RIFAQUIN trial proves new TB regimen

The results of the much-anticipated RIFAQUIN trial were announced at 20^th CROI by Amina Jindani of St Georges Hospital, University of London. Jindani has been involved in TB trials since the 1960s and her work has informed WHO guidelines.

The RIFAQUIN trial found that a regimen using moxifloxacin and rifapentine instead of isoniazid and rifampicin was non-inferior. Moreover, in the continuation phase, moxifloxacin and rifapentine were taken once weekly compared to the daily dosing of the standard regimen. [1]

In mice, a rifapentine, moxifloxacin and pyrazinamide regimen sterilised TB at two months. However, Jindani explained that in clinical studies of rifapentine at 600mg, relapse rates have been unacceptably high and patients with HIV developed rifamycin group (rifampicin, rifabutin and rifapentine) resistance. The RIFAQUIN trial regimens sought to address this. In RIFAQUIN, patients were randomised to three arms:

• Control regimen (standard WHO): Two months of daily ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months of daily isoniazid and rifampicin.

• Four-month study regimen: Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months of twice weekly moxifloxacin (500mg) and rifapentine (900mg).

• Six-month study regimen: Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by four months of once weekly moxifloxacin (500mg) and rifapentine (1200mg).

This trial was designed to detect non-inferiority within a six percent margin. Patients were followed up for 18 months after randomisation. The primary endpoint was the absolute difference in the proportion of unfavourable outcomes, calculated using modified intention-to-treat and per-protocol analyses. The planned sample size was 1,100.

Recruitment began in August 2008 and was completed in August 2011 at which point 827 patients had been enrolled from Johannesburg (n=255), Cape Town (209), Macha (15), Harare (203), Marondera (89) and Botswana (56). After exclusions, withdrawals, losses-to-follow-up and missing or contaminated cultures were accounted for, there were 592 patients included in the modified intention-to-treat analysis, of whom 188 were on the control arm, 191 on the four-month regimen and 213 in the six-month regimen.

Baseline characteristics were similar across the three groups. Men comprised 64% of participants. Median age was 32, with the youngest participant at 18 and oldest at 75. Median weight was 53kg, with the lowest being 35kg and the highest 82kg About a third (28%) of the participants were HIV-positive with a median CD4 count of 312 (IQR: 253-441).

The primary outcomes in the per-protocol analysis of the control and six-month arms were almost identical. In the control arm, in which 163 patients were assessable, there were two culture-confirmed treatment failures, one death during treatment, four culture-confirmed relapses and one clinical relapse for a total of eight unfavourable outcomes (5%). In the six-month regimen arm, in which 187 patients were assessable, there was one death during treatment, five culture-confirmed relapses and one clinical relapse for a total of seven unfavourable outcomes (4%).

Likewise in the modified intention-to-treat analysis outcomes were almost identical between these two arms. In the control arm, in addition to the unfavourable outcomes listed above, eleven patients changed their regimens, five were lost to follow-up and two were inadequately treated. There was also one further clinical relapse not included in the per-protocol analysis, for a total of 27 unfavourable outcomes out of 188 patients (14%). For the six-month regimen there were also eleven regimen changes, ten lost to follow-up and one inadequately treated patient for a total of 30 unfavourable outcomes out of 213 patients (14%).

The four-month regimen had significantly worse outcomes on both analyses. In the per-protocol analysis of 163 patients there were 28 unfavourable outcomes (17%) including two culture-confirmed failures, 18 culture-confirmed relapses, six clinically assessed relapses and two patients who were culture-positive when last seen. In the modified intention-to-treat analysis there were 50 unfavourable outcomes (26%). A Kaplan-Meier graph showed that most of the unfavourable outcomes in the four-month regimen were due to relapses in months five to nine.

After the two-month intensive phase, 90% of the six-month intervention arm were culture-negative versus 85% of the control arm. This was on the border of significance (p=0.058).

There were 39 grade three and four adverse events, 13 in the control arm, 11 in the four-month study regimen and 15 in the six-month study regimen.

Jindani clarified that adherence rates on all three regimens were high. There were no differences across arms according to HIV status. No rifamycin mono-resistance occurred in any of the arms.

Jindani concluded that the six-month study regimen was non-inferior, safe and well tolerated. The four-month study regimen was safe and well tolerated but its efficacy was inferior to the control.

Comments

This trial has exciting implications for TB treatment. The 6-month study regimen appears more convenient than the current standard of care. In settings were treatment is directly observed it will require less health worker time to administer, at least from the third month of treatment, and patients will have lower transport to clinic costs and interruptions to their normal schedule.

A barrier to wider adoption is the cost of these drugs. In the South African private sector ten 400mg moxifloxacin pills costs over R250 per month. [2] Rifapentine is not available in South Africa, but the price In the United States has varied recently between R450 and R660 per month. [3] By comparison, a 4-in-1 fixed dose combination of the standard regimen costs R38. [2] Unless the cost of rifapentine comes down dramatically, there is no prospect of this regimen being used at scale in poor countries. Campaigning to bring down the prices of rifapentine and moxifloxacin should be an activist priority.

Perhaps the four-month study regimen should not be discarded. If a patient-profile can be developed to predict who in the four-month regimen was likely to relapse, then it might be possible to treat these patients with a six-month regimen and all others for four months, though it must be remembered that at twice-weekly dosing the four-month regimen is not necessarily more convenient to patients and health-workers than the six-month study regimen.

Comparing cost of trials

An interesting piece of information provided by Jindani, not often presented with trial results, was the funding amount RIFAQUIN received excluding drug contributions. This multi-centre medium-sized trial was funded 5.4 million Euros (5.1m Euros from the European & Developing Countries Clinical Trials Partnership and 270,000 Euros from the Wellcome Trust). Drugs were supplied by Sanofi, Genus and Sandoz. We can roughly compare the cost of this public-institution run trial to a phase III industry-run one.

According to a report in 2011 in an online pharmaceutical magazine, Pharmalot, the average cost per patient of a phase III trial is $47,000, or approximately 36,000 Euros. [4] It’s not clear if this estimate is per patient screened, or based on the final patient count. At the very most, using only the most unfavourable private sector South African drug prices and assuming that drugs for patients, even in the control arm, cost as much as moxifloxacin and rifapentine (using the US price for the latter), the cost of drugs per patient on the RIFAQUIN trial was 600 Euros. It must be emphasised that this is an overestimate, with the actual cost likely substantially less than this. Dividing the amount of funding for the trial by 592 (the final number of enrolled patients) and adding on 600 Euros per patient for drugs gives a total cost of less than 10,500 Euros per patient on the trial.

If the pharmaceutical industry calculates cost per patient based on the total enrolled (827), then the comparative amount for RIFAQUIN would be less than 7,500 Euros.

Any which way you calculate it, this public funded trial cost a fraction of what the pharmaceutical industry claims it is spending on comparable phase III trials. There are either massive inefficiencies in industry-run trials, their cost is vastly overestimated or St. George’s Hospital Medical School is extraordinarily efficient.

Thank you to Erica Lessem for assistance with pricing information.

References

1. Jindani A et al. 2013. A Multicentre Randomized Clinical Trial to Evaluate High-dose Rifapentine with a Quinolone for Treatment of Pulmonary TB: The RIFAQUIN Trial. Oral abstract and paper 147LB. 20th Conference on Retroviruses and Opportunistic Infections, March 3-6. Atlanta.

http://www.retroconference.org/2013b/Abstracts/48012.htm

http://webcasts.retroconference.org/console/player/19443?mediaType=podiumVideo

2. TAC. 2013. Private Sector Single Exit Medicine Prices on Monday 11th of March 2013.

http://www.tac.org.za/community/node/2021

3. TB Online. Moxifloxacin.

http://www.tbonline.info/posts/2011/10/18/rifapentine/

4. Silverman E. 2011. Clinical Trial Costs Are Rising Rapidly. Pharmalot, 26 July.

http://www.pharmalot.com/2011/07/clinical-trial-costs-for-each-patient-rose-rapidly/

Source: HIV i-Base