Twelve weeks of antibiotic therapy proved ineffective at combating the long-term symptoms seen in some people who have had Lyme disease, a new test of 280 sufferers found.

The new study, known as PLEASE, was the largest ever done in patients with chronic symptoms following a Lyme infection. It was designed to see if either of two antibiotic regimens might make a difference. They didn’t.

After 12 weeks of therapy with the antibiotic doxycycline, 86 volunteers taking a health status questionnaire logged a score of 35 on a scale of 15 to 61, with 61 being the highest quality of life. With 12 weeks of treatment with the antibiotic combination clarithromycin and hydroxychloroquine, the average score of 96 patients was 35.6. Twelve weeks of placebo therapy produced an average score of 34.8 in the remaining patients.

“The patients reported no benefit of prolonged antibiotics on any of the scales compared to those who received placebo,” said senior author Dr. Bart Jan Kullberg, a professor of medicine and infectious disease at Radboud University Medical Center in Nijmegen, the Netherlands.

The findings, published in New England Journal of Medicine, show that an active Lyme infection is not causing the symptoms of pain, fatigue, disrupted sleep and a loss of mental acuity that can persist in 10 to 20 percent of patients who develop the disease.

In 2014, the United States had 25,359 confirmed cases of Lyme, according to the Centers for Disease Control and Prevention. The disease is typically cured by short-term antibiotic therapy.

But when it comes to persistent symptoms, “we don’t really know what is the cause of this syndrome,” Kullberg told Reuters Health. “It could be an immune response to the prior infection, sensitization to the infection or genetic variation that makes them sensitive to prolonged symptoms after an infection. But the answer may not be found in prescribing a prolonged course of antibiotics.”

Previous studies have shown the same thing and “this is sort of a further nail in the coffin in the controversy over chronic Lyme disease, or whatever you want to call it when people who have had Lyme disease have residual symptomatology,” said Dr. Charles Ericsson, head of clinical infectious diseases at McGovern Medical School at UTHealth and a member of the medical staff at Memorial Hermann-Texas Medical Center in Houston.

“You can treat the inciting agent until the cows come home and nothing will change,” Ericsson, who was not involved in the research, told Reuters Health. “You have to find a way to control this disregulated immune system.”

He likened it to chronic fatigue syndrome, where doctors seem no closer to finding a cause, yet, “there’s something going on there.”

“We clearly need more research into how to deal with patients with this disease,” Ericsson said.

At the start of the test, all volunteers received two weeks of intravenous antibiotic therapy with the drug ceftriaxone to clear any active short-term infection they might have. The patients had typically already undergone two courses of antibiotic therapy to get rid of their symptoms, which had persisted for a median of two to three years.

By the end of the study, patients in all three groups reported less fatigue and said they felt better physically and mentally, but the improvements were not significantly greater in either group that received active medication.

And the quality of life they had in the end was “not different from patients with cancer or rheumatoid arthritis,” Kullberg said.

“In addition, no significant changes over time were observed during the 26-week follow-up after the end of the treatment period in any of the study groups,” the researchers concluded.

The only serious side effects showed up when ceftriaxone was used for the first two weeks.

“Although the side effects were mostly minor, 68.6 percent of the patients reported at least one adverse reaction that was thought to be drug related, which should lessen the temptation among physicians to prescribe longer courses of antibiotics just in case they might help,” write Drs. Michael Melia and Paul Auwaerter of Johns Hopkins University School of Medicine in Baltimore in a Journal editorial.

Lyme disease in Europe is caused by a different species of bacteria than in North America.