Clinical trial NCT04007562: 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
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
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: LIPIN1 Deficiency
Keywords: LIPIN1 deficiency
Acute episodes of rhabdomyolysis
Myoglobinuria
Hydroxychloroquine Sulfate
Orphan drug
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-07-05
Enrollment: 0
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
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.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Creatine kinase dosage in plasma
timeFrame: 36 months
measure: Inflammatory cytokines in plasma
timeFrame: 36 months
measure: Quantification of mitochondrial DNA in plasma
timeFrame: 36 months
Secondary outcomes:
measure: Occurrence of intercurrent event
timeFrame: 36 months
measure: Occurrence of rash
timeFrame: 36 months
measure: Gowers sign appearance
timeFrame: 36 months
measure: Occurrence of shortness of breath
timeFrame: 36 months
measure: Occurrence of muscular fatigability
timeFrame: 36 months
measure: Treatment compliance
timeFrame: 36 months
measure: Occurrence of adverse effect
timeFrame: 36 months
measure: Dosing of Hydroxychloroquine Sulfate in plasma
timeFrame: 36 months
measure: Occurence of retinopathy.
timeFrame: 36 months
measure: Quotation of the different muscles
timeFrame: 36 months
measure: 6-min walking test
timeFrame: 36 months
measure: Test of the number of steps during a 3-min walk
timeFrame: 36 months
measure: Assessment of pain: VAS
timeFrame: 36 months
measure: Quality-of-life assessment: Pediatric Quality of Life InventoryTM (PedsQL) questionnaire
timeFrame: 36 months
measure: Echocardiography
timeFrame: 36 months
measure: Absence of cardiac arrhythmia
timeFrame: 36 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Pascale de Lonlay, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Caroline Tuchmann-Durand, Pharm. D
role: STUDY_DIRECTOR
References:
citation: Hamel Y, Mauvais FX, Madrange M, Renard P, Lebreton C, Nemazanyy I, Pelle O, Goudin N, Tang X, Rodero MP, Tuchmann-Durand C, Nusbaum P, Brindley DN, van Endert P, de Lonlay P. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis. Cell Rep Med. 2021 Aug 17;2(8):100370. doi: 10.1016/j.xcrm.2021.100370. eCollection 2021 Aug 17.