PubTransformer

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PMID- 29710166
OWN - NLM
STAT- MEDLINE
DCOM- 20180516
LR  - 20180516
IS  - 1538-3598 (Electronic)
IS  - 0098-7484 (Linking)
VI  - 319
IP  - 16
DP  - 2018 Apr 24
TI  - Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in
      Patients With Hutchinson-Gilford Progeria Syndrome.
PG  - 1687-1695
LID - 10.1001/jama.2018.3264 [doi]
AB  - Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare
      fatal premature aging disease. There is no approved treatment. Objective: To
      evaluate the association of monotherapy using the protein farnesyltransferase
      inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, 
      and Participants: Cohort study comparing contemporaneous (birth date >/=1991)
      untreated patients with HGPS matched with treated patients by age, sex, and
      continent of residency using conditional Cox proportional hazards regression.
      Treatment cohorts included patients from 2 single-group, single-site clinical
      trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated
      patients originated from a separate natural history study (n = 103). The cutoff
      date for patient follow-up was January 1, 2018. Exposure: Treated patients
      received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no 
      clinical trial medications. Main Outcomes and Measures: The primary outcome was
      mortality. The primary analysis compared treated patients from the first
      lonafarnib trial with matched untreated patients. A secondary analysis compared
      the combined cohorts from both lonafarnib trials with matched untreated patients.
      Results: Among untreated and treated patients (n = 258) from 6 continents, 123
      (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were 
      classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death
      was heart failure (79.4%). The median treatment duration was 2.2 years. Median
      age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in
      the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There
      was 1 death (3.7%) among 27 patients in the first trial group and there were 9
      deaths (33.3%) among 27 patients in the matched untreated group. Treatment was
      associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P 
      = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in
      the treated group and 17 deaths (27.0%) among 63 patients in the matched
      untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and
      Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no
      treatment, was associated with a lower mortality rate after 2.2 years of
      follow-up. Study interpretation is limited by its observational design.
FAU - Gordon, Leslie B
AU  - Gordon LB
AD  - Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital,
      Providence, Rhode Island.
AD  - Warren Alpert Medical School of Brown University, Providence, Rhode Island.
AD  - Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Shappell, Heather
AU  - Shappell H
AD  - Department of Mathematics and Statistics, Boston University, Harvard Clinical
      Research Institute, Boston, Massachusetts.
FAU - Massaro, Joe
AU  - Massaro J
AD  - Department of Mathematics and Statistics, Boston University, Harvard Clinical
      Research Institute, Boston, Massachusetts.
FAU - D'Agostino, Ralph B Sr
AU  - D'Agostino RB Sr
AD  - Department of Mathematics and Statistics, Boston University, Harvard Clinical
      Research Institute, Boston, Massachusetts.
FAU - Brazier, Joan
AU  - Brazier J
AD  - Center for Gerontology and Health Care Research, Brown University, Providence,
      Rhode Island.
FAU - Campbell, Susan E
AU  - Campbell SE
AD  - Center for Gerontology and Health Care Research, Brown University, Providence,
      Rhode Island.
FAU - Kleinman, Monica E
AU  - Kleinman ME
AD  - Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Kieran, Mark W
AU  - Kieran MW
AD  - Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical
      School, Boston, Massachusetts.
AD  - Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical
      School, Boston, Massachusetts.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - JAMA
JT  - JAMA
JID - 7501160
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lamin Type A)
RN  - 0 (Piperidines)
RN  - 0 (Pyridines)
RN  - 0 (prelamin A)
RN  - EC 2.7.4.- (Phosphotransferases (Phosphate Group Acceptor))
RN  - EC 2.7.4.- (farnesyl phosphate kinase)
RN  - IOW153004F (lonafarnib)
SB  - AIM
SB  - IM
CIN - JAMA. 2018 Apr 24;319(16):1663-1664. PMID: 29710145
MH  - Adolescent
MH  - Adult
MH  - Cause of Death
MH  - Child
MH  - Cohort Studies
MH  - Enzyme Inhibitors/*therapeutic use
MH  - Female
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Lamin Type A/biosynthesis/metabolism
MH  - Male
MH  - Phosphotransferases (Phosphate Group Acceptor)/*antagonists & inhibitors
MH  - Piperidines/*therapeutic use
MH  - Progeria/*drug therapy/genetics/mortality
MH  - Protein Processing, Post-Translational
MH  - Pyridines/*therapeutic use
MH  - Young Adult
PMC - PMC5933395
EDAT- 2018/05/02 06:00
MHDA- 2018/05/17 06:00
CRDT- 2018/05/01 06:00
PMCR- 2018/10/24 00:00
PHST- 2018/10/24 00:00 [pmc-release]
PHST- 2018/05/01 06:00 [entrez]
PHST- 2018/05/02 06:00 [pubmed]
PHST- 2018/05/17 06:00 [medline]
AID - 2679278 [pii]
AID - 10.1001/jama.2018.3264 [doi]
PST - ppublish
SO  - JAMA. 2018 Apr 24;319(16):1687-1695. doi: 10.1001/jama.2018.3264.