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Propionyl-L-Carnitine Hydrochloride in Patients With Mild Ulcerative Colitis; Efficacy, Safety and Tolerability Study

This study has been terminated.
(Evidence of very low probability to success. No safety issues)
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
sigma-tau i.f.r. S.p.A.
ClinicalTrials.gov Identifier:
NCT01567956
First received: March 28, 2012
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Ulcerative Colitis
Drug: Propionyl-L-Carnitine
Drug: Placebo
Phase 3

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by sigma-tau i.f.r. S.p.A.:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Enrollment: 150
Study Start Date: April 2012
Study Completion Date: January 2014
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Propionyl-L-Carnitine
Modified release tablets containing 500 mg of propionyl-L-carnitine
Drug: Propionyl-L-Carnitine
500 mg modified release tablets, 500 mg bid; treatment duration 8 weeks
Placebo Comparator: Placebo
Modified release tablets containing inert substances
Drug: Placebo
500 mg inert substances modified release tablets, 500 mg bid; treatment duration 8 weeks

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have read the Information for the Patient and signed the Informed Consent Form.
  • Diagnosis of active ulcerative colitis since at least 4 weeks as confirmed endoscopically and histologically.
  • Disease Activity Index comprised between 3 and 6, inclusive (mild ulcerative colitis), with rectal bleeding sub-score of at least 1.
  • Stable background oral aminosalicylates (mesalazine, balsalazide, olsalazine) or sulfasalazine standard therapy for greater than or equal to 4 weeks prior to screening assessments.
  • If female, not pregnant or nursing. For women of childbearing potential, willingness to avoid a pregnancy during the treatment period and for at least 4 weeks from the last dose of drug and utilization of an efficient method of birth control for the entire duration of the trial and until the first menses after a 30-day period after the last dose of trial medication.

Exclusion Criteria:

  • Crohn's disease and indeterminate colitis.
  • Current or previous (in the last 10 days preceding the screening) use of systemic corticosteroids.
  • Use of systemic antibiotics in the last 10 days preceding the screening.
  • Use of systemic Nonsteroidal anti-inflammatory drugs on a repeat basis in the last 10 days preceding the screening.
  • Use of probiotics started within 10 days preceding the screening. A stable regimen from at least 10 days prior to screening is allowed but the patient must be willing to continue up to the end of the study.
  • Use of immunosuppressants or biological agents within the last 6 weeks preceding the screening.
  • Treatment with L-carnitine or its esters derivatives within the last 3 months.
  • Stool culture positive for enteric pathogens (eg, Shigella, Salmonella, Yersinia, Campylobacter) or toxins (C.difficile).
  • Significantly impaired liver, renal, pulmonary or cardiovascular function as assessed by the investigator.
  • History of colon resection.
  • Diverticulitis, symptomatic diverticulosis.
  • Active peptic ulcer disease.
  • Proctitis (extent of inflammation < 15 cm from the anus).
  • Bleeding disorders
  • Rectal therapy with any therapeutic enemas or suppositories with the exception of those required for endoscopy during the 10 days preceding the screening.
  • Active or chronic infection(s) or malignancies.
  • Known hypersensitivity to the active ingredient and excipients of the study drug
  • Patients treated with L-Carnitine or its esters derivatives during the 3 months preceding the screening phase.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01567956

  Show 58 Study Locations
Sponsors and Collaborators
sigma-tau i.f.r. S.p.A.
PRA Health Sciences
Investigators
Study Chair: Sandro Ardizzone, MD Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY
  More Information

No publications provided

Responsible Party: sigma-tau i.f.r. S.p.A.
ClinicalTrials.gov Identifier: NCT01567956     History of Changes
Other Study ID Numbers: ST261DM11006, 2011-004770-28
Study First Received: March 28, 2012
Last Updated: April 9, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by sigma-tau i.f.r. S.p.A.:
Ulcerative colitis

Additional relevant MeSH terms:
Colitis
Colitis, Ulcerative
Ulcer
Colonic Diseases
Digestive System Diseases
Gastroenteritis
Gastrointestinal Diseases
Inflammatory Bowel Diseases
Intestinal Diseases
Pathologic Processes
Carnitine
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on November 20, 2014