How Ideal Is the IDEAL Trial?

By Daniel Raymond and Tracy Swan

Introduction/Background

Pegasys- or Peg-Intron-based combination therapy? Which is better? This is a key question that hundreds of people with chronic hepatitis C and their physicians are asking every day when considering treatment with pegylated interferon and ribavirin. 

Peg-Intron is the Schering-Plough version of pegylated interferon; Roche manufactures Pegasys.  The two brands of pegylated interferon have never been directly compared to each other in the same study, although in data from large clinical trials, it appears that their efficacy and side effects profile are similar. 

However, without a head-to-head comparison, it’s not possible to compare results across different trials.  Major studies of pegylated interferon and ribavirin treatment have differed according to the dose of ribavirin used, the characteristics of people in the trial (age, weight, amount of liver damage), and the way side effects are managed.  That leaves little basis for making decisions about which brand of pegylated interferon is preferable. Now Schering –Plough has launched a large new clinical trial, called IDEAL, that includes a promise to provide that information.

What is IDEAL?

IDEAL stands for “Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy.”  The IDEAL trial will compare three different hepatitis C treatment regimens.  Two regimens will use Schering’s Peg-Intron, while the third will use Roche’s Pegasys.  The trial will enroll 2,880 adults with hepatitis C at about 100 sites across the United States (see the IDEAL web site [www.idealstudy.com] for study locations).  Study volunteers will be randomly assigned to one of three arms, each providing up to 48 weeks of treatment (study drugs provided for free):

Arm 1: High-dose Peg-Intron (1.5 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants.

Arm 2: Low-dose Peg-Intron (1.0 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants.

Arm 3: Pegasys (180 μg/week) with weight-based ribavirin (Roche’s Copegus, at 1,000-1,200 mg/day) – 960 study participants.

IDEAL is designed to see whether there are differences between the three regimens in the proportion of study participants achieving a sustained virologic response (SVR), defined as an undetectable hepatitis C viral load 6 months after the end of treatment.  People who do not experience a 2 log (100-fold) decrease in hepatitis C viral load at 12 weeks, or an undetectable viral load at 24 weeks, will be taken off treatment.

The eligibility criteria for IDEAL includes male or female, age 18-70, weight 88-275 pounds, and hepatitis C genotype 1 (the strain most common in the U.S., but least responsive to treatment).  Study participants must have a prior liver biopsy and compensated liver disease.  IDEAL is open only to treatment-naďve patients (those never before treated for hepatitis C).  Excluded from the trial are people with HIV or hepatitis B co-infection, substance abuse within the past two years, or significant psychiatric disease (see complete inclusion and exclusion criteria [http://www.idealstudy.com/who.html]).

How Were the Doses Selected?

IDEAL is really two studies in one: a comparison between Peg-Intron and Pegasys, and a comparison between high-dose and low-dose Peg-Intron.  The pegylated interferon and ribavirin doses for the Pegasys arm are based on the current prescribing information for genotype 1. 

Roche is currently conducting a separate, small pilot study, requested by the US Food and Drug Administration (FDA), looking at higher doses of Pegasys and/or ribavirin in individuals weighing over 187 pounds who have genotype 1 and high hepatitis C viral loads—the group with the lowest chance of achieving an SVR. 

Approximately 80 study participants will be randomized to 180 μg or 270 μg of Pegasys once a week, with 1,200 mg or 1,600 mg of daily ribavirin.  This study will evaluate the safety and efficacy (based on viral load changes at 12 weeks) of these dose combinations to determine whether higher doses of Pegasys and/or ribavirin should be examined in a larger study.  Results of the pilot study are expected in December (for enrollment information see http://clinicaltrials.gov/ct/show/NCT00077649?order=19).

The FDA asked Schering-Plough to conduct a study comparing high-dose and low-dose Peg-Intron in combination with ribavirin for people with genotype 1.  The FDA requested this study because other data showed that when used without ribavirin, higher-dose Peg-Intron wasn’t any more effective than lower-dose Peg-Intron.  IDEAL will examine differences in combination therapy by Peg-Intron dose:  does low-dose Peg-Intron (with ribavirin) have fewer side effects, and does it work as well as high-dose Peg-Intron?

The doses of ribavirin used in the Peg-Intron arms reflect data from WIN-R (Weight-Based Dosing of Interferon and Ribavirin), another Schering-Plough study requested by the FDA.  WIN-R compares low-dose ribavirin (800 mg/day) to weight-based ribavirin dosing (800-1,400 mg/day), both in combination with high-dose Peg-Intron (1.5 μg/kg/week). With nearly 5,000 enrolled participants, WIN-R is the largest hepatitis C study ever conducted.  WIN-R has been completed, but final data have not yet been presented.

What Are the Implications of the Different Pegylated Interferon and Ribavirin Doses for Treatment Success and Side Effects?

Dosing of pegylated interferon and ribavirin affects treatment success and toxicity. If the doses are too low, an SVR is unlikely, and if the doses are too high, side effects may be worse, potentially leading to withdrawal from the study.  Proper dosing is important for people with genotype 1, the group that IDEAL will study, since they do not respond as well to treatment.

Dosing may have particular significance for people with genotype 1 and high HCV viral loads (above 2,000,000 copies or 800,000 million International Units)—that is, the majority of people with genotype 1.  This group is the least likely to achieve a sustained virologic response to treatment.

Data from three large hepatitis C treatment trials (two of Pegasys plus ribavirin, and one of Peg-Intron plus ribavirin) show that viral loads in genotype 1 influence the likelihood of achieving an SVR.  In these trials, response rates among people with genotype 1 and a high viral load ranged from 30% (for 1.5 μg/kg of Schering’s Peg-Intron plus 800 mg/day of ribavirin) to 41% (for 180 μg of Roche’s Pegasys plus 1,000–1,200 mg day of ribavirin).  

Response Rates In Genotype 1 by Study, Regimen
and Baseline Viral Load

People with genotype 1 and high viral loads face the following pressing questions about treatment:

• Is there any difference between Peg-Intron and Pegasys?
  
  
• For Peg-Intron, will the lower dose (1.0 µg/kg) be as effective as the higher dose (1.5 µg/kg)?
  
  
• What’s the best dose of ribavirin?

The question about proper dosing of Peg-Intron should be answered by IDEAL.  But a closer look at the data from a study comparing lower and higher doses of Peg-Intron monotherapy may give people with high viral loads cause for concern:

End of Treatment Response (ETR) and SVR in Genotype 1 by Viral Load and Dose of Peg-Intron

The SVR rates for both Peg-Intron doses were similar.  But the end-of-treatment response rates (the percentage of people with undetectable viral loads at the time of stopping therapy) are substantially better in people taking higher dose Peg-Intron (35% vs. 20%) for people with high viral loads.  This raises questions about how people with high viral loads will fare in the low-dose Peg-Intron arm.

Ribavirin dosing raises other important concerns.  Growing evidence suggests that maintaining an adequate dose of ribavirin increases the likelihood of achieving an SVR.  But ribavirin can also cause hemolytic anemia (a drop in hemoglobin levels, reflecting the destruction of red blood cells).  Hemolytic anemia can result in fatigue and other side effects.  As a result, many people starting HCV treatment have to reduce their ribavirin doses, potentially lowering their chances of achieving an SVR. 

To counter act this toxicity, physicians are increasing prescribing red cell growth factors (erythropoietin or EPO, marketed as Procrit and Aranesp) to reverse anemia and maintain people on adequate ribavirin doses.  Many leading clinicians are even using EPO proactively, to prevent the need for ribavirin dose reduction before hemoglobin levels drop too far.  Final research data supporting this strategy is not yet available, but the goal is to increase SVR rates by maintaining original ribavirin doses.

Based on data from large HCV treatment studies, Schering-Plough has estimated that between 14% and 22% of people in IDEAL will require ribavirin dose reductions due to drops in hemoglobin levels.  The IDEAL study protocol dictates a reduction in ribavirin dose when hemoglobin levels fall below 10 g/dL.  After dose reduction, EPO can be used to restore hemoglobin levels and allow a return to original ribavirin dosing, at the discretion of the treating physician.

The catch is that the protocol mandates different reductions in ribavirin dosage, depending on whether the study participant is in the Pegasys arm or a Peg-Intron arm.  People in the Pegasys arm will have their ribavirin dose reduced to 600 mg.  But people in a Peg-Intron arm will have a two-step dose reduction, first lowering the ribavirin dose 600-1,000 mg, depending on original dose, and then down another 200 mg if necessary. 

This apparent double standard led some IDEAL study investigators to raise concerns that the different dose reduction protocols would bias the results of the Pegasys/Peg-Intron comparison in favor of Peg-Intron.

Schering-Plough explains that the FDA required different dose reduction protocols based on available data.  The two-step dose reduction for the Peg-Intron arms has been studied in the WIN-R trial, but never researched in Pegasys studies.  The Pegasys dose reduction scheme is based on the protocol used in the original trials leading to FDA approval of Pegasys.

In response to these concerns, Schering-Plough has countered that overall, people in the Pegasys arm will actually receive marginally higher average doses of ribavirin than people in the Peg-Intron arms.  This projection presumably rests on the assumption that a substantial number of people receiving 1,400 mg of ribavirin with Peg-Intron will require ribavirin dose reductions.

A final question is how the different ranges of initial weight-based ribavirin doses (800-1,400 mg for Peg-Intron arms, vs. 1,000-1,200 for the Pegasys arm) will affect treatment responses.  Schering-Plough estimates that about 14% of study participants will fall into the lowest weight category, receiving 800 mg of ribavirin with Peg-Intron or 1,000 mg of ribavirin with Pegasys.  In theory, the 800 mg dose (with Peg-Intron) may be more tolerable and easier to maintain in this group, while the 1,000 mg dose (with Pegasys) may require more reductions to 600 mg (thus possibly compromising treatment efficacy).

Schering-Plough also estimates that about 11% of study participants will fall into the highest weight category, receiving 1,400 mg of ribavirin with Peg-Intron or 1,200 mg of ribavirin with Pegasys.  In theory, the higher 1,400 mg ribavirin dose may be more effective for this sub-group.

What Will We Learn from IDEAL?

IDEAL will tell us if there are any significant differences in SVR rates between the three treatment regimens.  In particular, IDEAL should tell us whether low-dose Peg-Intron works as well as high-dose Peg-Intron when used in combination with ribavirin in people with genotype 1.

IDEAL will also look at whether there are differences in SVR rates between the three regimens based on whether people have a high or low hepatitis C viral load.  In the case of viral load, unless the differences are very large, IDEAL will not be able to determine which is the best treatment regimen.

IDEAL will not be able to tell us whether Peg-Intron is better or worse than Pegasys, because different doses of ribavirin will be used.  All study participants will get a ribavirin dose that is based on their weight, but IDEAL lacks the statistical power to compare SVR rates between different weight groups.  About 75% of study participants will fall into the middle weight range and receive 1,000-1,200 mg of ribavirin regardless of which arm they are assigned to.  That leaves 25% of study participants who will receive lower (800 mg) or higher (1,400 mg) doses of ribavirin if they are assigned to the Peg-Intron arms, which may influence SVR rates. 

IDEAL results will be analyzed to see whether different ribavirin dose reduction protocols affect final SVR rates.  But if there are overall differences between the Pegasys and Peg-Intron arms, we won’t know if that’s because of the type of pegylated interferon used or the ribavirin dosing scheme.

Also, the Roche pilot study could show that higher doses of Pegasys and/or ribavirin are more effective in people weighing over 187 pounds who have genotype 1 and high hepatitis C viral loads.  In that case, the recommended Pegasys/Copegus doses might change, making the IDEAL results irrelevant to this group.

Conclusions

The design of IDEAL represents the results of a complex negotiation between scientific research, marketing imperatives, and regulatory demands.  Schering-Plough and Roche have predictably different perspectives on the value of IDEAL:

“These two treatment regimens have never before been directly compared in a study of this magnitude.  We are confident that the results of this large head-to-head study between Peg-Intron and Pegasys will help doctors and patients determine the therapy that offers them the best chance for achieving a sustained virologic response.” –

Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute, quoted in a 5/13/04 Schering-Plough press release

“We think what is relevant is the data that are available today.  We have great confidence in Pegasys and the wealth of data supporting it.  We would welcome a fair comparative trial, where Pegasys would be given an equal chance.  We do not believe this is the case for Schering-Plough's study including Pegasys.  It is our understanding that the ribavirin dosing regimen and dose reductions for side effects in the trial will favor the Peg-Intron arms.  Therefore, we do not believe this study will ever yield any unbiased information beyond what the optimal doses of Peg-Intron and Rebetol might be.”

– Pamela Van Houten, director of public affairs, Roche

Regardless of company rhetoric, people considering enrolling in IDEAL—particularly those with high viral loads—should think carefully about whether this study is right for them.  By joining IDEAL, study participants are randomly assigned to one of three treatment regimens, thus sacrificing the ability to work with their doctor on choosing a regimen that best suits their individual needs. In many cases, the best regimen is unclear, highlighting the potential value of IDEAL.  Some doctors would chafe at IDEAL’s restrictions on the preemptive use of EPO to head off the need for protocol-dictated ribavirin dose reductions.

That’s not to say that the study is unethical.  The design has been carefully thought out, based on the best available data from clinical trials, with the input of many leading clinicians, and approved by both the FDA and local Institutional Review Boards (IRBs).  IDEAL will certainly provide a wealth of valuable data to guide future treatment decisions.  But this study may not be ‘IDEAL’ for everyone.

6/02/04