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

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

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 Overview

• Status: Terminated
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Propionyl-L-Carnitine; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen
    • Bonheiden, Antwerpen, Belgium, 2820
      • Imelda Ziekenhuis
  • Flemish Brabant
    • Leuven, Flemish Brabant, Belgium, 3000
      • Universitaire Ziekenhuis Gasthuisberg
  • Oost-vlaanderen
    • Ghent, Oost-vlaanderen, Belgium, 9000
      • Universitair Ziekenhuis Gent
  • West-vlaanderen
    • Roeselare, West-vlaanderen, Belgium, 8800
      • H. Hartziekenhuis Roeselare-Menen vzw
• Czech Republic
  • Ceské Budejovice, Czech Republic, 370 01
    • Derma Plus s.r.o.
  • Hradec Kralove, Czech Republic, 500 12
    • Hepato-Gastroenterology HK s.r.o.
  • Olomouc, Czech Republic, 775 20
    • Fakultni Nemocnice Olomouc
  • Praha 1, Czech Republic, 118 33
    • MONSE s.r.o
  • Praha 10, Czech Republic, 100 00
    • G.E.P. Clinic s.r.o.
  • Praha 4 - Krc, Czech Republic, 140 59
    • Fakultni Thomayerova nemocnice s poliklinikou
  • Praha 5, Czech Republic, 15006
    • Fakultni nemocnice v Motole
  • Tábor, Czech Republic, 390 03
    • Nemocnice Tabor, a.s.
  • Ústí nad Orlicí, Czech Republic, 562 18
    • Orlickoústecká Nemocnice a.s
• Israel
  • Beer Sheva, Israel, 84100
    • Soroka University Medical Center
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center
  • Jerusalem, Israel
    • Hadassah Medical Organization, Ein Kerem
  • Kfar-Saba, Israel, 44281
    • Meir Medical Center
  • Petah Tikva, Israel, 49100
    • Rabin Medical Center
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Souraski Medical Center
  • Zerifin, Israel, 70300
    • Assaf Harofeh Medical Centre
• Italy
  • Milano, Italy, 20157
    • Ospedale Luigi Sacco - Az. Osp. Dept. of Gastroenterology
  • Napoli, Italy, 80131
    • Policlinico Universitario Federico II
  • Pavia, Italy, 27100
    • IRCSS Policlinico San Matteo
  • Roma, Italy, 00168
    • Policlinico Universitario Agostino Gemelli
  • Roma, Italy, 00152
    • Azienda Ospedaliera S. Camillo Forlanini, Roma
  • Forli-cesena
    • Forlì, Forli-cesena, Italy, 47100
      • Ospedale "G.B.Morgagni - L. Pierantoni"
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Istituto Clinico Humanitas
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • UMC Utrecht
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1091 AC
      • Onze Lieve Vrouwe Gasthuis
  • Zuid-holland
    • Leiden, Zuid-holland, Netherlands, 2333 ZA
      • Leids Universitair Medisch Centrum
• Romania
  • Brasov, Romania, 500283
    • Neomed Research
  • Bucuresti, Romania, 011025
    • Centrul Medical Sana
  • Bucuresti, Romania, 021978
    • Endocenter Medicina Integrativa SRL
  • Iasi, Romania, 700506
    • GastroMedica SRL
  • Sibiu, Romania, 550245
    • Spitalul Clinic Judetean De Urgenta Sibiu
  • Timisoara, Romania, 300002
    • Policlinic Algomed SRL
  • Mures
    • Tirgu Mures, Mures, Romania, 540461
      • CMI de Gastroenterologie Dobru Daniela
• Russian Federation
  • Moscow, Russian Federation, 123423
    • State Scientific Centre of Coloproctology
  • Novosibirsk, Russian Federation, 630091
    • State Educational Institution of Higher Professional Education Novosibirsk State Medical University
  • Novosibirsk, Russian Federation, 630117
    • State Research Institute of Physiology of Siberian Branch of Russian Academy of Medical Sciences
  • Rostov-on-Don, Russian Federation, 344022
    • GOU VPO Rostov State Medical University
  • Saint Petersburg, Russian Federation, 193015
    • Saint Petersburg GUZ City Policlinic 38
  • Saint Petersburg, Russian Federation, 193124
    • Regional Military Clinical Hospital ¿ 442 named after Z.P. Solovyov of Ministry of Defence of Russia
  • Saint Petersburg, Russian Federation, 196247
    • Saint-Petersburg State Institution of Health Protection City Hospital # 26
  • Saint Petersburg, Russian Federation, 197110
    • Krestovsky Medical Institute
  • Saratov, Russian Federation, 410053
    • Saratov City Hospital #2
  • St. Petersburg, Russian Federation, 195067
    • Saint-Petersburg Medical Academy
  • Stavropol, Russian Federation, 355017
    • State Educational Institution of Higher Professional Education "Stavropol State Medical Academy"
  • Yaroslavl, Russian Federation, 150010
    • Clinical Hospital #2
• Slovakia
  • Banská Bystrica, Slovakia, 974 01
    • NovaMed spol. s.r.o.
  • Bratislava, Slovakia, 813 69
    • UNB Nemocnica Staré Mesto
  • Bratislava, Slovakia, 82101
    • ABAWI spol.s.r.o.
  • Bratislava, Slovakia, 831 04
    • Lama Medical Care s.r.o., Gastroentero-hepatologicke centrum Thalion
  • Bratislava, Slovakia, 851 01
    • Neštátna Gastroenterologická Ambulancia
  • Nitra, Slovakia, 950 01
    • KM Management sro
  • Prešov, Slovakia, 08001
    • Gastro I.s.r.o.
  • Trnava, Slovakia, 91701
    • GEA s.r.o Gastroenterologicka ambulancia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Propionyl-L-carnitine; modified release tablets 500 mg	Drug: Propionyl-L-Carnitine; Modified release tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.
Placebo Comparator: Placebo; Modified release tablet 500 mg	Drug: Placebo; Tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of clinical/endoscopic remissions	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.	End of treatment (week 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Rectal bleeding evaluation	Evaluation will be performed by means of Disease Activity Index (DAI) sub-score (from 0 to 3).	At week 2, 6 and 8 of treatment and after 4 week follow-up
Change from baseline in stool frequency evaluation	Evaluations will be performed by means of Disease Activity Index (DAI) sub-score (from 0 to 3).	At week 2, 6 and 8 of treatment and after 4 week follow-up
Histological response to the treatment	Evaluated as an improvement of the histological index of at least 1 point	End of treatment (week 8)
Change from baseline in C-reactive protein (CRP) and Fibrinogen		End of the treatment (week 8) and after 4 week follow-up
Improvement of patients quality of life	A validated specific questionnaire, the SIBDQ by McMaster university will be administered to evaluate changes in patients' quality of life	End of treatment period (week8) and after 4 week follow-up
Haematology		Baseline and end of treatment (week8)
Electrocardiogram		At baseline and at the end of treatment period (week8)
Adverse Events collection		8 weeks
Serum Chemistry		At baseline and at the end of treatment period (week8)

Collaborators and Investigators

• Sponsor: sigma-tau i.f.r. S.p.A.
• Investigators: Study Director: Sandro Ardizzone, MD, Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: February 20, 2012
• First Submitted That Met QC Criteria: February 23, 2012
• First Posted (Estimate): February 24, 2012

Study Record Updates

• Last Update Posted (Estimate): November 6, 2016
• Last Update Submitted That Met QC Criteria: November 4, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: ulcerative colitis; propionyl-l-carnitine
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: ST261DM11005; 2011-004765-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No