January 23, 2013
Santarus and VeroScience Announce Publication of Positive Data from Pivotal CYCLOSET® (bromocriptine mesylate) Efficacy Study
CYCLOSET add-on therapy provided significant improvement in glycemic control versus placebo in patients with type 2 diabetes poorly controlled on one or two oral anti-diabetes medications
Additionally, among the EPP population with no concomitant change in diabetes medication, treatment with CYCLOSET resulted in:
- Reductions in HbA1c levels of 0.69% to 0.83% (CYCLOSET vs. placebo between group difference, p < 0.0001)
- Five to seven times more subjects reaching the goal of HbA1c ≤7.0 in the CYCLOSET treated groups compared with placebo (32%-42% vs 5%-7%, respectively) (p < 0.0001).
CYCLOSET is a unique, quick release form of bromocriptine, a dopamine receptor agonist that is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The study included 515 patients with type 2 diabetes with baseline HbA1c of ≥7.5% and ≤10.0% (average baseline HbA1c: 8.3) taking one or two oral anti-diabetes medications (metformin, sulfonylurea and/or thiazolidinediones). These poorly controlled patients were randomized 2:1 to CYCLOSET add-on (1.6 mg/day to 4.8 mg/day) or placebo add-on for a 24-week treatment period. Study investigators were allowed to adjust patient anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of CYCLOSET treatment was assessed in patients taking: (1) one or two oral anti-diabetes medications, (2) metformin with or without another oral anti-diabetes medication, or (3) metformin plus a sulfonylurea. The study was conducted in a cohort of patients imbedded in a larger randomized safety study.
The results of the primary endpoint analysis for the intent-to-treat (ITT) and EPP populations are summarized in the table below.
Effect of CYCLOSET Versus Placebo on Change from Baseline HbA1c (%)a
|and Odds Ratio of Achieving Goal of HbA1c ≤ 7.0|
Any one or two oral anti-diabetes
No concomitant change
in diabetes medication
|Between group difference HbA1c||-0.51 (-0.70, -0.31)b||-0.60 (-0.83, -0.38)b||-0.69 (-0.97, -0.41)b|
|Odds ratio of achieving HbA1c ≤ 7.0||3.48 (1.96, 6.18)b||5.80 (2.93, 11.47)b||6.50 (2.67, 15.84)b|
|Metformin with or without another||No concomitant change|
|oral anti-diabetes medication||in diabetes medication|
|Between group difference HbA1c||-0.56 (-0.78, -0.34)b||-0.68 (-0.93, -0.42)b||-0.81 (-1.12, -0.51)b|
|Odds ratio of achieving HbA1c ≤ 7.0||3.98 (1.98, 7.98)b||6.69 (2.98, 15.04)b||12.03 (3.53, 40.99)b|
|Metformin plus a sulfonylurea||No concomitant change|
|in diabetes medication|
|Between group difference HbA1c||-0.49 (-0.75, -0.24)c||-0.70 (-1.00, -0.40)b||-0.83 (-1.18, -0.48)b|
|Odds ratio of achieving HbA1c ≤ 7.0||3.77 (1.72, 8.30)d||7.26 (2.92, 18.01)c||11.45 (3.19, 41.12)c|
aValues are based on mean (95% Confidence Interval), adjusted by baseline HbA1c
bp < 0.0001
cp < 0.0002
dp < 0.001
The most frequent adverse events in the study for CYCLOSET and placebo were, respectively, nausea (33% vs. 6%), fatigue (11% vs. 8%), dizziness (14% vs. 11%), headache (12% vs. 8%), constipation (7% vs. 3%), back pain (6% vs. 3%) and vomiting (6% vs. 2%). The discontinuation rate due to any adverse event was 20% for CYCLOSET-treated and 9% for placebo-treated patients.
"The results of this pivotal study show that the addition of CYCLOSET to the treatment regimen in this poorly controlled type 2 diabetes patient population produces significant and clinically relevant improvements in glycemic control markedly increasing the percent of patients reaching the HbA1c goal of ≤ 7.0 vs. placebo," stated
The article, titled Effect of Bromocriptine-QR on Glycemic Control in Subjects with Uncontrolled Hyperglycemia on One or Two Oral Anti-Diabetes Agents can be found online at http://www.ncbi.nlm.nih.gov/pubmed/23186965.
Important Safety Information
CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
CYCLOSET is contraindicated in:
- Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET.
- Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. CYCLOSET is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.
- Women who are nursing their children. CYCLOSET may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven.
Warnings and Precautions
- Hypotension: Can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking anti-hypertensive medications. Assess orthostatic vital signs prior to initiation of CYCLOSET and periodically thereafter. Advise patients during early treatment to avoid situations that could lead to injury if syncope was to occur.
- Psychosis: May exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis. Use in patients with severe psychotic disorders is not recommended.
- Somnolence: May cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur.
- Interaction with dopamine antagonists: Concomitant use with dopamine antagonists such as neuroleptic agents may diminish the effectiveness of both drugs. Concomitant use is not recommended.
- Other dopamine receptor agonists: Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications. Concomitant use is not recommended.
- Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET or any other anti-diabetes drug. CYCLOSET does not increase the risk of macrovascular events.
In controlled clinical trials, adverse reactions reported in ≥5% of patients treated with CYCLOSET and reported more commonly than in patients treated with placebo, included nausea, fatigue, dizziness, vomiting, and headache.
Postmarketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications.
- May increase the unbound fraction of highly protein-bound therapies, altering their effectiveness and safety profiles.
- May increase ergot-related side effects or reduce ergot effectiveness for migraines if co-administered within 6 hours of ergot-related drugs.
- Extensively metabolized by CYP3A4. Use caution when co-administering strong inhibitors, inducers, or substrates for CYP3A4.
The Important Safety Information does not include all the information needed to use CYCLOSET safely and effectively. See Full Prescribing Information for CYCLOSET for additional information, available at www.cycloset.com or by contacting
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