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

Ulcerative Colitis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01538251
• Other study ID #: ST261DM11005
• Secondary ID: 2011-004765-32
• Status: Terminated
• Phase: Phase 3
• First received: February 20, 2012
• Last updated: November 4, 2016
• Start date: April 2012
• Est. completion date: December 2013

Study information

• Verified date: November 2016
• Source: sigma-tau i.f.r. S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 147
• Est. completion date: December 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• Propionyl-L-Carnitine
Modified release tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.
• Placebo
Tablets containing 500 mg of propionyl-L-carnitine. one tablet twice a day.

Locations

Country	Name	City	State
Belgium	Imelda Ziekenhuis	Bonheiden	Antwerpen
Belgium	Universitair Ziekenhuis Gent	Ghent	Oost-vlaanderen
Belgium	Universitaire Ziekenhuis Gasthuisberg	Leuven	Flemish Brabant
Belgium	H. Hartziekenhuis Roeselare-Menen vzw	Roeselare	West-vlaanderen
Czech Republic	Derma Plus s.r.o.	Ceské Budejovice
Czech Republic	Hepato-Gastroenterology HK s.r.o.	Hradec Kralove
Czech Republic	Fakultní nemocnice Olomouc	Olomouc
Czech Republic	MONSE s.r.o	Praha 1
Czech Republic	G.E.P. Clinic s.r.o.	Praha 10
Czech Republic	Fakultní Thomayerova nemocnice s poliklinikou	Praha 4 - Krc
Czech Republic	Fakultní Nemocnice v Motole	Praha 5
Czech Republic	Nemocnice Tábor, a.s.	Tábor
Czech Republic	Orlickoústecká Nemocnice a.s	Ústí nad Orlicí
Israel	Soroka University Medical Center	Beer Sheva
Israel	Hadassah Medical Organization, Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Center	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	Zerifin
Italy	Ospedale "G.B.Morgagni - L. Pierantoni"	Forlì	Forli-cesena
Italy	Ospedale Luigi Sacco - Az. Osp. Dept. of Gastroenterology	Milano
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	Istituto Clinico Humanitas	Rozzano	Milano
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam	Noord-holland
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-holland
Netherlands	UMC Utrecht	Utrecht
Romania	Neomed Research	Brasov
Romania	Centrul Medical Sana	Bucuresti
Romania	Endocenter Medicina Integrativa SRL	Bucuresti
Romania	Gastromedica SRL	Iasi
Romania	Spitalul Clinic Judetean De Urgenta Sibiu	Sibiu
Romania	Policlinic Algomed SRL	Timisoara
Romania	CMI de Gastroenterologie Dobru Daniela	Tirgu Mures	Mures
Russian Federation	State Scientific Centre of Coloproctology	Moscow
Russian Federation	State Educational Institution of Higher Professional Education Novosibirsk State Medical University	Novosibirsk
Russian Federation	State Research Institute of Physiology of Siberian Branch of Russian Academy of Medical Sciences	Novosibirsk
Russian Federation	GOU VPO Rostov State Medical University	Rostov-on-Don
Russian Federation	Krestovsky Medical Institute	Saint Petersburg
Russian Federation	Regional Military Clinical Hospital ¿ 442 named after Z.P. Solovyov of Ministry of Defence of Russia	Saint Petersburg
Russian Federation	Saint Petersburg GUZ City Policlinic 38	Saint Petersburg
Russian Federation	Saint-Petersburg State Institution of Health Protection City Hospital # 26	Saint Petersburg
Russian Federation	Saratov City Hospital #2	Saratov
Russian Federation	Saint-Petersburg Medical Academy	St. Petersburg
Russian Federation	State Educational Institution of Higher Professional Education "Stavropol State Medical Academy"	Stavropol
Russian Federation	Clinical Hospital #2	Yaroslavl
Slovakia	NovaMed spol. s.r.o.	Banská Bystrica
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	UNB Nemocnica Staré Mesto	Bratislava
Slovakia	KM Management sro	Nitra
Slovakia	Gastro I.s.r.o.	Prešov
Slovakia	GEA s.r.o Gastroenterologicka ambulancia	Trnava

Sponsors (1)

Lead Sponsor	Collaborator
sigma-tau i.f.r. S.p.A.

Countries where clinical trial is conducted

Belgium,  Czech Republic,  Israel,  Italy,  Netherlands,  Romania,  Russian Federation,  Slovakia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	Histological response to the treatment	Evaluated as an improvement of the histological index of at least 1 point	End of treatment (week 8)	No
Secondary	Change from baseline in C-reactive protein (CRP) and Fibrinogen		End of the treatment (week 8) and after 4 week follow-up	No
Secondary	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	No
Secondary	Haematology		Baseline and end of treatment (week8)	Yes
Secondary	Electrocardiogram		At baseline and at the end of treatment period (week8)	Yes
Secondary	Adverse Events collection		8 weeks	Yes
Secondary	Serum Chemistry		At baseline and at the end of treatment period (week8)	Yes