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

NCT ID: NCT01538251

Last Updated: 2016-11-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 147 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-04-30
• Study Completion Date: 2013-12-31

Brief Summary

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.

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.

Conditions

Ulcerative Colitis

Keywords

ulcerative colitis; propionyl-l-carnitine

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Propionyl-L-carnitine

modified release tablets 500 mg

Group Type: EXPERIMENTAL

Propionyl-L-Carnitine

Intervention Type: DRUG

Modified release tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

Placebo

Modified release tablet 500 mg

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

Interventions

Propionyl-L-Carnitine

Modified release tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

Intervention Type: DRUG

Placebo

Tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

sigma-tau i.f.r. S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sandro Ardizzone, MD

Role: STUDY_DIRECTOR

Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY

Locations

Imelda Ziekenhuis

Bonheiden, Antwerpen, Belgium

Universitaire Ziekenhuis Gasthuisberg

Leuven, Flemish Brabant, Belgium

Universitair Ziekenhuis Gent

Ghent, Oost-vlaanderen, Belgium

H. Hartziekenhuis Roeselare-Menen vzw

Roeselare, West-vlaanderen, Belgium

Derma Plus s.r.o.

České Budějovice, , Czechia

Hepato-Gastroenterology HK s.r.o.

Hradec Králové, , Czechia

Fakultní nemocnice Olomouc

Olomouc, , Czechia

G.E.P. Clinic s.r.o.

Prague, , Czechia

MONSE s.r.o

Prague, , Czechia

Fakultní Nemocnice v Motole

Prague, , Czechia

Fakultní Thomayerova nemocnice s poliklinikou

Praha 4 - Krc, , Czechia

Nemocnice Tábor, a.s.

Tábor, , Czechia

Orlickoústecká Nemocnice a.s

Ústí nad Orlicí, , Czechia

Soroka University Medical Center

Beersheba, , Israel

Shaare Zedek Medical Center

Jerusalem, , Israel

Hadassah Medical Organization, Ein Kerem

Jerusalem, , Israel

Meir Medical Center

Kfar Saba, , Israel

Rabin Medical Center

Petah Tikva, , Israel

Kaplan Medical Center

Rehovot, , Israel

Tel Aviv Souraski Medical Center

Tel Aviv, , Israel

Assaf Harofeh Medical Centre

Ẕerifin, , Israel

Ospedale "G.B.Morgagni - L. Pierantoni"

Forlì, Forli-cesena, Italy

Istituto Clinico Humanitas

Rozzano, Milano, Italy

Ospedale Luigi Sacco - Az. Osp. Dept. of Gastroenterology

Milan, , Italy

Policlinico Universitario Federico II

Napoli, , Italy

IRCSS Policlinico San Matteo

Pavia, , Italy

Azienda Ospedaliera S. Camillo Forlanini, Roma

Roma, , Italy

Policlinico Universitario Agostino Gemelli

Roma, , Italy

Onze Lieve Vrouwe Gasthuis

Amsterdam, North Holland, Netherlands

Leids Universitair Medisch Centrum

Leiden, South Holland, Netherlands

UMC Utrecht

Utrecht, Utrecht, Netherlands

CMI de Gastroenterologie Dobru Daniela

Târgu Mureş, Mureș County, Romania

Neomed Research

Brasov, , Romania

Centrul Medical Sana

Bucharest, , Romania

Endocenter Medicina Integrativa SRL

Bucharest, , Romania

Gastromedica SRL

Iași, , Romania

Spitalul Clinic Judetean De Urgenta Sibiu

Sibiu, , Romania

Policlinic Algomed SRL

Timișoara, , Romania

State Scientific Centre of Coloproctology

Moscow, , Russia

State Educational Institution of Higher Professional Education Novosibirsk State Medical University

Novosibirsk, , Russia

State Research Institute of Physiology of Siberian Branch of Russian Academy of Medical Sciences

Novosibirsk, , Russia

GOU VPO Rostov State Medical University

Rostov-on-Don, , Russia

Saint Petersburg GUZ City Policlinic 38

Saint Petersburg, , Russia

Regional Military Clinical Hospital ¿ 442 named after Z.P. Solovyov of Ministry of Defence of Russia

Saint Petersburg, , Russia

Saint-Petersburg Medical Academy

Saint Petersburg, , Russia

Saint-Petersburg State Institution of Health Protection City Hospital # 26

Saint Petersburg, , Russia

Krestovsky Medical Institute

Saint Petersburg, , Russia

Saratov City Hospital #2

Saratov, , Russia

State Educational Institution of Higher Professional Education "Stavropol State Medical Academy"

Stavropol, , Russia

Clinical Hospital #2

Yaroslavl, , Russia

NovaMed spol. s.r.o.

Banská Bystrica, , Slovakia

UNB Nemocnica Staré Mesto

Bratislava, , Slovakia

ABAWI spol.s.r.o.

Bratislava, , Slovakia

Lama Medical Care s.r.o., Gastroentero-hepatologicke centrum Thalion

Bratislava, , Slovakia

Neštátna Gastroenterologická Ambulancia

Bratislava, , Slovakia

KM Management sro

Nitra, , Slovakia

Gastro I.s.r.o.

Prešov, , Slovakia

GEA s.r.o Gastroenterologicka ambulancia

Trnava, , Slovakia

Countries

Belgium; Czechia; Israel; Italy; Netherlands; Romania; Russia; Slovakia

Other Identifiers

2011-004765-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ST261DM11005

Identifier Type: -

Identifier Source: org_study_id