• Introduction
• Patient eligibility
• Study conduct
• Complications

Introduction

The ASTIS Trial is an international clinical study for patients suffering from severe, progressive systemic sclerosis. The aim of the study is to compare two treatments with respect to their beneficial effect on the disease course as well as their safety: high dose immunoablation followed by autologous stem cell transplantation (considered the investigative treatment) versus pulse-therapy cyclophosphamide (considered the control treatment).

Systemic sclerosis

Progressive systemic sclerosis (‘scleroderma’) is a rare but severe disease of the skin and internal organs that impairs quality of life and survival. Based on studies in experimental animal models and in patients, it is thought that a dysregulated immune system is responsible for progressive fibrosis of skin and internal organs at early stages of the disease. The chemotherapeutic agent cyclophosphamide is the only drug with potential survival benefit in severe systemic sclerosis, based on scientific peer-reviewed literature. Cyclophosphamide probably exerts its effects through modulation of the immune system.

Pulse-therapy

In many institutions (worldwide) the drug cyclophosphamide is administered repetitively as monthly, so-called pulse-therapy during a period of 12 months. Although no single standard-therapy exists, pulse-therapy cyclophosphamide is regarded by many as the treatment of choice in severe forms of systemic sclerosis, when heart, lungs or kidneys are affected as well as large areas of skin. Unfortunately, some patients fail to respond to this therapy, and some only experience temporary benefit, which is why the search for more effective treatments is continuing.

High dose immunoablation followed by autologous stem cell transplantation

Recently, a new treatment modality has been developed for severe systemic sclerosis, called ‘high dose immunoablation followed by autologous stem cell transplantation’. The term immunoablation refers to the elimination of existing immune cells (rather than suppression of their function as mediated by pulse-therapy). This goal is achieved by combining high doses of cyclophosphamide and antithymocyte globulin, both administered by infusion, followed by transplantation (=reinfusion) of autologous stem cells that have been isolated from blood by a procedure called mobilization.

The reinfused stem cells give rise to a new generation of immune cells, replacing cells of the original ‘sick’ immune system that has been eliminated with cyclophosphamide and ATG. It is hoped that this will halt the disease process, although a successful outcome of this therapy cannot be predicted.

World-wide experience so far

More than 65 patients suffering from systemic sclerosis have been accordingly treated world-wide. The results from these studies suggest that the therapy may be effective, but it cannot be concluded whether this treatment modality is better than existing pulse-therapy.

Aim 

Both study treatments are considered effective for patients with severe systemic sclerosis, but the extent and duration of effect are unknown. By intervening at an early stage of the disease, the likelihood of a longlasting beneficial response may increase, before irreversible organ damage occurs. The control treatment is aimed at combining effectiveness and safety. The investigational treatment may yield superior effects, although this must be balanced against a potentially greater toxicity.

If considered necessary, certain immunosuppressive drugs may be used in the study period but switching to the alternative study treatment is not allowed before the end of the study. In case of deterioration after the study period, the treatment options include the alternative study treatment.

Patient eligibility

For patients to participate, the following eligibility criteria must be met:

-         age 16-60 yr

-         a diagnosis of generalized scleroderma (not limited to face and hands)

-         clinically important involvement of heart, lungs or kidneys as assessed by specific investigations

-         disease duration 4 yrs or less

-         acceptable mental and physical condition as determined by extensive screening investigations

-         written informed consent 

Study conduct

If after screening eligibility is confirmed and informed consent has been documented, registration at the SAO (Study Administration Office, astistrial-fps@unibas.ch) can be completed followed by allocation to either one of the two study treatments by a procedure called ‘randomization’. This term refers to the random selection by a computer, meaning the treatment will be determined by chance to enable balancing of the two groups of patients. The treating physician can explain the importance of this procedure in more detail.

Either therapy will then be initiated within several weeks after your entry in the study.

In case of randomization to pulse-therapy cyclophosphamide, 12 monthly single bolus infusions cyclophosphamide at moderately high doses will be given. Some patients may have been pretreated with cyclophosphamide-tablets or infusions, usually in lower doses. Unless major side-effects occur, all 12 pulses will be administered - even when no immediate effects are observed. Depending on each institute’s common practice, pulse-therapy is given in an ambulatory setting or during short-stay visits. Hospitalization may be indicated when specific (rare) complications occur, such as severe infections. Other (reversible) side-effects include: transient nausea, alopecia, anemia, hematuria due to irritation of bladdermucosa, infertility.  

In case of randomization to the investigative treatment, the following consecutive procedures will be executed:

1. ‘mobilization’ refers to interventions that lead to procurement of stem cells: at first a 2-day infusion with 2 bolusses high dose cyclophosphamide will be administered, followed by daily subcutaneous injections of a specific growth factor (filgrastim) starting 5 days after the last infusion of cyclophosphamide. As a result, stem cells will migrate from the bone marrow to the blood, and sufficient numbers can usually be counted in bloodsamples after 5-8 days of filgrastim administration.
2. ‘leukapheresis’ is the subsequent technical procedure that enables stem cells to be isolated from blood. This is done by draining blood via a venous catheter that is connected to a bloodcell separation device. With this  machine white blood cells including stem cells can be removed from blood, which then flows back via another venous catheter. As a result, most components of blood with the exception of white cells and stem cells return to the circulation. The white cell collection will be processed in the laboratory to obtain a purified stem cell fraction, and cryopreserved until later use at transplantation (see below).
3. ‘high dose immunoablation’ will be initiated 2-4 weeks after mobilization, consisting of infusions with high doses cyclophosphamide in combination with antithymocyte globulin (‘ATG’), and followed by reinfusion of the blood stem cells (‘autologous stem cell transplantation’) on the day after the last infusion ATG. ATG is a protein derived from rabbits with effective depleting effects on immune cells. Hospitalization of several weeks is generally required to carry out these steps, and to cover any unwanted consequences that may occur as a result of the therapy. Antibiotic treatment and transfusions of red blood cells or platelets usually are necessary in the period immediately following the transplantation.  

Complications

High dose immunoablation followed by autologous stem cell transplantation is an intensive treatment with risks on severe complications which occasionally become fatal.

These complications include: infections, bleeding, heart failure, respiratory insufficiency, renal failure, lymphoma. Less severe, but more frequent (reversible) toxicities include: nausea, fever, alopecia, infertility, arthralgia, myalgia, menstrual disorders. Of course, the treating physicians will do their utmost best to prevent these from occuring or treat them as best as they can in case serious complications do occur.

The official study duration is 2 years, with annual follow-up thereafter.

Study-evaluations will be performed at 3-monthly intervals. These include blood tests, blood gas analysis, performance, side-effects, skin score, assessment of heart, lung and kidney function, and quality of life. The final analysis of the study results will be done when all participating patients have completed 2-year follow-up. No definitive conclusions can be reasonably drawn before the study is terminated.

The data gathered from the study will be centrally stored at the Study Administration Office in Basel, Switzerland. Patients’ identities will be kept anonymous (e.g. in publications), and access to the registry will be limited to persons involved in the study alone.

An Independent Safety Monitoring Committee will review safety in consecutive groups of patients.

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Last change: 16 december 2002