Clinical trial NCT01538251: Efficacy, Safety and Tolerability of Propionyl-L-Carnitine Hydrochloride in Patients With Mild Ulcerative Colitis
Official title: 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
propionyl-l-carnitine
Lead sponsor: sigma-tau i.f.r. S.p.A.
Sponsor class: INDUSTRY
First posted: 2012-02-24
Enrollment: 147
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.

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: 8 weeks
measure: Serum Chemistry
timeFrame: At baseline and at the end of treatment period (week8)
Other outcomes:
Locations:
city: Bonheiden
country: Belgium
facility: Imelda Ziekenhuis
state: Antwerpen
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuis Gasthuisberg
state: Flemish Brabant
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
state: Oost-vlaanderen
city: Roeselare
country: Belgium
facility: H. Hartziekenhuis Roeselare-Menen vzw
state: West-vlaanderen
city: Ceské Budejovice
country: Czech Republic
facility: Derma Plus s.r.o.
city: Hradec Kralove
country: Czech Republic
facility: Hepato-Gastroenterology HK s.r.o.
city: Olomouc
country: Czech Republic
facility: Fakultní nemocnice Olomouc
city: Praha 10
country: Czech Republic
facility: G.E.P. Clinic s.r.o.
city: Praha 1
country: Czech Republic
facility: MONSE s.r.o
city: Praha 4 - Krc
country: Czech Republic
facility: Fakultní Thomayerova nemocnice s poliklinikou
city: Praha 5
country: Czech Republic
facility: Fakultní Nemocnice v Motole
city: Tábor
country: Czech Republic
facility: Nemocnice Tábor, a.s.
city: Ústí nad Orlicí
country: Czech Republic
facility: Orlickoústecká Nemocnice a.s
city: Beer Sheva
country: Israel
facility: Soroka University Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Organization, Ein Kerem
city: Kfar-Saba
country: Israel
facility: Meir Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Souraski Medical Center
city: Zerifin
country: Israel
facility: Assaf Harofeh Medical Centre
city: Forlì
country: Italy
facility: Ospedale "G.B.Morgagni - L. Pierantoni"
state: Forli-cesena
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Milano
country: Italy
facility: Ospedale Luigi Sacco - Az. Osp. Dept. of Gastroenterology
city: Napoli
country: Italy
facility: Policlinico Universitario Federico II
city: Pavia
country: Italy
facility: IRCSS Policlinico San Matteo
city: Roma
country: Italy
facility: Azienda Ospedaliera S. Camillo Forlanini, Roma
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
state: Noord-holland
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid-holland
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Tirgu Mures
country: Romania
facility: CMI de Gastroenterologie Dobru Daniela
state: Mures
city: Brasov
country: Romania
facility: Neomed Research
city: Bucuresti
country: Romania
facility: Centrul Medical Sana
city: Bucuresti
country: Romania
facility: Endocenter Medicina Integrativa SRL
city: Iasi
country: Romania
facility: Gastromedica SRL
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean De Urgenta Sibiu
city: Timisoara
country: Romania
facility: Policlinic Algomed SRL
city: Moscow
country: Russian Federation
facility: State Scientific Centre of Coloproctology
city: Novosibirsk
country: Russian Federation
facility: State Educational Institution of Higher Professional Education Novosibirsk State Medical University
city: Novosibirsk
country: Russian Federation
facility: State Research Institute of Physiology of Siberian Branch of Russian Academy of Medical Sciences
city: Rostov-on-Don
country: Russian Federation
facility: GOU VPO Rostov State Medical University
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg GUZ City Policlinic 38
city: Saint Petersburg
country: Russian Federation
facility: Regional Military Clinical Hospital ¿ 442 named after Z.P. Solovyov of Ministry of Defence of Russia
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg State Institution of Health Protection City Hospital # 26
city: Saint Petersburg
country: Russian Federation
facility: Krestovsky Medical Institute
city: Saratov
country: Russian Federation
facility: Saratov City Hospital #2
city: St. Petersburg
country: Russian Federation
facility: Saint-Petersburg Medical Academy
city: Stavropol
country: Russian Federation
facility: State Educational Institution of Higher Professional Education "Stavropol State Medical Academy"
city: Yaroslavl
country: Russian Federation
facility: Clinical Hospital #2
city: Banská Bystrica
country: Slovakia
facility: NovaMed spol. s.r.o.
city: Bratislava
country: Slovakia
facility: UNB Nemocnica Staré Mesto
city: Bratislava
country: Slovakia
facility: ABAWI spol.s.r.o.
city: Bratislava
country: Slovakia
facility: Lama Medical Care s.r.o., Gastroentero-hepatologicke centrum Thalion
city: Bratislava
country: Slovakia
facility: Neštátna Gastroenterologická Ambulancia
city: Nitra
country: Slovakia
facility: KM Management sro
city: Prešov
country: Slovakia
facility: Gastro I.s.r.o.
city: Trnava
country: Slovakia
facility: GEA s.r.o Gastroenterologicka ambulancia
Study officials:
affiliation: Head of Inflammatory Bowel Diseases Unit Hospital "Luigi Sacco" Milan - ITALY
name: Sandro Ardizzone, MD
role: STUDY_DIRECTOR
References: