HAROSA II

Clinical Question

Does Pitolisant reduce excessive daytime sleepiness compared to placebo in those who have moderate-to-severe Obstructive Sleep Apnea (OSA) who are non-adherent to or refuse CPAP therapy?

Bottom Line

Pitolisant could be considered as an alternative therapy before Modafinil or Armodafinil to those who suffer from moderate-to-severe Obstructive Sleep Apnea due to its mild side effect profile, no withdrawal effects upon abrupt discontinuation unlike C-IV stimulants, and no significant cardiovascular effects.

Major Points

One previous study conducted with Pitolisant assessed the use in patients who suffer from excessive daytime sleepiness in narcolepsy, and by merit of the findings, was approved for use by the FDA in 2019. One objective of this trial was to expand the horizons for which it could be used and to treat those who might suffer from sleep-related disorders outside of narcolepsy. Pitolisant's favorable side effect profile that was elucidated in its trial with narcolepsy was confirmed in this trial with patients who have Obstructive Sleep Apnea.

Guidelines

So far, the guidelines for obstructive sleep apnea have not reflected the findings of this article.

Design

• Phase III, prospective, double-blinded, placebo-controlled, multicenter study
• N=268
  • Pitolisant (n=200)
  • Placebo (n=68)
• Setting: 28 hospital sleep clinics throughout 10 European countries
• Timeframe: October 6th, 2011 to May 7th, 2014
• Analysis: Intention-to-treat (per-protocol within the intention-to-treat)
• Primary outcome: Evaluate the change from baseline to week 12 in the Epworth Sleepiness Scale

Population

Inclusion Criteria

• Patients clinically diagnosed with obstructive sleep apnea who still complain of excessive daytime sleepiness symptoms also refusing or are non-adherent to CPAP therapy
• ESS score >12
• >18 years old

Exclusion Criteria

• Patients suffering from insomnia without OSA
• Co-existing narcolepsy
• Patients with a sleep debt not due to OSA
• Recent illicit drug use or substance use disorder
• ESS <12
• BMI >40
• Acute or chronic severe disease

Baseline Characteristics

• Mean age: 52 years (75.4% male, 24.6% female)
• Mean nocturnal SaO2: 90.1%
• Mean BMI: 32.9
• 54% having a prior cardiovascular disease

Interventions

• Patients were randomized in a 3:1 fashion (Pitolisant:placebo)
• Doses came in 5mg, 10mg, and 20mg
  • Patients initiated on 5mg for a two week titration period, then were evaluated for whether their dose could be increased
• Their dose was given within one hour of awakening on an empty stomach
  • In weeks 3-7, patients doses were increased or decreased based upon efficacy and safety parameters
  • In weeks 7-12, patients were locked into a dose until week 12 when the results were analyzed

Outcomes

Primary Outcomes

Primary endpoint evaluated the change in ESS score from Pitolisant vs placebo, respectively

A decrease in ESS in the Pitolisant group by 6.3 points (CI 8.8-10.1) compared to the placebo group by a decrease of 3.6 points (CI 10.7-13.5) (p<0.001)

Secondary Outcomes

Change from baseline to week 12 in the Oxford Sleep Resistance test (OSLER)

14.79 ± 10.95 minutes and 15.92 ± 11.04 minutes for the pitolisant and placebo groups, respectively. The percentages of patients exhibiting the maximum of 40 minutes were 5.5% and 6%, whereas those in the 30–40-minute range were 6.5% and 4.5%, in the pitolisant and placebo groups, respectively

The ratios of increase in mean sleep latency during OSLER tests were 1.65 and 1.39 in the pitolisant and placebo groups, respectively (P = 0.108 using a mixed model)

ESS Response (Normalization of ESS Score <10)

Pitolisant normalized the ESS score (ESS, ≤10) in 67.2% of patients in the study arm versus 44.8% in the placebo group. An “ESS response,” defined as either an ESS score ≤10 or improvement by 3 or more points, was observed in 80.6% in the pitolisant group and 53.7% in the placebo group (P < 0.001)

NNT = 4

Adverse Events

• Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concern

Criticisms

• Study was conducted for a 12-week duration
  • Long-term maintenance of efficacy and safety are being conducted in an extension of this trial
• Dr. Partinen is a medical advisory committee member of clinical trials at Bioprojet
• Drs. Lecomte and Schwartz are employees and shareholders of Bioprojet
• Dr. Verbraecken received funding outside of the submitted work from the following:
  • Antwerp University Hospital
  • Grants from Bioprojet
  • Grants from Jazz Pharmaceuticals
  • Grants from UCB Pharma

Funding

• University of Turku (Finland)
• AstraZeneca, VitalAire (Canada), Boehringer Ingelheim, Philips, ResMed
• Bioprojet - Paris, France

Further Reading

• HAROSA I Trial
  • Pépin JL, Georgiev O, Tiholov R, Attali V, Verbraecken J, Buyse B, Partinen M, Fietze I, Belev G, Dokic D, Tamisier R, Lévy P, Lecomte I, Lecomte JM, Schwartz JC, Dauvilliers Y; HAROSA I Study Group. Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP: A Randomized Trial. Chest. 2021 Apr;159(4):1598-1609. doi: 10.1016/j.chest.2020.09.281. Epub 2020 Oct 26. PMID: 33121980.