Assessment of Desogestrel in Ondine Syndrome (RESPIRONDINE)

November 13, 2013 updated by: Assistance Publique - Hôpitaux de Paris

Assessment of Desogestrel for a Pharmacological Recovery of Ventilatory Activity in Congenital Central Hypoventilation Syndrome - Ondine Syndrome

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

6

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75013
        • Pitie Salpetriere Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 56 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion criteria :

  • Ondine syndrome
  • Pubescent female

Exclusion criteria :

  • Contra-indications to a treatment with desogestrel.
  • Other treatment with estrogens or progestin that cannot be stopped.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: desogestrel
Tablets of 75 µg, once daily during 112 days
Drug: desogestrel
Tablets of 75 µg, once daily during 112 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Increase in the ventilatory response to hypercapnia
Time Frame: 112 days
112 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Ventilatory response to hypoxia
Time Frame: 112 days
112 days
Activation of new cerebral regions in fMRI
Time Frame: 112 days
112 days
Weaning from mechanical ventilation during sleep
Time Frame: 112 days
112 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: STRAUS Christian, MD, PhD, Pitié Salpétrière hospital (APHP)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2011

Primary Completion (Actual)

September 1, 2013

Study Completion (Actual)

September 1, 2013

Study Registration Dates

First Submitted

November 17, 2010

First Submitted That Met QC Criteria

November 17, 2010

First Posted (Estimate)

November 18, 2010

Study Record Updates

Last Update Posted (Estimate)

November 14, 2013

Last Update Submitted That Met QC Criteria

November 13, 2013

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P101001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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