Open randomised prospective comparative multi-centre intervention study of patients with cystic fibrosis and early diagnosed diabetes mellitus

The primary objective of this trial is to compare the glycaemic control on oral therapy with repaglinide tid with that on insulin therapy with three daily injections of regular Insulin over 2 years in patients with CF and CFRD.

The secondary objectives of this trial are to compare the two treatment regimen (oral therapy with Repaglinide and insulin therapy with regular insulin) in terms of efficacy and safety.

The efficacy objectives are change in glycaemic control after 12 months of treatment, glycaemic control assessed by glucose profile done monthly (6 values), change in nutritional status and pulmonary function at 12 and 24 months, as well as the need for antibiotic treatments.

The safety objectives are the incidence and quality (mild, severe, other) of hypoglycaemic episodes and adverse events.

The Mukoviszidose Institut gGmbH is the sponsor for this trial. Collaborators are Novo Nordisk, Mucoviscidose-ABCF2, Vaincre la Mucoviscidose and Assistance Publique - Hôpitaux de Paris. The protocol and all trial documents have been approved by the ethic committees responsible for the respective trial sites. The first vote was received from the ethical committee of the MHH Hannover (22.08.2001, No. 2739). The responsible competent authorities gave approval (so far applicable) under EudraCT Number 2006-001254-27 [for France and Italy], BfArM Number 4019636 [for Germany] and BMSG Number 21.405/219 [for Austria]. The trial was public registered under ClinicalTrials.gov Identifier NCT00662714.

Informed consent was to be obtained before any trial-related activities. CF was diagnosed by positive sweat test and/or two disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations. Patients had diagnosed diabetes mellitus by OGTT done less than six months before (one year before in Italy). The subjects were over 10 years of age (12 years in France and Italy). Diabetes was confirmed by a second OGTT test. Patients in France needed in addition fasting blood glucose levels ≤170 mg/dl. Patients have been excluded with diagnosis of type 1 diabetes or diabetic keto-acidosis (blood glucose > 350 mg/dl and arterial pH < 7.25). Already treated diabetes mellitus by oral antidiabetic medication or insulin led to exclusion of these patients. Severe pulmonary insufficiency with FEV1 < 25% (France and Italy) or < 40% (Germany and Austria), participation in another clinical trial less than one month before inclusion in this trial, severe liver insufficiency or PEG/gastric tube/total parenteral nutrition for more than 4 weeks were not at inclusion. Patients must not be pregnant and in France and Italy breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures were not allowed. Patients after transplantation or in France patients which have been planned for transplantation could not be included. For Germany subjects receiving concomitant medication known to interfere with repaglinide therapy were not included. In France and Italy proliferative retinopathy, type 2 diabetes, severe renal insufficiency, history of alcoholism, drug abuse, psychiatric disease or personality disorders likely to invalidate voluntary consent or to prevent good compliance with the trial protocol, legal incapacity or limited legal capacity, known or suspected allergy to the insulin or any compositional component, known or suspected allergy to repaglinide or receiving concomitant medication known to interfere with glucose metabolism prevented inclusion in this trial.

In all CF-patients 10 years or older, an oral glucose tolerance test (OGTT) following standard WHO recommendations has be performed. Oral medication was postponed until after the test, however, inhalation therapy could be performed prior to the test. During acute infections or exacerbations of a chronic infection, the test was postponed for 3 to 4 weeks until acute symptoms improved. OGTT were classified as normal glucose tolerance, impaired glucose tolerance/impaired fasting glucose or diabetes mellitus according to the WHO cut off values [6].

After detailed information by the physicians of the local CF centre, the patient or legal guardian decided to give written informed consent to participate in the study. The trial was open-labelled in order to avoid use of double-dummy technique which would have required an unacceptable increase in the number of injections for the patients. The patients were allocated to the treatment regimen according to a randomisation list generated by a geigy random number table by central fax randomisation. Stratification was conducted according to gender and two age groups (10–15 years, >15 years). Every randomised patient should have been observed for at least 2 years and be included in the final analysis (“intention-to-treat” analysis).

The trial procedures are summarised in the following Table 1.

Insulin therapy should have been conducted by three injections of Regular Insulin, each time immediately before the main meals. With asymptomatic patients, therapy should begin with 0.05 units per kg weight and injection. The dose was adjusted with regard to postprandial (2 hours after meal) glucose levels: The dose should be adjusted by about 10–20%, approximated to full or half units (see Figure 2). Patients injected insulin using insulin pens.

During the adjustment phase, up to 6 blood glucose measurements were recommended (each pre- and postprandial). After a stable metabolism adjustment was attained, this number could have been reduced individually; however, every postprandial level had to be checked once a week. 3 daily measurements were the minimum, especially when using higher insulin doses (>0.3 units/kg and day). Patients with varying blood glucose levels should have been educated about blood glucose corrections based on body weight and insulin demand. If the absorbable carbohydrate content of meals changed significantly on a daily basis, then a separate carbohydrate exchange unit factor for every meal based on pre- and postprandial measurements had to be determined.

For insulin therapy of CF patients, conventional schemes (1–2 injections a day, fixed or varying mixtures of regular- and NPH-insulin) are advocated as well as intensified therapy schemes with 3, 4 or more injections and flexible adaptation of insulin doses to the expected food intake and the measured blood glucose level [9]. The study described here aimed at CF patients who have been diagnosed early, thus making an intensified therapy scheme unnecessary. In the case of type 2-therapy, which shows some parallels to CFRD, recent years have shown a development away from doses of premixed insulin with high NPH contents and towards pre-prandial doses of regular insulin [10]. Most CF diabetes patients show very high postprandial blood glucose levels, whereas fasting values and pre-prandial values remained normal for a long time. Therefore, a therapy of 3 regular insulin injections is advisable from a pathophysiological viewpoint. A dose of 3 injections a day for CF patients with an early diagnosis of diabetes mellitus appeared to be a viable compromise between the two aims – to apply a therapy scheme as simple as possible and to optimise a patient’s blood glucose levels at the same time.

All CF patients with newly diagnosed diabetes mellitus had to be educated intensively about food formulations, effects of food on blood glucose, blood glucose measuring, blood glucose documentation, risk of hypoglycaemia during therapy, treatment of hypoglycaemia, long-term effects of high blood glucose levels, and characteristics of diabetes mellitus with CF. Patients who have been randomised to insulin therapy had to be taught additionally about injecting, storage of insulin and dose adjustment.

Patients in both therapy strains hade to be monitored for 2 years; every 3 months, a standardised examination and documentation was intended.

No relevant short-term changes have been expected among early diagnosed patients, especially concerning weight development and lung function [11]. Evidence of successful diabetes therapy with an oral anti-diabetic stretching over 2 years was planned to show constitute clinically relevant results compared with a shorter duration.

The therapy in one of the therapy strains should have been considered ineffective if one of the following discontinuation criteria had been met: No acceptable metabolic control obtainable over a time span of 3 months regardless of dose adjustment according to protocol and therapy compliance; occurrence of non-tolerable undesired side effects under therapy; transaminase increase to 3 times the initial value; non tolerable allergic reactions; discontinuation of study by patient/family; se of systemic steroids necessary; desired or occurring pregnancy; PEG/nasal tube feeding/completely parental alimentation of at least 4 successive weeks or transplantation.

a. Insufficient metabolism control during therapy with repaglinide.

Generally, a shift to insulin would have been necessary; doses of 3 injections of regular insulin before meals were recommended. If fasting blood glucose levels had been high, an additional dose of intermediate/long-lasting insulin before going to sleep was advisable. A shift from repaglinide to glibenclamide would have make sense only if allergic reactions to repaglinide occurred. The use of other oral anti-diabetics could not be recommended based on current scientific knowledge.

b. Insufficient metabolic/glycaemic control during therapy with three injections of regular insulin.

Usually a standard intensified therapy of 4–5 injections a day was recommended.

Primary endpoint:

Primary endpoint was the change in HbA1c after 24 months of treatment.

Secondary endpoints:

Secondary endpoints were glycaemic control assessed by mean HbA1C and mean blood glucose profile; change in BMI-Z-score; change in FEV1% predicted and safety assessed by antibiotic therapy, incidence of adverse events, number of hypoglycaemic episodes, all symptomatic hypoglycaemia, hypoglycaemia that necessitates the help of other persons, hypoglycaemia with unconsciousness or coma and number of blood glucose levels below 50 mg/dl in relation to all blood glucose measurements.

Clinical on-site monitoring in all trial centres was done by personal visits of a clinical monitor according to standard operating procedures of the Interdisciplinary Centre for Clinical Trials (IZKS) Mainz starting 2008. The monitor checked the informed consent forms and reviewed the entries into the case report form (CRF) on the basis of source documents. The physician allowed the monitor access to at all essential documents and provides support to the monitor. The IZKS Mainz assisted the physician to conduct the study according to the protocol as well as to regulatory and ethical requirements.

University of Ulm conducted the data management of the trial. All protocol-required information collected during the study had been entered by the investigator, or a designated representative in the CRF. CRF data were entered by University of Ulm into the database. During the study, data were exported into the statistical analysis system and checked additionally for plausibility, consistency and completeness. Based on these checks, queries have been produced. Any missing data or inconsistencies were reported back to the respective site and clarified by the responsible investigator. After all corrections were done, the database was closed and used for statistical analysis. All collected data have been processed according to the German Data Protection Law and handled in strictest confidence.

Which number of patients was necessary to show a significant difference between therapy strains of 80% power on the one hand and p <0.05 on the other? Retrospective HbA1c data from a database of the CF centre at Medical School Hannover were used. Measurements of n = 132 HbA1c within the first two years after diabetes diagnosis of n = 44 patients older than 10 years at the date of diagnosis resulted in an average value of HbA1c = 5.6 ± 1.5 (average value ± SD). Within a similar group (older than 10 years) but without diabetes n = 763 measurements yielded an HbA1c of 4.6 ± 0.68 (average value ± SD). A difference of 1 (which is in the range of individual variations during treatment especially in youngsters and young adults) between therapy groups was considered relevant [12]. Calculation with n Query® of necessary patients for each group was done with these parameters: Two group t-test of equal means (equal n’s) 1; Test significance level, α 0,050; 2 sided test; Group 1 mean, μ₁ 5,600; Group 2 mean, μ₂ 4,760; Difference in means, μ₁ - μ₂ 1,000; Common standard deviation, σ 1,500; Effect size, δ = |μ₁ - μ₂|/σ 0,667; Power 80%. Based on the above assumptions the number of patients in each group was calculated as n = 37. Over a treatment time of 2 years, about 30% of patients were assumed to drop out of the study. Therefore, n = 111 patients have been necessary at the beginning of the study to ensure a number of n = 74 remaining patients at the end of the study.

1093 CF patients with no previous diagnosis of CFRD and age of 10 years or older were screened for eligibility by at least two valid OGTTs each. For 145 patients CFRD could be diagnosed [14]. The first patient was included on 13.03.2002 and the last patient on 01.12.2009. The analysis of trial data is ongoing.