A randomized trial to evaluate the toxicity and efficacy of 1200mg and 1800mg rifampicin daily for 4 months in the treatment of pulmonary tuberculosis

Lead Research Organisation: St George's University of London
Department Name: Institute of Infection & Immunity

Abstract

Approximately 20 million people globally are infected with tuberculosis, and about 1.5 million people die of the disease annually, i.e. one death every 20 seconds. Currently, tuberculosis of the lungs is treated with four drugs ethambutol, isoniazid, rifampicin, and pyrazinamide daily for the first two months, followed by the two drugs isoniazid and rifampicin for the next four months. This drug combination is recommended by the World Health Organisation and is used in most countries of the world.
The combination is highly effective if taken properly, but despite this about 15% patients worldwide are not cured. Factors such as patients not completing the course, missing multiple doses, or taking (or being prescribed) the wrong dose contribute to treatment failure. Although the drugs are free to patients, there is a substantial cost, in terms of time and administration, to both the patient and the treatment services. A recent study by Gospodarevskaya et al (Int J Tub Lung Dis. 18: 810-817) has found that patients have to terminate productive/economic activities and are often forced to borrow money and/or sell assets to cover cost of treatment, which can amount to more than three-quarters of patients' income, in the last 2 months of treatment. Reducing the duration of treatment should increase the number of people who successfully complete treatment and reduce the cost to them.
A reduction could be achieved in one of two ways: using combinations of the new drugs currently under development, or by using the currently available drugs more effectively. Given the enormous cost and long time required to develop new drugs the second option is attractive. Increasing the dose of one of the currently available drugs may allow the duration of treatment to be shortened in the very near future.
Three recently published Phase III trials (RIFAQUIN, ReMOX, OFLOTUB) have failed to demonstarte that treatment shortening can be achieved with the quinolones. hus, the rifamycins offer the best hope if higher doses can be shown to be safe.
Rifampicin which is responsible for killing most tuberculosis bacteria, appears to be the best choice since increasing doses of rifampicin increases its ability to kill TB bacilli in vitro and animal studies. A similar result could be obtained in human tuberculosis. However, one concern would be a possible increase in unwanted serious side effects with increasing doses. Liver damage by rifampicin appears to be rare and not connected to dose size. In the RIFATOX Trial, a dose of 1200mg, in 100 patients did not increase its toxicity.
The central question this trial aims to answer is therefore: does an increase in the dosage of rifampicin allow us to shorten treatment from 6 to 4 months? We are assessing whether giving double or triple the usual dose of rifampicin (1200mg, or 1800mg rather than 600mg daily) is safe and, when given for 4 months only, will result in relapse rates similar to (or better than) those found in the standard 6 month course of treatment. Patients with newly diagnosed tuberculosis of the lung, who agree to participate and have signed a consent form, will receive either the standard 6 month treatment or a 4 month treatment containing the standard drugs but with a double or triple dose of rifampicin. Treatment allocation will be random. The success of treatment in each method will be closely monitored both clinically and by regular microscopic examination of sputum, and the safety of the increased dose of rifampicin will be monitored clinically and with blood tests.
If the trial is successful, it will lead to a shorter treatment course for pulmonary tuberculosis. The expected consequences would be: more patients completing the course and higher rates of cure, reduction in rates of transmission of tuberculosis with fewer people becoming infected, a reduced cost of treatment for both patients and treatment facilities and, perhaps, a reduction in the emergence of bacterial drug resistance.

Technical Summary

Tuberculosis (TB) is one of the major causes of death in the world, responsible for 1.5 million deaths annually. Currently, the most effective form of control of tuberculosis is treatment of clinical disease. The current WHO recommended 6 month regimen for the treatment of TB is too long. An estimated 15% of patients worldwide do not successfully complete treatment. If treatment duration could be reduced, adherence and cure rates would improve, and treatment costs would decrease.
Of the four drugs in standard tuberculosis treatment, rifampicin and pyrazinamide are responsible for most of the sterilising activity. Increasing the dose of rifampicin both results in significantly greater M. tuberculosis killing in pre-clinical studies, and also in greater early bactericidal activity in the sputum of patients with pulmonary tuberculosis. Preliminary results suggest that, unlike pyrazinamide, higher doses of rifampicin are safe.
The principal objectives of the trial are:
1)To determine whether an increase in the daily dose of rifampicin from 600 mg to 1200 or 1800mg results in more rapid sterilisation of the lungs, allowing a reduction of treatment duration to 4 months.
2) To assess whether the increased dose results in an increase in serious (grade 3 or 4) adverse events.
In this multicentre randomised, controlled clinical trial, 654 smear positive patients with pulmonary tuberculosis will be randomly allocated to either the standard 6 month regimen, or a 4 month regimen with rifampicin at 1200 or 1800mg daily and other drugs at standard dose. They will be followed up for 12 months after stopping treatment, with monthly clinical, sputum and laboratory examinations.
If the new regimen is shown to be effective and safe, results will be presented to the WHO and to National Tuberculosis Control Programmes and to the wider academic community, to inform treatment guidelines and routine practice. If positive, the results of this trial will have major public health benefit

Planned Impact

One of The United Nations' Millennium Development Goals is the elimination of tuberculosis by the year 2050. In the absence of an effective vaccine, treatment duration must be much shorter than the current 6 months. A vast amount of resources are being devoted to new drug development. But it will be many years before regimens with new drugs will be available for routine treatment in low income countries because of the enormous cost of drug development, and the very long time taken from discovery to marketing.
The standard dose quinolones, too, have, in 3 well conducted trial, failed to demonstrate treatment reduction. This leaves the high dose rifamycins as the only drugs which could achieve treatment shortening in the forseeable future.
The WHO recommended 6 month regimen for pulmonary tuberculosis (responsible for disease transmission) is highly effective and, under trial conditions, has a relapse rate of around 5%. The cost of the drugs is low at approximately £20, around 11 pence daily. However, the cost to the patients is high with loss of earnings, increased risk of early treatment abandonment and subsequent relapse. More concerning is the possible emergence of drug resistance through intermittent drug taking.
Then there is the economic cost and social, in terms of days of sickness, loss of earnings as well as continuing disease transmission. Moreover, the recorded incidence of tuberculosis is highest in men between the ages of 15 and 40 who, at the time when they can be most productive, are, through sickness, a drain on their country's economic resources.
If the RIFASHORT Trial succeeds in identifying an efficacious and safe regimen of four months duration, there will be a significant impact, on all these adverse outcomes, to the patient, the community and the resources of the country.
The most immediate impact will be to the patients who will be able to complete treatment in four months. Their quality of life will be improved and they will be able to retur to their daily activities and work earlier. Overall cure rates will increase and mortality and disease transmission will be reduced. The risk of the emergence of drug resistance will fall. All these outcomes will also benefit their families and communities.
Secondly, should the results show that GeneXpert, positive, microscopy negative patients have significantly lower relapse rates, it will be possible to start the microscopy negative patients on treatment earlier without waiting for the culture result. This will be particularly beneficial for HIV positive patients with pulmonary tuberculosis who are frequently microscopy negative.
Thirdly, the resulting reduction in treatment duration will be of enormous benefit to the National Tuberculosis Control Programmes. Although the increase in the number of tablets of rifampicin may increase the cost of the regimen marginally, this would be offset by the reduction in the cost of supervision, higher cure rates, lower relapse rates, lower mortality, reduced disease transmission and a reduction in administration costs. Particularly important would be the reduction in the emergence of drug resistance and consequential costs of the treatment where third line drugs are vastly expensive, difficult to source and have many adverse effects.
Fourthly, there will be an impact on organisations directing global health policies such as the WHO and national agencies, such as the UK Department for International Development. They will be able to channel financial and material aid to resource poor countries more appropriately.
Lastly, should the WHO guidelines recommend change and a 4 month regimen can become standard practice in the next 6 to 7 years, disease transmission would be reduced and it may be possible to see a reduction in the number of new cases in the next ten years. It is also possible that the results would lead to achieving the Millennium Development Goal for the elimination of tuberculosis by 2050

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