NCT00916747

Brief Summary

Hutchinson-Gilford Progeria Syndrome (Progeria) is a rare autosomal disease that results in premature death at a median age of 13 years due to cardiovascular and cerebralvascular compromise. The mutation for this disease has been identified and results in a mutant form of lamin A that cannot be de-farnesylated. This study evaluates the combination of pravastain (a statin), lonafarnib (a farnesyltransferase inhibitor) and zoledronic acid (a bisphosphonate) in an open label phase II efficacy trial in children with Progeria. These agents all target farnesylation pathways at different points. Patients with genetically confirmed progeria will be eligible for this protocol. Treatment will be initiated for 24 months duration. Clinical and biologic parameters will be examined to assess response.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
85

participants targeted

Target at P50-P75 for phase_2

Timeline
Completed

Started Aug 2009

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

June 5, 2009

Completed
4 days until next milestone

First Posted

Study publicly available on registry

June 9, 2009

Completed
2 months until next milestone

Study Start

First participant enrolled

August 1, 2009

Completed
12.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 1, 2022

Completed
1.8 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2023

Completed
Last Updated

February 27, 2023

Status Verified

February 1, 2023

Enrollment Period

12.5 years

First QC Date

June 5, 2009

Last Update Submit

February 23, 2023

Conditions

Progeria

Keywords

Progeria

Outcome Measures

Primary Outcomes (1)

  • To evaluate the therapeutic effects of the combination of zoledronic acid, pravastatin and lonafarnib in patients with HGPS.

    2 years

Secondary Outcomes (8)

  • To describe any acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib.

    2 years

  • To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity.

    2 years

  • To assess the pharmacokinetics of lonafarnib in patients with progeria.

    2 years

  • To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL).

    2 years

  • To assay for changes in research-based potential markers of efficacy such as levels of prelamin A, mature lamin A, progerin, and HP1 in protein isolated from PBL.

    2 years

  • +3 more secondary outcomes

Study Arms (1)

Treatment arm

EXPERIMENTAL

All patients will receive zoledronic acid, pravastatin and lonafarnib

Drug: Lonafarnib, Zoledronic Acid, and Pravastatin

Interventions

Lonafarnib, Zoledronic Acid, and PravastatinDRUG

Lonafarnib: Lonafarnib dosing will begin at 150 mg/m2 by mouth twice daily. Lonafarnib will be orally administered without planned breaks, approximately every 12 hours, for a period of 24 months. For patients unable to swallow capsules, the capsules can be opened and dissolved into Ora Blend SF or Ora-Plus. Zoledronic Acid: Zoledronic acid will be administered intravenously at week one, and months 6, 12, 18 and 24 of this treatment trial. Treatment will consist of one infusion over a 30 minute period. Pravastatin: Pravastatin will be orally administered once daily without planned breaks, approximately every 24 hours, for a period of 24 months. The drug may be taken with meals. For patients unable to swallow pills, pills can be crushed into food. Pravastatin will be dosed according to the patient weight. Patients less than 10 kg will receive 5 mg pravastatin orally, once daily. Patients weighing 10 kg or greater will receive 10 mg pravastatin daily.

Treatment arm

Eligibility Criteria

Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • Genetic Diagnosis: All patients must have confirmatory mutational analysis showing mutation in the lamin A gene.
  • Clinical Diagnosis: Patients must display clinical signs of progeria as per the clinical trial team.
  • Travel: Patients must be willing and able to come to Boston for appropriate studies and examinations at initiation of study and at months 6, 12, 18 and 24 on study.
  • Patient must have adequate organ and marrow function as defined by the following parameters:
  • Blood: APC (ANC + bands + monocytes = APC) \> 1,000/microliters, Platelets \> 75,000/microliters (transfusion independent); Hemoglobin \>9g/dl.
  • Renal: creatinine Less than or equal 1.5 times normal for age or GFR \> 70 ml/min/1.73m2.
  • Hepatic: bilirubin Less than or equal to 1.5 x upper limit of normal for age; SGPT (ALT) \< and SGOT (AST) \< 5 x normal range for age.
  • PT/PTT: PT/PTT \< 120% upper limit of normal OR PI approval
  • No overt renal, hepatic, pulmonary disease or immune dysfunction.
  • hydroxyvitamin D ≥ 20 ng/ml within 4 weeks of bisphosphonate infusion.
  • Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within twenty eight (28) days.

You may not qualify if:

  • Other than the drugs used in this protocol, drugs targeted to treat Progeria are excluded. Drugs to treat symptoms of Progeria are permitted.
  • Patients must not be taking medications that significantly affect the metabolism of lonafarnib at the time they start lonafarnib
  • Patient must have no uncontrolled infection.
  • Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
  • Patients must not be pregnant or breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Related Publications (4)

  • Gordon LB, Norris W, Hamren S, Goodson R, LeClair J, Massaro J, Lyass A, D'Agostino RB Sr, Tuminelli K, Kieran MW, Kleinman ME. Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation. Circulation. 2023 Jun 6;147(23):1734-1744. doi: 10.1161/CIRCULATIONAHA.122.060002. Epub 2023 Mar 15.

    PMID: 36919608DERIVED

  • Suzuki M, Jeng LJB, Chefo S, Wang Y, Price D, Li X, Wang J, Li RJ, Ma L, Yang Y, Zhang X, Zheng N, Zhang K, Joseph DB, Shroff H, Doan J, Pacanowski M, Smpokou P, Donohue K, Joffe HV. FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies. Genet Med. 2023 Feb;25(2):100335. doi: 10.1016/j.gim.2022.11.003. Epub 2022 Dec 12.

    PMID: 36507973DERIVED

  • Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW. Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188.

    PMID: 27400896DERIVED

  • Gordon LB, Massaro J, D'Agostino RB Sr, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW; Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014 Jul 1;130(1):27-34. doi: 10.1161/CIRCULATIONAHA.113.008285. Epub 2014 May 2.

    PMID: 24795390DERIVED

Related Links

MeSH Terms

Conditions

Progeria

Interventions

lonafarnibZoledronic AcidPravastatin

Condition Hierarchy (Ancestors)

LaminopathiesGenetic Diseases, InbornCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesMetabolism, Inborn ErrorsMetabolic DiseasesNutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

DiphosphonatesOrganophosphonatesOrganophosphorus CompoundsOrganic ChemicalsImidazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsNaphthalenesPolycyclic Aromatic HydrocarbonsHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsPolycyclic Compounds

Study Officials

  • Mark Kieran, MD, PhD

    Children's Hospital Boston/ Dana-Farber Cancer Instittue

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Masking Details
Open Label
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Principal Investigator

Study Record Dates

First Submitted

June 5, 2009

First Posted

June 9, 2009

Study Start

August 1, 2009

Primary Completion

February 1, 2022

Study Completion

December 1, 2023

Last Updated

February 27, 2023

Record last verified: 2023-02

Locations

US(1)