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

NCT ID: NCT01567956

Last Updated: 2016-11-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-04-30
• Study Completion Date: 2014-01-31

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

Study Design

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

Study Groups

Propionyl-L-Carnitine

Modified release tablets containing 500 mg of propionyl-L-carnitine

Group Type: EXPERIMENTAL

Propionyl-L-Carnitine

Intervention Type: DRUG

500 mg modified release tablets, 500 mg bid; treatment duration 8 weeks

Placebo

Modified release tablets containing inert substances

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

500 mg inert substances modified release tablets, 500 mg bid; treatment duration 8 weeks

Interventions

Propionyl-L-Carnitine

500 mg modified release tablets, 500 mg bid; treatment duration 8 weeks

Intervention Type: DRUG

Placebo

500 mg inert substances modified release tablets, 500 mg bid; treatment duration 8 weeks

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
• Patients treated with L-Carnitine or its esters derivatives during the 3 months preceding the screening phase.

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

Sponsors

PRA Health Sciences

INDUSTRY

Sponsor Role: collaborator

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

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sandro Ardizzone, MD

Role: STUDY_CHAIR

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

Locations

Landeskrankenhaus-Universitätskliniken Innsbruck - Klinische Abteilung für Gastroenterologie und Hepatologie

Innsbruck, , Austria

Krankenhaus der Barmherzigen Brüder - Abteilung für Innere Medizin

Salzburg, , Austria

Allgemeines Krankenhaus Wien - Universitätsklinik Klinik für Innere Medizin III

Vienna, , Austria

Ordinationszentrum Döbling

Vienna, , Austria

Centre Hospitalier Intercommunal Créteil 40 avenue de Verdun

Créteil, , France

Centre Hospitalier Universitaire Hôpital Nord - Service D'Hépato-Gastro-Entérologie

Marseille, , France

Centre Hospitalier Universitaire Hotel Dieu Service d'hépato-gastroentérologie

Nantes, , France

Hôpital de I´Archet 2 Service d'Hépato-Gastroentérologie et de Nutrition Clinicque, Pôle Digestif

Nice, , France

Hôpital Nord - Dept. of Gastroenterology

Picardie, , France

Hôpital Robert Debré Service et Consultation d'Hépato-Gastro-Entérologie

Reims, , France

Hopital Nord - CHU de Saint-Etienne Service de Gastro-Entérologie

Saint-Etienne, , France

Hôpital Rangueil Service de gastro-enterologie

Toulouse, , France

Hôpital Brabois Service de gastro-enterologie

Vandœuvre-lès-Nancy, , France

Charité Universitätsmedizin Berlin Universitätsklinik Charité, Campus Mitte Medizinische Poliklinik

Berlin, , Germany

Saint Josef Hospital Ruhr Universitaet Bochum Gudrunstraße 56

Bochum, , Germany

Klinikum Braunschweig

Braunschweig, , Germany

Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I

Dresden, , Germany

Universtätsklinikum Schleswig-Holstein Gastroenterologie

Lübeck, , Germany

Universitätsklinikum Magdeburg A.ö.R. Klinik für Gastroenterologie, Hepatologie und Infektiologie

Magdeburg, , Germany

Universitätsmedizin Mannheim II. Medizinische Klinik

Mannheim, , Germany

Praxis Prof. Dr. med. Herbert Kellner

München, , Germany

Universitätklinikum Münster Medizinische Klinik und Poliklinik für Innere Medizin

Münster, , Germany

Gastroenterologische Fachpraxis am Germania Campus

Münster, , Germany

Elbe Klinikum Stade Innere Medizin, Abteilung Gastroenterology

Stade, , Germany

Fovárosi Önkormányzat Péterfy Sándor Utcai Kórház

Budapest, , Hungary

Semmelweis Egyetem 1st Internal Dept.

Budapest, , Hungary

Pannónia Magánorvosi Centrum Kft.

Budapest, , Hungary

Semmelweis Egyetem II. sz. Belgyógyászati Klinika

Budapest, , Hungary

Békés Megyei Képviselotestület Pándy Kálmán Kórháza Semmelweis ulica 1

Gyula, , Hungary

Kaposi Mór Megyei Oktató Kórhaz Belgyógyászati Osztály

Kaposvár, , Hungary

Borsod Abaúj Zemplén Megyei Kórház és Egyetemi Oktató Kórház II. sz. Belgyógyászati Osztály

Miskolc, , Hungary

Karolina Kórház Rendelointézet Belgyógyászat- Gasztroenterológiai Osztály

Mosonmagyaróvar, , Hungary

Clinfan Kft. SMO

Szekszárd, , Hungary

CRU Hungary Kft.

Szikszó, , Hungary

Daugavpils Central Regional Hospital

Daugavpils, , Latvia

Paula Stradina Clinical University Hospital Gastroenterology Centre

Riga, , Latvia

Latvian Maritime Medicine Centre

Riga, , Latvia

Digestive Disease Center GASTRO

Riga, , Latvia

Lietuvos sveikatos mokslu universiteto ligonine VšI Kauno klinikos Gastroenterologijos skyrius

Kaunas, , Lithuania

Klaipedos jurininku ligonine Diagnostikos skyrius

Klaipėda, , Lithuania

VšI Mykolo Marcinkeviciaus ligonines

Vilnius, , Lithuania

Vilniaus universiteto ligonine Santariškiu klinikos Hepatologijos, gastroenterologijos ir dietologijos centras

Vilnius, , Lithuania

Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska Sp.J

Ksawerów, , Poland

SPZOZ Uniwersytecki Szpital Kliniczny Nr 1 im. Norberta Barlickiego Oddzial Gastroenterologii Ogólnej i Onkologicznej

Lódz, , Poland

Wojewódzki Szpital Specjalistyczny w Olsztynie Oddzial Gastroenterologii

Olsztyn, , Poland

Endoskopia Sp. z o.o.

Sopot, , Poland

Nzoz Vivamed

Warsaw, , Poland

Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu Klinika Gastroenterologii i Hepatologii

Wroclaw, , Poland

Wojewodzki Szpital Specjalistyczny im. J. Gromkowskiego we Wroclawiu Oddzial Gastroenterologii

Wroclaw, , Poland

LexMedica

Wroclaw, , Poland

ARS MEDICA s.c., Rybak Maria, Rybak Zbigniew

Wroclaw, , Poland

Fundación Hospital de Alcorcón Servicio de Gastroenterología

Alcorcón, , Spain

Centro Medico Teknon Servicio de Aparato Disgestivo

Barcelona, , Spain

Hospital Universitario Virgen de la Arrixaca Servicio de Digestivo

El Palmar, , Spain

Hospital Universitario La Princesa Unidad de Hepatología, Servicio de Gastroenterologia

Madrid, , Spain

Hospital Universitario La Paz Servico de Gastroenterologia

Madrid, , Spain

Corporació Sanitaria Parc Taulí Servicio de Digestivo

Sabadell, , Spain

Hospital Universitario Marques de Valdecilla Servicio de Digestivo

Santander, , Spain

Countries

Austria; France; Germany; Hungary; Latvia; Lithuania; Poland; Spain

Other Identifiers

2011-004770-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ST261DM11006

Identifier Type: -

Identifier Source: org_study_id