Propionyl-L-Carnitine Hydrochloride in Patients With Mild Ulcerative Colitis; Efficacy, Safety and Tolerability Study
The aim of the trial is to test safety, tolerability and efficacy of Propionyl-L-carnitine modified release tablets 1g/die in reducing the symptoms of the disease with respect to the proportion of patients with disease remission at the end of the 8 weeks of treatment. It will also aim to investigate capability of the treatment in the maintenance of remission after four weeks of treatment interruption; histological changes will be also evaluated and finally, improvement in the overall quality of life as measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) will be investigated.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Phase III Randomized Multicenter International Study to Investigate the Safety and Efficacy of Propionyl-L-Carnitine Hydrochloride Modified Release Tablets in Patients Affected by Mild Ulcerative Colitis Under Oral Stable Treatment|
- Proportion of clinical/endoscopic remissions [ Time Frame: End of treatment (week 8) ] [ Designated as safety issue: No ]Remission will be defined according with the overall modified Mayo score (Disease Activity Index). A score ≤ 2 with rectal bleeding sub-score = 0 and no other individual sub-score >1 will be considered necessary to classify the patient in remission state.
- Change from baseline in Rectal bleeding evaluation [ Time Frame: At week 2, 6 and 8 of treatment and after 4 week follow-up ] [ Designated as safety issue: No ]Evaluation will be performed by means of Disease Activity Index (DAI) sub-score (from 0 to 3).
- Change from baseline in stool frequency evaluation [ Time Frame: At week 2, 6 and 8 of treatment and after 4 week follow-up ] [ Designated as safety issue: No ]Evaluations will be performed by means of Disease Activity Index (DAI) sub-score (from 0 to 3).
- Histological response to the treatment [ Time Frame: End of treatment (week 8) ] [ Designated as safety issue: No ]Evaluated as an improvement of the histological index of at least 1 point
- Change from baseline in C-reactive protein (CRP) and Fibrinogen [ Time Frame: End of the treatment (week 8) and after 4 week follow-up ] [ Designated as safety issue: No ]
- Improvement of patients quality of life [ Time Frame: End of treatment period (week8) and after 4 week follow-up ] [ Designated as safety issue: No ]A validated specific questionnaire, the SIBDQ by McMaster university will be administered to evaluate changes in patients' quality of life
- Haematology [ Time Frame: Baseline and end of treatment (week8) ] [ Designated as safety issue: Yes ]Haemoglobin, Haematocrit, RBC, WBC and differential count.
- Electrocardiogram [ Time Frame: At baseline and at the end of treatment period (week8) ] [ Designated as safety issue: Yes ]Standard intervals (PR, RR, QRS, QT) will be collected plus all rhythm abnormalities
- Adverse Events collection [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
- Serum Chemistry [ Time Frame: At baseline and at the end of treatment period (week8) ] [ Designated as safety issue: Yes ]Standard evaluation including renal and liver function, electrolytes and blood glucose
|Study Start Date:||April 2012|
|Estimated Study Completion Date:||January 2014|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Modified release tablets containing 500 mg of propionyl-L-carnitine
500 mg modified release tablets, 500 mg bid; treatment duration 8 weeks
Placebo Comparator: Placebo
Modified release tablets containing inert substances
500 mg inert substances modified release tablets, 500 mg bid; treatment duration 8 weeks
Although it seems clear that an abnormal function of the colonic epithelium is the central problem causing inflammation and the unusual immunological response to the normal gut flora in inflammatory bowel disease (IBD), the actual causes of these dysfunctions are still unknown. Short Chain Fatty Acids (SCFA) are the main fuel of the colonic epithelium, and are normally produced by the bacterial flora by fermentation of the complex carbohydrates forming non soluble fibers usually introduced with everyday diet. Butyrate alone contributes 70% of the normal colonocyte energy. Studies done using animal models and colonic mucosa biopsies from patients suffering form ulcerative colitis (UC) have consistently shown that a metabolic change occurs in diseased colonic mucosa, with an impairment of butyrate oxidation (and of beta-oxidation) and an energy shortage that is only incompletely compensated by oxidation of glucose and other substrates such as glutamine. It is also well known that matrix metalloproteases production is highly increased in IBD and that serum transglutaminase activity is significantly reduced in patients with IBD. Transglutaminases are enzymes contributing to the crosslinking of matrix proteins and the reduction seen in patients affected by IBD correlates well with the endoscopic and histopathologic grading in UC, meaning that part of the circulating enzyme is sequestered in the injured colonic tissue in the effort to re-build the extracellular matrix during the healing process. Propionyl-L-carnitine Hydrochloride (PLC) is a molecule that has already been shown to reduce membrane lipid peroxidation in endothelial cells from bovine aorta and coronary vessels, to reduce the effects of hypoxia in coronary endothelial cells, and to play a role in the cardiac metabolic abnormalities that contribute to the mechanical dysfunctions leading to heart failure. Given these properties of Propionyl-L-carnitine Hydrochloride (ST 261) and given the peroxidative damage suffered by colonocytes in UC together with their metabolic impairment, the use of this molecule for the treatment of UC seemed to be appropriate and sound, in particular as a carrier of a propionate moiety that, once transformed into succinate, enters the Kreb cycle, acting as an extra burst fuel improving the balance of energy production inside tissues. Previous clinical experience has shown that PLC promoted complete or nearly complete regression of cutaneous trophic ulcers in a large number of vasculopathic patients refractory to all other therapies. As far as the UC pathology is concerned, the effects of ST 261, given orally or intrarectally, were investigated at different dosages, in preclinical experimentation, either after a single trinitrobenzene sulphonic acid (TNBS) administration (acute colitis) or after repeated TNBS administrations (reactivated colitis). The results showed a reduction in the damaged colon area both in acute model and reactivated colitis, even if the beneficial effect of restoration of TNBS-induced alterations of tissue morphology is more evident in the reactivated colitis model, particularly after oral administration. Based on the above-described results a development plan in humans started to investigate the activity of PLC in the treatment of ulcerative colitis.
|Contact: Giovanni Valentini, MD||+39 06 9139 ext firstname.lastname@example.org|
|Contact: Raffaella Nicolai, PhD||+39 06 9139 ext email@example.com|
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|Study Chair:||Sandro Ardizzone, MD||Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY|