Clinical trial NCT01567956: Propionyl-L-Carnitine Hydrochloride in Patients With Mild Ulcerative Colitis; Efficacy, Safety and Tolerability Study
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Ulcerative Colitis
Keywords: Ulcerative colitis
Lead sponsor: sigma-tau i.f.r. S.p.A.
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2012-03-30
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Proportion of clinical/endoscopic remissions
timeFrame: End of treatment (week 8)
Secondary outcomes:
measure: Change from baseline in Rectal bleeding evaluation
timeFrame: At week 2, 6 and 8 of treatment and after 4 week follow-up
measure: Change from baseline in stool frequency evaluation
timeFrame: At week 2, 6 and 8 of treatment and after 4 week follow-up
measure: Histological response to the treatment
timeFrame: End of treatment (week 8)
measure: Change from baseline in C-reactive protein (CRP) and Fibrinogen
timeFrame: End of the treatment (week 8) and after 4 week follow-up
measure: Improvement of patients quality of life
timeFrame: End of treatment period (week8) and after 4 week follow-up
measure: Haematology
timeFrame: Baseline and end of treatment (week8)
measure: Electrocardiogram
timeFrame: At baseline and at the end of treatment period (week8)
measure: Adverse Events collection
timeFrame: 12 weeks
measure: Serum Chemistry
timeFrame: At baseline and at the end of treatment period (week8)
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Landeskrankenhaus-Universitätskliniken Innsbruck - Klinische Abteilung für Gastroenterologie und Hepatologie
city: Salzburg
country: Austria
facility: Krankenhaus der Barmherzigen Brüder - Abteilung für Innere Medizin
city: Vienna
country: Austria
facility: Ordinationszentrum Döbling
city: Wien
country: Austria
facility: Allgemeines Krankenhaus Wien - Universitätsklinik Klinik für Innere Medizin III
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal Créteil 40 avenue de Verdun
city: Marseille
country: France
facility: Centre Hospitalier Universitaire Hôpital Nord - Service D'Hépato-Gastro-Entérologie
city: Nantes
country: France
facility: Centre Hospitalier Universitaire Hotel Dieu Service d'hépato-gastroentérologie
city: Nice cedex 3
country: France
facility: Hôpital de I´Archet 2 Service d'Hépato-Gastroentérologie et de Nutrition Clinicque, Pôle Digestif
city: Picardie
country: France
facility: Hôpital Nord - Dept. of Gastroenterology
city: Reims cedex
country: France
facility: Hôpital Robert Debré Service et Consultation d'Hépato-Gastro-Entérologie
city: Saint-Etienne
country: France
facility: Hopital Nord - CHU de Saint-Etienne Service de Gastro-Entérologie
city: Toulouse Cedex 4
country: France
facility: Hôpital Rangueil Service de gastro-enterologie
city: Vandoeuvre Les Nancy Cedex
country: France
facility: Hôpital Brabois Service de gastro-enterologie
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin Universitätsklinik Charité, Campus Mitte Medizinische Poliklinik
city: Bochum
country: Germany
facility: Saint Josef Hospital Ruhr Universitaet Bochum Gudrunstraße 56
city: Braunschweig
country: Germany
facility: Klinikum Braunschweig
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
city: Lübeck
country: Germany
facility: Universtätsklinikum Schleswig-Holstein Gastroenterologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg A.ö.R. Klinik für Gastroenterologie, Hepatologie und Infektiologie
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim II. Medizinische Klinik
city: München
country: Germany
facility: Praxis Prof. Dr. med. Herbert Kellner
city: Münster
country: Germany
facility: Universitätklinikum Münster Medizinische Klinik und Poliklinik für Innere Medizin
city: Münster
country: Germany
facility: Gastroenterologische Fachpraxis am Germania Campus
city: Stade
country: Germany
facility: Elbe Klinikum Stade Innere Medizin, Abteilung Gastroenterology
city: Budapest
country: Hungary
facility: Fovárosi Önkormányzat Péterfy Sándor Utcai Kórház
city: Budapest
country: Hungary
facility: Semmelweis Egyetem 1st Internal Dept.
city: Budapest
country: Hungary
facility: Pannónia Magánorvosi Centrum Kft.
city: Budapest
country: Hungary
facility: Semmelweis Egyetem II. sz. Belgyógyászati Klinika
city: Gyula
country: Hungary
facility: Békés Megyei Képviselotestület Pándy Kálmán Kórháza Semmelweis ulica 1
city: Kaposvár
country: Hungary
facility: Kaposi Mór Megyei Oktató Kórhaz Belgyógyászati Osztály
city: Miskolc
country: Hungary
facility: Borsod Abaúj Zemplén Megyei Kórház és Egyetemi Oktató Kórház II. sz. Belgyógyászati Osztály
city: Mosonmagyaróvar
country: Hungary
facility: Karolina Kórház Rendelointézet Belgyógyászat- Gasztroenterológiai Osztály
city: Szekszárd
country: Hungary
facility: Clinfan Kft. SMO
city: Szikszó
country: Hungary
facility: CRU Hungary Kft.
city: Daugavpils
country: Latvia
facility: Daugavpils Central Regional Hospital
city: Riga
country: Latvia
facility: Paula Stradina Clinical University Hospital Gastroenterology Centre
city: Riga
country: Latvia
facility: Latvian Maritime Medicine Centre
city: Riga
country: Latvia
facility: Digestive Disease Center GASTRO
city: Kaunas
country: Lithuania
facility: Lietuvos sveikatos mokslu universiteto ligonine VšI Kauno klinikos Gastroenterologijos skyrius
city: Klaipeda
country: Lithuania
facility: Klaipedos jurininku ligonine Diagnostikos skyrius
city: Vilnius
country: Lithuania
facility: VšI Mykolo Marcinkeviciaus ligonines
city: Vilnius
country: Lithuania
facility: Vilniaus universiteto ligonine Santariškiu klinikos Hepatologijos, gastroenterologijos ir dietologijos centras
city: Ksawerów
country: Poland
facility: Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska Sp.J
city: Lódz
country: Poland
facility: SPZOZ Uniwersytecki Szpital Kliniczny Nr 1 im. Norberta Barlickiego Oddzial Gastroenterologii Ogólnej i Onkologicznej
city: Olsztyn
country: Poland
facility: Wojewódzki Szpital Specjalistyczny w Olsztynie Oddzial Gastroenterologii
city: Sopot
country: Poland
facility: Endoskopia Sp. z o.o.
city: Warszawa
country: Poland
facility: Nzoz Vivamed
city: Wroclaw
country: Poland
facility: Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu Klinika Gastroenterologii i Hepatologii
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. J. Gromkowskiego we Wroclawiu Oddzial Gastroenterologii
city: Wroclaw
country: Poland
facility: LexMedica
city: Wroclaw
country: Poland
facility: ARS MEDICA s.c., Rybak Maria, Rybak Zbigniew
city: Alcorcón
country: Spain
facility: Fundación Hospital de Alcorcón Servicio de Gastroenterología
city: Barcelona
country: Spain
facility: Centro Medico Teknon Servicio de Aparato Disgestivo
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca Servicio de Digestivo
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa Unidad de Hepatología, Servicio de Gastroenterologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz Servico de Gastroenterologia
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí Servicio de Digestivo
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla Servicio de Digestivo
Study officials:
affiliation: Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY
name: Sandro Ardizzone, MD
role: STUDY_CHAIR
References: