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LymphangioleiomyomatosisPhase 2LAMNCT03062943

A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)

A Phase 2 study testing Nintedanib in people with Lymphangioleiomyomatosis, run by IRCCS Multimedica at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This trial is conducted locally. The aim of this trial is assess the efficacy and a favorable benefit-risk ratio for nintedanib in the treatment of LAM at the dose of 150 mg bid Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Lymphangioleiomyomatosis
What is being tested?
Nintedanib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteItaly
Study dates
6 Dec 2016to Dec 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written Informed Consent for participating to trial.
  • Patient aged ≥ 18 years at visit 1.
  • Sporadic or TSC associated LAM, classified as ''definite'' by the European Respiratory Society criteria and /or serum VEGFD level >/= 800 mg/ml, and evidence of a 10% deterioration in FEV1 and /or loss of 80 ml of FEV1 or more in the last year (post bronchodilator). Also LAM patients with proven side effects and/or toxicities/ contraindications to sirolimus therapy will be eligible for this study.

Who cannot join

  • Laboratory parameters have to satisfy entry criteria as shown below:
  • Laboratory parameters (screening)
  • AST, ALT > 1.5 x ULN
  • Bilirubin > 1.5 x ULN
  • Positivity for HIV or Hepatitis.
  • Chylous effusions.
Show all 37Show fewer
  • Relapsing pneumothorax.
  • Angiomyolipoma > 5 cm.
  • Treatment with mTOR inhibitors in the last month.
  • Patient eligible for Lung Transplantation.
  • Hormone therapy.
  • Patients are excluded if they are post lung transplant or had previously been diagnosed with a pneumothorax, chylous effusion, bleeding angiomyolipoma within the previous 6 months.
  • Current smokers.
  • Other diseases:
  • Cardiac disease.
  • Myocardial infarction within 6 months of visit 2.
  • Unstable angina within 1 month of visit 2.
  • Bleeding Risk:
  • Known genetic predisposition to bleeding.
  • Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, heparin, NOA) or high dose antiplatelet therapy2.
  • History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1.
  • History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1.
  • International normalised ratio (INR) > 2 at visit 1.
  • Prothrombin time (PT) and partial thromboplastin time (PTT) > 150% of institutional ULN at visit 1.
  • Planned major surgery during the trial participation, including lung transplantation, major abdominal or major intestinal surgery.
  • History of thrombotic event (including stroke and transient ischemic attack) within 12 months of visit 1.
  • History of end-stage renal disease requiring dialysis.
  • Alcohol or drug abuse which in the opinion of the treating physician would interfere with treatment.
  • Pts that cannot perform PFT and cannot give informed consent.
  • Known hypersensitivity to the trial drug or its components.
  • Other disease that may interfere with testing procedures or in the judgement of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
  • General Exclusion Criteria:
  • Previous treatment with nintedanib.
  • Other investigational therapy (participation in research trial) received within 8 weeks of visit.
  • Thoracic, abdominal, gynecological, neurologic surgical procedures planned to occur during trial period.
  • Pregnant women or women who are breast feeding or of child bearing potential not using two effective methods of birth control (one barrier and one highly effective non-barrier) for at least 1 month prior to enrolment (and until 3 months after treatment end).
  • Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or postmenopausal for at least two years.

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • Pneumology unit

    Milan, 20123

Other trials in Italy

About this study

Official title: A Pilot Study of Nintedanib for LymphAngioleioMyomatosis (LAM)

This trial is conducted locally. The aim of this trial is assess the efficacy and a favorable benefit-risk ratio for nintedanib in the treatment of LAM at the dose of 150 mg bid

Read the detailed description

There is a high unmet medical need for efficacious and safe treatment of LAM, to halt lung function decline, improve patient-reported outcome, reduce size of angiomyolipomas and ultimately decrease mortality. Guidelines recommend participation in research trials if possible.

To date, therapeutic options include mTOR inhibitors sirolimus and everolimus. Among these, sirolimus, has been approved by FDA based on a clinical trial which showed a stabilization of lung function expressed as FEV1 during the 12 month treatment period. Thus the stabilization of lung function appears to require continuous exposure to the drug. Sirolimus is associated with an increased frequency of adverse events like mucositis, gastrointestinal events, hypercholesterolemia, acneiform rash, and swelling in the lower extremities.

Nintedanib was shown to dose-dependently inhibit PDGFR phosphorylation and subsequent signaling via protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) 1/2 in lung tissue from mice. Akt and ERK 2 can both phosphorylate tuberin resulting in inactivation of hamartin-tuberin complex and consequent activation of mTOR .

It has been demonstrated that platelet-derived growth factor β receptor (PDGFRβ) is present and active in human and murine TSC lesions. Thus, an inhibition of PDGFR may be effective in LAM. Moreover, the inhibition of VEGF, PDGF and FGF signaling pathways reduces tumor angiogenesis in lung. As angiogenesis and lymphangiogenesis are mechanisms involved in dissemination of LAM cells, potential inhibition of angiogenesis by nintedanib may contribute to prevent disease progression in LAM.

Therefore, a non-randomized, efficacy, safety, and tolerability trial of nintedanib in sporadic and TSC-associated LAM is proposed.

The objective of the trial is to assess the efficacy and a favorable benefit-risk ratio for nintedanib in the treatment of LAM at the dose of 150 mg bid.

Being tested
Nintedanib
Medical subject headings
Lymphangioleiomyomatosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NintedanibDrug

    Also called OFEV

Study groups in NCT03062943
Study groupRoleWhat they receive
Nintedanib 150mg BIDExperimentalnintedanib soft gelatine capsules Dose: 150 mg bid Mode of admin. : Oral Duration of treatment: 1 year Duration of follow-up: 12 months after treatment discontinuation
Receives: Drug: Nintedanib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. FEV1 rate decline

    Change in FEV1 (Force Expiratory Volume in 1 second) in milliliters per month. The FEV1 slope will be calculated at baseline and at 3, 6, 9 and up to 12 months during the treatment phase.

    Measured: up to 12 months

Secondary outcomes (1)

  1. Safety and Tolerability in terms of AEs, particularly for liver function and level of hepatic enzymes.

    Safety and Tolerability profile: assessment of any AEs, increased levels of hepatic enzymes, kidney and gastrointestinal tract functionality. All the adverse events will be classified depending of time of occurency: treatment emergent adverse events if they occur after the first dose of study medication up to a period of 28 days or alternatively as either to the screening or post treatment, or post study phase, as appropriate.

    Measured: up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Feb 2017
  2. Study start6 Dec 2016
  3. Primary completionDec 2021
  4. Study completionDec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03062943
Sponsor's protocol ID
IISS LAM
Acronym
LAM
Status last verified
Sep 2022
First submitted
7 Oct 2016
Last updated
28 Sep 2022
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005 Apr 22;121(2):179-93. doi: 10.1016/j.cell.2005.02.031.

    PubMed 15851026

  • Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014 May;349(2):209-20. doi: 10.1124/jpet.113.208223. Epub 2014 Feb 20.

    PubMed 24556663

  • Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002 Sep;4(9):648-57. doi: 10.1038/ncb839.

    PubMed 12172553

  • Crino L, Metro G. Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev. 2014 Mar 1;23(131):79-91. doi: 10.1183/09059180.00008913.

    PubMed 24591665

  • Harari S, Elia D, Caminati A, Geginat J, Luisi F, Pelosi G, Specchia C, Torre O, Trevisan R, Vasco C, Zompatori M, Cassandro R. Nintedanib for patients with lymphangioleiomyomatosis: a phase 2, open-label, single-arm study. Lancet Respir Med. 2024 Dec;12(12):967-974. doi: 10.1016/S2213-2600(24)00217-0. Epub 2024 Oct 25.

    PubMed 39489895

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nintedanib in people with Lymphangioleiomyomatosis, run by IRCCS Multimedica at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

FEV1 rate decline (time frame: up to 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03062943, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2022.

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