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

LIPIN1 Deficiency Clinical Trial

— LIPIN-1-METAB  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04007562
• Other study ID #: APHP190368
• Status: Withdrawn
• Start date: July 2019
• Est. completion date: July 2020

Study information

• Verified date: November 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 2020
• Est. primary completion date: July 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• LIPIN1 Deficiency
• Myalgia
• Rhabdomyolysis

Intervention

Drug:
• Hydroxychloroquine Sulfate
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.

Locations

Country	Name	City	State
France	Hôpital Necker-Enfants Malades	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Creatine kinase dosage in plasma		36 months
Primary	Inflammatory cytokines in plasma	Quantitative flow cytometry based mutliplex assays (flow cytometry-based systems (BD™ Cytometric Bead Array)).	36 months
Primary	Quantification of mitochondrial DNA in plasma	Quantitative PCR to detect mitochondrial DNA, 12s gene.	36 months
Secondary	Occurrence of intercurrent event	Clinical examination.	36 months
Secondary	Occurrence of rash	Clinical examination.	36 months
Secondary	Gowers sign appearance	Clinical examination.	36 months
Secondary	Occurrence of shortness of breath	Clinical examination.	36 months
Secondary	Occurrence of muscular fatigability	Clinical examination.	36 months
Secondary	Treatment compliance	Patient interrogation.	36 months
Secondary	Occurrence of adverse effect	Patient interrogation.	36 months
Secondary	Dosing of Hydroxychloroquine Sulfate in plasma	Compliance.	36 months
Secondary	Occurence of retinopathy.	Fundus eye and electroretinogram.	36 months
Secondary	Quotation of the different muscles	Muscle testing by a physiotherapist.	36 months
Secondary	6-min walking test		36 months
Secondary	Test of the number of steps during a 3-min walk		36 months
Secondary	Assessment of pain: VAS	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
Secondary	Quality-of-life assessment: Pediatric Quality of Life InventoryTM (PedsQL) questionnaire	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
Secondary	Echocardiography	Measurement of the wall of the ventricles, ejection fraction.	36 months
Secondary	Absence of cardiac arrhythmia	Electrocardiography	36 months