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An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: The A1chieve study

Philip Home, Nabil El Naggar, Mohammed Khamseh, Guillermo Gonzalez-Galvez, Chunduo Shen, Praful Chakkarwar and Wenying Yang

Diabetes Research and Clinical Practice, Issue 3, Volume 94, pages 352 - 363

Received 20 September 2011, Revised 10 October 2011, Accepted 13 October 2011, Published online Nov-2011


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2. Methods

2.1. Study design

This was a 24-week, international, prospective, multicentre, non-interventional, observational study of people with T2D who had begun using basal insulin detemir (Levemir®, Novo Nordisk, Denmark), bolus insulin aspart (NovoRapid®, Novo Nordisk) and biphasic insulin aspart 30 (NovoMix® 30, Novo Nordisk), alone or in combination, to evaluate their clinical safety and effectiveness in routine clinical use outside the Western economies [23] x S.N. Shah, L. Litwak, J. Haddad, P.N. Chakkarwar, I. Hajjaji. The A1chieve study: a 60,000-person, global, prospective, observational study of basal, meal-time, and biphasic insulin analogs in daily clinical practice. Diabetes Res Clin Pract. 2010;88(Suppl. 1):S11-S16 Abstract, Full-text, PDF, Crossref. . The study was carried out in 3166 centres in 28 countries across Asia, Africa, Latin America and Europe, grouped into seven geographical regions: China; South Asia (Bangladesh, India, Pakistan); East Asia (Indonesia, Korea, Malaysia, Philippines, Singapore, Taiwan); north Africa (Algeria, Morocco, Tunisia, Libya); Middle East/Gulf (Egypt, Iran, Jordan, Turkey, Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE, Yemen); Latin America (Argentina, Mexico) and Russia. Participants were recruited between January 2009 and June 2010.

The insulin therapies were prescribed by a physician in the course of normal clinical practice, were commercially available and were funded according to local practice in normal routine care. Thus, the participant and advising physician determined the choice of insulin, the starting dose, administration frequency and any later changes to either dose or frequency. In the study, insulin analogues were used in accordance with the licensed approval from the local regulatory authority. Changes to OGLDs at the time of starting the insulin analogue, or thereafter, were entirely at the discretion of the participant and advising physician.

There were no defined study-related procedures; measurements were made by the treating physician team only as determined by normal clinical care. Thus, safety and effectiveness of therapy were determined from measurements made at usual clinic visits. Trial visits were defined as baseline, interim (around 12 weeks from baseline) and final (around 24 weeks from baseline) visit. Data were collected from the physicians’ clinical notes, and participants’ recall and self-monitoring diary/meter at each visit, as available. This information was transferred to a standard case report form (CRF).

2.2. Participants

A total of 66,726 people were included in the study. Any current and prior medications were acceptable for participant inclusion other than the insulin analogues being evaluated. Women who were pregnant, breast-feeding or had the intention of becoming pregnant were excluded. Ethics committee approval was obtained for each country, and signed informed consent from all participants. Participants were free to withdraw at will at any time. If they withdrew, the data collected were used for analysis until the point when consent was withdrawn. Safety events were reported according to the protocol. All investigators underwent specific training on the study protocol, CRF completion, informed consent and safety reporting procedures.

2.3. Assessments and outcome measures

The primary objective of this study was to evaluate the clinical safety of the insulin analogues by the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events, considered related to the study insulin between baseline and final visit. Secondary safety assessments were the change in number of hypoglycaemic events in the last 4 weeks before interim and final visits, compared with the last 4 weeks before baseline visit, the change in number of nocturnal hypoglycaemic events during these periods and the number of adverse drug reactions (ADRs) from baseline to final visit. Major hypoglycaemic events were defined as events with severe central nervous system symptoms, consistent with hypoglycaemia, for which the person was unable to self-treat, and accompanied by plasma glucose <3.1 mmol/L or 56 mg/dL, or reversal of symptoms after either food intake or glucagon or intravenous glucose administration. Minor hypoglycaemia was any event, with or without symptoms of hypoglycaemia, with a plasma glucose reading below 3.1 mmol/L or 56 mg/dL that the participant was able to self-treat. Nocturnal hypoglycaemia was defined as a symptomatic event consistent with hypoglycaemia that occurred during sleep between bedtime after the evening insulin injection and before getting up in the morning.

Efficacy assessments were change in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and body weight between baseline and interim and final visits, and change in systolic blood pressure (SBP) and lipid profile at final visit. All laboratory measurements were made in local laboratories and were thus subject to local standardisation and quality control procedures. Quality-of-life assessments were made at baseline and final visit, and are communicated in a separate report. The rationale for choosing each study insulin regimen was recorded, with the aim of determining which factors influence the selection criteria of the specific regimen.

2.4. Statistical methods

Analyses were performed for the entire cohort (all participants), for the entire cohort divided as prior insulin-treated or insulin-naïve, for the insulin analogue regimen used and by geographical regions (as above). As this was not a randomised trial, and as the characteristics determining choice of insulin regimen, time of starting insulin and concomitant medical conditions were not fully known, comparison between regimens, prior insulin use or not and regions is reported as a matter of observation only. The insulin regimens were defined as biphasic insulin aspart (premix) alone, insulin detemir alone, insulin aspart alone or insulin aspart with a basal insulin (this could include insulin detemir), or other. In each instance, the use or non-use of concurrent OGLDs was allowed.

The sample size was based on the number of people (20,000) exposed for 6 months required to confirm at 95% confidence a frequency of any one ADR of ≥15 events/100,000 person-years. This rate, for example, would detect a rate of major hypoglycaemia as reported in any published clinical trial. Analysis of all variables, including safety and efficacy outcomes, was performed using any participant entered into the study who had the data relevant to that analysis. Continuous variables were summarised using descriptive statistics and discrete variables were summarised using frequency tables (n, %). All statistical analyses were two-sided, using a pre-specified 5% significance level, unless otherwise stated. For hypoglycaemia change from baseline, the percentage of people reporting at least one event was analysed using Fisher's exact test. Prevalence data rather than incidence rate were tested as low event rates, in the circumstances where some people had recurrent events, could not be modelled in a statistically sensitive way. Change from baseline HbA1c, FPG, PPPG and blood lipids was analysed using an analysis of covariance (ANCOVA) model with baseline characteristics as covariates. The percentage of patients having HbA1c <7.0% at 24 weeks was analysed using a logistic regression model using the factors and covariates of treatment, country, region, age, gender, ethnicity, body mass index (BMI), duration of diabetes, smoking status, total blood cholesterol, high-density lipoprotein (HDL) cholesterol, SBP and pre-study glucose-lowering therapy. Corresponding baseline HbA1c was included as a fixed effect. All data were analysed by Novo Nordisk using SAS (Version 9.1.3).

References

Label Authors Title Source Year
[23]

References in context

  • This was a 24-week, international, prospective, multicentre, non-interventional, observational study of people with T2D who had begun using basal insulin detemir (Levemir®, Novo Nordisk, Denmark), bolus insulin aspart (NovoRapid®, Novo Nordisk) and biphasic insulin aspart 30 (NovoMix® 30, Novo Nordisk), alone or in combination, to evaluate their clinical safety and effectiveness in routine clinical use outside the Western economies [23].
    Go to context

S.N. Shah, L. Litwak, J. Haddad, P.N. Chakkarwar, I. Hajjaji The A1chieve study: a 60,000-person, global, prospective, observational study of basal, meal-time, and biphasic insulin analogs in daily clinical practice Abstract, Full-text, PDF, Crossref. Diabetes Res Clin Pract. 2010;88(Suppl. 1):S11-S16 2010

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