Acute Rhabdomyolysis and Muscle Pain Associated With Mutations in the LPIN1 Gene - A Retrospective Study Describing the Safety and Efficacy of Hydroxychloroquine Sulfate Given on a Compassionate Basis to Patients Suffering From Lipin-1 Deficiency (LIPIN-1-METAB)

November 7, 2022 updated by: Assistance Publique - Hôpitaux de Paris

Lipin-1 deficiencies are responsible for severe rhabdomyolysis and muscle pain in childhood. A specific treatment does not exist. Our research team (Pr de Lonlay, Pr Van-Endert, Marine Madrange and Perrine Renard) identified the mechanism of this disease and propose a treatment to decrease rhabdomyolysis outcome and muscle pain. Further to a CPP approval in 2015, several patients have been treated by Hydroxychloroquine Sulfate off label use on a compassionate basis.

The objective of this retrospective study is to describe the safety and efficacy of Hydroxychloroquine Sulfate given on a compassionate basis to patients suffering from Lipin-1 deficiency within a period between 6 and 36 months.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The Lipin-1 deficiency is an inherited autosomal recessive disease caused by two mutations in the LPIN1 gene. Homozygous or compound heterozygous Lipin-1 deficiency causes recurrent acute episodes of rhabdomyolysis and myoglobinuria in children, associated with permanent muscle pain and weakness. The onset of the disease is usually early (before the age of 6 years old) and the disease is severe. The number of acute episodes' ranges from 1 to 10 per patient, mostly during the first 6 years of life (period where illness episodes are most frequent). Some patients die of myoglobinuric bouts, from cardiac arrhythmia, possibly due to hyperkalemia, with a heart probably more sensitive to hyperkaliemia. Mortality rate is around 10%, and is significantly higher when rhabdomyolysis is complicated by renal failure or by cardiac arrest with arrhythmia due to hyperkalemia. A specific treatment does not exist. Altogether these observations indicate that there is a crucial need to identify a treatment.

Our research team (Pr de Lonlay, Pr Van-Endert, Marine Madrange and Perrine Renard) identified the mechanism of this disease. The consequences on myoblasts of patients are TLR9 sequestration in late endosomes and mitophagy impairment, with consecutively mitochondrial DNA accumulation, TLR9 activation, inflammatory cytokines, calcium release and cell death in the presence of TLR9 ligands and a nutrient-poor environment.

Hydroxychloroquine Sulfate, thanks to an anti-TLR9 activity restores control cell phenotypes. In vivo and in vitro results are spectacular. This treatment seems to be able to both decrease the signaling cascade resulting from the activation of TLR9 and to correct the phenotype of patients suffering from the Lipin-1 deficiency.

Further to a CPP approval, several patients have been treated by Hydroxychloroquine Sulfate off label use on a compassionate basis. The objective of this retrospective study is to describe the safety and efficacy of Hydroxychloroquine Sulfate given on a compassionate basis to patients suffering from Lipin-1 deficiency within a period between 6 and 36 months.

Study Type

Observational

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

      • Paris, France, 75015
        • Hôpital Necker-Enfants Malades

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

3 months to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The population to be studied consists of 8 paediatric patients with Lipin-1 deficiency followed-up by the metabolic diseases center of Necker hospital and having been treated by Hydroxychloroquine sulfate for at least 6 months.

Description

Inclusion Criteria:

  • Age ≥ 3 months
  • Minors with Lipin-1 deficiency which were diagnosed with familiar context analysis followed by genetic diagnosis (two causal mutations on the LPIN1 gene) and treated by Hydroxychloroquine Sulfate off label use on a compassionate basis in the Metabolic Diseases Center of Necker Hospital
  • Patients treated by Hydroxychloroquine Sulfate for at least 6 months

Exclusion Criteria:

- Opposition of parental authority holders

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

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Lipin-1 deficiency
Patients suffering from Lipin-1 deficiency havebenefited from an off-label use treatment by Hydroxychloroquine Sulfate as part of their care for at least 6 months.

The dosage and the route of administration of Hydroxychloroquine Sulfate was the same than in Lupus disease:

Oral administration: administered in soluble form in patients under the age of 6 years old and administered in tablets in patients other the age of 6 years old with Lipin-1 deficiency.

The soluble form was prepared at the Necker Hospital Pharmacy. Dose: 6.5 mg/kg/day (max 400 mg/day). The plasma concentration of the drug during follow-up was made, in order to follow a possible overdose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Creatine kinase dosage in plasma
Time Frame: 36 months
36 months
Inflammatory cytokines in plasma
Time Frame: 36 months
Quantitative flow cytometry based mutliplex assays (flow cytometry-based systems (BD™ Cytometric Bead Array)).
36 months
Quantification of mitochondrial DNA in plasma
Time Frame: 36 months
Quantitative PCR to detect mitochondrial DNA, 12s gene.
36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of intercurrent event
Time Frame: 36 months
Clinical examination.
36 months
Occurrence of rash
Time Frame: 36 months
Clinical examination.
36 months
Gowers sign appearance
Time Frame: 36 months
Clinical examination.
36 months
Occurrence of shortness of breath
Time Frame: 36 months
Clinical examination.
36 months
Occurrence of muscular fatigability
Time Frame: 36 months
Clinical examination.
36 months
Treatment compliance
Time Frame: 36 months
Patient interrogation.
36 months
Occurrence of adverse effect
Time Frame: 36 months
Patient interrogation.
36 months
Dosing of Hydroxychloroquine Sulfate in plasma
Time Frame: 36 months
Compliance.
36 months
Occurence of retinopathy.
Time Frame: 36 months
Fundus eye and electroretinogram.
36 months
Quotation of the different muscles
Time Frame: 36 months
Muscle testing by a physiotherapist.
36 months
6-min walking test
Time Frame: 36 months
36 months
Test of the number of steps during a 3-min walk
Time Frame: 36 months
36 months
Assessment of pain: VAS
Time Frame: 36 months
Visual analogue scale (VAS) : scale from 1 to 10; compare from one examination to another for a patient (which is his own control).
36 months
Quality-of-life assessment: Pediatric Quality of Life InventoryTM (PedsQL) questionnaire
Time Frame: 36 months
Pediatric Quality of Life InventoryTM (PedsQL) questionnaire adapted to age: child questionnaire and parent questionnaire. Questionnaire of 23 questions scored on 5 points, from 0 (never) to 4 (almost always). The scores are linearly transformed on a scale between 0 and 100, added together and divided by the number of items completed; high scores are associated with a better quality of life related to health.
36 months
Echocardiography
Time Frame: 36 months
Measurement of the wall of the ventricles, ejection fraction.
36 months
Absence of cardiac arrhythmia
Time Frame: 36 months
Electrocardiography
36 months

Collaborators and Investigators

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

Investigators

  • Principal Investigator: Pascale de Lonlay, Professor, Assistance Publique - Hôpitaux de Paris
  • Study Director: Caroline Tuchmann-Durand, Pharm. D, Assistance Publique - Hôpitaux de Paris

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.

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 (Anticipated)

July 1, 2019

Primary Completion (Anticipated)

July 1, 2020

Study Completion (Anticipated)

July 1, 2020

Study Registration Dates

First Submitted

May 29, 2019

First Submitted That Met QC Criteria

July 2, 2019

First Posted (Actual)

July 5, 2019

Study Record Updates

Last Update Posted (Actual)

November 8, 2022

Last Update Submitted That Met QC Criteria

November 7, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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