Assessment of Desogestrel in Ondine Syndrome
Condition: Ondine Syndrome
MeSH terms: Sleep Apnea, Central; Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The congenital central hypoventilation syndrome (CCHS), also known as the Ondine syndrome, is
      a very rare genetic disorder. In contrast with healthy people, patients do not increase
      breathing in response to an excess of carbon dioxide (CO2). As a consequence, they do not
      breath sufficiently, or even stop breathing, during sleep. Their survival depends only on
      mechanical respiratory assistance, all life long.

      We have recently published two cases of recovery of a response to CO2 in patients taking
      desogestrel as a contraceptive pill. The goal of the study is therefore to assess the
      hypothesis that desogestrel will restore a respiratory response to CO2 in CCHS patients and
      allow them to breath sufficiently during sleep without mechanical assistance.
    

Detailed description: 
      Rationale of the study The congenital central hypoventilation syndrome (CCHS), also called
      Ondine syndrome or Ondine's curse, is a rare orphan disease associated with mutations of the
      PHOX 2B gene. It is characterized by an absence or a deep reduction in the ventilatory
      response to hypercapnia and hypoxia. As a consequence, life-threatening hypoventilation or
      apneas occur during sleep and, in some patients, also during wakefulness. Survival thus
      depends on mechanical ventilatory assistance (or on phrenic pacing), all life long. There is
      no pharmacological treatment.

      We have fortuitously observed two cases of recovery of ventilatory response to hypercapnia in
      patients taking desogestrel, a very potent progestin, as a contraceptive treatment ("Straus,
      C., et al. Respir. Physiol. Neurobiol. 2010 ; 171 : 171-174").

      The hypothesis of the research project stems from these observations. It assumes that
      desogestrel will restore a chemosensitivity to hypercapnia in Ondine patients that will allow
      them to breath sufficiently without mechanical ventilatory assistance during sleep.

      The primary goal of the study will be to assess whether a treatment with desogestrel will
      restore a ventilatory response to hypercapnia. The secondary goal will be to evaluate whether
      this response will allow the patients to be weaned from mechanical ventilatory assistance
      during sleep.

      Methods The study will take place in one unique hospital, the Pitie-Salpetriere Hospital in
      Paris, France. It will be conducted in volunteer pubescent female patients. Patients with
      contra-indications to desogestrel will not be included.

      The ventilatory response to hypercapnia will be assessed through the rebreathing method and
      through a blinded procedure specifically designed for the study. Sleep and breathing during
      sleep will be assessed through polysomnography. Blood gas analysis as well as hormonal and
      ionic analysis of the blood will be performed. The ventilatory response to hypoxia will also
      be assessed. Changes in cerebral activation will be looked for using functional magnetic
      resonance imaging (fMRI).

      Protocol Patients will be first assessed with all the tests mentioned in the above paragraph,
      except fMRI. Polysomnography will be performed under mechanical ventilation.

      Patients who will not take any contraceptive oral treatment with estrogens or progestin and
      whose response to hypercapnia will be low enough will immediately continue the study. An fMRI
      will be performed and the patients will be prescribed desogestrel 75 µg daily.

      Patients who will be under an oral contraceptive treatment with estrogens or progestin will
      have to stop it and to use mechanical contraception (condom). All the patients taking an oral
      contraceptive treatment will be assessed after having stopped these drugs, with all the tests
      mentioned in the "methods" paragraph, except fMRI. Polysomnography will be performed under
      mechanical ventilation. If their ventilatory response to hypercapnia will be low enough an
      fMRI will be performed and the patients will be prescribed desogestrel 75 µg daily.

      All the patients will be assessed under treatment with desogestrel. If the slope of the
      ventilatory response to hypercapnia is more than 1L/min/mmHg, an attempt of weaning from
      mechanical ventilation during sleep will replace the usual polysomnography under mechanical
      ventilation. The patients will be admitted in an intensive care unit where they will sleep
      without ventilatory assistance. Polysomnographic recordings will be performed with a portable
      device. In case of prolonged hypopneas or apneas or in case of arterial desaturation,
      patients will be awakened and mechanical ventilation will be resumed. The attempt of weaning
      will be regarded as a failure. In the absence of those criteria, the weaning will be regarded
      as a possible success. However, the investigators will not prescribe to the patient to sleep
      without ventilatory assistance. Their attending physician will have to take the final
      decision regarding this issue.
    

Intervention name(s): desogestrel
Intervention type(s): Drug
Intervention description(s): Tablets of 75 µg, once daily during 112 days
Intervention MeSH terms: Desogestrel
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Desogestrel; Chemosensitivity