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

Ulcerative Colitis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01567956
• Other study ID #: ST261DM11006
• Secondary ID: 2011-004770-28
• Status: Terminated
• Phase: Phase 3
• First received: March 28, 2012
• Last updated: November 4, 2016
• Start date: April 2012
• Est. completion date: January 2014

Study information

• Verified date: April 2014
• Source: sigma-tau i.f.r. S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• 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: 150
• Est. completion date: January 2014
• 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

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

Study Design

Allocation: Randomized, Endpoint Classification: 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
500 mg modified release tablets, 500 mg bid; treatment duration 8 weeks
• Placebo
500 mg inert substances modified release tablets, 500 mg bid; treatment duration 8 weeks

Locations

Country	Name	City	State
Austria	Landeskrankenhaus-Universitätskliniken Innsbruck - Klinische Abteilung für Gastroenterologie und Hepatologie	Innsbruck
Austria	Krankenhaus der Barmherzigen Brüder - Abteilung für Innere Medizin	Salzburg
Austria	Ordinationszentrum Döbling	Vienna
Austria	Allgemeines Krankenhaus Wien - Universitätsklinik Klinik für Innere Medizin III	Wien
France	Centre Hospitalier Intercommunal Créteil 40 avenue de Verdun	Creteil
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 cedex 3
France	Hôpital Nord - Dept. of Gastroenterology	Picardie
France	Hôpital Robert Debré Service et Consultation d'Hépato-Gastro-Entérologie	Reims cedex
France	Hopital Nord - CHU de Saint-Etienne Service de Gastro-Entérologie	Saint-Etienne
France	Hôpital Rangueil Service de gastro-enterologie	Toulouse Cedex 4
France	Hôpital Brabois Service de gastro-enterologie	Vandoeuvre Les Nancy Cedex
Germany	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	Gastroenterologische Fachpraxis am Germania Campus	Münster
Germany	Universitätklinikum Münster Medizinische Klinik und Poliklinik für Innere Medizin	Münster
Germany	Elbe Klinikum Stade Innere Medizin, Abteilung Gastroenterology	Stade
Hungary	Fovárosi Önkormányzat Péterfy Sándor Utcai Kórház	Budapest
Hungary	Pannónia Magánorvosi Centrum Kft.	Budapest
Hungary	Semmelweis Egyetem 1st Internal Dept.	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
Latvia	Daugavpils Central Regional Hospital	Daugavpils
Latvia	Digestive Disease Center GASTRO	Riga
Latvia	Latvian Maritime Medicine Centre	Riga
Latvia	Paula Stradina Clinical University Hospital Gastroenterology Centre	Riga
Lithuania	Lietuvos sveikatos mokslu universiteto ligonine VšI Kauno klinikos Gastroenterologijos skyrius	Kaunas
Lithuania	Klaipedos jurininku ligonine Diagnostikos skyrius	Klaipeda
Lithuania	VšI Mykolo Marcinkeviciaus ligonines	Vilnius
Lithuania	Vilniaus universiteto ligonine Santariškiu klinikos Hepatologijos, gastroenterologijos ir dietologijos centras	Vilnius
Poland	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	Warszawa
Poland	Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu Klinika Gastroenterologii i Hepatologii	Wroclaw
Poland	ARS MEDICA s.c., Rybak Maria, Rybak Zbigniew	Wroclaw
Poland	LexMedica	Wroclaw
Poland	Wojewodzki Szpital Specjalistyczny im. J. Gromkowskiego we Wroclawiu Oddzial Gastroenterologii	Wroclaw
Spain	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 Paz Servico de Gastroenterologia	Madrid
Spain	Hospital Universitario La Princesa Unidad de Hepatología, Servicio de Gastroenterologia	Madrid
Spain	Corporació Sanitaria Parc Taulí Servicio de Digestivo	Sabadell
Spain	Hospital Universitario Marques de Valdecilla Servicio de Digestivo	Santander

Sponsors (2)

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

Countries where clinical trial is conducted

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

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	Haemoglobin, Haematocrit, RBC, WBC and differential count.	Baseline and end of treatment (week8)	Yes
Secondary	Electrocardiogram	Standard intervals (PR, RR, QRS, QT) will be collected plus all rhythm abnormalities	At baseline and at the end of treatment period (week8)	Yes
Secondary	Adverse Events collection		12 weeks	Yes
Secondary	Serum Chemistry	Standard evaluation including renal and liver function, electrolytes and blood glucose	At baseline and at the end of treatment period (week8)	Yes