insulin therapy results in improved glycemic control via activation of hepatic enzymes, e.g., hepatic glucokinase (hexokinase IV), phosphofructokinase, and pyruvate kinase. Hexokinase IV has been studied via glucokinase activators and by genetic over-expression. (Ajius 1995, 2009, Coughlan 2008, Gunn 1973, Hariharan 1997, Mateo 1989, Matschinsky 2006, Pal 2009, Payne 2007, Postic 2001, Soane 1996, Takeuchi 1996, Tilley 2009) In a rodent model using titrated doses of the hexokinase IV gene in a viral vector, even gene activity that was six-times the normal did not result in euglycemia. (Torres 2009) Other studies have suggested that activation of this enzyme could result in hypertriglyeridema and pathologic lipid deposition. (O’Doherty 1999, Pal 2009)The Torres paper listed below and cited in the appendix appears to describe a result different from that stated above.Restoration of Hepatic Glucokinase Expression Corrects Hepatic Glucose Flux and Normalizes Plasma Glucose in Zucker Diabetic Fatty Rats 1. Tracy P. Torres1, 2. ReEtta L. Catlin1, 3. Robert Chan1, 4. Yuka Fujimoto1, 5. Noriyasu Sasaki1, 6. Richard L. Printz1, 7. Christopher B. Newgard2 and 8. Masakazu Shiota1 CONCLUSIONS—Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux. Diabetes January 2009 vol. 58 no. 1 78-86

The cautionary suggestions regarding over expression of hexokinase have to do with the utilization of gene therapy or targeted drugs to cause large increases of hexokinase production in the liver. MAT only uses insulin. There have been no reported cases of hypertrigliceridedema or pathologic lipid deposition associated with the use of MAT. In fact, in many cases, lipids have been reported to have been improved. This has no bearing on MAT.

Published Studies of Pulsatile IV Insulin: Exploratory and Physiologic: HumanHalf of the 19 studies listed are “clamp studies”. The euglycemic clamp is a very different procedure from the therapies CMS chose to include in the OVIT category. Again, if CMS wants to use this as evidence, it should provide a clear description of the clamp technique and its limitations.CMS also incorrectly describes the Foss and Aoki studies referenced as “clamp studies”.If the papers were read, it clearly describes glucose control by the Biostator GCIIS not glucose clamping.

Many of the other studies included in this discussion and references are not clearly related to outpatient insulin therapy. The quality of the analysis may have suffered from the plethora of unrelated papers in the reference section, i.e. the 7 on inhaled insulin, 2 on intraperitoneal insulin, 2 on protamine zinc insulin (not an iv product), and others such as pulses of magnetic energy by NMR and gas chromatographic analysis of fosfomycin.Again, how the clamp studies relate to MAT is unclear.

Published Studies of Pulsatile IV Insulin: Extended Use: HumanCritiques of these studies appear to be little more than restatements of the original Blue Cross/Blue Shield technology assessment based on the analysis by McPhee.That assessment has been rebutted several times. It is interesting that no reference to any of the responses to critiques have been published or referenced to in this NCA.I’ll repost those comments again in case you missed them:1) Clinical Case Series.

In a prospective clinical study (Aoki et al, Am J Med, 1995), we reported the correction of severe postural hypotension in three type 1 diabetic patients after 3 months of CIIIT. The patients served as their own controls (historical control design.) They had previously failed to improve their severe postural symptoms on an intensive 4 - injection insulin program together with conventional therapy for orthostatic hypotension, including fluorinef and salt tablets. After adding CIIIT to their intensive insulin therapy, they all experienced improvement in their orthostatic hypotension symptoms after about one month and became asymptomatic in that regard by 3 months. Furthermore, following the deliberate discontinuation of CIIIT after 3 months, the postural symptoms reoccurred within 1-2 months. Resumption of CIIIT 3 months later again resolved the problem. Therefore, contrary to MPCQT interpretation, this study was controlled (had a historical control design). Since 1995, similar good outcomes in resistant-to-treatment orthostatic hypotension have been reproduced by another endocrinologist, elsewhere, with a larger group of patients.

3. Retrospective Clinical Studies.

1) Aoki et al, ( Lancet, 1993) In a study of the long term effects of CIIIT on 20 “brittle” type I diabetic patients, we reported improved glycemic control as well as a dramatic decrease in the incidence of both major and minor hypoglycemic events. Again, the patients served as their own controls, i.e. historical control design), to avoid the clearly unacceptably risky and unethical utilization of a "true" control group (i.e. sham CIIIT using saline rather than insulin pulses together with the ingestion of ~300 grams of glucose by a brittle type I DM subject.) A similar degree of glycemic control (HbA1c ~7%) was achieved in relatively recently diagnosed type I DM subjects, intensively treated, with mild or no complications, in the DCCT study, but at the cost of a threefold increase in hypoglycemic events. The MPCQT interpretation of the dramatic reduction in frequency of hypoglycemic events reported with CIIIT (compared to the DCCT) was that "the increased attention to participants" contributed to "the avoidance of hypoglycemic reactions". I believe the DCCT patients were contacted weekly or more frequently. CIIIT patients are seen weekly. The true explanation for our study results, however, was implied but not fully articulated in the article. All the patients in our study presented with hypoglycemia unawareness, many with severe hypoglycemic episodes while sleeping. All were on intensive insulin therapy and despite this had at least 3 severe hypoglycemic episodes per month requiring intervention by someone other than themselves. After 6 months of CIIIT, 100% of these patients regained partial or total awareness of impending hypoglycemic events. The results achieved with CIIIT in this study were superior to those reported in the DCCT. Thus, we do not understand how the MPCQT finds it "difficult to conclude that CIIIT improves net health outcomes as much as or more than the established alternatives". In this group of patients who were already on intensive insulin therapy, and whose average HBA1c was still 8.5 % and who still had major problems with hypoglycemic events, the addition of CIIIT led to a ~ 97% reduction of major hypoglycemic events combined with a reduction in HbA1c from 8.5 to 7%. CIIIT provided two improved outcomes:
2) In “brittle” type 1 diabetic patients the ability to pursue intensive insulin therapy without the risk of serious hypoglycemic events.
3) The reduction of HBA1c to normal levels (as shown by the DCCT to predict improved health outcomes in diabetes.) CIIIT is not an alternative to the many insulin regimens currently available, CIIIT is a totally different therapy with different pharmacologic effects than subcutaneous insulin and is used as an additional therapy when intensive insulin alone does not prevent complications or when intensive insulin therapy puts the patient at risk for severe hypoglycemic reactions.
4) Aoki et al, (The Online J Curr Clin Trials, 1995) Our clinical observation that CIIIT lowered the blood pressure in hypertensive diabetics led to this investigation. In this randomized controlled study, three months of CIIIT on 74 type 1 diabetic subjects resulted in a significant improvement in glycemic control (HbAIc) and reversal of the abnormal circadian BP pattern seen in hypertensive diabetic patients, The MPCQT finds that "the clinical significance of the effect on circadian BP pattern is unclear". Unlike MPCQT, we feel that the reversal of an abnormality in a disease process is a favorable and desirable net health outcome. We believe that a significant decrease in blood pressure at night should result in decreased end organ damage over the long term. Furthermore, just as in the Lancet paper above, CIIIT again proved clearly superior in reducing HbAIc compared to intensive subcutaneous insulin therapy alone (control group) despite an identical amount of "attention to participants" (all patient were seen weekly by the same physician.) The MPCQT review comments on the fact that in this study the effects on hypoglycemic episodes were not reported. As you might expect, when an intervention normalizes a very basic metabolic activity such as fuel metabolism, many different outcomes in many different organ systems are affected. This is both the joy and the grief of researching CIIIT – we cannot afford to measure and report the entire list of parameters that CIIIT affects in other systems that are not the focus of the current study. This brief (3 months) study focused on restoration of the normal circadian blood pressure rhythm and glycemic control.
5) Aoki et al, (Endocrine Practice, 1999)Finally, in the multi-center, retrospective, longitudinal study assessing the effects of CIIIT on progression of overt diabetic nephropathy in 31 patients, we reported the stabilization of progression of overt nephropathy. Stabilization consisted of no significant change in 1.) creatinine clearance, 2.) the reciprocal of the serum creatinine, or 3.) proteinuria over a mean period of 37 months. The MPCQT review felt it was a point against the therapy that there was no significant change in the 24-hr urinary protein". That comment seemed very illogical to us since, no change in the protein excretion is to be expected when no change in CrCl or in reciprocal serum creatinine were noted during the observation period. (Parenthetically, the literature would have predicted an increase in daily urinary protein excretion at the rate of 300-500 mg/day/year. Thus, the lack of a significant increase in proteinuria we reported is very significant since it is in accord with the stabilization of the creatinine clearance.) The point of this paper is that CIIIT halted the progression of the nephropathy. Diabetic renal disease is a relentlessly progressive disease with patients experiencing a 12-15 ml/min/year loss in creatinine clearance each year once it starts. All the findings in this paper are consonant with the interpretation of arrested progression of overt diabetic nephropathy with CIIIT.

Until this report by Aoki, there was no known way to halt the progression of diabetic nephropathy. As the MPCQT review notes (page11, paragraph 1), “once diabetic nephropathy has progressed to the stage of hypertension, proteinuria, or early renal failure, glycemic control is not generally beneficial in influencing its course: instead, anti-hypertensive medications and restriction of dietary protein are recommended (Masharani and Karam, 2001.” In the Aoki study, most participants were already on ACE inhibitors and other anti-hypertensive agents resulting in good BP control and were on dietary protein restriction prior to entering the study. It was the failure of these conventional modalities that prompted them to enroll in the CIIIT program. The MPCQT review kept referring to “alternative” therapies that could be used instead of CIIIT, but in this situation, there are none. The alternatives he mentions are already being employed, and the disease is still relentlessly progressing.

We therefore find it puzzling that the MPCQT review concludes that "it is possible it was the weekly adjustments in regimen rather than the CIIIT that were responsible for the apparent stability in renal function". No researchers have ever reported stabilization of overt diabetic nephropathy with "weekly adjustments in therapeutic regimen." In the report by Dailey reviewed below, a randomized controlled trial of CIIIT in nephropathy, the control group getting intensive insulin therapy was being monitored weekly, and their renal disease progressed significantly.

4. Prospective, Randomized, Controlled Clinical Trials

1) Aoki et al, (Diabetes Care, 1995) We had observed clinically that adding CIIIT to intensive insulin therapy (4 insulin injections/day or insulin pump) in hypertensive diabetic patients often led to a pronounced decrease in their blood pressure - requiring the physician to decrease the dose or reduce the number of anti-hypertensive agents during their months on CIIIT therapy. That observation prompted this prospective study that showed a 46% reduction in anti-hypertensive medication requirements, for the same degree of BP control, at the end of 3 months of CIIIT in 26 patients with type I DM, hypertension, and nephropathy. The MPCQT review stated that because there was no change in glycemic control with CIIIT, the resultant improvement in blood pressure control seen with CIIIT could not have been due to improvement in the patient’s metabolism. This statement is not correct. As far as we know in humans, the regulation of blood sugar and the regulation of blood pressure are separate independent processes. These patients were selected because they had hypertension, not problems with glycemic control. During the 1 to 3 month stabilization period, efforts were made to optimize their blood pressure and glucose control prior to the initiation of the study. In patients who achieved good glycemic control during the stabilization period, no further improvement in glycemic control was expected with the addition of CIIIT. The MPCQT review was incorrect in assigning caution to the study because of a high dropout rate "15 (31%) of the original 41 enrollees were excluded from the study.” The dropout rate is actually much less. All patients recruited for this study underwent an initial 1-3 month run-in/ stabilization period (intensive s.c. insulin therapy and lowering of BP to or below 140/90 mm Hg with medication). Only patients who successfully completed this run-in/ stabilization period were randomized and entered the actual study (randomized cross-over design). Fifteen patients did not successful complete this run-in/stabilization period for various reasons (explained in the paper.) All 26 patients stabilized and then randomized to the actual study completed this study. Thus, the actual dropout rate for the study was 0% during a 6-month study that involved a crossover at 3 months. The run-in period was necessary to determine medication doses required at steady state prior to actually beginning the study. It then became possible to calculate the reduction in dosage during the randomized study. By providing a more uniform population for the randomized study, the run-in actually strengthened the study by decreasing the likelihood that the significant difference in outcome detected was due to something other than CIIIT. Those 15 excluded during the run-in period have no bearing on the acceptability by patients of the CIIIT procedure, since none of these patients were on CIIIT during the run-in. The MPCQT reviewer’s discussion regarding the lack of a significant decrease in proteinuria (a parameter not monitored in this short term study ) (page 8, paragraph 3) is completely inappropriate in the context of this anti-hypertensive study. The MPCQT reviewer asks of all these prospective -randomized- controlled trials why intention-to-treat type of analysis was not done. (A reminder to the reviewer, intention to treat analysis begins at the point of randomization, not prior to the run in period.) Intention–to-treat is not the best analysis to use in initial studies of a therapeutic modality in which the point of the study is to ascertain whether or not the treatment is effective. In these studies, there is a great requirement for internal validity. Later, after the therapy has been proven effective, larger studies using intention to treat can be used to pinpoint more exactly the acceptability of the therapy in a diverse population. Besides these issues, in the case of our anti-hypertensive medication study, intention-to-treat is not recommended because this was a crossover study involving a relatively small number of patients.
2) Dailey et al, (Metabolism, 2000)This multi-center, parallel group, prospective, randomized, controlled trial) re-affirms and reproduces the results of the retrospective multi-center study previously published by Aoki et al (Endocrine Practice, 1999). CIIIT clearly significantly slows the progression of overt diabetic nephropathy. In reviewing this study, the MPCQT review makes a serious error in stating that: "the absence of a reduction in urinary protein excretion in both groups was also unexpected". This study very clearly shows that the progression of overt nephropathy was slower (but continued nevertheless!) in the treated group (essentially identical treatment except for the added CIIIT) compared with the attention control group. In the face of progressing diabetic nephropathy in both groups (albeit slower in one group than the other), why anyone would expect a decrease in proteinuria? As noted previously, without intervention, urinary protein excretion is expected to increase 300-500 mg/day/year.

The MPCQT discussion of the known relative effectiveness of anti-hypertensive therapy and dietary protein restriction in overt diabetic nephropathy is superfluous. Both patients groups (C and T) in the Dailey study underwent similar anti-hypertensive therapy, mild sodium restriction, moderate dietary protein restriction, and DCCT type diabetic diets. The patients in both the treatment and control groups were seen weekly. However, the rate of decline in creatinine clearance was significantly reduced only in the CIIIT (T) group.

The repeated statement by the MPCQT review that there was a 46 % dropout rate is also misleading. This study was designed for 12 months but also was planned to be extended another 6 months if the treatment appeared effective but had not yet reached statistical significance. There was only a 21% dropout rate with 71/ of f 90 patients completing the 12-month study. Only 8 patients dropped out of the CIIIT group, while 11 dropped out of the control group. This is very admirable considering the time-intensiveness of the study and the severity of the disease. At the end of the 12-month study, an extension of the study for 6 more months was offered to participants. The primary reason that 22 / 71 (31%) patients dropped out at that time was the time required for weekly clinic visits. However, 1 dropped out of the treatment group when gangrenous cholecystitis led to dialysis.

The only significant difference between patients completing only 12 months and those who continued for 18 months was that those who chose to continue had a higher baseline serum creatinine and thus presumably more severe renal disease. (see attached graph, Fig. 1)

Dialysis/transplant is usually required when creatinine clearance falls to 15 ml/min. One is tempted to extrapolate the curves shown above. Since both groups had an average of approximately 60 ml/min creatinine clearance at baseline, one would anticipate the time-to-dialysis/transplant for the control group to average 6 1/2 years, but average 15 years for the CIIIT treatment group.

Because the MPCQT reviewer was troubled by the dropout rate in these studies, we reviewed other nephropathy papers to see what the “expected” or “usual” dropout rate in 18-month time-intensive studies of chronic disease. We show two studies on the next page.   Other diabetic nephropathy studies

Dropouts Observation/Follow-up Time and Effort required Study Citation

108/409 (26%) median, 3 years monthly visitspill T.I.D Effect of ACE-inhibition on Diabetic nephropathy Lewis et al, 199343/143 (30%) 2 years 4 visits per yearpill B.I.D ACE-inhibitor in normotensive IDDM pts. with microalbuminuria. Mogensen et al, 1995

An important point regarding the acceptance of CIIIT therapy by the patients in our clinical studies does not appear in any of the published papers. At the end of each clinical study, many patients on CIIIT wanted to continue CIIIT because in addition to the improved outcome mentioned in the study, they also experienced other improvements in quality of life such as more energy and improved or complete remission of other diabetic complications such as painful peripheral neuropathy, gastroparesis, or foot ulcers. Patients also discovered that after several months without CIIIT, their previous complications gradually returned. Because of this, many have continued on CIIIT for years (some are in their 15th year) necessitating establishment of an off- campus CIIIT facility.

The MPCQT review discusses the DCCT results but these have no bearing on the CIIIT nephropathy studies because patients with overt diabetic nephropathy were excluded from the DCCT! DCCT enrollees were drawn from a much healthier patient population and thus cannot be compared to the enrollees in the Dailey study.

The MPCQT review speculates that the result of an intention-to-treat analysis of the Dailey study would be negative. In fact, based on the information in the paper, there is no way to know what an intention-to-treat analysis would show! It may be more favorable than the current analyses.

The MPCQT reviewer also speculates that it would take years of CIIIT to prevent progression of end-stage renal disease. This speculation is incorrect. Actually, this study showed CIIIT postponing the progression of renal disease even in the first few months of CIIIT therapy. In fact, this study and the study by Aoki (Endocrine Practice, 1999) discussed above, suggest that CIIIT can stave off renal failure for years. Postponing dialysis/transplant for even one year is a significant health benefit!

The MPCQT reviewer raised a caution because hypoglycemic episodes were not an endpoint measured in this study on nephropathy. Since hypoglycemia is not known to have any influence on the progression of renal failure and was not a criterion for entry into the study, it is unclear what the reviewer’s caution is. We thought that saving money by not measuring non-contributory data was a virtue in research.

Risks

The MPCQT review correctly stated that no adverse effects have been reported with CIIIT. This is a very important point. Over 20,000 CIIIT 6-hour procedures have been performed to date without serious side effect. Included are several hundred patients treated over a span of more than 15 years, with many patients remaining in therapy for as much as 10 to 15 years with no serious side effects. That is quite a safety record.

One reason for the lack of serious side effects with CIIIT is that the procedure mimics nature in providing more normal insulin levels in the liver and other tissues, enabling a more normal fuel metabolism. The other reason is that glucose levels are monitored during the procedure and insulin and glucose doses are carefully adjusted. CIIIT uses a complicated therapy algorithm involving high doses of insulin and should never be casually imitated. Providers and staff must complete a training course in the use of this patented procedure, including understanding the physiology and the reasoning behind it and the detailed plans for the use of pulsatile insulin and the monitoring of glucose levels and patient status. In practice, a small percentage of patients experience nausea if large amounts of oral glucose are given during the procedure – adaptations are made to avoid this at the next treatment. A caution already alluded to above is the increased responsiveness to anti-hypertensive medications that occurs on CIIIT requiring monitoring of blood pressure and downward medication adjustment during the first few months on CIIIT. No patient has discontinued therapy because of either of these effects. CIIIT has been a novel therapy in that rather than complaints, the patients often tell us of some unexpected health improvement they noticed while on CIIIT, and on formal study, we discover this improvement in other patients on CIIIT.

Conclusion

We strongly disagree with the MPCPQT review conclusion that "it is difficult to conclude that CIIIT improves net health outcomes as much as or more than established alternatives". We feel the MPCQT conclusion contradicts the evidence published in prestigious peer-reviewed specialty medical journals.

We appreciate the opportunity to respond to the MPCQT review and the opportunity to discuss CIIIT further with you at the policy meeting. We strongly believe that the published research reviewed here shows an important role for CIIIT as an effective therapy when diabetic complications do not respond adequately to other standard therapies. Current indications for CIIIT supported by this research include: 1) treatment-resistant ‘brittle” diabetes, 2) diabetic nephropathy,3) hypoglycemia unawareness, 4) inability to tolerate intensive insulin therapy due to frequent or severe hypoglycemic attacks, 5) inadequately controlled blood pressure despite optimal medications, and 6) treatment-resistant orthostatic hypotension.

As noted above, we have also had many successes using CIIIT to treat other complications not yet studied in prospective randomized clinical trials. At some future date, we would be happy to provide further observational data on health outcomes or cost-effectiveness.

CIIIT provides important health benefits for patients with severe diabetes. We are delighted that Blue Shield is moving to become informed about this effective therapy that many patients with severe diabetes so desperately need.

References

Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. NEJM 1993; 329:1456-1462.

Mogensen VG, Groop LC, Pauls JF. Effect of captopril on the progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria JAMA 1994; 271:275-9

As stated in this NCA:Blue Cross/Blue Shield (California) and the Hayes Group have performed technology assessments of this therapeutic modality and concluded that the data did not support use of this treatment regimen. Many of the usual reviewers of technology, e.g., the Agency for Healthcare Research and Quality
1. Blue Cross/Blue Shield-California (BCBS 2001)The therapeutic regimen was reviewed on February 14, 2001. The following was extracted from the assessment:"Other alternatives to PIVIT exist for treatment of blood sugar, blood pressure, and kidney disease. Intensive insulin therapy has been documented to produce more sustained effects on glycemic control and antihypertensive therapy (particularly with ACE [angiotensin converting enzyme] inhibitors) to produce excellent control of blood pressure adequate to reduce or prevent progression of diabetic nephropathy. Based on the two randomized, controlled trials, it is difficult to conclude that PIVIT improves net health outcomes as much as or more than the established alternatives. Finally, the substantial drop-out rates in the randomized, controlled trials suggest that maintaining the schedule of weekly PIVIT in addition to daily intensive insulin needed to achieve its potential benefits may be difficult for many patients under conditions of usual medical practice. Therefore, TA criteria 2-5 are not met.If this assessment is to be believed, why is there such a high incidence of diabetic renal failure? Isn’t this the reason given by CMS for initiation of this review?BC/BS of California in light of the litigation that it has lost cannot be considered as unbiased.
2. Hayes (A proprietary technology assessment and rating firm in Landsdale, PA) (Hayes 2007) This therapeutic regimen was initially reviewed July 14, 2006 and subsequently updated August 15, 2007 and September 29, 2008. The following was extracted from the Executive Summary:"Important questions regarding CIIIT are:

Does CIIIT improve glycemic control and/or reduce incidence or progression of sequelae of diabetes, compared with conventional intensive insulin therapy?

Is CIIIT safe?

Have definitive patient selection criteria for CIIIT been established?" "Major complications of CIIIT have not been reported.Definitive patient selection criteria for CIIIT have not been established.Conclusions: There is insufficient evidence from the limited number of published studies to conclude that CIIIT is effective in reducing symptoms, improving glycemic control, or preventing diabetic sequelae inpatients with type 1 diabetes. Although results of several of the studies suggest that CIIIT may improve glycemic control, facilitate blood pressure control, and/or slow progression of nephropathy, the lack of adequate controls, randomization, and blinding, and the small sample sizes of the available studies preclude definitive conclusions regarding the health benefit of CIIIT. Double-blind RCTs of adequate size are necessary to evaluate this therapy adequately."Thank you for extracting from this assessment, but to be completely open about this, should not you include the assessment rating that Hayes gave CIIIT (MAT)?This is the Hayes Rating System:The Hayes Rating, a proprietary rating system, reflects the strength and direction of the evidence regarding the safety and efficacy of a medical technology (procedure, test, device, biologic, or drug), its impact on health outcomes, indications for use, patient selection criteria, and comparison with other technologies. The ratings are scaled A through D and are defined as follows:The Hayes Rating, a proprietary rating system, reflects the strength and direction of the evidence regarding the safety and efficacy of a medical technology (procedure, test, device, biologic, or drug), its impact on health outcomes, indications for use, patient selection criteria, and comparison with other technologies. The ratings are scaled A through D and are defined as follows:
A Established benefit. A high level of positive published evidence regarding safety and efficacy supports use of the technology for the cited application(s). Drugs, biologics, and devices with an A rating have FDA approval, but not necessarily for the specific clinical application.
B Some proven benefit. A moderate level of positive published evidence regarding safety and efficacy supports use of the technology for the cited application(s). Further research is required to fully clarify clinical indications, contraindications, treatment parameters, comparison with other technologies, and/or impact on health outcomes. Drugs, biologics, and devices with a B rating have FDA approval, but not necessarily for the specific clinical application.
C Potential but unproven benefit. Some positive published evidence regarding safety and/or efficacy support use of the technology for the cited application(s), but a beneficial impact on health outcomes has not been proven because data are sparse and the level of evidence is low, or data are inconsistent or conflicting.
D No proven benefit and/or not safe. This rating conveys one of two conclusions: (1) The technology has been shown to be unsafe and/or published evidence does not show that its use improves health outcomes; or (2) The research regarding use of the technology is so limited that an appraisal of safety and efficacy cannot be made. Hayes gave CIIIT (MAT) a C rating not a D as This NCA proposes.This is the only independent, assessment to date.The only conclusion CMS can reasonably reach is that more study should be undertaken as was one of the stated purposes of this NCA:“If the evidence is determined to be inadequate for coverage, we are especially interested in what types of studies are needed.”We would be more than happy to collaborate with CMS on the design of studies to further elucidate the effects of MAT.

Perhaps the published data to date is not enough to allow national coverage by CMS, but there is more than an ample amount of both study and actual patient data to refute any conclusion that MAT shows no benefit to patients.

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October 24, 2009

This opinion is written by Mr. Bruce Parsons, an individual who has first hand knowledge of the history of and a keen interest in attempting to make Metabolic Activation Therapy available to diabetic patients worldwide. Mr. Parsons is a member of the class of 1962 from West Point.

Summary of Issues with CMS NCA

I. CMS Conclusion:
“The evidence is adequate to conclude that outpatient intravenous insulin therapy does not improve health outcomes in Medicare beneficiaries.” There has been a serious misunderstanding of the Metabolic Activation Therapy (MAT®) technology and the data to support the technology by CMS. In addition CMS has steadfastly refused to consider anecdotal evidence of long-term use of the technology by 38 patients over an average of more than 13 years which at least points to areas where Dr. Aoki and CMS may cooperate to develop conclusive clinical trials that show either the technology does or does not improve health outcomes in Medicare beneficiaries. It is precisely the kind of technology envisioned when the Medical Clinical Trials’ program was established by Congress.

If members of CMS passing judgment on this promising new technology took the time to actually visit with patients and doctors using Metabolic Activation Therapy, some of the more esoteric (and just incorrect) complaints they have listed in their decision will inevitably be disregarded in favor of the outstanding results at the clinic level. It was those outstanding results that swayed the courts of California to conclude eight years ago that Metabolic Activation Therapy is both safe and effective. Without such first hand visits CMS will continue to “hide behind” the pontification of “experts in the field” with no actual experience using the technology and conclude that “The evidence is adequate to conclude that outpatient intravenous insulin therapy does not improve health outcomes in Medicare beneficiaries.” A major advancement in the treatment of diabetes most likely would be destroyed by this CMS decision.

II. Listening to the Voice of Patients
If CMS listens directly to the many patients who have been helped by Metabolic Activation Therapy, CMS would not come to the conclusion that the technology is ineffective. These patients are willing to not only spend 6 hours a week at a treatment clinic, but to spend many hours appealing payment denials by insurance organizations. Only diabetic patients know the true meaning of suffering from complications of diabetes, such as constant vomiting and nausea because their digestive system fails to move food in the intestines (gastroparesis); sudden and frequent loss of consciousness (leading to loss of driving ability or loss of a job) and frequent, costly hospital visits (hypoglycemic unawareness); becoming dizzy and falling when they stand up (orthostatic hyootension); the fear of amputation of limbs; the fear of loss of eyesight; entering kidney dialysis with the knowledge that it will not be for long before death; debilitating painful nerve disease which restricts body motion dramatically; etc. ADRI welcomes a visit from CMS personnel any time and will make all current users of the technology and appropriate family members available to CMS for in depth interviews. Obviously CMS did not interview any of the patients or listen to the comments contributed by patients or they would never have made such a statement as “Moreover, CMS is concerned that the procedure is invasive and potentially burdensome to patients due to the perpetual weekly 6-hour session.”

III. Importance and Use of the RQ to Guide Treatment of Patients
In MAT® treatment, the respiratory quotient (RQ) is measured at baseline and at hourly intervals to provide a measure of therapeutic efficacy (an increase in value from .75 to .90 or higher) that the desired results of infusing intravenous insulin while ingesting glucose in fact have altered the metabolic process of the patient. RQ measurements have been an essential tool in obtaining clinical data for all peer-reviewed, published papers.

IV. Safety Issues
With regard to the long term safety record of MAT® treatment at ADRI, the main adverse event has been hypoglycemia (50 mg/dl or less). Hypoglycemia that occurred during 0.025% of 23,431MAT® treatments at ADRI and U.C. Davis was resolved by medical personnel in attendance. Although this data is not published and peer-reviewed, CMS is welcome to visit ADRI and to examine how this data was obtained and its validity. CMS could then form its own opinion even though peer-reviewed and published data is not at hand.

V. Short Term vs. Long Term effects
CMS clearly needs to include in their analysis and their coverage decision the long-term effects of the technology being evaluated. MAT® Treatment has a short-term effect seen within 3 to 6 months of therapy, which is improvement in diabetic complications. But MAT® Treatment has also been used as a chronic therapy to prevent future complications. Clinical results of long-term usage were presented to CMS but CMS did not comment on those results presumably on the basis that the data were not published and peer-reviewed. Monitoring multiple complications simultaneously in a group of treated patients is statistically extremely complex as the severity of such complications will vary significantly over the patient population. Once the technology is accepted for use and reimbursed at least for limited complications doctors would embrace use of the technology and such long term, wide-ranging studies would be possible and economically feasible as real, costly, actual, acute complications are being resolved.

VI. Clearly Identify Each Different Technology and Evaluate Each Individually
OIVIT is a brand new field of medical therapeutics. Because of the promising results seen with one therapy in this field, Dr. Aoki''s Metabolic Activation Therapy (CIIIT, PIVIT, or Metabolic Activation Therapy), many more therapies may arise in this category in the future. However, for the current analysis it is important that CMS specifically identify those therapies it has considered for this particular NCA and to evaluate them individually. To categorize the entire group as the same under OIVIT is a gross simplification that can only lead to incorrect conclusions.

CMS has incorrectly named other entities “authorized” to use the equivalent of Metabolic Activation Therapy. There is only one procedure with published, peer reviewed clinical data and long term anecdotal clinical data to support its claims, and that is Metabolic Activation Therapy (also known as CIIIT, Metabolic Activation Therapy, hepatic activation, and PIVIT). ADRI and MI, and only those organizations, are licensed by Dr. Thomas Aoki to use that therapy. CMS’ claim that others are authorized is incorrect and could be considered contributing to willful patent infringement by those organizations. If other organizations claim that their processes are different from Metabolic Activation Therapy, such processes cannot claim the outcomes in the list of peer-reviewed, published clinical data for Metabolic Activation Therapy. It is highly recommended that CMS segregate their analysis by specific technologies and evaluate each separately.

As members of CMS know well, there is no clinical trial, not even the DCCT and UKPDS studies which form the basis of current treatment regimen that cannot be ridiculed for some academic reason.

VII. Using Progression of Actual Complications Instead of Blood Glucose Control as the End Point of Metabolic Activation Therapy
Initially doctors using Metabolic Activation Therapy were impressed by the fact the treatment was able to provide considerable improvement in blood glucose control (HbA1c) over “tight control”, the accepted standard of treatment since the DCCT and UKPDS studies. However, as experience with the new treatment progressed it became obvious that improvement in the complications of diabetes improved independent of HbA1c readings and blood glucose control. In the Dailey Study of the effects of MAT® treatment for diabetic nephropathy, an effort was made to show that the improvement in complications occurred even though there was no significant change in HbA1c, a major shift in understanding of treating complications. CMS used this lack of improvement in HbA1c to prove that Metabolic Activation Therapy was not effective in treating nephropathy even though deterioration of creatinine clearance, the chosen end point of the Kidney disease clinical study, was significantly slowed in the treated group of patients. This simple but profound error in CMS’ evaluation should be corrected.

VIII. Understanding the scientific basis for OIVIT procedures.
It is not necessary to know the exact biochemical actions triggered by a treatment to decide it''s worth. Outcomes are more important than explanations. Empirical evidence is evidence as well. Sometimes the outcomes are obvious such as the ability to stand up without fainting (orthostatic hypotension), elimination of continuous vomiting and nausea (gastroparesis), elimination of sudden episodes of unconsciousness due to unawareness of low blood sugar (hypoglycemic unawareness), reduction or elimination of painful neuropathy, fear of loss of eyesight, etc. However in the medical field, good outcomes are believed more readily to be due to a therapy that "makes scientific sense".

Unfortunately many have failed to understand the underlying concept of Dr. Aoki''s therapy - to provide an enhanced insulin effect on the liver and other body tissues. Since no one but diabetic patients get diabetic complications, it seems obvious that the cause of complications is the lack of an insulin effect. Dr. Aoki merely invented a way to provide large doses of insulin using boluses to mimic the action of the normal pancreas, primarily 1st phase insulin release, and provided safeguards to avoid hypoglycemia.

IX. Court Action in the State of California
In a suit by six people who had been treated with Metabolic Activation Therapy but for whom the California Public Employees’ Retirement System (CalPERS) refused payment, a California judge concluded in 2002: “Metabolic Activation Therapy is now, and has been since at least 1987, in accordance with generally accepted medical professional standards as being safe and effective for use in the treatment of Type 1 and Type 2 diabetes and its complications. There was significant, persuasive, credible proof of this in this record, with respect to respondents, and others as well.” The judge’s clear analysis of the issues at hand in his 60 page detailed decision stands in stark contrast to the decision by CMS of this NDA. Blue Shield has challenged this decision twice in the courts of California, once as a third party administrator of CalPERS and the second as a health insurance provider. In both cases Blue Shield was not allowed to assert that Metabolic Activation Therapy was “experimental” and one case was appealed to and lost at the Supreme Court of California in September 2008. CMS’ current decision would further exacerbate the dichotomy in California between what the courts have ruled with a long, in-depth analysis of the technology and what insurance companies are attempting to claim with a very limited understanding of Metabolic Activation Therapy. CMS has made no mention of these court decisions even though evidence of the proceedings was presented to CMS.

X. Inclusion in the CMS Decision of Non-Published Non-Peer Reviewed Data
Quoting CMS’ decision “Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.” The clear implication is that anecdotal evidence will not be reviewed seriously no matter how compelling or accurate such data might be. Such was the case in their superficial analysis of Metabolic Activation Therapy.

On the one hand CMS writes, “We believe that health outcomes are more important than test characteristics.” On the other hand CMS has given no weight to unpublished clinical data of health outcomes clearly showing that 38 patients most of whom suffered from multiple complications of diabetes have been treated an average of more than 13+ years with Metabolic Activation Therapy with no significant deterioration and in most cases improvement or reversal of those complications. Additionally no new complication emerged in those patients.

While agreeing that additional clinical data is strongly desirable, the decision by the Judge in CalPERS decision provides a more balanced approach to the use of compelling anecdotal evidence. He is quoted: “But to use its (scientific literature support) adequacy or inadequacy as the sole gatekeeper for access to a promising therapy that has an outstanding track record of actually working when used with real patients in real clinical settings suffering from real complications, without any meaningful side effects as revealed by that clinical experience is not reasonable or balanced.”

XI. Conclusions based on Clinical Studies
CMS claims that their Conclusion that metabolic activation therapy has no clinical value is based on the clinical studies. However, in their discussion CMS claimed that the clinical papers published on the effects of the treatment did not have the statistical power to show that metabolic activation therapy was effective. If CMS''s conclusion regarding the statistical power of the studies is correct, then it follows logically that the studies also DO NOT prove that the therapy was not effective. So CMS has made a major error in rigorous scientific thought when they state that they have proven that in fact Metabolic Activation Therapy does not work and has no clinical value.

CMS may want to rethink their statistical analysis of the published studies. Because this is a treatment that is added to conventional therapy, and used only in patients who have failed to improve on conventional therapy, a "compassionate use" analysis seems more in order.

XII. Extensive List of Animal Studies Have Are not Related to Metabolic Activation Therapy in Any Way
CMS went to considerable effort to research a number of animal studies supposedly related to Metabolic Activation Therapy and that supposedly provided some indication of how the therapy works in animal studies. The list provided by CMS unfortunately was not related to Metabolic Activation Therapy and hence any conclusions from those studies were irrelevant.

XIII. Peer-reviewed, Published Data Shows MAT® Treatment to be Effective in Treating Complications of End Stage Renal Disease and Severe Hypoglycemia in Patients with Multiple Hospitalizations and ER Visits
CMS further decided to reject any data from the clinical trial evidence supporting the conclusion that at least in the cases of nephropathy and hypoglycemia in type 1 diabetic patients that Metabolic Activation Therapy is significantly effective in treating those two complications when compared to the current gold standard of intensive blood glucose control. CMS’ reasons for rejection were not clear nor did they attempt to ascertain what could be done to resolve any deficiencies in the data. While CMS elegantly proposes to be concerned about the morbidity of the patient population, this lack of rigorous analysis is in stark contrast to those lofty principles. These two complications alone cause untold misery and suffering in long term diabetic patients, presumably the Medicare patient population. Diabetic kidney disease patients who do not use Metabolic Activation Therapy have no long-term effective Medicare supported therapy and face either death, expensive kidney transplant with its concurrent problems of immune-suppression and rejection, or kidney dialysis leading to near certain death in an average 5 to 6 years. This compares to peer-reviewed, published paper of 31 long term patients from the Aoki Diabetes Research Institute suffering kidney disease treated for a average of 37+/-4.6 months showed that average creatinine clearance changed from 46.1 mL/min to 46.0 mL/min. This compares to the typical reduction of creatinine clearance of 7-12 mL/min/year. In unpublished clinical results of 25 patients suffering various degrees of diabetic nephropathy were treated an average of 13+ years with MAT® treatment. Of those 25 patients, two patients with particularly aggressive nephropathy entered dialysis, one of whom entered dialysis after 14 years of treatment.

XIV. Potential Cost Savings to Medicare for Reduction of Kidney Dialysis, Reduction in costs of Premature Disability from Diabetes, and Reduction in Costs of Hospitalization for Severe Hypoglycemia

CMS stated in a meeting in CMS’ facility to Dr. Aoki that the potential cost savings to Medicare are of no concern to them for this NCA. Spending obviously scant resources CMS has passed judgment on a technology in use for 23 years and promises to save tens of billions of dollars annually in direct and indirect costs of diabetes. It seems natural to the layman that CMS would spend the resources to bring a technology to market which can save considerable costs compared to current treatment regimens, especially as there are no alternatives as stated in the reason CMS was conducting this NCA.

Establishing a network of clinics countrywide will require initial onetime capital expenditures considerably more than the running costs of each clinic once established. Investors will be asked to support the roll-out of MAT® clinics initially in large metropolitan areas and gradually to more and more rural locations. These clinics can be started in existing offices of practicing endocrinologists as the treatment requires the medical expertise of a trained endocrinologist. These start-up costs can be more than covered by cost savings from reduction in new diabetic kidney dialysis, hospitalization from frequent hypoglycemia, and the removal from disability of many of the 445,000 patients currently disabled by complications of diabetes.

However, once the clinics are established the costs and subsequent reimbursement rates for a single treatment day should decrease with time as the clinics become more efficient and as more and more patients are treated. An analogy can be seen in the current day kidney dialysis clinics.

There have been no formal cost benefit analyses done for MAT® treatment. Clinical data exists which would be useful to pinpoint areas wherein there should be significant savings to Medicare and the general treatment costs of complications of the diabetes. Some of the anecdotal experience points to a significant saving compared to diabetic kidney dialysis, a reduction of frequent hospitalization of treated patients compared to their own historical control, a virtual elimination of hypoglycemic unawareness as a major reason for hospitalization for type 1 and type 2 patients, return to work of patients who had been unable to work because of complications of diabetes, a reported major reduction in hospitalization for pediatric and adolescent patients suffering frequent hospitalization from complications of diabetes, a reported decreases in the costs of seeing specialists in treating various complications of diabetes, a reduction in the length of stay for hospitalization not directly related to diabetes but for which diabetic patients typically require considerably longer to recover, and others.

Since each of these are anecdotal in nature, more rigorous peer-reviewed, published data will be required to detail exact savings to the costs of treating diabetes in general. Presumably these data could be collected as part of any focused longitudinal studies of the efficacy of MAT® treatment.

Aside from the cost benefits to Medicare of using MAT® treatment, the universal comment from patients using the treatment is that their quality of life is improved to where they can function as normal members of society. The almost universal comment from treated patients is “I have gained back control of my body that I had once lost to the disease.”

XV. Use of Expert Opinion
CMS stated it failed to get any expert opinions on OIVIT (and more specifically Metabolic Activation Therapy) prior to publishing its Proposed Decision. It is suggested that any such opinion will be tainted by the “expert’s” own practical experience and fundamental beliefs in the way to treat diabetes. To mitigate such uninformed opinions, it is highly recommended that the majority of such opinion come from doctors who have actually used Metabolic Activation Therapy. For experts chosen who do not have specific experience with the technology, it is highly recommended that, as a minimum, those experts visit the Aoki Diabetic Research Institute in Sacramento, California and discuss the technology first hand with Dr. Thomas Aoki, the medical staff at ADRI with such a long history of use, and actual patients using the therapy. Otherwise, those doctors might miss some salient points of the technology. It is recommended that any expert opinions be qualified by explaining exactly what experience the expert has with Metabolic Activation Therapy. Experts with no experience in using the technology will invariably say that it does not work. Such opinions are next to useless.

XVI. The Next Step
It seems a double standard to state that all of the clinical data produced over years of treatment with Metabolic Activation Therapy cannot be believed and then for CMS to opine that they have proved that in fact Metabolic Activation Therapy does not work. That CMS so concludes without any attempt to conduct peer reviewed published papers to prove their conclusions is at least a double standard that should not be condoned by academically rigorous analysis. It is easily resolved with a well-defined clinical study to once and for all settle the issue. Dr. Aoki welcomes the opportunity to jointly conduct a definitive clinical trial together with CMS that answers the question of whether or not Metabolic Activation Therapy does or does not work in treating complications of diabetes. If Metabolic Activation Therapy is safe and effective as the State Courts of California has concluded, then it would be a major development in the treatment of diabetic complications. If Medicare and Dr. Aoki jointly define such a study, there is little doubt that funds could be found to support the study, either from private or public funding or both. As stated above, it will take years and a great deal of funding and cooperation to demonstrate the entire value of MAT® Treatment. Clinical demonstration projects would be another way to demonstrate the effectiveness of this therapy in specific populations such as those served by Medicare or Indian Health.

Detailed Discussion of the Key Issues has been forwarded as an attachment under separate cover to CAGinquiries@cms.hhs.gov. as the format used in this comment section is not optimum for easy understanding.

Bruce B. Parsons

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I failed to detect any internal logic in the Proposed Decision Memo.

The first item under the proposed decision states: “The evidence is adequate to conclude that outpatient intravenous insulin therapy does not improve health outcomes in Medicare beneficiaries.” How is “adequate” measured? Where is it defined?

No evidence is presented that MAT does not improve health outcomes. The Proposed Decision bases its findings on reservations about the 28 cited published studies of MAT. If these cited studies, published from 1989 through 2009, were flawed, one must ask how were they published in the first place? A number of the cited studies were published by the NIH, the Institute of Experimental Clinical Research, Danish Diabetic Association, Danish Medical Research Council, the National Health & Medical Research Council of Australia, Royal Australasian College of Physicians, the Fonds de la Recherche Scientifique, Medical of Belgium, Fonds de la Recherche Facultaire of Liege. These reputable agencies would not have published the studies if they had the same reservations.

Apparently CMS holds that a physician’s duty to “first do no harm” is overridden by the need to subject a diabetic to a double blind study in which they would be undergoing a MAT with an inert solution rather than insulin in order to determine if the MAT improves their health outcomes. Please explain your position? Do you hold that such a blind study is either ethical or in the interests of either the diabetic or public health? How long should such an unethical study be conducted before CMS would view any findings as evidence of MAT outcomes? How many Type I diabetics with complications must participate in a study where they spend six hours or so with no insulin while ingesting glucose? A study that will actually knowingly harm those in the control group? Under what regulation or statute would an IRB approve such a study? Please cite any basis for a study that puts the life of a patient at such a known risk?

Pages 11 and 26 of the Proposed Decision states that Blue Cross/Blue Shield-California reviewed MAT and quotes an extract from that assessment. But the Proposed Decision does not mention, let alone address, the fact that Blue Shield of California was sued by subscribers over non-payment for MAT and lost the case. The trial court ruled in favor of coverage and ordered Blue Shield to pay for coverage. Blue Shield subsequently appealed the decision all the way to the California Supreme Court and lost at each level. In addition, the California state public employee’s retirement system, CalPERS, was sued by MAT patients for non-payment and after a two-week, open court trial, the administrative law judge concluded that MAT was not experimental or investigational, was safe and effective.

The Proposed Decision does not even acknowledge these court cases/decisions! In the Blue Shield Case, they appealed to both the Appeals Court and the California Supreme Court and were rejected by those courts. In the CalPERS case, the witnesses for the defense presented many of the same arguments against coverage by CalPERS as are cited in this Proposed Decision. The judge rejected them then, and they were no more valid then than they are in this Proposed Decision. Why were these court cases not mentioned?

As for further evidence that MAT improves health outcomes, CMS received 187 public comments, Page 26. Except for .02% of the comments, all were in favor of coverage. 73.3% of the comments were from patients who have undergone MAT or members of their families and all were in favor of coverage. If anyone should know the impact of MAT on medical outcomes patients or their families would be in the best position. Clearly the 98% of public comments that were in favor of coverage are in the best position to provide living evidence of improved medical outcomes. The Proposed Decision states that: “The CMS uses the initial public comments to inform its proposed decision.” and “…no new scientific publications were uncovered.”. These public comments from MAT patients, family members and physician clinicians are dismissed in one paragraph as just some numbers. I was not aware that public comments were intended to be a form of free public bibliographical research for CMS.

In the Section labeled Analysis, beginning on Page 26 it is stated: National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act §1869(f)(1)(B). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions the expenses incurred for items or services must be "reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member." See §1862(a)(1)(A) of the Act (emphasis added). The 98% of public comments in favor of coverage comprise first hand evidence that MAT improves the functioning of the patient.

Diabetes is a chronic disease that effects millions of Americans, and the numbers seem to be getting even worse. The disease also negatively impacts multiple organs and physiological systems resulting in intensive and costly treatment. MAT is a proven treatment that reduces the impact of diabetes on multiple physical systems and improves a patient’s functioning.

In conclusion, I can only conjecture that CMS’s Proposed Decision was pre-determined and the experience of the 137 patients or family members, 28 cited published studies, and two court cases was discounted or ignored.

The fiscal implications of diabetes are huge. The American Diabetes Association estimates the costs of diabetes in the US exceeds $170 billion. A treatment that reduces the detrimental effects of diabetes on other body systems alone would result in greatly reduced treatment costs. Avoiding the cost of one multi- day hospital stay alone would fund several preventative MAT treatments. Prevention is always the most cost effective medical policy.

I request that this Proposed Decision be set aside and that an objective review be undertaken that will examine the real life experiences of MAT patients, review the court records and decisions regarding coverage prior to releasing a fact based decision.

Gordon V. Scott

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Addition of pulsatile infusions of insulin to a standard DCCT protocol blunted progression of renal deterioration of type 1 DM in a pilot study published in 2000. A threefold increase in time to dialysis (2 years vs. 7 years) was estimated. Cost savings for 3 dialysis treatments per week vs. one insulin infusion per week are potentially substantial.

Symptoms related to neuropathy were extracted from a quality of life questionnaire. A high correlation of positive responses was documented in the pulsatile insulin patients whose renal function was relatively preserved. Diminution of postural hypotension (faintness, dizziness on assumption of upright posture, published in 2009) symptoms may be interpreted as decreasing the risk of falls in individuals with diabetic neuropathy. Despite reported improvement in visual blurring findings with respect to retinopathy indicated no benefit (presented at the ADA in June 2009).

These small prospective, randomized, and short-term registered studies (ClinicalTrials.gov, NCT00594152), and others reflecting the effect of this therapy in type 1 diabetic patients have given significant clinical research information. Increasing the size, power and duration of such studies to determine whether there is a significant long-term benefit on avoidance of dialysis, or blindness represent a prohibitively expensive project in the private sector. We believe that further are clinical investigational studies are warranted in the select populations in which benefit has been suggested. This is in accordance with the Hayes technology assessment (2008) conclusions: "There is insufficient evidence from the limited number of published studies to conclude that CIIIT is effective in reducing symptoms, improving glycemic control, or preventing diabetic sequelae inpatients with type 1 diabetes. Although results of several of the studies suggest that CIIIT may improve glycemic control, facilitate blood pressure control, and/or slow progression of nephropathy, the lack of adequate controls, randomization, and blinding, and the small sample sizes of the available studies preclude definitive conclusions regarding the health benefit of CIIIT. Double-blind RCTs of adequate size are necessary to evaluate this therapy adequately." And is not different from the cautions from the Blue Cross Blue Shield- California Technology Assessment of 2001. "Based on the two randomized, controlled trials, it is difficult to conclude that PIVIT improves net health outcomes as much as or more than the established alternatives. Finally, the substantial drop-out rates in the randomized, controlled trials suggest that maintaining the schedule of weekly PIVIT in addition to daily intensive insulin needed to achieve its potential benefits may be difficult for many patients under conditions of usual medical practice." Feasibility and funding issues led to our institutions' discontinuation of the technique in the 1990's We believe that continued studies with prespecified end points is advisable. The criticisms regarding blinding health professionals to a treatment that has potential clinical risk as severe as hypoglycemia, or using intention to treat analysis in such a rigorous regimen we believe are unwise.

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