4. 4
9
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria at enrolment (Visits 1 and 2)
■ Provide a written informed consent at enrolment
■ Men or women who are ≥ 18 years of age at time of
consent
■ Female patients who are post menopausal,
hysterectomized, or if of childbearing age using a
highly effective method of birth control
◆ Post menopausal patients are defined as
patients with natural or induced menopause
with last menstruation > one year ago or
bilateral oophoretectomy
◆ Highly effective birth control is defined as
double barrier method (condoms with
spermicide, diaphragm with spermicide), oral
contraceptive, implant, long-term injectable
contraceptive, intrauterine device (IUD), or
tubal ligation. However, female patients using
oestrogen containing
hormonal anti conception method (oral,
transdermal, vaginal ring or combination
injectables) must agree to use an additional
barrier method for contraception (condom or
diaphragm)
■ Diagnosed with type 2 diabetes for less than 20 years
and receiving at least 30 U insulin per day
■ HbA1c ≥ 7.5% and ≤ 10.0%
Exclusion criteria at enrolment (Visits 1 and 2)
■ Type 1 diabetes, history of diabetic ketoacidosis,
corticosteroid-induced type 2 diabetes, or type 2
diabetes for more than 20 years
■ Treatment with thiazolidinediones within 16 weeks of
randomisation
■ Active arterial disease such as unstable angina,
myocardial infarction, transient ischemic attack (TIA),
cerebrovascular accident (CVA), myocardial or
peripheral vascular disease (PVD), revascularisation,
or angioplasty within 24 weeks prior to enrolment
5. ■ NYHA class III or IV, or unstable class I or II as judged
by the investigator
■ History of thyroid ophthalmopathy
■ History of malignancy within the last five years,
excluding successful treatment of basal or squamous
cell skin carcinoma
■ History of blood lipid induced eruptive xanthomas or
hypertriglyceridaemia induced pancreatitis
■ Pregnant or breastfeeding patients
■ Suspicion that the patient is infected according to
World Health Organization (WHO) risk categories two
to four
■ Treatment with fibrates, within 4 weeks prior to
Visit 1
■ Treatment with glucocorticoids (equivalent to oral
prednisone > 10 mg per day), within 4 weeks prior to
Visit 1
■ Treatment with probenecid that cannot be stopped at
Visit 1
■ History of hypersensitivity or intolerance to any PPAR
agonist
■ History of drug-induced myopathy or drug-induced
CK elevation
■ History of drug-induced liver enzyme elevations
■ History of drug-induced neutropenia
■ History of alcohol or drug abuse within the last five
years
■ Other serious or unstable medical or psychological
condition identified in the patient’s medical history
that, in the judgment of the investigator, would
compromise the patient’s safety or successful
participation in the Clinical Study
■ Receiving any investigational product within twelve
weeks prior to Visit 1
■ Previous enrolment in this study
5
6. INCLUSION/EXCLUSION
CRITERIA AT RANDOMISATION
6
9
Inclusion criteria at randomisation
(Visit 3, lab values from Visit 2)
■ HbA1c ≥ 7.5% AND ≤ 10%
■ FPG ≤ 13.3 mmol/L (240mg/dL)
Exclusion criteria at randomisation
(Visit 3, lab values from Visit 2)
■ Any clinically significant abnormality identified on
physical examination, laboratory tests or ECG which,
in the judgement of the investigator, would compro-
mise the patient’s safety or successful participation in
the Clinical Study
■ Fasting TG > 7.0 mmol/L (620 mg/dL)
■ Absolute neutrophil count (ANC) < 1.0 x 109/L
■ Any alanine aminotransferase (ALT), aspartate
aminotransferase (AST) or alkaline phosphatase (ALP)
> 2.5 times the upper limit of normal
■ Total bilirubin above the upper limit of normal unless
exclusively caused by Gilbert’s syndrome
■ Creatinine > 2 times the upper limit of normal. For
patients using metformin, creatinine cannot be above
the upper limit of normal for their age
■ CK > 3 times the upper limit of normal
■ Hb < 90 g/L (9 g/dL)
■ Other serious or unstable medical or psychological
condition identified on medical history that, in the
judgement of the investigator, would compromise the
patient’s safety or successful participation in the study
■ High blood pressure (mean diastolic BP > 120 mm
Hg) or malignant hypertension
7. 7
LAB DISCONTINUATION
CRITERIA (section 3.3.5.2)
TG > 11.3 mmol/L (1000 mg/dL) at or after V3
Hb < 90 g/L (9 g/dL)
ANC < 1.0 x 109/L
Creatinine ↑ > 50% up to 1.5 x ULN – repeated value
↑ > 50% up to 1.5 x ULN after handling
plan 2 x
> 2 x ULN at V3
(patients on metformin cannot be >ULN for
age)
ALT, AST,
ALP
> 5 x ULN at or after V3
> 3 x ULN + bilirubin >1.5 x ULN at or
after V3
> 3 but ≤ 5 x ULN for four weeks
> 3 x ULN after entering and concluding
handling plan 1 x
CK > 10 x ULN at or after V3
> 5 x ULN after entering and concluding
handling plan 1 x
Refer to protocol for other discontinuation criteria
9. TIPS FOR ENTERING
DIAGNOSES, AEs, and MEDs
9
9
1. Do not use abbreviations. On the Medical History,
Surgical History, AE, or Concomitant Medication
pages as these will be queried for expansion.
2. Be specific when entering verbatim terms on these
pages.
Example:
Angina – Angina Pectoris, Intestinal Angina
Chest Pain – Cardiac Chest Pain, Non-Cardiac
Chest Pain
3. Do not add extraneous information in the verbatim
term. (commas, quotes, parenthesis, dates, etc.)
Example:
“Anemia, 1980” should be entered as “Anemia”
“Arthritis (Hands and Knees) 1999” should be
entered as “Rheumatoid arthritis” or “Osteo
arthritis”
“Bronchitis (2001)” should be entered as
“Bronchitis”
4. Be precise with medication spelling
Example:
Migranol vs Migranal
10. 10
9
HANDLING PLANS
Hb ≥ 90g/L (9.0 g/dL) but < 100 g/L (10g/dL)
at or after randomisation (Visit 3)
Enter plan in parallel with Clinical Study
Protocol
Measure every two weeks
Hb < 90g/L, (9.0g/dL)
Discontinue investigational product
Handling Plan for
Decreased Haemoglobin (Hb)
ANC > 1.0 x 109 / L but < 1.5 x 109 / L at or
after randomisation (Visit 3)
Enter plan in parallel with Clinical Study
Protocol
Measure every two weeks
ANC < 1.0 x 109 / L
Discontinue investigational product
Handling Plan for
Decreased Absolute Neutrophil Count (ANC)
11. 11
Increase of creatinine > 50% from baseline to a
level >1.5 x ULN
Enter plan in parallel with Clinical
Study Protocol
Once in the plan: Creatinine increased ≤ 50%
from baseline or ≤ 1.5 x ULN
Creatinine plan is concluded
Increase of creatinine remains > 50% from
baseline to a level >1.5 x ULN
or
Entering plan a third time
Discontinue investigational product
* Patients on metformin cannot have creatinine > ULN for their age
Handling Plan for
Increased Creatinine
ALT, AST, ALP > 3 x ULN but ≤ 5 x ULN
Enter plan in parallel with Clinical Study
Protocol
ALT, AST, ALP ≤ 3 x ULN
LFT plan is concluded
ALT, AST, ALP > 5 x ULN, or
ALT, AST, ALP > 3 x ULN and bilirubin > 1.5 x
ULN, or
ALT, AST, ALP > 3 x ULN but ≤ 5 x ULN after
entering and concluding LFT plan once, or
Repeated ALT, AST, ALP are persistently > 3 x
ULN but ≤ 5 x ULN for four weeks
Discontinue investigational product
Handling Plan for
Increased LFTs
12. 12
9
HANDLING PLANS
Unexplained muscle symptoms, or
CK > 5 x ULN but ≤ 10 x ULN
Enter plan in parallel with Clinical Study
Protocol
CK ≤ 5 x ULN
CK plan is concluded
CK > 10 x ULN, or
CK > 5 x ULN but ≤ 10 x ULN after entering
and concluding the CK handling plan once
Discontinue investigational product
Handling Plan for
Increased CK
Suspected new onset of CHF
Discontinue investigational product
temporarily
Criteria for CHF not confirmed
CHF plan is concluded – restart
investigational product
Unless CHF not confirmed on third time
into the plan, then D/C
Criteria for CHF is confirmed
Discontinue investigational product
Handling Plan for
CHF
13. Handling Plan for
CHF continued . . .
Suspected worsening of pre-existing CHF
Discontinue investigational product
temporarily
Worsening of CHF not confirmed
CHF plan is concluded – restart investigational
product
Unless CHF not confirmed on third time into the
plan, then D/C
Worsening of CHF is confirmed
Discontinue investigational product
NOTES
13
