Program-specific Objective:To assess the impact of MK-3102 25 mg q.w. on time to confirmed CV outcomes as measured by the time to first event in the CVcomposite endpoint of CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the safety and tolerability of MK-3102 25 mg q.w.
Secondary outcome
To assess the impact of MK-3102 25 mg q.w. on:
a. change from baseline in A1C over time;
b. in subjects not receiving insulin at baseline, time to initiation of
long-term insulin therapy (long-term insulin therapy is defined as a continuous
period of insulin use of more than 3 months).
Background summary
MK-3102 is a novel dipeptidyl peptidase-IV (DPP-4) inhibitor that is in Phase
III clinical
development for the treatment of patients with T2DM. Unlike the presently
marketed
DPP-4 inhibitors, which are administered once- or twice-daily, MK-3102 has a
half-life
that supports once-weekly dosing. T2DM is associated with an elevated risk of
cardiovascular (CV) disease, which is the leading cause of morbidity and
mortality in this
patient population. In recent years, regulatory agencies including the United
States Food
and Drug Administration (FDA), the European Medicines Agency (EMA), and Health
Canada have mandated that, prior to filing for marketing approval, new
antihyperglycemic agents (AHA) developed to treat T2DM undergo an enhanced
CV-risk
assessment. Details of the required assessment vary between the EMA and
FDA/Health
Canada, but the guidelines of each state that patients at higher risk of CV
events should
be included in Phase II and Phase III studies in numbers sufficient to allow a
metaanalysis
(pooled analysis) to evaluate the CV safety profile of the new medication. The
FDA guidance also requires that Sponsors establish an independent CV endpoints
committee to prospectively, and in a blinded manner, adjudicate CV events
occurring
during the clinical development program. The present trial was designed to
address these
requirements and the data will, therefore, contribute to the assessment of the
safety
profile of MK-3102, including the requisite assessment of the CV safety
profile.
Study objective
Program-specific Objective:
To assess the impact of MK-3102 25 mg q.w. on time to confirmed CV outcomes as
measured by the time to first event in the CV
composite endpoint of CV-related death, nonfatal MI, nonfatal stroke, or
unstable angina requiring hospitalization.
Study specific Objective:
When added to usual background therapy in subjects with T2DM and established CV
disease with inadequate glycemic control:
To assess the effect of treatment with MK-3102 25 mg q.w. compared with placebo
on A1C.
Insulin Sub-study-specific Objectives:
In subjects with T2DM and established CV disease with inadequate glycemic
control on
insulin with or without metformin:
Objective: After 18 weeks, to assess the effect of MK-3102 25 mg q.w. as
compared with placebo on A1C.
Objective: To assess the safety and tolerability of MK-3102 25 mg q.w.
Study design
This is a multicenter, double-blind, randomized, placebo-controlled, parallel
group, Phase
III clinical trial. Approximately 4,000 subjects with T2DM and established CV
disease
who have inadequate glycemic control (A1C *7.0 and *10.0%) and who, at the time
of
screening, are being treated with a diabetis treatment regimen as specified in
the protocol will be randomized in a 1:1 ratio to MK-3102 25 mg q.w. or placebo.
There will be a 2 week run in period where all patients receive single blind
placebo before they are randomized.
The duration of the trial will be "event driven" and will continue at least
until the number
of confirmed CV events across the Phase II/III program is sufficient to meet
regulatory
requirements for the assessment of CV safety. It is estimated (based on a CV
event rate
of 2.25%) that subjects will participate in the trial for as long as 2.5 to 3
years. However,
the trial may be continued and expanded (by amendment) post-filing for further
CV
assessment. An external data monitoring committee (DMC) will be monitoring this
trial
(and the entire Phase III program) and will be charged with overseeing the
conduct of the
trial.
Intervention
MK-3102 or placebo once weekly.
Study burden and risks
MK-3102 is a structurally distinct and potent DPP-4 inhibitor, which is being
developed for
the treatment of T2DM. Unlike the presently marketed DPP-4 inhibitors, which are
administered once- or twice-daily, MK-3102 has a t1/2 that supports once-weekly
dosing.
Weekly dosing of an efficacious, well-tolerated, safe, oral agent that reduces
pill burden has
the potential to increase adherence to AHA therapy, which in turn may improve
long-term
outcomes. Such an agent would represent a welcome addition to the existing
armamentarium
of oral agents for the treatment of T2DM and may help shape future treatment
paradigms. In developed
countries CV disease accounts for 65-75% of deaths in people with T2DM.
Monitoring of AE's ECG's, vital signs and lab safety tests will be performed to
support patient safety and evaluation of the safety profile.
The risks and burden to the patient are thought to be in perspective to the
treatment of the patient and the need to study new compounds with added
benefits.
One Merck Drive 1
Whitehouse Station NJ 08889
US
One Merck Drive 1
Whitehouse Station NJ 08889
US
Listed location countries
Age
Inclusion criteria
1. Having T2DM and is *40 years of age.;2. Subject is on one of the following diabetes treatment regimens that is stable for at least 12 weeks (except for pioglitazone for at least 16 weeks) and is within the associated A1C range for that treatment regimen:
- An A1C *6.5 and *10.0% (*48 mmol/mol and *86 mmol/mol) on
diet and exercise alone (not on an AHA for *12 weeks)
OR
monotherapy with metformin (MF); pioglitazone (PIO); an alpha-glucosidase inhibitor (AGI); or an SGLT2 inhibitor (SGLT2i)
OR
dual combination therapy with MF, PIO, AGI or SGLT2i
OR
- An A1C *7.0% and *10.0% (*53 mmol/mol and *86 mmol/mol) on
monotherapy with a sulfonylurea or meglitinide
OR
dual combination therapy with a sulfonylurea or a meglitinide and MF, PIO, AGI, or SGLT2i
OR
- An A1C *7.0% and *10.0% (*53 mmol/mol and *86 mmol/mol) on one of the following insulin regimens (with or without metformin)
basal insulin (e.g., insulin glargine, insulin detemir, NPH insulin, degludec)
prandial insulin (e.g., regular, aspart, lispro, glulisine)
basal/prandial insulin regimen consisting of multiple dose insulin injections of basal and prandial insulin or the use of pre-mixed insulin (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30®);3. Having following preexisting vascular disease:;(a) History of a major clinical manifestation of coronary artery disease (i.e., myocardial infarction, surgical or percutaneous [balloon and/or stent] coronary revascularization procedure, or coronary angiography showing at least one stenosis *50% in a major epicardial artery or branch vessel);;(b)Ischemic cerebrovascular disease, including:;- History of ischemic stroke ;- History of carotid arterial disease as documented by *50% stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit.;(c) Atherosclerotic peripheral arterial disease, as documented by objective - amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index of less than 0.9 or a toe-brachial pressure index less than 0.7 or history of surgical or percutaneous revascularization procedure.;4.Meets one of the following criteria:;a. Subject is a male ;b. Subject is a female not of reproductive potential defined as one who has either:;(1) reached natural menopause (defined as *12 months of spontaneous amenorrhea in women >45 years of age, or *6 months of spontaneous amenorrhea with serum follicular stimulating hormone [FSH] levels in the postmenopausal range as determined by the laboratory), or ;(2)had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to screening;c. Subject is a female of reproductive potential and:;1. agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control) or;2. agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 21 days after the last dose of blinded study medication. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:;*Use of one of the following double-barrier methods:diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom. ;*Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following:diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intrauterine device (IUD).;*Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge, vasectomy; or hormonal contraception (see above).;* Vasectomy with one of the following:diphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above). ;5. Understanding the trial procedures, alternative treatments available, providing the providing written informed consent, consent for Future Biomedical Research can be provided (not obligatory).
Exclusion criteria
1. History of type 1 diabetes mellitus or a history of ketoacidosis or possibly having type 1 diabetes ;2. Beeing treated with rosiglitazone, a DPP-4 inhibitor or a GLP-1 receptor agonist within the prior 12 weeks of Visit 1/Screening or previously treated with MK-3102.;3. Having a history of hypersensitivity to a DPP-4 inhibitor;4. Participation in trial with investigational compound prior 12 weeks of signing the informed consent or is not willing to refrain from participating in another trial.;5. Subject is on a weight loss program and is not in the maintenance phase; has been on a weight loss medication in the past 6 months; or has undergone bariatric surgery within 12 months prior to signing the informed consent.;6. Surgical procedure within 4 weeks prior to signing informed consent or has planned major surgery during the trial.;7. Treatment for *14 consecutive days or repeated courses of pharmacologic doses of corticosteroids;8. Treatement for hyperthyroidism or thyroid replacement therapy and has not been on a stable dose for at least 6 weeks.;9. Medical history of active liver disease;10. Human immunodeficiency virus (HIV) as assessed by medical history.;11. Worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months.;12. Poorly-controlled hypertension ;13. History of malignancy *5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.;14. Clinically important hematological disorder;15. Exclusionary laboratory values;16. Positive urine pregnancy test.;17.Subject is pregnant or breast-feeding, or is expecting to conceive during the trial, including 21 days following the last dose of blinded study medication. OR is expecting to undergo hormonal therapy in preparation to donate eggs during the period of the trial, including 21 days following the last dose of blinded study medication.;18. Subject is,at the time of signing informed consent,a user of recreational or illicit drugs or has had a recent history of drug abuse.;19. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per;week, or engages in binge drinking.;20. History or current evidence of condition, therapy, lab abnormality or other circumstance that;*makes participation not in the subject*s best interest;*might interfere with subject*s participation for the full duration of the trial, or;*might confound the result of the trial.;21.Subject has donated blood products or has had phlebotomy of >300 mL within 8 weeks of signing informed consent, or intends to donate blood products within the projected duration of the trial OR received, or anticipated to receive blood products within 12 weeks of signing informed consent or within the projected duration of the trial.;22. Subject is unlikely to adhere to the trial procedures, keep appointments.;23.Symptomatic hyperglycemia that, in the investigator's opinion, requires immediate initiation, adjustment, or addition of AHA therapy or has a FPG consistently (i.e., measurement repeated and confirmed within 7 days) >260 mg/dL (14.4 mmol/L).;24.Clinically significant ECG abnormality which in the opinion of the investigator exposes the subject to risk by enrolling in the trial.;25.Poorly controlled hypertension defined as systolic blood pressure of *160 mm Hg or diastolic blood pressure of *90 mm Hg.;26.Subject is on lipid-lowering medication or thyroid replacement therapy, and has not been on a stable therapy for the 4 weeks (lipid-lowering medication), or 6 weeks (thyroid replacement therapy) prior to Visit 3/Day 1. In this case the current visit can be changed to an Unscheduled Visit, and the subject should be rescheduled for a Visit 3/Day 1.;27.Subject has a positive urine pregnancy test.;28.Subject has a site fasting-fingerstick glucose (FFSG) <126 mg/dL (7.0 mmol/L) or >260 mg/dL (14.4 mmol/L).;29.Subject has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory or ECG abnormality, or required a new treatment or medication during the pre-randomization period which meets any previously described trial exclusion criteria or which, in the opinion of the investigator, exposes the subject to risk by enrolling in the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002414-39-NL |
| CCMO | NL41552.091.12 |