D‐penicillamine for primary sclerosing cholangitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the beneficial and harmful effects of D‐penicillamine in patients with PSC based on randomised clinical trials.
Background
Primary sclerosing cholangitis is a cholestatic disease of unknown etiology (Wiesner 1980; Angulo 1999; LaRusso 1999; Lazaridis 1999). Initially the disease was perceived by clinicians as rare. However, due to the increasing use of endoscopic retrograde cholangio‐pancreatography, primary sclerosing cholangitis is being increasingly diagnosed and currently is one of the most common indications for liver transplantation (Angulo 1999; LaRusso 1999; Alba 2002).
Primary sclerosing cholangitis is characterized by diffuse inflammation and fibrosis of the intra‐ and extrahepatic bile ducts. It generally follows a slowly progressive course and may lead to biliary cirrhosis, portal hypertension, and death from hepatic failure (Wiesner 1980; Lazaridis 1999). Some patients remain asymptomatic, whereas others present with jaundice, pruritus, non‐specific abdominal pain, fatigue, fever, or weight loss. In addition, the disease is commonly associated with inflammatory bowel disease, usually chronic ulcerative colitis (Wiesner 1980; Chapman 1984; LaRusso 1999; Lazaridis 1999; Meier 2001). Bacteriatoxins, viral infections, and genetic and/or immunologic factors may contribute to the pathogenesis and progression of primary sclerosing cholangitis.
Currently, no therapy achieves a complete clinical, biochemical, or histological remission of primary sclerosing cholangitis. Nevertheless, therapeutic approaches include mechanical, surgical, and medical interventions. Until now there is no clinical evidence backing the introduction of mechanical or surgical methods for treatment of primary sclerosing cholangitis (LaRusso 1999; Lazaridis 1999). Medical approaches include corticosteroids, colchicine, bile acids, and D‐penicillamine (LaRusso 1999; Lazaridis 1999; Meier 2001). Colchicine has been tested in a randomised trial; however, without a beneficial effect (Olsson 1995). The evidence for treating primary sclerosing cholangitis with glucocorticosteroids will be published in a systematic Cochrane Review (Chen 2003a) and the beneficial and harmful effects of bile acids in patients with primary sclerosing cholangitis has been evaluated in another systematic Cochrane Review (Chen 2003b). The reviews found that there was insufficient evidence either to support or refute beneficial effects of glucocorticosteroids for patients with primary sclerosing cholangitis, and bile acids were found to improve liver biochemistry, but there was not sufficient evidence to either support or refute their effects on clinical outcomes (Chen 2003b). In both cases, there is a need for large randomised clinical trials of high methodological quality (Chen 2003a; Chen 2003b).
Patients with primary sclerosing cholangitis are found to have abnormal copper metabolism (Wiesner 1980; Gross 1985). Hepatic copper accumulates and urinary excretion of copper increases with the progress of the disease (Wiesner 1980; Gross 1985; LaRusso 1999). The reason for this may be deterioration of hepatocyte function (Gross 1985). D‐penicillamine is a heavy metal chelating agent with antifibrogenic and immunosuppressive actions (Ludwig 1990). It has a mercapto group (‐SH) capable of binding a copper‐ion forming a soluble complex excreted in the urine, thereby decreasing the toxic levels of the metal (Sherlock 1975). Previous studies on D‐penicillamine have shown improvement of primary biliary cirrhosis, another chronic cholestatic disease with many similarities to primary sclerosing cholangitis. Therefore, a randomised trial of D‐penicillamine for treatment of patients with primary sclerosing cholangitis was initiated (LaRusso 1986a; LaRusso 1988a). However, no beneficial effect on disease progression was observed, and the drug was found to have considerable toxicity (LaRusso 1986a; LaRusso 1988a; LaRusso 1999). Until now we have been unable to find meta‐analyses or systematic reviews on D‐penicillamine for primary sclerosing cholangitis.
Objectives
To evaluate the beneficial and harmful effects of D‐penicillamine in patients with PSC based on randomised clinical trials.
Methods
Criteria for considering studies for this review
Types of studies
All randomised clinical trials, regardless of publication status, language, or blinding.
Types of participants
Patients with PSC diagnosed on the basis of the following criteria:
1. Hepatic histological criteria, including cholangitis or portal hepatitis (stage 1); periportal fibrosis with periportal hepatitis (stage 2); septal fibrosis, necrosis, or both (stage 3); or biliary cirrhosis (stage 4).
2. Radiological criteria, including cholangiographic demonstration of diffusely distributed, short and annular strictures with intervening segments of normal or slightly dilated ducts; short band‐like strictures and diverticulum‐like outpouchings of the biliary tree.
3. Biochemical criteria, including elevated levels of serum alkaline phosphatases, serum transaminases (alanine aminotransferase or aspartate aminotransferase), and/or increase in total serum bilirubin.
Types of interventions
D‐penicillamine at any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Co‐interventions will be allowed if used in both intervention arms.
Types of outcome measures
Primary outcome measures:
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All cause mortality.
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Morbidity related to the liver (liver transplantation, biliary cirrhosis, bile duct cancer, and signs of hepatic decompensation such as ascites, bleeding varices, and/or splenomegaly).
Secondary outcome measures:
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Histological response (number of patients with histological deterioration).
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Radiological response (number of patients with radiological deterioration).
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Biochemical responses (serum activities of alkaline phosphatases, alanine aminotransferase, and aspartate aminotransferase, serum bilirubin concentration, and/or number of patients with abnormal values of alkaline phosphatases, alanine aminotransferase, aspartate aminotransferase, and/or serum bilirubin).
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Clinical findings (e.g., pruritus and fatigue).
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Adverse events (defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment, but did, however, result in a dose reduction or discontinuation of treatment. Serious adverse events will be defined according to the ICH guidelines (ICH‐GCP 1997) as any event that leads to death, is life‐threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or congenital anomaly/birth defect, or any important medical event which may jeopardize the patient or requires intervention to prevent it.
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Quality of life.
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Cost effectiveness.
Search methods for identification of studies
We will search The Cochrane Hepato‐Biliary Group's Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library (latest issue at the time the search is performed), MEDLINE (1966 ‐ until the time the search is performed), and EMBASE (Excerpta Medica Database) (1980 ‐ until the time the search is performed). We will apply the search strategies as planned in 'Table 1' (see 'Additional tables'). We will improve the search strategies during the performance of the searches if necessary and possible.
| Database | Time span | Search strategy |
| Cochrane Hepato‐Biliary Group Specialized Register | (Searched Nov 2002) | cholangitis AND penicillamine |
| The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 4, 2002) | Issue 4, 2002 (Searched Nov 2002) | #1 CHOLANGITIS‐SCLEROSING*:ME |
| EMBASE | 1980 to 2002 (Searched Nov 2002) | #1 explode "primary‐sclerosing‐cholangitis"/ all subheadings |
| MEDLINE | 1966 to 2002 (Searched Nov 2002) | #1 explode "Cholangitis‐Sclerosing"/ all subheadings |
In addition, we will scan reference lists from retrieved articles to identify additional trials.
Finally, we will contact the principal authors of the included randomised clinical trials as well as pharmaceutical companies producing D‐penicillamine about additional published or unpublished randomised clinical trials they might know of.
Data collection and analysis
Trial selection
We will both independently decide which trials to include. We will resolve disagreements by discussion. We will list excluded trials with the reason for exclusion.
Data extraction
We will both extract the following data independently from the included trials.
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Primary author.
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Trial characteristics: date, location and funding of the trial, length of follow‐up, use of intention‐to‐treat analyses, as well as the publication status.
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Patient characteristics: number of patients randomised, inclusion and exclusion criteria, mean (or median) age, sex ratio, proportion of intra‐ and extrahepatic PSC, and presence of inflammatory bowel disease.
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Intervention characteristics: dose, duration, and mode of administration of D‐penicillamine and/or of additional intervention(s).
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Outcome measures: number of events in the intervention group and in the control group (including the number and type of adverse events).
Methodological quality
We will define the methodological quality as the confidence that the design and report will restrict bias in the intervention comparison (Moher 1998; Kjaergard 2001). Due to the risk of overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001), we will assess the influence of methodological quality.
Generation of the allocation sequence
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Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
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Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
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Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and will be excluded from the present review when assessing beneficial effects.
Allocation concealment
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Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes.
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Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
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Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Blinding (or masking)
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Adequate, if the trial was described as double blind and the method of blinding involved identical placebo or active drugs.
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Unclear, if the trial was described as double blind, but the method of blinding was not described.
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Not performed, if the trial was not double blind.
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Follow‐up
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Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
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Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
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Inadequate, if the number or reasons for dropouts and withdrawals were not described.
Furthermore, we will register whether or not the randomised clinical trials have used an intention‐to‐treat analysis (Gluud 2001) and sample size calculation.
In case data have not been reported sufficiently or are not published at all, we will seek further information by correspondence with the authors.
Statistical methods
We will perform the analyses in Review Manager 4.1.1 according to the intention‐to‐treat method using the last reported observed response ('carry forward') and including all patients irrespective of compliance or follow‐up. Regarding death, both a worst case scenario analysis considering all dropped out patients as dead and a best case scenario analysis considering all dropped out patients alive will be carried out. We will perform per protocol analyses in the assessment of the histological response. We plan to perform a meta‐analysis by both random effects (DerSimonian 1986) and fixed effect model (DeMets 1987). The results of the fixed effect model will be reported if there are no differences between the two methods; otherwise we will report all results produced by the two models. We will assess the presence of publication bias and other biases by funnel plots (Egger 1997). We will express binary outcome measures as relative risks (RR) and continuous data as weighted mean difference (WMD), both with 95% confidence intervals.
If possible, we will perform sensitivity analyses regarding:
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Methodological quality of the randomised clinical trial ‐ comparing adequately with inadequately performed trials.
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Dose and duration of treatment with D‐penicillamine ‐ comparing trials with D‐penicillamine intervention at or above the median dose or duration given with trials administrating less doses or shorter duration.
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Trials with or without co‐interventions.
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Extension of PSC ‐ intra‐ versus extrahepatic PSC.
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Publication status ‐ comparing full manuscript trials with all other identified trials.
| Database | Time span | Search strategy |
| Cochrane Hepato‐Biliary Group Specialized Register | (Searched Nov 2002) | cholangitis AND penicillamine |
| The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 4, 2002) | Issue 4, 2002 (Searched Nov 2002) | #1 CHOLANGITIS‐SCLEROSING*:ME |
| EMBASE | 1980 to 2002 (Searched Nov 2002) | #1 explode "primary‐sclerosing‐cholangitis"/ all subheadings |
| MEDLINE | 1966 to 2002 (Searched Nov 2002) | #1 explode "Cholangitis‐Sclerosing"/ all subheadings |
