Pilot Study of the Effects of the Desipramine on the Neurovegetative Parameters of the Child With Rett Syndrome

Rett syndrome is a neurodevelopmental disorder characterized by cognitive impairment, communication dysfunction, stereotypic movement disorder, and growth failure. Rett syndrome is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment.

A mouse experimental model of Rett syndrome created by genetic invalidation of the MECP2 gene is available. It had been then observed that adult MECP2-deficient mice show respiratory alterations and found that endogenous noradrenaline helps to maintain a normal respiratory rhythm. Desipramine, a selective inhibitor of norepinephrine reuptake, seems to be efficient to reduce the respiratory alteration occuring in MECP2-deficient mice (Insem patent 2005, Villard and Roux 2006).

The aim of the study is to evaluate these obtained results in MECP2-deficient mice on patients with Rett syndrome.

Study Overview

• Status: Completed
• Conditions: Rett Syndrome
• Intervention / Treatment: Drug: Administration of a high dose of desipramine; Drug: Administration of a low dose of desipramine; Drug: Administration of a placebo

Detailed Description

Rett syndrome is a neurodevelopmental disorder characterized by cognitive impairment, communication dysfunction, stereotypic movement disorder, and growth failure. The diagnosis of Rett syndrome is based on consensus clinical criteria. Rett syndrome is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment.

Only a few improved cases have been reported concerning buspirone (Andaku, 2005, 1 patient), topiramate (Goyal, 2004, 8 patients), diazepam (Kurihara, 2001, 1 patient) and carnitin (Plochl, 2004, 1 patient).

Only one randomized study versus placebo has been published about a treatment by naltrexone including 25 patients. A light improvement of respiratory parameters was then observed with a deterioration of the cognitive function (Percy, 2004).

A mouse experimental model of Rett syndrome created by genetic invalidation of the MECP2 gene is available. It had been then observed that adult MECP2-deficient mice show respiratory alterations and found that endogenous noradrenaline helps to maintain a normal respiratory rhythm. Desipramine, a selective inhibitor of norepinephrine reuptake, seems to be efficient to reduce the respiratory alteration occuring in MECP2-deficient mice (Insem patent 2005, Villard and Roux 2006).

The aim of the study is to evaluate these obtained results in MECP2-deficient mice on patients with Rett syndrome.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Marseille, France
    • Assistance Publique - Hopitaux de Marseille

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Rett syndrome;
• Girls weighing less than 60 kg;
• Respiratory alteration;
• Diagnosis of Rett syndrome confirmed by MECP2 genotyping (Xq28).

Exclusion Criteria:

• Boys;
• Pregnancy and breath feeding;
• Case history of status epilepticus;
• Patient treated by IMAO or sultopride;
• Hepatic or renal failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Desipramine high dose; 12 patients with Rett syndrome receiving a daily dose of desipramine correlated with the weight : From 15 to 25 kg : 50 mg ;; From 26 to 35 kg : 75 mg ;; From 36 to 45 kg : 100 mg ;; > 46 kg : 150 mg.	Drug: Administration of a high dose of desipramine; Administration of a daily dose of desipramine correlated with the patient's weight : From 15 to 25 kg : 50 mg ;; From 26 to 35 kg : 75 mg ;; From 36 to 45 kg : 100 mg ;; > 46 kg : 150 mg.
Experimental: Desipramine low dose; 12 patients with Rett syndrome receiving a daily dose of desipramine correlated with the weight : From 15 to 25 kg : 25 mg ;; From 26 to 35 kg : 50 mg ;; From 36 to 45 kg : 75 mg ;; > 46 kg : 100 mg.	Drug: Administration of a low dose of desipramine; Administration of a daily dose of desipramine correlated with the patient's weight : From 15 to 25 kg : 25 mg ;; From 26 to 35 kg : 50 mg ;; From 36 to 45 kg : 75 mg ;; > 46 kg : 100 mg.
Placebo Comparator: Placebo; 12 patients with Rett syndrome receiving a daily dose of placebo.	Drug: Administration of a placebo; Administration of a daily dose of placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To study the efficacy of the desipramine on the respiratory disturbations	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
To study the safety of the desipramine in the studied population	2 years

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille
• Investigators: Principal Investigator: Josette Mancini, Assistance Publique Hopitaux de Marseille

Publications and helpful links

General Publications

• Mancini J, Dubus JC, Jouve E, Roux JC, Franco P, Lagrue E, Castelnau P, Cances C, Chaix Y, Rougeot-Jung C, Cornu C, Desportes V, Vallee L, Bahi-Buisson N, Truillet R, Attolini L, Villard L, Blin O, Micallef J. Effect of desipramine on patients with breathing disorders in RETT syndrome. Ann Clin Transl Neurol. 2017 Dec 27;5(2):118-127. doi: 10.1002/acn3.468. eCollection 2018 Feb.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2009
• Primary Completion (Actual): August 11, 2014
• Study Completion (Actual): August 21, 2017

Study Registration Dates

• First Submitted: October 6, 2009
• First Submitted That Met QC Criteria: October 6, 2009
• First Posted (Estimate): October 7, 2009

Study Record Updates

• Last Update Posted (Actual): July 26, 2018
• Last Update Submitted That Met QC Criteria: July 25, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Rett syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Syndrome; Rett Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Antidepressive Agents, Tricyclic; Adrenergic Uptake Inhibitors; Desipramine
• Other Study ID Numbers: 2007-37; 2007-006739-30