Intec Pharma announced the complete enrollment of a Phase 3 clinical trial evaluating the safety and effectiveness of its Accordion Pill Carbidopa/Levodopa (AP-CD/LD) in easing motor fluctuations in people with advanced Parkinson’s disease.
Levodopa is considered the most effective and widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that helps ease levodopa’s side effects.
Together, these two components increase the level of dopamine in the brain, which normally is low in Parkinson’s patients, leading to the motor impairments associated with the disease.
However, patients with advanced disease being treated with levodopa (or Sinemet) often develop motor fluctuations, which result from “off” periods (a return of symptoms) between levodopa doses due to its short-term effects.
This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.
Intec Pharma’s AP-CD/LD was created to solve this problem through a specific gastric retention and release system containing carbidopa and levodopa. This system is intended to allow the therapy to be released in both immediate and controlled-release modes.
Controlled release enables a slow discharge of the therapy in the stomach over 8 to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.
Previous results from a randomized Phase 2 clinical study in 60 Parkinson’s patients showed that AP-CD/LD treatment was safe and significantly reduced “off” times by 45%, giving patients two extra hours a day of controlled motor function. AP-CD/LD treatment also significantly reduced the total number of levodopa doses per day.
“By providing more uniform levodopa plasma [blood] concentrations than those provided by currently available orally-administered levodopa products, we expect to improve the duration and consistency of symptom relief provided by levodopa with a simpler dosing regimen,” R. Michael Gendreau, MD, PhD, Intec Pharma’s chief medical officer, said in a press release.
The multi-center, randomized, double-blind, Phase 3 clinical trial (NCT02605434), named ACCORDANCE, is comparing the safety and effectiveness of AP-CD/LD and Sinemet (immediate release of carbidopa-levodopa) in hundreds of adults with advanced Parkinson’s.
Prior to the 13-week randomized part of the study 462 patients were first stabilized and optimized on Sinemet and then on AP-CD/LD during two open-label periods lasting six weeks.
About 300 of these patients are now receiving either an AP-CD/LD capsule — containing 50 mg of carbidopa with 400 or 500 mg of levodopa — twice or three times a day and a matching Sinemet placebo. Or they are being given an immediate release Sinemet tablet — consisting of 25 mg of carbidopa and 100 mg of levodopa — and a matching AP-CD/LD placebo at least four times a day.
In this type of study design, called double-blind, both tester and subject are blinded until a trial outcome is known. This allows researchers to reduce or eliminate bias in the study’s outcome.
The study’s primary goal is the reduction in the percentage of daily “off” time during waking hours, which will be considered statistically significant if it leads to at least one-hour difference between Sinemet and AP-CD/LD.
Secondary goals include the reduction of involuntary movements during “on” periods, and improvement in the scores of the Clinical Global Impression Scale-Improvement (CGI-I) — as recorded by the physician and patient — and the Unified Parkinson’s Disease Rating Scale (UPDRS), which assesses both motor and non-motor symptoms.
ACCORDANCE is taking place at about 90 clinical sites throughout the U.S., Europe and Israel (some 32% of participants were enrolled in the U.S.). At enrollment, 65% of patients were men with a mean age of 63, who have lived with the disease for a mean of 8.8 years. Participants’ mean daily “off” time was 6.1 hours, and over 40% were taking more than 800 mg of levodopa daily.
Participants who complete the 13-week randomized period can chose to move to an open-label extension study, where all patients will receive AP-CD/LD for one year. To date, more than 90% of eligible patients have chosen to enter the extension study, the company reports.
According to an Israel newspaper, results of the ACCORDANCE study are expected in mid-2019.
Intec Pharma believes these results, along with the long-term data provided by the extension study and the results of a Phase 2 clinical study (NCT03576638) evaluating how the most common dose of AP-CD/LD in the ACCORDANCE study is processed by the human body, will be essential for regulatory submission and AP-CD/LD launch.