“This association may improve wakefulness and cognition probably by modifying the interaction between neuronal and glial networks in the brain,” said lead author Jean-Christophe Corvol, MD, PhD, of Sorbonne University, Paris.
The results were presented at a late-breaking poster presentation at the Movement Disorders Society virtual congress.
Corvol said during his presentation of the study that modafinil alone had previously shown inconsistent results in PD patients with EDS.
The combination, being developed as THN102, contains modafinil 200 mg/day plus a low dose of flecainide, either 2 mg (THN200/2) or 18 mg (THN200/18) daily. In a phase 2, international, double-blind, 3-period crossover trial, investigators randomly assigned PD patients with EDS to placebo or either active dose of the drug. EDS was defined as an Epworth Sleepiness Scale (ESS) total score of ≥ 14, which indicates moderate to severe daytime sleepiness.
Each intervention period lasted 2 weeks, separated by a 1- to 2-week washout period, followed by crossover to a different intervention. “The efficacy analysis showed no carry-over effect,” between the periods, Corvol reported.
Of 77 randomly assigned patients, 75 were exposed to treatment, and 72 were evaluable for efficacy. The mean age of the cohort was 63.5 ± 9.35 years, 50 were male, and the ESS at baseline was 16.5 ± 2.
The primary objectives of the trial were efficacy as assessed with the ESS and safety. Patients were also evaluated for vigilance as measured by the Psychomotor Vigilance Test (PVT) and for cognition using the Montreal Cognitive Assessment (MoCA).
THN200/2 lowered ESS scores (least squares means ± standard error) by 3.84 ± 0.5 points from baseline compared with a reduction of 2.44 ± 0.5 points with placebo (P = .012). Interestingly, THN200/18 was less effective, lowering ESS scores by 3.18 ± 0.5 points, which did not reach statistical significance compared with placebo (P = .177).
“So that’s kind of unusual that there isn’t a dose-dependent effect,” Alberto Espay, MD, MSc, director of the Parkinson’s Disease and Movement Disorders Center at the University of Cincinnati, Ohio, commented to Medscape Medical News. Given the modest effects, “I don’t know if this will translate into clinical significance.”
There was a trend in remission of sleepiness, defined as ESS < 11, in 27.5% of the patients on THN200/2 and in 25.4% on THN200/18 vs 16.2% on placebo (P = .052 and P = .102, respectively).
The fact that only about one quarter of patients showed remission of EDS may explain the rather modest reduction in overall ESS scores since the nonresponders may have skewed the overall ESS score. The responders may have done better than the cohort as a whole.
Espay said it may be interesting to see if the investigators “see anything in the data they collected that could speak about predictors of response, as well as predictors of lack of response, so that they can perhaps fine-tune the selection of patients most likely to benefit for the next study.”
Good Safety and No Negative Effects
“The safety analysis showed no treatment-related serious adverse events,” Corvol said. Most of the adverse events occurred in the higher dosage periods, with four occurrences of headache, three each of nausea and nasopharyngitis, and two each of insomnia, confusional state, nightmare, and dry mouth. In the THN200/2 phases, there were two reports of nausea and one of insomnia. Six participants discontinued the study (three in each THN102 dosage treatment period). No adverse effects were noted during the placebo periods.
There were no changes in the cognitive assessments as measured by the PVT and MoCA tests. There were also no significant changes in Parkinson’s symptoms as measured on Parts I-IV of the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale, nor were there any issues regarding vital signs, cardiac, or laboratory assessments.
When asked if placebo was the most appropriate control, Espay said a study against modafinil alone would be possible, “and in reality, the most important question to answer is not whether you have something that includes modafinil that’s better than placebo, but something in principle definitely that works better than…modafinil alone.”
He questioned the choice of placebo as a control and suggested that for “a company that wants to get these out in the market, it’s easier to demonstrate efficacy against placebo than it is to demonstrate efficacy against an already existing active medication.”
Theranexus Pharma sponsored the trial. Corvol served on an advisory board for Theranexus Pharma for the design and conduct of the trial, has an advisory relationship with CleveXel Pharma, and has received honoraria from Biogen. Espay has disclosed no relevant financial relationships.
MDS Virtual Congress 2020: Abstract LBA3. Presented September 12, 2020.