WO2006022585A1

WO2006022585A1 - Composition and method for long-term glycemic control

Info

Publication number: WO2006022585A1
Application number: PCT/SE2005/001233
Authority: WO
Inventors: Mats Lake; Ulf Smith
Original assignee: Metcon Medicin Ab
Priority date: 2004-08-26
Filing date: 2005-08-24
Publication date: 2006-03-02
Also published as: SE0402084D0

Abstract

Improved long-term control of blood glucose in a diabetic patient, the improvement measured as one of i) a lowering of the HbA1c value of said patient compared to the HbA1c value recorded before the treatment commences; ii) the stabilization of the HbA1c value at a value typical for patients with well-managed diabetes; iii) a lowering of the HbA1c value compared to a HbA1c value indicative of potentially harmful variations in blood glucose; or iv) a reduction of the incidence of nocturnal hypoglycemia, can be achieved by ingesting a therapeutic amount of starch at bedtime. A method and composition are disclosed.

Description

Title of the invention

Composition and method for long-term glycemic control

Field of the invention

The present invention relates to the field of metabolic diseases, their prophy¬ laxis, alleviation and treatment, as well as methods and compositions for this purpose. In particular, the present invention relates to compositions and methods for long-term glycemic control in diabetic subjects, including Type 1 and Type 2 diabetics. The invention concerns both therapeutic and non- therapeutic methods.

Background

Diabetes

According to a recently published guideline, diabetes mellitus is a leading cause of morbidity and mortality in the United States (Snow et al., Lipid Control in the Management of Type 2 Diabetes Mellitus: A Clinical Practice Guideline from the American College of Physicians, Ann Intern Med. 2004;140:644-649).

Diabetes mellitus is a complex disorder of the carbohydrate, fat, and protein metabolism that is primarily a result of a relative or complete lack of insulin sec¬ retion by the beta cells of the pancreas or of defects of the insulin receptors. The various forms of diabetes are divided in several categories, the three most frequent being insulin-dependent diabetes mellitus (IDDM) or Type 1 diabetes, non-insulin-dependent diabetes mellitus (NIDDM) or Type 2 diabetes, and im¬ paired glucose tolerance (IGT). Type 1 diabetes, a chronic disease that occurs when the pancreas produces too little insulin to regulate blood sugar levels appropriately, was previously also called juvenile-onset diabetes, and includes patients dependent upon insulin to prevent ketosis. Type 2 diabetes was previously called maturity-onset diabetes. IGT is a condition closely related to Type 2 diabetes, where blood glucose levels are higher than normal, but not high enough to be classified as diabetes.

Type 2 diabetes mellitus is most common among the above (90% to 95% of persons with diabetes) and affects older adults, particularly those older than 50 years of age. An estimated 16 million Americans have Type 2 diabetes, and up to 800 000 new diagnoses are made each year. Most adverse diabetes outcomes are a result of vascular complications, which are generally classified as micro vascular (such as retinopathy, nephropathy, and neuropathy, although the latter may not be entirely a microvascular disease) or macrovascular (such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease).

Both IGT and Type 2 diabetes are characterized by insulin resistance. They are parts of a major risk factor complex called the Insulin Resistance Syndrome (IRS). Individuals suffering from IGT or Type 2 diabetes exhibit important changes in diurnal insulin sensitivity, with an enhanced insulin resistance, and in Type 2 diabetes an increased endogenous glucose production at dawn, 4-9 AM. The first meal of the day, usually breakfast, produces a rapid switch from glucose production to glucose utilization. This event takes place under relative hypoinsulinemic conditions in diabetic patients. Both subjects with IGT and Type 2 diabetic patients have decreased carbohydrate tolerance at breakfast. This is also the case with Type 1 diabetic patients, but their postprandial hyperglycemia may be alleviated by an increased dose of exogenous insulin, However, in Type 2 diabetes, where the blood glucose is usually not well controlled by either endogenous or exogenous insulin, a sustained glucose production leads to an accentuated hyperglycemia at breakfast.

HbAIc

It is known that glucose in the blood binds slowly to hemoglobin A (HbA), forming the A1c subtype. The reverse reaction, or decomposition, proceeds relatively slowly, so any build-up persists for about 4 to 6 weeks. Because of the reverse reaction, the actual HbAIc level is strongly weighted toward the present. Some of the HbAIc is also removed when erythrocytes (red blood cells) are recycled after their normal lifetime of about 90-120 days. These factors combine, so that the HbA1 c level represents the average blood glucose level of the past approximately 4 to 6 weeks, strongly weighted toward the most recent weeks.

In non-diabetic persons, the formation, decomposition and destruction of HbAIc reach a steady state with about 3.0% to 6.5% of the hemoglobin being the A1 c subtype, depending on the method used. Most diabetic individuals have a higher average blood glucose level than non-diabetics, resulting in a higher HbAIc level. The actual HbAIc level can be used as an indicator of the average recent blood glucose level. This in turn indicates the possible level of glycation damage to tissues, and thus of diabetic complications, if continued for years. Although it is known that HbAd levels vary among individuals with the same average blood glucose, is generally stable and reliable for any given individual.

For more information about HbAIc (also written HbAi₀), see e.g. Mortensen HB, Volund A: Application of a biokinetic model for prediction and assessment of glycated haemoglobins in diabetic patients, Scandinavian Journal of Clinical and Laboratory Investigation, 48:595-602, October 1988.

One problem, frequently encountered by patients suffering from diabetes, is the nocturnal drop in blood glucose levels, hypoglycaemia, in mild cases resulting in morning dizziness and/or nausea. Occasionally the blood glucose level sinks so low during the night, or early in the morning, that the state of hypoglycaemia becomes severe, leading to unconsciousness or convulsions. Importantly, severe hypoglycaemia is more likely to occur at night, when the patient is asleep, rather than during the day, when the patient can feel the onset of hypoglycaemia and prevent it by eating carbohydrates, e.g. a lump of sugar or specific glucose tablets, energy gels or bars, marketed for diabetic patients. Moreover, both mild and severe hypoglycemia predisposes the patient to a condition known as hypoglycemic unawareness, which in turn means that hypoglycemia can occur more frequently and at any time of the day, due to attenuation of the typical warning symptoms of a declining blood glucose level, e.g. hunger, perspiration etc.

Notably, the incidence of hypoglycemia is rapidly increasing as diabetic patients seek better control of their blood glucose levels, in order to avoid hyperglycemia. An active life, involving exercise as prescribed for diabetics, also adds to the risk of hypoglycaemia unless the patient carefully controls his/her carbohydrate intake, insulin dosage and regularly monitors their blood glucose level.

Quite generally, it is known in the art to treat diabetic patients to diminish fluctuations in blood sugar levels and prevent hypoglycemic episodes using slowly absorbed or digested complex carbohydrates, such as native cornstarch.

Prior art

U.S. 6,316,427 discloses a method for improving tolerance in a human suffering from impaired glucose tolerance including both IGT and Diabetes Mellitus Type 2, comprising ingesting a therapeutic amount of slow-release starch at bedtime. The preferred type of starch for use in this method is natural cornstarch. Notably, the HbAI c value was recorded in this study and no changes recorded.

Axelsen et al. (Am J Clin Nutr, 2000; 71 :1108-14) found that bedtime ingestion of slow-release carbohydrates leads to sustained nocturnal fatty acid suppression and improved glucose tolerance in Type 2 diabetic patients. While fasting blood glucose concentrations improved, there were no improvements in HbAIc.

WO 02/34271 discloses how dysglycemia is treated and/or prevented by the administration of granulated starch, enzymatically degraded and releasing reducing sugars at a rate, adjusted to the metabolism of the patient, suffering from dysglycemia. For instance nocturnal hypoglycaemia in diabetic patients is prevented by administering to said patients a pharmaceutical preparation in granulate or tablet form, said preparation comprising granulated cornstarch and a low calorie sweetener. The inventive granulation minimises the available surface area and retards the enzymatic degradation of the cornstarch and ensures a controlled, substantially linear release of reducing sugars, such as glucose, and results in a stable blood glucose level during several hours. Said pharmaceutical preparation, whether in granulate or tablet form, is low in calories and contains no free sugar.

One aim underlying the present invention is to make it possible to improve the long-term glycemic control in diabetic subjects, and in particular to lower and possibly to maintain a normal HbAI c level. Further aims, objectives as well as problems underlying the invention, and the solutions provided, will become evident from the following description, examples and claims.

Summary of the invention

The present inventors have surprisingly found that long-term treatment with a granulated starch composition results in a significant lowering of the HbIAc value, indicating that blood glucose fluctuations can be minimized, and in particular that hyperglycemic episodes are significantly reduced.

This finding has now been confirmed in a clinical trial, commenced during the priority year. Interim results, based on data from 49 patients, observed for hypogycaemic episodes during a total of 281 nights, indicate that a treatment regime according to the present invention is safe and effective to prevent or at least significantly reduce the incidence of nocturnal hypoglycaemia. Further, the interim results indicate that no unacceptable increase in HbAIc was recorded for any single patient, and that the HbAIc on average was stable or reduced. The results are truly surprising, as it could be expected that the administration of a considerable amount of excess carbohydrates at bedtime would lead to increased fluctuations of blood glucose, and therefore have an unwanted effect on the long term management of diabetes, measured as the HbAIc value.

Consequently, the inventors make available a method, a pharmaceutical composition, as well as the use of granulated starch for the manufacture of a pharmaceutical product as defined in the attached claims, incorporated herein by reference.

Detailed description

Before the present invention is described, it is to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

Definitions

The term "lowering" when used in the context of "lowering the HbAIc value" is intended to include any measurable lowering, as even small reductions in HbAIc are know to give a health benefit in the long term management of diabetes. Thus, already a lowering of the HbAIc by 0.1 % may be significant for the patient. Further, considering that diabetes is a lifelong condition, the effects of even a small reduction may accumulate, resulting in improved health.

The term "stabilization" is intended to include keeping the HbAIc value constant, at a given value or within a given interval, or to reduce and minimize fluctuations.

The expression "reducing and/or preventing" as used in "reducing and/or preventing nocturnal hypoglycemic episodes" means a reduction of at least 10 %, preferably at least 20 %, and most preferably at least 30 %, of the incidence of nocturnal hypoglycemic episodes during the observation period.

The expression "strict insulin regimen" is used as understood by a skilled person, meaning that the patient monitors their blood glucose level regularly, e.g. four times daily, and that the insulin dose is adjusted depending on measured value, the intake of food, activity the patient engages in, and other factors. One aim of such "strict insulin regimen" is to keep the blood glucose level within 5 - 7 mmol/l at all times.

Near normalization of blood glucose levels in diabetes is associated with around 50% less risk of nephropathy and retinopathy. However, the aim of normalizing the blood glucose levels is tempered by the risk of inducing hypoglycemia and severe hypoglycemia is 4-5 times increased in patients with near-normal blood glucose levels. A majority of these episodes occur during sleep. Nocturnal hypoglycemia represents a particularly threatening condition to the patient. At daytime, it is possible for the patient himself, or people in close proximity, to recognize and treat the early warning symptoms. At nighttime, however, when the patient is asleep hypoglycemia is usually not enough to awaken the patient. Therefore an initially mild hypoglycemic episode may easily progress into a severe episode at a time when assistance may not be available.

The causes of hypoglycemia may be summarized into a few key-determining factors. Commercial basal insulin formulations do not provide a constant and reliable insulin supply. Neither is food consumed in a standardized and consistent manner. Moreover, the nocturnal insulin effect peaks around 2-4 am, a time when the dietary glucose is absorbed and the risk of hypoglycemia is at its greatest. Lowering the insulin dose is not a practical alternative because of the loss of blood glucose control on the following day. In contrast, a dietary therapy that provides a 'timed' nocturnal glucose delivery may balance an excessive insulin effect without distorting blood glucose levels the following day. Different snacks have been tested when exploring the options to optimize the nocturnal glucose delivery. Normal snacks, such as bread or milk, produce a peak in glucose delivery around 1-1.5 hours after ingestion. Such a snack provokes early hyperglycemia without protecting against hypoglycemia after midnight. A solution appears to have been found in the use of particular starches characterized by a slow rate of glucose delivery. Native cornstarch has a peak glucose delivery at about 4 hours. Cornstarch as such has been used to avert nocturnal hypoglycemia in young children with glycogen storage disease. Cornstarch has also been tested in Type 1 diabetic children. The comparison with a normal snack was clearly in favor of the cornstarch regimen with regard to averting nocturnal hypoglycemia. In 1999, Axelsen et al. (J Internal Med, 1999; 245(3):229-36) showed that cornstarch consumption at bedtime led to a reduced number of hypoglycemic episodes at 3 am by 70% in Type 1 diabetic adults.

The study product is a formulated complex carbohydrate providing a delayed release of glucose. The composition and manufacturing is the subject of earlier patent applications, WO 02/34271 , published on May 2, 2002, and WO 03/070148, published on August 28, 2003.

A phase II, double blind, placebo controlled, crossover study was recently conducted in 60 Type 1 diabetic subjects to study the effects on nocturnal hypoglycemia of different doses (5 g, 10 g and 20 g) of a granulated starch product made in accordance with the above patent applications (Unpublished results, Metcon Medicin AB, Study GLU-004). The aim was to further optimize nocturnal glucose delivery to provide a 'timed¹ and effective prophylaxis for nocturnal hypoglycemia to persons with diabetes. The results from this study showed a dose-related reduction in the number of nights with biochemical hypoglycemia.

However, scarce data on the long term effects were available, and a further study was initiated during the priority year (Unpublished data, Metcon Medicin AB, Study GLU-005). The rationale for the present study was to systematically assess the effects of a long-term treatment (eight weeks) with a granulated starch product as prophylaxis for nocturnal hypoglycemia in insulin treated Type 1 diabetic subjects.

The present inventors make available a method for improved long-term control of blood glucose in a diabetic patient, the improvement measured as as one of

- a lowering of the HbAI c value of said patient compared to the HbAIc value recorded before the treatment commences,

- the stabilization of the HbA1 c value at a value typical for healthy patients or patients with well-managed diabetes, or

- a lowering of the HbA1 c value compared to a HbA1 c value indicative of potentially harmful variations in blood glucose,

wherein a therapeutic amount of starch is ingested. Alternatively, the improvement is defined as reducing and/or preventing nocturnal hypoglycemic episodes, and the therapeutic amount of starch is ingested at bedtime.

The inventive method is very advantageous when said diabetic patient is on insulin medication, particularly when said diabetic patient follows a strict insulin regimen.

The inventive method is advantageously applied to patient suffering from diabetes mellitus type 1 or diabetes mellitus type 2.

The starch may be any starch from cereals, legumes or tubers, such as potato starch or cornstarch. According to one embodiment of the invention, the starch is native cornstarch, preferably granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

The starch is preferably given at bedtime, in a dose in the interval of about 100 mg/kg body weight to about 500 mg/kg body weight. A suitable dose for an adult is thus in the interval of about 5 to about 50 g depending on the body weight of the patient, more preferably about 10 to about 40 g, and most preferably about 20 to about 30 g.

The present inventors also make available a composition for improved long- term control of blood glucose in a diabetic patient, the improvement measured as one of

- a lowering of the HbAIc value of said patient compared to the HbAIc value recorded before the treatment commences,

- the stabilization of the HbAIc value at a value typical for healthy patients or patients with well-managed diabetes, or

- a lowering of the HbAIc value compared to a HbAIc value indicative of potentially harmful variations in blood glucose,

wherein said composition consists essentially of a therapeutic amount of starch. In the alternative, the improvement is defined as reducing and/or preventing nocturnal hypoglycemic episodes.

As above, the starch may be any starch from cereals, legumes or tubers, such as potato starch, corn starch and the like. According to an embodiment of the invention, the starch is preferably native cornstarch, most preferably granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

According to an embodiment of the invention, the composition consists essentially of granulated native cornstarch, a low calorie sweetener, an organic acid and conventional, pharmaceutically acceptable adjuvants.

The present inventors also suggest the use of starch for the manufacture of a pharmaceutical product for improved long-term control of blood glucose in a diabetic patient, the improvement measured as one of - a lowering of the HbAIc value of said patient compared to the HbAIc value recorded before the treatment commences,

- a lowering of the HbA1 c value compared to a HbA1 c value indicative of potentially harmful variations in blood glucose.

In the alternative, the pharmaceutical product is a product for reducing and/or preventing nocturnal hypoglycemic episodes in diabetic patients. Both are particularly advantageous for patients taking insulin medication, and most advantageous when said diabetic patient follows a strict insulin regimen.

As above, the starch may be any starch from cereals, legumes or tubers, and is preferably native cornstarch, most preferably granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

The pharmaceutical product is preferably produced and packed in the form of a dose granulate, as tablets, cakes or bars, suitable for administration, including self-administration, in a dose in the interval of about 100 mg/kg body weight to about 500 mg/kg body weight. A suitable dose for an adult is thus in the interval of about 5 to about 50 g depending on the body weight of the patient, preferably about 10 to about 40 g, and most preferably about 20 to about 30 g. The product according to the invention can be manufactured in the shape of a cake or bar, having a total weight of 50 g and having notches or kerfs, making it possibly to easily and accurately divide the cake or bar into subunits of 10 g.

Examples

The efficacy of a granulated starch composition was tested as prophylaxis for nocturnal hypoglycemia in insulin treated Type 1 diabetic subjects. A double blind, randomized, placebo-controlled phase Il multi-center study in three parallel arms was set up.

General

The study was randomized, double-blinded and placebo-controlled, utilizing approximately 15 clinics in Sweden to provide a target of 150 randomized subjects equally distributed in three parallel arms to be treated for eight weeks. The study assesses the efficacy of granulated starch in daily doses of 2Og and 3Og as prophylaxis for nocturnal hypoglycemia in insulin treated subjects with Type 1 diabetes. The duration of each subject's involvement in the study was 11 weeks, including seven visits at the clinic.

Subjects were screened for eligibility and entered the run-in period with placebo treatment. Eligible subjects will receive placebo treatment for 3 weeks in order to assess compliance with treatment instructions.

At the second visit, three days before the randomization visit, a compliance check was performed. For subjects with at least 80% compliance during run-in, a sensor to a continuous glucose measurement system (a commercial CGMS unit, Medtronic MiniMed Inc., Northridge, CA, USA) was placed on the back of the hip and samples of the interstitial fluid constantly sampled from the tissue and analyzed automatically on-line during three consecutive days. The results were entered into a data logger and downloaded to a computer at the randomization visit.

Eligible subjects were randomized at visit 3 to treatment with either one of two doses (2Og, 3Og) of granulated starch or placebo. The subjects took the study product as a single oral dose every evening at 10 p.m. for eight weeks.

The subject visited the clinic three times after start of study treatment. At visit 5 (7 weeks plus 4 days after start of treatment) B-glucose monitoring by CGMS as described above was performed. The results were entered into a data logger and downloaded to a computer at the next hospital visit. A diary was used by the subjects for recording the study drug intake, symptoms of hypoglycemia and blood glucose concentration (HemoCue® B-Glucose Analyzer, Hemocue AB, Angelholm, Sweden). The time for food intake and type of food taken to cure the hypoglycemic event were also recorded in the diary.

Female subjects were not allowed in the CGMS sampling period 3-4 days before expected start of menstruation. The study visits were scheduled so that measurements during these days could be avoided.

The subjects were instructed to maintain their normal routines during the whole study (e.g. extent of exercise, use of alcohol and tobacco). They were also instructed to maintain the same time points for food intake during the whole study and to maintain fixed insulin regimens.

The subjects were informed that the insulin dose may be changed if there is an obvious risk for hypoglycemia, but that any change in insulin dose and the reason for it must be registered in the case report form. The subjects were also requested to bring the empty medication bags and any possible unused product to the clinic at the third and fifth visits.

Inclusion criteria: Age >20 to <65 years; Informed consent given; Type 1 diabetes, treated with short acting insulin (including insulin analogues) and or intermediate- and or long acting insulin (including insulin analogues); A history of hypoglycemic events, i.e. subjects who regularly (at least 4 times/month during the last 3 months) experience blood glucose < 3.0 mmol/L; Duration of diabetes >3 years; HbA_1c < 8.0 %; C-peptide < 0.20 nmol/L; BMI > 19 to < 30 kg/m². For the HbAIc analysis, see Jeppsson et al., Approved IFCC reference method for the measurement of HbA1 c in human blood, Clin Chem Lab Med. 2002 Jan;40(1 ):78-89.

Exclusion criteria: Clinically significant symptoms of autonomic neuropathy experienced by the subject; Untreated proliferative retinopathy; Nephropathy (creatinine > 150 μmol/L); Use of medication known to influence gastrointestinal motility (currently or during past 4 weeks); Untreated hypertension (systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 95 mm Hg); Cardiac insufficiency (severity grade Il or higher according to NYHA); Ischemic heart disease (severity grade Il or higher according to NYHA); Pregnancy or lactation; Increased liver enzymes (ASAT or ALAT or alkaline phosphatase or bilirubin 2 times above the upper reference value); Suspected alcohol or drug abuse; Inability to understand information or comply with the study procedures; Participation in another clinical intervention study within 30 days prior to screening; Gastrointestinal inflammatory diseases including celiac disease; Untreated hypothyreosis (diagnosed by TSH assay).

The primary objective was to assess the efficacy of a granulated starch composition in doses of 2Og and 3Og compared to placebo as prophylaxis for nocturnal hypoglycemia in insulin treated Type 1 diabetic subjects with a history of biochemical hypoglycemic events.

Related objectives were to assess the change from baseline in HbA-ic after eight weeks treatment with the granulated starch composition compared to placebo, as well as to assess the difference in HbAIc between granulated starch and placebo treated subjects after eight weeks of treatment.

Also assessed was the change from baseline in the lipid profile (cholesterol LDL and HDL cholesterol, triglycerides and apoproteins Ai and B) of subjects treated with granulated starch compared to placebo. In this context, also the difference in lipid profile between granulated starch and placebo treated subjects after eight weeks of treatment was assessed.

One parameter was the number of nights (11 p.m.-7 a.m.) with at least one biochemical hypoglycemia event (B-glucose < 3.0 mmol/L) as measured by CGMS during two periods, each consisting of three consecutive nights, in the second and seventh weeks of treatment with granulated starch or placebo. A blood glucose level at or below 3.0 mmol/L is a generally accepted definition of hypoglycemia. The number of nights with biochemical hypoglycemia is considered as a relevant clinical endpoint.

Further, the B-glucose level was assessed in the fourth and eight weeks of treatment with granulated starch or placebo as follows: before breakfast (6 a.m. to 10 a.m.); after breakfast; before lunch; and after lunch.

Glycated fraction of haemoglobin (HbAic): A total amount of 9 ml_ blood was drawn at 0, 4, 8 and 12 weeks for analysis of HbAic. This test reflects the average blood glucose level during the past approximately 4 to 6 weeks. The analysis was performed at one central laboratory using the IFCC reference method (Jeppsson et al., supra).

Blood glucose: The subject performed daily blood sugar measurements at home using a HemoCue® blood glucose meter. During weeks 1-8 the patients recorded seven daily blood glucose measurements on two days of each week, out of which one day being a working day. The following glucose measurements were performed: Glucose level before breakfast (6 - 10 am); Glucose level before lunch; Glucose level before dinner; Postprandial glucose peak at breakfast (30 minutes after); Postprandial glucose peak at lunch (30 minutes after); Postprandial glucose peak at dinner (30 minutes after); and Glucose level at bedtime. The values were recorded in the subject diary.

During run-in and after seven weeks + 4 days the blood glucose was monitored during three consecutive nights using a commercially available continuous blood glucose monitoring system (CGMS) from Medtronic's MiniMed®. The user instructions from the manufacturer were applied in this study.

A sensor to the CGMS was placed to the back of the hip at the clinic and samples of the interstitial fluid were constantly sampled from the tissue and analyzed automatically on-line. The data from the HemoCue® were entered into the CGMS as calibration values. The results were entered into a data logger and downloaded to a computer at the following hospital visit. Lipid analysis: Blood samples for lipid analyses and apoproteins Ai and B were collected at visit 1 , 3 and 6. A total amount of 12 mL of blood was drawn during the study for these assessments. All laboratory samples were analyzed at a central hospital laboratory using a common routine for all centers. Subjects had to fast for at least 8 hours and were seated for at least 5 minutes before blood samples are taken for lipid assays. The following variables were measured: P- Triglycerides; S-Cholesterol; S-HDL-Cholesterol; S-LDL-Cholesterol; S- Apoprotein A-i; and S-Apoprotein B.

Routine analysis: Blood samples for routine biochemistry analyses were collected at visit 1 , 3 and 6. A total amount of 12 mL of blood was drawn during the study for these assessments. All laboratory samples were analyzed at the hospital laboratory using the hospital's standard routines.

The following safety variables were measured: B-glucose; B-hemoglobin; B- leukocytes; B-throm oocytes; P-sodium; S-potassium; S-bilirubin; S-alkaline phosphatase; S-creatinine (used to verify eligibility); S-ASAT; S-ALAT; S-C- peptide (used to verify eligibility); and S-TSH

Packaging, labeling and storage: Both the granulated starch product and placebo were manufactured by Boots Manufacturing, Nottingham, United Kingdom. The packaging and labeling of the granulated starch product and placebo, as well as the distribution to the local pharmacies was the responsibility of Apoteket AB, Produktion & Laboratorier, Stockholm, Sweden. The granulate and placebo was packed in plastic bags. Both the drug and the placebo were stored at a temperature between +15°C and +30°C.

First visit - Recordation of basic data, information to the subjects

Demographic data, height, weight, maximum waist circumference, diabetes history (age at onset, duration of diabetes), concomitant medication and the medical history was recorded and a physical examination performed. Vital signs (systolic/diastolic blood pressure and heart rate) in the sitting position were measured and recorded. By asking the subject to rise from a lying to a standing position any possible postural hypotension was assessed. The maximum acceptable decrease in the systolic blood pressure 20 mmHg.

Fasting blood was collected for biochemistry analyses. The diagnosis diabetes type 1 is confirmed by the C peptide value < 0.20 nmol/L, i.e. the detection limit of the assay method used, if the diagnosis has not been confirmed and documented previously

The tested granulated starch was distributed as a dry granulate, and the subjects instructed to suspend the granulate in 2-2,5 dl of water and take it at 10.p.m, preferably at the same time as the bedtime insulin.

The reason for the run-in period was to assess compliance with treatment instructions and assessments performed at home prior to randomisation and start of active study treatment. Any changes in concomitant medication and medical status were recorded and placebo treatment for four weeks will be dispensed.

A diary for recording of study drug intake, symptoms of hypoglycemia at any time of the day, blood glucose concentration (HemoCue®, supra) and food taken to cure the hypoglycemic event, was given to the subject.

Second visit - Compliance check and 2^nd week CGMS reading

This visit was scheduled in the afternoon, since the initiation of the CGMS in the afternoon was believed to increase the possibility of having a successful CGMS recording the third night.

Compliance with study drug intake was assessed based on recordings in the subject diary and by examining the returned plastic bags and, if applicable, unused study medication. Subjects with less than 80% compliance were not randomized to treatment with study medication. No further assessments will be performed for these subjects. For subjects with at least 80% compliance with the run-in medication, a CGMS sensor (MiniMed®, supra) was placed on the back of the hip by a trained staff and the subject will be carefully instructed by the study personnel how to use the continuous blood glucose monitor. The user instructions from the manufacturer were followed during the study. CGMS was performed during three consecutive nights of week 2.

Any changes in concomitant medication and medical status were recorded.

Third visit - Randomization

This visit was scheduled in the morning. A fasting blood sample including HbAIc was obtained. The inclusion and exclusion criteria were confirmed. Eligible subjects were given the lowest available subject number and are thereby randomized to treatment with either one of two doses of granulated starch (2Og or 3Og) or placebo.

The subject diary was collected and checked for completeness. Data from the CGMS monitor was downloaded into a local computer on the investigational site. Any changes in the concomitant medication since last visit were recorded and the subjects asked about the occurrence of any adverse events since the screening visit.

Vital signs (systolic/diastolic blood pressure and heart rate) in the sitting position were measured and recorded.

A new diary for recording of study drug intake, symptoms of hypoglycemia at any time of the day, blood glucose concentration (HemoCue®, supra) and food taken to cure the hypoglycemic event, was given to the subject.

Study drug for three weeks treatment at home was dispensed. The subject was instructed to suspend the granulate in 2-2,5 dl of water and take it at 10 p.m, preferably at the same time as the bedtime insulin. Fourth visit

The subject diary was collected and checked for completeness. Treatment compliance was assessed by examining the returned plastic bags and, if applicable, unused study medication.

Vital signs (systolic/diastolic blood pressure and heart rate) in the sitting position and body weight was measured and recorded.

The subject will be asked about the occurrence of any adverse event since last visit. All reported adverse events and any changes in concomitant medication were recorded.

Study drug for five weeks was dispensed, and a new diary given to the subject for recording of study drug intake, symptoms of hypoglycemia at any time of the day, blood glucose concentration (HemoCue®, supra) and food taken to cure the hypoglycemic event.

Fifth visit

The subject diary was collected and checked for completeness. Treatment compliance will be assessed by examining the returned plastic bags and, if applicable, unused study medication. A new diary handed out for recording of study drug intake, symptoms of hypoglycemia at any time of the day, blood glucose concentration (HemoCue®) and food taken to cure the hypoglycemic event

Vital signs (systolic/diastolic blood pressure and heart rate) in the sitting position and body weight were measured and recorded. A CGMS sensor was placed on the back of the hip by a trained staff and the subject will be carefully instructed by the study personnel how to use the continuous blood glucose monitor. The user instructions from the manufacturer ware applied during the study. CGMS was performed during three consecutive nights.

The subject was asked about the occurrence of any adverse event since last visit. All reported adverse events and any changes in concomitant medication were recorded.

Sixth visit - end of study

The visit was scheduled in the morning since fasting blood samples were collected. Data from the MiniMed® monitor were downloaded into a local computer on the investigational site. Vital signs (systolic/diastolic blood pressure and heart rate) in sitting position and weight will be measured and recorded.

Blood was collected for biochemistry analyses. The subject diary was collected and checked for completeness. Treatment compliance was assessed by examining the returned plastic bags and, if applicable, unused study medication.

Follow-up call

The investigator/study nurse called the subject by phone 30 days after the end of the study treatment to secure information regarding adverse events that might have occurred since the last dose of study treatment. All adverse events reported were recorded. Results

Before the international filing date, interim results from 49 patients were available. The study was conducted as disclosed above. The patients were observed for hypogycaemic episodes during a total of 281 nights. The results, although preliminary, clearly indicate that a treatment regime according to the present invention is safe and effective to prevent or at least significantly reduce the incidence of nocturnal hypoglycaemia. Further, the interim results showed that no unacceptable increase in HbAIc was recorded for any single patient, and that the HbA1 c on average was stable or reduced. The study is therefore to be continued, until the planned amount of subjects have been reached.

The patients had no dietary restrictions during the study, and the starch was thus taken in addition to any other food or snacks, normally ingested by the patient. This makes the results even more surprising, as it could be expected that the intake of a considerable amount of excess carbohydrates at bedtime would lead to increased fluctuations of blood glucose, and therefore have an unwanted effect on the long term management of diabetes, measured as the HbAIc value.

Discussion

Hb1A1c reflects long-term glycemic control, but has in previous studies not been systematically evaluated. It would moreover be expected that additional carbohydrates, such as the granulated starch product, leads to increased HbAIc levels. This logical expectation explains that previous studies contain statements along the lines that "HbAIc was not adversely influenced". The finding that HbAIc was instead significantly lowered, and stabilized at a lower level, is therefore truly surprising.

A majority of hypoglycemic events occur during sleep when the symptoms may not be enough to awaken the subject. Incidents of only slight hypoglycemic states have therefore not been properly recorded previously. Hyperglycemic states, often not associated with immediately noticeable symptoms, are likely to have passed unobserved to an even larger extent. In the evaluation of long- term glycemic control, the inclusion of HbAIc as a parameter was an important choice, making it possible to study the true glycemic control without relying on subjective assessment or blood glucose measurements, which fail to give the entire picture.

It can be expected that the recorded lowering of HbAIc would be even greater during a longer study period, e.g. after treatment over a period of 6 - 12 months. It is not unlikely that a longer treatment using the granulated starch product would lead to the HbAIc value approaching the normal interval associated with non-diabetic persons. It is speculated that a normalization of the HbAI c in diabetic patients would be an indication that the damaging fluctuations in blood glucose, typical for diabetic patients, were substantially avoided. This means that the method of administering a granulated starch product essentially simultaneously with the evening insulin would be a promising long-term treatment, avoiding many of the complications of diabetes.

In the present study, the patients were observed for 8, and in some cases 12 weeks. The results give reason to assume that the positive effects would become even more accentuated over long treatment periods, and that this would be an effective, yet safe life long treatment.

In summary, granulated starch taken in a consistent manner has been shown to optimize nocturnal glucose delivery and provide a 'timed' and effective prophylaxis for nocturnal hypoglycemia, and at the same time, a simple and effective treatment to stabilize and even reduce HbAIc values in diabetic patients.

The inventive method and composition is expected to be very advantageous in the treatment of diabetes following a strict insulin regimen, as the side effects of a stricter insulin regimen can be significantly reduced or avoided. The combined administration of a slow-release starch product and insulin will make it possible to achieve an improved glucose control with only minor fluctuations, no discomfort to the patient, and improved long term health.

Although the invention has been described with regard to its preferred embodiments, which constitute the best mode presently known to the inventors, it should be understood that various changes and modifications as would be obvious to one having the ordinary skill in this art may be made without departing from the scope of the invention which is set forth in the claims appended hereto.

Claims

1. The use of starch for the manufacture of a pharmaceutical product for improved long-term control of blood glucose in a diabetic patient, the improvement measured as one of

- a lowering of the HbA1 c value of said patient compared to the HbA1 c value recorded before the treatment commences,

- the stabilization of the HbAIc value at a value typical for patients with well- managed diabetes, or

- a lowering of the HbAIc value compared to a HbAIc value indicative of potentially harmful variations in blood glucose.

2. The use of starch for the manufacture of a pharmaceutical product for improved long-term control of blood glucose in a diabetic patient taking insulin medication, the improvement measured as one of

3. The use of starch for the manufacture of a pharmaceutical product reducing and/or preventing nocturnal hypoglycemic episodes in diabetic patients.

4. The use of starch for the manufacture of a pharmaceutical product reducing and/or preventing nocturnal hypoglycemic episodes in diabetic patients on insulin medication.

5. The use according to any one of claims 1 - 4, wherein said diabetic patient follows a strict insulin regimen.

6. The use according to any one of claims 1 - 5, wherein the starch is from a cereal, tuber or legume plant.

7. The use according to any one of claims 1 - 5, wherein the starch is one of potato starch and cornstarch.

8. The use according to any one of claims 1 - 5, wherein the starch is native cornstarch.

9. The use according to any one of claims 1 - 5, wherein the starch is granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

10. The use according to any one of the claims above, wherein the dose of starch is in the interval of about 100 mg/kg body weight to about 500 mg/kg body weight, given at bedtime.

11. A composition for improved long-term control of blood glucose in a diabetic patient, the improvement measured as one of

- the stabilization of the HbA1 c value at a value typical for patients with well- managed diabetes, or

wherein said composition consists essentially of a therapeutic amount of starch.

12. The composition according to claim 11 , wherein the improvement is defined as reducing and/or preventing nocturnal hypoglycemic episodes.

13. The composition according to claim 11 , wherein the starch is from a cereal, tuber or legume plant.

14. The composition according to claim 11 , wherein the starch is one of potato starch and cornstarch.

15. The composition according to claim 11 , wherein the starch is native cornstarch.

16. The composition according to claim 11 or 12, wherein the starch is granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

17. The composition according to claim 14, consisting essentially of granulated native cornstarch, a low calorie sweetener, an organic acid and conventional, pharmaceutically acceptable adjuvants.

18. A method for improved long-term control of blood glucose in a diabetic patient, the improvement measured as one of

wherein a therapeutic amount of starch is ingested.

19. The method according to claim 18, wherein the improvement is defined as a reduction of the incidence of or a prevention of nocturnal hypoglycemic episodes, and the therapeutic amount of starch is ingested at bedtime.

20, The method according to claim 18, wherein said diabetic patient is on insulin medication.

21, The method according to claim 18, wherein said diabetic patient follows a strict insulin regimen.

22. The method according to any one of claims 18 - 21, wherein said diatβtic patient suffers from diabetes mellitus type 1.

23. The method according to any one of claims 18 - 21 , wherein said diabetic patient suffers from diabetes mellitus type 2.

24. The method according to any one of claims 18 - 21 , wherein the starch is from a cereal, tuber or legume plant.

25. The method according to any one of claims 18 -21 , wherein the starch is one of potato starch and cornstarch.

26. The method according to any one of claims 18 -21, wherein the starcπ is native cornstarch.

27. The method according to any one of claims 18 - 21 , wherein the starch is granulated native cornstarch, having a reduced surface available for enzymatic degradation, which granulation delays said enzymatic degradation of the starch into reducing sugars.

28. The method according to any one of claims 18 - 21, wherein the starch is given in a dose in the interval of about 100 mg/kg body weight to about 50I) mg/kg body weight, given at bedtime.