High blood glucose levels (hyperglycaemia) and Moxifloxacin (a commonly used antibiotic)
have both been shown independently to affect heart activity in healthy volunteers as
recorded by ECG. i. e. Both cause prolongation of the QTc interval which is a measure of the
time between the start of the Qwave and the end of the Twave during a heartbeat cycle. In
this study, the investigators want to find out whether moxifloxacin and hyperglycaemia cause
QTc prolongation in Type 1 diabetic patients. The investigators also want to assess whether
C-peptide (a fragment if insulin normally found in the blood but not present in not present
in the blood of Type 1 diabetics) which has the opposite effect on heart activity i. e it
shortens the QTc interval will reverse the effect of QTc prolongation in Type 1 diabetes as
this may be useful for preventing 'dead in bed' syndrome also known as 'Sudden Cardiac
Death' which is more common in diabetic patients compared to healthy volunteers.
Minimum age: 20 Years.
Maximum age: 64 Years.
Gender(s): Both.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following
criteria apply:
1. Subject is a male or female with a confirmed diagnosis of Type 1 diabetes mellitus,
20 - 64 years of age (inclusive) at screening.
2. Signed informed consent in the local language prior to any study-mandated procedure.
3. No clinically significant findings on the physical examination at screening and at
admission on Day −1.
4. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at screening and at
admission on Day −1, body weight at least 48 kg.
5. Systolic blood pressure (SBP) 90-160 mmHg, diastolic blood pressure (DBP) 40-90 mmHg,
and heart rate (HR) 40-90 bpm (all inclusive), measured on the left arm, after 10
minutes in the supine position at screening and at admission on Day - 1.
6. Triplicate 12 lead ECG without clinically relevant abnormalities measured after ten
minutes in the supine position at screening and on admission on Day - 1.
7. 24 hour 12 lead Holter ECG or an equivalent assessment and/or submaximal exercise
test without clinically relevant abnormalities measured at screening.
8. Haematology, biochemistry and urinalysis test results not deviating from the normal
range to a clinically relevant extent at screening and at admission.
9. Subjects must agree to use acceptable methods of contraception:
Male subjects
Male subjects must use medically acceptable methods of contraception if their female
partner(s) is (are) pregnant or lactating from the time of the first administration
of treatment or study medication until three months following administration of the
last treatment or dose of study medication. Acceptable methods include:
- Condom used with spermicidal foam/gel/film/cream/suppository
- If the subject has undergone surgical sterilisation (vasectomy with
documentation of azoospermia) a condom with spermicidal
foam/gel/film/cream/suppository must be used.
Use acceptable methods of contraception if the male subject's partner could become
pregnant from the time of the first administration of treatment or study medication
until three months following administration of the last treatment or dose of study
medication. The acceptable methods of contraception are as follows:
- Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository;
- Surgical sterilisation (vasectomy with documentation of azoospermia) and a
barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used
with spermicidal foam/gel/film/cream/suppository);
- The female partner uses oral contraceptives (combination oestrogen/progesterone
pills), injectable progesterone or subdermal implants and a barrier method
(condom or occlusive cap [diaphragm or cervical/vault caps] used with
spermicidal foam/gel/film/cream/suppository);
- The female partner uses medically prescribed topically-applied transdermal
contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
- The female partner has undergone documented tubal ligation (female
sterilisation). In addition, a barrier method (condom or occlusive cap
[diaphragm or cervical/vault caps] used with spermicidal
foam/gel/film/cream/suppository) must be used;
- The female partner has undergone documented placement of an IUD or IUS and the
use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault
caps] used with spermicidal foam/gel/film/cream/suppository);
- True abstinence: When this is in line with the preferred and usual lifestyle of
the subject. (Periodic abstinence [e. g., calendar, ovulation, symptothermal,
post-ovulation methods] and withdrawal are not acceptable methods of
contraception).
Female subjects
Female subjects of childbearing potential must use medically acceptable methods of
contraception from the time of the first administration of treatment or study
medication until three months following administration of the last treatment or dose
of study medication. Acceptable methods include:
- A documented placement of an intrauterine device (IUD) or intrauterine system
(IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
- Documented tubal ligation (female sterilisation). In addition, a barrier method
(condom or occlusive cap [diaphragm or cervical/vault caps] used with
spermicidal foam/gel/film/cream/suppository) should also be used;
- Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/suppository;
- Oral contraceptive pill in addition, a barrier method (condom or occlusive cap
[diaphragm or cervical/vault caps] used with spermicidal
foam/gel/film/cream/suppository) should also be used;
- True abstinence: When this is in line with the preferred and usual lifestyle of
the subject. (Periodic abstinence [e. g., calendar, ovulation, symptothermal,
post-ovulation methods] and withdrawal are not acceptable methods of
contraception).
10. Ability to communicate well with the Investigator in the local language, and to
understand and comply with the requirements of the study.
11. Subject has a stable diabetic treatment regimen.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following
criteria apply:
1. History or clinical evidence of any disease and/or existence of any surgical or
medical condition which might interfere with the absorption, distribution, metabolism
or excretion of the study drug (appendectomy and herniotomy allowed, cholecystectomy
not allowed).
2. History or clinical evidence of microvascular disease including chronic kidney
failure, macular degeneration or any other disease attributed to the microvascular
system, that in the Investigator's opinion may affect the outcome of the study.
3. Recent hospitalisation due to hypoglycaemia or hyperglycaemia within the past one
month.
4. History of clinically significant syncope.
5. Family history of sudden death.
6. Clinically significant history or family history of congenital long QT syndrome (e. g.
Romano-Ward syndrome, Jervell and Lange-Nielson syndrome) or Brugada's syndrome.
7. History of clinically significant arrhythmias and ischemic heart disease (especially
ventricular arrhythmias, atrial fibrillation (AF), recent conversion from AF or
coronary spasm).
8. Conditions predisposing the volunteer to electrolyte imbalances other than Type 1
diabetes (e. g. altered nutritional states, chronic vomiting, anorexia nervosa,
bulimia nervosa).
9. ECG abnormalities in the standard 12-lead ECG (at screening and Day - 1) and 24-hour
12 lead Holter ECG or an equivalent assessment and/or submaximal exercise test (at
screening) which in the opinion of the Investigator will interfere with the ECG
analysis.
10. Any clinically important abnormalities in rhythm, conduction or morphology of resting
ECG that may interfere with the interpretation of QTc interval changes. This includes
subjects with any of the following (at screening and Day - 1 of Period 1):
- Sinus node dysfunction.
- Clinically significant PR (PQ) interval prolongation.
- Intermittent second or third degree AV block.
- Incomplete or complete bundle branch block.
- Abnormal T wave morphology.
- Prolonged QTcB >450 msec or shortened QTcB < 350 msec or family history of long
QT syndrome.
Subject with borderline deviations from these criteria may be included if the
deviations do not pose a safety risk, and if agreed between the appointed
Cardiologist and the PI.
11. Signs and/or symptoms of a clinically relevant acute illness in the four-week period
prior to screening.
12. Veins unsuitable for intravenous puncture or cannulation on either arm (e. g. veins
that are difficult to locate, access or puncture, veins with a tendency to rupture
during or after puncture).
13. Known hypersensitivity to any medicines administered in the trial.
14. Treatment with any over-the-counter (OTC) medications during the two weeks prior to
admission.
15. You have taken antibiotics 7 days prior to the admission for the study or plan to
take antibiotics during the study.
16. Treatment with vitamins and/or minerals within 48 hours prior to admission.
17. Treatment with another investigational drug within four weeks prior to dosing or
having participated in more than three investigational drug studies within one year
prior to dosing.
18. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
cocaine, cannabinoids, opiates, barbiturates and methadone) or from the alcohol
breath test at screening and on Day −1.
19. History or clinical evidence of alcoholism or drug abuse. Alcohol abuse is defined as
regular weekly intake of more than 14 units if female and 21 units if male; drug
abuse is defined as compulsive, repetitive and/or chronic use of drugs or other
substances with or without problems related to their use and/or where stopping or a
reduction in dose will lead to withdrawal symptoms.
20. Excessive caffeine consumption, defined as ≥800 mg per day at screening (800 mg = 7
cups of coffee or 16 cups of tea).
21. Smoking within three months prior to screening or during the screening period.
22. Loss of 250 mL or more blood within three months prior to screening.
23. Positive results from the hepatitis serology, except for vaccinated subjects, at
screening.
24. Positive results from the HIV serology at screening.
25. Any circumstances or conditions, which, in the opinion of the Investigator, may
affect full participation in the study or compliance with the protocol.
26. Legal incapacity or limited legal capacity at screening.
Ulrike Lorch, MD FRCA FFPM, Phone: +44 20 8664 5200, Email: u.lorch@richmondpharmacology.com
Taubel J, Lorch U, Ferber G, Singh J, Batchvarov VN, Savelieva I, Camm AJ. Insulin at normal physiological levels does not prolong QT(c) interval in thorough QT studies performed in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):392-403. doi: 10.1111/j.1365-2125.2012.04376.x.
Taubel J, Naseem A, Shakeri-Nejad K, Dingemanse J, Ferber G and Camm A. J. Comparison of digital 12-lead ECG and digital 12-lead holter ECG recordings in healthy male subjects. Clinical Pharmacology and Therapeutics / 89:Supplement 1 (2011) / S11.