High-dose Ribavirin in Treatment of Chronic Hepatitis C Genotype 1 or 4 (VIRID)
High-dose Versus Standard-dose Weight-based Ribavirin in Combination With Peginterferon Alfa-2a for Patients Infected With Hepatitis C Virus Genotype 1 or 4
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
Optimal ribavirin dosages are essential in achieving SVR. The initial evidence supporting higher doses of ribavirin for peginterferon alfa-2b comes from a secondary analysis of the pivotal multicenter trial of peginterferon alfa-2b and ribavirin. Patients receiving more than 10.6 mg/kg/day ribavirin experienced significantly higher SVR rates (48% vs. 38%). A large multicenter trial designed to test standard dose ribavirin (1000-1200 mg/day) versus low-dose ribavirin (800 mg/day) in combination with peginterferon alfa-2a, showed 52% SVR in the standard dose group versus 41% in the low-dose group for genotype 1 infected patients. In the pooled data from two pivotal studies with peginterferon alfa-2a and ribavirin, the probability of achieving an SVR for genotype 1 patients was influenced by the ribavirin dose per kg body weight. A 40-50% increase in the probability of SVR was found for a 12-16 mg/kg dose increase of ribavirin. For peginterferon alfa-2b it was also shown among genotype 1 patients, that weight-based ribavirin (800-1400 mg/day) leads to higher SVR rates compared to fixed dose ribavirin (800 mg/day) (34% vs. 29%). Moreover, ribavirin dosing up to 1400 mg/day was safe and the rate of treatment discontinuation was the same for both treatment groups. In a small pilot study, 10 genotype 1 patients with a high baseline load were treated with peginterferon alfa-2a and individualized high-dose ribavirin in order to achieve a ribavirin target concentration in serum of 15 μmol/l. The mean ribavirin dose of 2540 mg/day (range 1600-3600 mg/day) was high, but resulted in 90% SVR. All patients experienced severe anemia, which was treated with concomitant epoetin beta and blood transfusion.
As mentioned before, the main concern of high-dose ribavirin will be a dose-dependent hemolytic anemia and the addition of epoetin alfa has shown significant increase of haemoglobin during (peg)interferon/ribavirin therapy. Erythropoietin doses from 9,000 to 60,000 IU/week have been used in order keep the highest possible ribavirin doses. A recent trial showed a significant higher SVR rate in genotype 1 patients treated with peginterferon alfa-2b, increased dose ribavirin (15.2 mg/kg/day) and epoetin alfa than in patients treated with peginterferon alfa-2b and standard dose ribavirin (13.3 mg/kg/day) with or without epoetin alfa. Using the standard ribavirin dose, routine use of erythropoietin significantly decreased the frequency of anemia and the mean ribavirin dose reduction. Moreover, with the addition of erythropoietin, a significant higher mean dose could be given to patients in the increased ribavirin dose arm.
Tipo di studio
Iscrizione (Effettivo)
Fase
- Fase 3
Contatti e Sedi
Luoghi di studio
-
-
-
Groningen, Olanda, 9713GZ
- Groningen University Medical Center
-
Utrecht, Olanda, 3584CX
- Universitair Medisch Centrum Utrecht
-
-
Gelderland
-
Arnhem, Gelderland, Olanda, 6815AD
- Rijnstate
-
Nijmegen, Gelderland, Olanda, 6532 SZ
- Canisius-Wilhelmina Ziekenhuis
-
Nijmegen, Gelderland, Olanda, 6525GA
- St. Radboud University Medical Center
-
-
Groningen
-
Winschoten, Groningen, Olanda, 9670RA
- St. Lucas Hospital
-
-
Limburg
-
Heerlen, Limburg, Olanda, 6401CX
- Atrium medisch centrum
-
-
Noord Brabant
-
Breda, Noord Brabant, Olanda, 4818CK
- Amphia Hospital
-
Eindhoven, Noord Brabant, Olanda, 5602ZA
- Catharina Hospital
-
Tilburg, Noord Brabant, Olanda, 5000LA
- Twee Steden Hospital
-
Tilburg, Noord Brabant, Olanda, 5000LC
- St. Elisabeth Hospital
-
-
Noord Holland
-
Alkmaar, Noord Holland, Olanda, 1815JD
- Medisch Centrum Alkmaar
-
Amsterdam, Noord Holland, Olanda, 1006BK
- Slotervaart Hospital
-
Amsterdam, Noord Holland, Olanda, 1007 MB
- VU Medisch Centrum
-
Amsterdam, Noord Holland, Olanda, 1090HM
- Onze Lieve Vrouwen Gasthuis
-
Hoofddorp, Noord Holland, Olanda, 2130 AT
- Spaarne Ziekenhuis
-
-
Overijssel
-
Deventer, Overijssel, Olanda, 7415CM
- Deventer Hospital
-
-
Zeeland
-
Terneuzen, Zeeland, Olanda, 4535PA
- ZorgSaam Hospital
-
Vlissingen, Zeeland, Olanda, 3200
- Walcheren hospital
-
-
Zuid Holland
-
Capelle aan de IJssel, Zuid Holland, Olanda, 2906ZC
- Ijsselland Hospital
-
Delft, Zuid Holland, Olanda, 2600GA
- Reinier de Graaf Gasthuis
-
Den Haag, Zuid Holland, Olanda, 2545CH
- Haga Ziekenhuis
-
Dordrecht, Zuid Holland, Olanda, 3300AK
- Albert Schweitzer Hospital
-
Leiden, Zuid Holland, Olanda, 2300 RC
- Leids Universitair Medisch Centrum
-
Rotterdam, Zuid Holland, Olanda, 3004BA
- St Franciscus hospital
-
Rotterdam, Zuid Holland, Olanda, 3015CE
- Erasmus MC University Medical Center
-
Rotterdam, Zuid Holland, Olanda, 3078HT
- Maasstad Hospital
-
-
Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
Inclusion Criteria:
- hepatitis C genotype 1 or 4
- high viral load (>400000 IU/ml)
- indication for antiviral treatment or patient's desire for antiviral treatment
- hepatitis C treatment naive
- liver biopsy within 3 years of screening visit or when biopsy is contraindicated e.g in patients with clotting diseases or when a patient refuses to undergo a new biopsy in case the liver biopsy is older than 3 years, substitution by fibroscan is allowed.
- age 18-70 years
Exclusion Criteria:
- serum bilirubin >35 μmol/l
- albumin <36 g/l
- prothrombin time >4 sec prolonged
- platelets <90x109/l
- decompensated cirrhosis (Child-Pugh Grade B or C)
- hepatic imaging (ultrasound, CT or MRI) with the evidence of hepatocellular carcinoma (hepatic imaging should be performed within 3 months prior to screening for cirrhotic patients and within 6 months prior to screening for non-cirrhotic patients)
- alcoholic liver disease (indicator: MCV>100)
- obesity induced liver disease (indicators: steatosis proven by biopsy or ultrasound in association with a body mass index >30)
- drug related liver disease (indicator: positive history of hepatic toxic drug intake with a causal relation)
- auto-immune hepatitis (indicators: IgG >30g/l, anti smooth-muscle or antinuclear antibodies titer ³1:40)
- hemochromatosis (indicator: ferritin >1000 μg/l)
- Wilson's disease (indicator: ceruloplasmin (<0.2 g/l)
- alpha-1 antitrypsin deficiency (indicator alpha-1 antitrypsin <0.8 g/L)
- co-infection with hepatitis B virus or human immunodeficiency virus (HIV)
- any cardiovascular dysfunction (e.g. cardiac decompensation, myocardial infarction, present or history of arrythmia)
- other medical illness that might interfere with this study: significant pulmonary or renal dysfunction, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g.: steroid therapy, organ transplants other than cornea and hair transplant)
- contra-indications for peginterferon and/or ribavirin:
- severe psychiatric disorder, such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression. Severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions. Subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject's mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient's mental status during the study
- visual symptoms related to retinal abnormalities
- pregnancy, breast-feeding or inadequate contraception
- thalassemia, spherocytosis
- females who are pregnant or intending to become pregnant or male partners of females who are pregnant or intending to become pregnant
- absolute neutrophil count (ANC) <1.40x109/l
- hemoglobin (Hb) <7.5 mmol/l (female) or <8.1 mmol/l (male)
- serum creatinine concentration >1.5 times the upper limit of normal at screening
- substance abuse, such as I.V. drugs or alcohol (indicator: >28 drinks/week). If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 1 year
- any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Nessuno (etichetta aperta)
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
|
Comparatore attivo: Standard dose
Standard-dose ribavirin (12-15 mg/kg/day) in combination with peginterferon 180µg QW
|
25-29 mg/kg/day
Altri nomi:
12-15 mg/kg/day
Altri nomi:
|
|
Sperimentale: High dose
High-dose ribavirin (25-29 mg/kg/day) in combination with peginterferon 180µg QW
|
25-29 mg/kg/day
Altri nomi:
12-15 mg/kg/day
Altri nomi:
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Lasso di tempo |
|---|---|
|
HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR)
Lasso di tempo: 72 weeks
|
72 weeks
|
Misure di risultato secondarie
Misura del risultato |
Lasso di tempo |
|---|---|
|
HCV-RNA negativity at week 4 (rapid virological response, RVR)
Lasso di tempo: 4 weeks
|
4 weeks
|
|
HCV-RNA negativity at week 12 (complete early virological response, cEVR)
Lasso di tempo: 12 weeks
|
12 weeks
|
|
HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR)
Lasso di tempo: 12 weeks
|
12 weeks
|
|
HCV- RNA negativity at week 48 (end of treatment response, ETR)
Lasso di tempo: 48 weeks
|
48 weeks
|
|
Relapse rate after ETR
Lasso di tempo: 48 weeks - end of follow up
|
48 weeks - end of follow up
|
|
Safety and tolerability of high-dose daily ribavirin (serious adverse events, grade 4 NCI toxicity, percentage of patients completing treatment on full or >80% of total intended dose and reasons for dose adjustments)
Lasso di tempo: week 0 till end of follow up
|
week 0 till end of follow up
|
|
Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up)
Lasso di tempo: week 0 - end of follow up
|
week 0 - end of follow up
|
|
Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires
Lasso di tempo: week 0 - week 72
|
week 0 - week 72
|
Collaboratori e investigatori
Sponsor
Collaboratori
Investigatori
- Investigatore principale: R J de Knegt, MD PhD, Erasmus Medical Center
- Investigatore principale: J PH Drenth, MD PhD, St Radboud Medical Center
Pubblicazioni e link utili
Collegamenti utili
Studiare le date dei record
Studia le date principali
Inizio studio
Completamento primario (Effettivo)
Completamento dello studio (Effettivo)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Stima)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Stima)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Malattie dell'apparato digerente
- Infezioni da virus a RNA
- Malattie virali
- Infezioni
- Infezioni a trasmissione ematica
- Malattie trasmissibili
- Malattie del fegato
- Flaviviridae Infezioni
- Epatite, virale, umana
- Infezioni da enterovirus
- Infezioni da Picornaviridae
- Epatite
- Epatite A
- Epatite C
- Epatite cronica
- Epatite C, cronica
- Effetti fisiologici delle droghe
- Meccanismi molecolari dell'azione farmacologica
- Agenti antinfettivi
- Agenti antivirali
- Antimetaboliti
- Fattori immunologici
- Interferone-alfa
- Ribavirina
- Peginterferone alfa-2a
Altri numeri di identificazione dello studio
- HCV07-01
- 2007-005344-25 (Numero EudraCT)
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .