Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes therapies, Pharmacogenetics
Brief summary
This proposal is to fund a pilot study to assess feasibility and refine methodology for an intended large Scotland wide study on Response to Oral Agents in Diabetes (ROAD). The study will collect cohorts of patients who have carefully controlled standardised dose titration and monitoring with an assessment of drug response and side effects over a 6 month period. The primary aim will be to use these cohorts to investigate phenotypic and genotypic (pharmacogenetic) determinants of response. Drug naïve patients will be treated with Metformin. Patients who have failed on Metformin or are intolerant of Metformin will be randomised to gliclazide, pioglitazone or sitagliptin. With the ability to capture patient data beyond 6 months via data linkage we will monitor time to treatment failure and therefore compare which of the 3 oral agents is the best therapy to use after Metformin in a cost efficient and real world RCT.
Detailed description
The Response to Oral Agents in Diabetes (ROAD) study aims to address the limitations of observational data by creating a prospective study of incident users of oral agents. For the first six months the research team will ensure a protocol driven dose titration, standardised monitoring of adherence, response and side effects and standardised deviations from therapy. Thereafter patients will receive 6 monthly monitoring and further protocol led dose titration by the GP. Biochemistry, prescribing data, morbidity and mortality data will be captured for up to 10 years from drug initiation. The ROAD study will provide a highly powered prospective cohort to investigate phenotypic and genotypic determinants of response in its own right. However, this cohort will be used synergistically with ongoing observational pharmacogenetics studies, allowing for crucial replication of 'positive' signals. Furthermore, by randomisation at drug initiation, long term community follow up will allow a comparison of time to treatment failure in patients treated with gliclazide, pioglitazone and sitagliptin in a much more cost effective and 'real-world' setting than traditional prospective randomised trials This pilot study is to assess the feasibility of the larger complex intervention. The primary outcome of the pilot is HbA1c change. Other measures regarding recruitment and dose titration will be assessed. With knowledge from this pilot, an application will be made for a large region or Scotland wide study to collect 2000 patients incident to oral diabetes treatment.
Interventions
DRUGGliclazide MR
30mg daily increased to 60mg if HbA1c \> 7% at 3 months
DRUGSitagliptin
Sitagliptin 100mg daily for 6 months
DRUGPioglitazone
Pioglitazone 30mg daily , increased to 45mg daily if HbA1c \>7% at 3 months. 6 months duration
DRUGMetformin
Metformin 500 mg od for 1 week, bd for 1 week, 1g mane 500 mg nocte 1 week, 1g bd there after. Total of 6 months treatment
Sponsors
University of Dundee
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
36 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Cohort 1 - metformin treatment * Type 2 diabetes diagnosed more than 6 weeks prior to visit 1 * GP considers adequate diet and lifestyle advice given * Age \>35 and \< 80 * Age of diabetes diagnosis \>35 * White European * HbA1c \>7% & \<=9% * eGFR\>=50 ml/min * ALT \<= 2.5\*ULN * Contactable by telephone * Cohort 2 - 2nd line treatment * Type 2 diabetes * Treated with metformin for more than 3 months; or metformin intolerant * Age \>35 and \< 80 * Age of diabetes diagnosis \>35 * White European * HbA1c \>7% & \<=9% * eGFR\>=50 ml/min * ALT \<= 2.5\*ULN * No previous history of heart failure; No patients with documented evidence of left ventricular systolic dysfunction OR with symptoms and signs consistent with a clinical diagnosis of heart failure * No treatment with Gemfibrozil or Rifampicin (CYP2C8 inhibitor or inducer respectively); or with Miconazole or phenylbutazone (increased hypoglycemic effect of gliclazide). * No diagnosis of osteoporosis * Contactable by telephone
Exclusion criteria
* Cohort 1 * Type 1 diabetes * HbA1c \>9% or \<=7% * eGFR\<50 ml/min * ALT \> 2.5\*ULN * Alcohol consumption in excess of 50 units per week * Pregnancy, lactation or a female planning to conceive within the study period * Any other significant medical reason for exclusion as determined by the investigator * Cohort 2 * Type 1 diabetes * HbA1c \>9% or \<=7% * eGFR\< 50 ml/min * ALT \> 2.5\*ULN * Previous history of heart failure OR documented evidence of left ventricular systolic dysfunction OR symptoms and signs consistent with a clinical diagnosis of heart failure * Ongoing treatment with Gemfibrozil or Rifampicin (CYP2C8 inhibitor or inducer respectively); or with Miconazole or phenylbutazone (increased hypoglycemic effect of gliclazide). * Previous diagnosis of osteoporosis * Pregnancy, lactation or a female planning to conceive within the study period * Any other significant medical reason for exclusion as determined by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change | 6 months | Units are absolute difference in %HbA1c (HbA1c being the percentage of glycated Haemoglobin, reflecting glucose exposure over the last 3 months) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gliclazide MR Gliclazide MR: 30mg daily increased to 60mg if HbA1c \> 7% at 3 months | 6 |
| Sitagliptin Sitagliptin: Sitagliptin 100mg daily for 6 months | 6 |
| Pioglitazone Pioglitazone: Pioglitazone 30mg daily , increased to 45mg daily if HbA1c \>7% at 3 months. 6 months duration | 6 |
| Metformin Metformin: Metformin 500 mg od for 1 week, bd for 1 week, 1g mane 500 mg nocte 1 week, 1g bd there after. Total of 6 months treatment | 11 |
| Total | 29 |
Baseline characteristics
| Characteristic | Gliclazide MR | Sitagliptin | Pioglitazone | Metformin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 4.6 | 61.5 years STANDARD_DEVIATION 9.9 | 61.3 years STANDARD_DEVIATION 11.8 | 59.6 years STANDARD_DEVIATION 8.8 | 60.9 years STANDARD_DEVIATION 9.2 |
| Region of Enrollment United Kingdom | 6 Participants | 6 Participants | 6 Participants | 11 Participants | 29 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 11 |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 11 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 11 |
Outcome results
Primary
HbA1c Change
Units are absolute difference in %HbA1c (HbA1c being the percentage of glycated Haemoglobin, reflecting glucose exposure over the last 3 months)
Time frame: 6 months
Population: Modified Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gliclazide MR | HbA1c Change | -0.42 absolute change in %HbA1c | Standard Deviation 0.72 |
| Sitagliptin | HbA1c Change | -0.58 absolute change in %HbA1c | Standard Deviation 0.63 |
| Pioglitazone | HbA1c Change | -1.04 absolute change in %HbA1c | Standard Deviation 0.71 |
| Metformin | HbA1c Change | -1.59 absolute change in %HbA1c | Standard Deviation 0.6 |