Arguments for Combination Trials

HD Lighthouse Contributing Editor's Comment: Following the recent 2CARE editorial, several Lighthouse readers have requested more information regarding our stated support of clinical trials using combinations. We believe the primary goal of clinical trials in Huntington’s should be to find effective treatment as soon as possible. Combination clinical trials have the best chance of achieving that goal.
Posted to the HDL: 12 Aug 2005

Walking the Talk

Following the recent 2CARE editorial, several Lighthouse readers have requested more information regarding our stated support of clinical trials using combinations. We believe the primary goal of clinical trials in Huntington’s should be to find effective treatment as soon as possible. Combination clinical trials have the best chance of achieving that goal.

We at the Lighthouse didn’t invent the concept of combinations. The history of medicine is full of examples of combination clinical trials that have found best therapy for many diseases: AIDS and other infectious disease, cancer, diabetes, kidney and heart disease, and a long list of others. HD scientists have shown that combinations work best in mouse models and have since 2003 stated that they believe combinations will likely be best treatment for people.

The Arguments for Combinations

While there are other arguments for the use of combinations in HD, the focus will be on (1) the example of rapid AIDS therapy development and (2) the example of HD mouse models with opinions from HD experts.

AIDS Drug Development

After the discovery of the HIV virus, there was the hope that a vaccine or a specific antiviral drug “cure” could be quickly developed. Though more than twenty years of research have passed with out vaccine or a drug cure, extraordinary therapeutic triumphs have been achieved by and for AIDS people. Except for the first experimental drug, all advances have been made in trials using drug combinations. AIDS history can teach us very important lessons along the road to successful therapy for Huntington’s, if we listen.

AIDS Clinical Trials

The first drug for AIDS (AZT) was available just four years after the discovery of the AIDS virus. In this first trial, death was the endpoint. Because more people died in the placebo arm during the first six months, the trial was halted early. Subsequently AZT was FDA approved in the record time of 3 months and prescribed for patients as soon as it was made available to pharmacies.

Though remarkable early benefit occurred in some patients, viral resistance to the drug soon appeared. In separate trials, the second AIDS drug (ddc) was initially tested both as single drug and in combination with AZT. Interestingly ddc didn’t work well as a single drug, but when used in combination with AZT, showed greater benefit than either drug alone. In fact, if the combination study had not been done, its significant benefit in AIDS would not have been found. FDA approval of this and following AIDS drugs was based on efficacy results from combination trials.

Shortly after this successful two-drug combination was available; a group of pharmaceutical companies formed the Inter-Company Collaboration for AIDS Drug Development (ICC) and conducted a shared large clinical trial with separate arms that rapidly tested four different three drug combinations. At the initiation of this historical effort, they cited the pharmaceutical concept that “builds on historical work with combinations . . . that has resulted in treatments to successfully control chronic . . . disease. To no ones surprise, they found that three drugs in combination gave better results than two; and they were able to directly compare effects of new drugs.

Now a dozen years after AZT, all AIDS trials are combination trials. There are more than 20 anti-HIV drugs used AIDS patients in combinations of up to five.

Though there is no vaccine or cure, AIDS people have greatly increased quality of life and life expectancy now by the use of combinations.

How was it done?

This achievement came through hard work and joint efforts of several groups; public and governmental institutions, health care professionals, pharmaceutical companies and patient volunteers. The speed at which drugs got to people was due in large part to patient advocates. While these activists were sometimes infuriating, they effectively put urgency into the AIDS equation. Early on, they tackled the conflict between scientists’ need for pure results and the practical needs of dying patients. They pushed at many levels for clinical trials that most quickly put “drugs into bodies”. They pushed for clinical trials that focused on evidence-based best therapy for patients now, not best answers about a single drug. They did this by pushing for trials that used several drug combinations in simultaneous trials. They pushed for trials that led directly from safety to efficacy phases and the use of surrogate marker endpoints. They pushed for expedited FDA approvals. They pushed for free drug programs for those who could not afford medicines. And the list goes on.

Combinations for Huntington's: Mice and Men

Combinations give best benefit in the mouse, and are projected to give best benefit in HD people. We quote the experts because they say it best.

The following is found in a question and answer session from a lecture by Dr. Flint Beal, a venerable expert in Huntington’s, “In Huntington’s mice . . . we have tested a combination of (up to) four different agents. When we use four . . . we can get better protective effects with increases in survival up to 46%. Therefore, we get increased benefits with multiple agents just as they have found with cancer chemotherapy.” (Ann Neurol 2003:53 (suppl3):S39-S48).

Dr. Robert Ferrante, a long-time noted HD expert, adds the following comment: “Like the way that treatment for cancer and AIDS has evolved, the most effective neuroprotection for HD will likely come from a cocktail of medications”. (Expert Opin Emerging Drugs (2005) 10(2).

Dr. Steven Hersch, who is in charge of HSG clinical trials, is among the authors in a recently published article that offered the following, “It is becoming clear that the most effective therapy for HD . . . will arise from polytherapies derived from safe and well tolerated drugs”. (J.pharmthera.2005,04,008)

Questions for HSG, NINDS, and Orphan Drug FDA

Clinical trials in HD are urgently needed. HD people want and should have the evidence-based results of clinical trials. But as patient advocates, we at Lighthouse ask for trials that specifically focus on those that will most likely deliver best treatments in the immediate future. While HD leaders are “talking the talk” about likely best therapy using combinations; it has not led to “walking the walk” of combination trials.

It is in this setting that those of us at HD Lighthouse (and those in the patient/family community we represent) are critical of 2CARE. We have questions regarding 2CARE and clinical trial goals. These and similar questions will be presented to those in the national organizations listed above. And though we aren’t expert HD scientists; we believe that Huntington’s people, who are the major stakeholders of clinical trials, have the right to ask these questions, and that we have the combined knowledge base to understand the answers.

AIDS history shows us that patient advocates and an educated patient community can add success to the clinical trial process that keeps it focus on patient need.

Questions

Specific to 2CARE

1. Why is 2CARE designed to test one drug when Huntington’s experts uniformly believe that combinations will lead to best therapy for HD people? Further, why is 2CARE for five years, which seems to incorporate a “built in” design to not help people now?
2. Are our research leaders aware that 2CARE is not relevant to many HD people? Those who read the scientific and medical literature reviewed at Lighthouse (or have a doctor that shares it with them) are already taking CoQ-10. It does not make common sense for a person with a terminal brain disease to be in a trial that risks five years of placebo.
3. Does NINDS have mechanisms to fund the testing of multiple drugs, as in other branches of NIH?
4. Does NINIDS have responsibility for funding trials that are likely to have best benefit for patients over those that don’t? Because the experts believe it is likely best therapy for people, should NINDS take the lead and invite grant requests for combination trials?

   General

5. Do HSG leaders have a clinical trial roadmap or plan? Is it to perform single agent trials like 2CARE before (or that will not lead directly into) combination trials?
   
6. Because time is important to HD people, how long do you estimate it will take to get to combinations? How long for a result?
   
7. Realistically speaking, how many ten million dollar studies will NINDS fund over the next decade?

We invite our readers to add to this list. Lighthouse will do its best to supply readers with answers received, because an educated patient community can add success to the clinical trial process.

This article was written by LaVonne Veatch Goodman, M.D. and endorsed by the following individuals: Malcolm Casale, Ph.D.; Nathan Goodman, Ph.D.; Linda Miller, M.S.; Marsha L. Miller, Ph.D.; Gayle Tinnerman, M.S.T.; Steve Ireland

The URL for the referenced 2CARE article is: http://www.hdlighthouse.org/TreatmentNow/updates/1176hsg2care.php

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