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MyelofibrosisPhase 3NCT00934544

Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial

A Phase 3 study testing Ruxolitinib and Best Available Therapy (BAT) in people with Myelofibrosis, run by Novartis Pharmaceuticals at 61 sites in 9 countries.

Completed

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

Official record
Search all trials

Trial summary

This was an open label, randomized study comparing the efficacy and safety of randomized 2:1 Ruxolitinib tablets versus best-available therapy, as selected by the investigator. The purpose was to compare the efficacy, safety and tolerability of Ruxolitinib (INC424/INCB018424) given twice daily to the best-available… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Myelofibrosis
What is being tested?
Ruxolitinib and Best Available Therapy (BAT)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
219 participants
Where
61 sitesin 9 countries
Study dates
1 Jul 2009to 4 Mar 2015
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

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
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects must be diagnosed with PMF, PPV-MF or PET-MF according to the 2008 World Health Organization criteria
  • Subjects with MF requiring therapy must be classified as high risk OR intermediate risk level 2 according to the prognostic factors defined by the International Working Group
  • Subjects with an ECOG performance status of 0, 1, 2 or 3
  • Subjects with peripheral blood blast count of < 10%.
  • Subjects who have not previously received treatment with a JAK inhibitor

Who cannot join

  • Subjects with a life expectancy of less than 6 months
  • Subjects with inadequate bone marrow reserve as demonstrated by specific clinical laboratory counts
  • Subjects with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason
  • Subjects with inadequate liver or renal function
  • Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy
  • Subjects with an active malignancy over the previous 5 years except specific skin cancers
  • Subjects with severe cardiac conditions
  • Subjects who have had splenic irradiation within 12 months

Trial locations and contacts

61 sites in 9 countries.

61 sites in 9 countries

France17 sites

  • Novartis Investigative Site

    Amiens, 80054

  • Novartis Investigative Site

    Caen, 14033

  • Novartis Investigative Site

    Grenoble, 38043

  • Novartis Investigative Site

    Lens, 62307

  • Novartis Investigative Site

    Lille, 59037

  • Novartis Investigative Site

    Lyon, 69437

  • Novartis Investigative Site

    Marseille, 13273

  • Novartis Investigative Site

    Nîmes, 30029

  • Novartis Investigative Site

    Paris, 75010

  • Novartis Investigative Site

    Paris, 75012

  • Novartis Investigative Site

    Paris, 75014

  • Novartis Investigative Site

    Pessac, 33600

  • Novartis Investigative Site

    Poitiers, 86021

  • Novartis Investigative Site

    Rennes, F-35043

  • Novartis Investigative Site

    Strasbourg, 67091

  • Novartis Investigative Site

    Toulouse, 31059

  • Novartis Investigative Site

    Villejuif, 94805

Other trials in France

Belgium10 sites

  • Novartis Investigative Site

    Antwerp, 2020

  • Novartis Investigative Site

    Antwerp, 2060

  • Novartis Investigative Site

    Bruges, 8000

  • Novartis Investigative Site

    Brussels, 1200

  • Novartis Investigative Site

    Hasselt, 3500

  • Novartis Investigative Site

    Kortrijk, 8500

  • Novartis Investigative Site

    La Louvière, 7100

  • Novartis Investigative Site

    Leuven, 3000

  • Novartis Investigative Site

    Roeselare, 8800

  • Novartis Investigative Site

    Yvoir, 5530

Other trials in Belgium

Germany9 sites

  • Novartis Investigative Site

    Berlin, 13353

  • Novartis Investigative Site

    Cologne, 50937

  • Novartis Investigative Site

    Frankfurt/M, 60590

  • Novartis Investigative Site

    Magdeburg, 39120

  • Novartis Investigative Site

    Mainz, 55131

  • Novartis Investigative Site

    Münster, 48149

  • Novartis Investigative Site

    Stuttgart, 70376

  • Novartis Investigative Site

    Tübingen, 72076

  • Novartis Investigative Site

    Ulm, 89081

Other trials in Germany

Italy6 sites

  • Novartis Investigative Site

    Florence, 50134

  • Novartis Investigative Site

    Milan, MI, 20162

  • Novartis Investigative Site

    Monza, MB, 20900

  • Novartis Investigative Site

    Orbassano, 10043

  • Novartis Investigative Site

    Pavia, (PV), 27100

  • Novartis Investigative Site

    Pavia, 27100

Other trials in Italy

Netherlands6 sites

  • Novartis Investigative Site

    Amsterdam, 1081

  • Novartis Investigative Site

    Groningen, 9713 GZ

  • Novartis Investigative Site

    Maastricht, 5800

  • Novartis Investigative Site

    Nijmegen, 6500 MB

  • Novartis Investigative Site

    Rotterdam, 3015 CE

  • Novartis Investigative Site

    The Hague, 2545 CH

Other trials in Netherlands

Austria4 sites

  • Novartis Investigative Site

    Innsbruck, 6020

  • Novartis Investigative Site

    Linz, 4010

  • Novartis Investigative Site

    Salzburg, 5020

  • Novartis Investigative Site

    Vienna, A-1090

Other trials in Austria

United Kingdom4 sites

  • Novartis Investigative Site

    Belfast, BT9 7AB

  • Novartis Investigative Site

    Cambridge, CB2 2QQ

  • Novartis Investigative Site

    London, SE1 9RT

  • Novartis Investigative Site

    Oxford, OX37LJ

Other trials in United Kingdom

Spain3 sites

  • Novartis Investigative Site

    Barcelona, Catalonia, 08036

  • Novartis Investigative Site

    Majadahonda, Madrid, 28222

  • Novartis Investigative Site

    Valencia, Valencia, 46010

Other trials in Spain

Sweden2 sites

  • Novartis Investigative Site

    Gothenburg, SE-413 45

  • Novartis Investigative Site

    Stockholm, SE-118 83

Other trials in Sweden

About this study

Official title: A Randomized Study of Ruxolitinib Tablets Compared to Best Available Therapy in Subjects With Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis

This was an open label, randomized study comparing the efficacy and safety of randomized 2:1 Ruxolitinib tablets versus best-available therapy, as selected by the investigator. The purpose was to compare the efficacy, safety and tolerability of Ruxolitinib (INC424/INCB018424) given twice daily to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post essential thrombocythemia myelofibrosis (PET-MF).

Read the detailed description

This study included a randomized treatment phase, followed by an extension phase. The treatment phase lasted from Study Day 1 (day of randomization) to the occurrence of a protocol-specified progressive disease event or study conclusion, whichever came first. The extension phase (including crossover of control group patients) lasted from the progressive disease event until the earliest of the following events: a) the patient was no longer receiving clinical benefit, b) the patient chose to withdraw from the study, or c) the study ended. All patients received ruxolitinib in the extension phase of the study. Maximum individual patient duration was 5 years.

Conditions
Myelofibrosis
Being tested
Ruxolitinib, Best Available Therapy (BAT)
Keywords
Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis
Medical subject headings
Primary Myelofibrosis

What participants receive

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

  • RuxolitinibDrug

    5 mg tablets packaged as 60-count in high-density polyethylene bottles

  • Best Available Therapy (BAT)Drug

    Prescribing and usage per respective package inserts

Study groups in NCT00934544
Study groupRoleWhat they receive
RuxolitinibExperimental5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule
Receives: Drug: Ruxolitinib
Best Available Therapy (BAT)Active comparatorCommercially available therapy, oral or parenteral, per manufacturer's instructions and Investigator discretion. BAT included the option of no treatment. Patients randomized to BAT were eligible to cross over to receive open-label ruxolitinib after a qualifying progression event, if they met the safety criteria. After the primary analysis in January 2011, patients randomized to receive BAT were allowed to cross over to receive ruxolitinib and move to the extension phase of the study without a qualifying progression event.
Receives: Drug: Best Available Therapy (BAT)

What is being measured

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

  1. Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 48

    The change in spleen volume from baseline to week 48 was measured by magnetic resonance imaging (MRI) (or by computer tomography (CT) for participants unable to undergo MRI) and was calculated only for participants who had an evaluable spleen volume at baseline. The percentage of participants achieving a greater than or equal to 35% reduction in spleen volume from baseline to week 48 was then calculated by treatment group.

    Measured: Baseline, Week 48

Secondary outcomes (10)

  1. Duration of Maintenance of Spleen Volume Reduction (Median)

    DoMSR is defined as the interval between the first spleen volume measurement that is >=35% reduction from baseline and the first scan that is no longer = 35% reduction AND that is a >25% increase over nadir. It was evaluated using the Kaplan-Meier estimate for each treatment arm. The analysis was performed only for subjects who achieved greater than 35% reduction in spleen volume.

    Measured: Baseline, up to Year 5

  2. Duration of Maintenance of Spleen Volume Reduction (Kaplan-Meier Estimates)

    This is defined as the interval between randomization and date of the first MRI showing a 35% reduction from baseline in spleen volume. The analysis was performed for participants who achieved a 35% reduction in spleen volume.

    Measured: Baseline, up to Year 5

  3. Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24

    The change in spleen volume from baseline to week 24 was measured by magnetic resonance imaging (MRI) (or by computer tomography (CT) for participants unable to undergo MRI) and was calculated only for participants who had an evaluable spleen volume at baseline. The percentage of participants achieving a greater than or equal to 35% reduction in spleen volume from baseline to week 24 was then calculated by treatment group.

    Measured: Baseline, Week 24

  4. Time to First at Least 35% Reduction in Spleen Volume From Baseline by Treatment (Primary Analysis)

    This is defined as the interval between randomization and date of the first MRI showing at least 35% reduction from baseline in spleen volume. The analysis was performed for participants who achieved a 35% reduction in spleen volume

    Measured: Time from randomization and date of the first MRI showing at least 35% reduction from baseline in spleen volume

  5. Progression-free Survival (PFS)

    Median of time progression free survival (95% CI), years

    Measured: Time from randomization and the earliest of either increase in spleen volume >=25% from on-study nadir, splenic irradiation, splenectomy, leukemic transformation or death

  6. Leukemia-free Survival (LFS)

    Time from randomization and earliest of either (1) date of bone marrow blast count of 20% or greater; (2) date of first peripheral blast count of 20% or greater that was subsequently confirmed to sustain for at least 8 weeks; (3) date of death from any cause

    Measured: Time from randomization and earliest of either leukemia or death

  7. Overall Survival (OS)

    Defined as the interval between randomization and the date of the bone marrow blast count of 20% or greater OR the date of the first peripheral blast count of 20% or greater that was subsequently confirmed to have been sustained for at least 8 weeks OR the date of death from any cause, whichever occurs first. OS was summarized using Kaplan-Meier estimates for each treatment arm. The estimates were supplemented by tables of number of events and probability estimates at several timepoints

    Measured: From randomization until death from any cause

  8. Percentage of Participants With Bone Marrow Histomorphology at Week 48 (Primary Analysis)

    This was noted as fibrosis density and was tabulated by fibrosis grade at baseline and at week 48 (post-baseline). Descriptive statistics (participant percentages) were used.

    Fibrosis grades: 0 Scattered linear reticulin with no intersections corresponding to normal bone marrow ; 1 Loose network of reticulin with many intersections, especially in perivascular areas; 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis

    Measured: 48 weeks

  9. Bone Marrow Histomorphology

    Shift table from baseline to last available postbaseline fibrosis grade by treatment

    The grade gives an indication of the activity or amount of inflammation and the stage represents the amount of fibrosis or scarring. The grade is assigned a number based on the degree of inflammation, which is usually scored from 0-4 with 0 being no activity and 3 or 4 considered severe activity

    Measured: Baseline, once a year

  10. Duration of Follow-up by Treatment

    Number of Participants with duration of Follow up

    Measured: baseline, 260 weeks (end of study)

Timeline

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

  1. First posted8 Jul 2009 (estimated)
  2. Study start1 Jul 2009
  3. Primary completion4 Mar 2015
  4. Study completion4 Mar 2015

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 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
219 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00934544
Sponsor's protocol ID
CINC424A2352
Other IDs
CINCB 18424-352, 2009-009858-24, 2009
Status last verified
Jul 2019
First submitted
6 Jul 2009
Last updated
19 Aug 2019
Data monitoring committee
Yes
FDA-regulated drug
No

Publications

  • Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian JJ, Cervantes F, Harrison CN, Paquette R, Sun W, Naim A, Langmuir P, Dong T, Gopalakrishna P, Gupta V. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017 Sep 29;10(1):156. doi: 10.1186/s13045-017-0527-7.

    PubMed 28962635

  • McMullin MF, Harrison CN, Niederwieser D, Demuynck H, Jakel N, Gopalakrishna P, McQuitty M, Stalbovskaya V, Recher C, Theunissen K, Gisslinger H, Kiladjian JJ, Al-Ali HK. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015 Sep 15;4:26. doi: 10.1186/s40164-015-0021-2. eCollection 2015.

    PubMed 26380150

  • Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, Sarlis NJ, Peng W, Sandor V, Gopalakrishna P, Hmissi A, Stalbovskaya V, Gupta V, Harrison C, Verstovsek S; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015 Sep;100(9):1139-45. doi: 10.3324/haematol.2014.119545. Epub 2015 Jun 11.

    PubMed 26069290

  • Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G, Harrison CN, Knoops L, Gisslinger H; COMFORT-II investigators. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013 Dec 12;122(25):4047-53. doi: 10.1182/blood-2013-02-485888. Epub 2013 Oct 30.

    PubMed 24174625

  • Wilkins BS, Radia D, Woodley C, Farhi SE, Keohane C, Harrison CN. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013 Dec;98(12):1872-6. doi: 10.3324/haematol.2013.095109. Epub 2013 Sep 20.

    PubMed 24056820

  • Mesa RA, Kiladjian JJ, Verstovsek S, Al-Ali HK, Gotlib J, Gisslinger H, Levy R, Siulnik A, Gupta V, Khan M, DiPersio JF, McQuitty M, Catalano JV, Hunter DS, Knoops L, Deininger M, Cervantes F, Miller C, Vannucchi AM, Silver RT, Barbui T, Talpaz M, Barosi G, Winton EF, Mendeson E, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Sun W, Sandor V, Kantarjian HM, Harrison C. Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica. 2014 Feb;99(2):292-8. doi: 10.3324/haematol.2013.087650. Epub 2013 Aug 2.

    PubMed 23911705

  • Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556.

    PubMed 22375970

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ruxolitinib and Best Available Therapy (BAT) in people with Myelofibrosis, run by Novartis Pharmaceuticals at 61 sites in 9 countries.

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 5 inclusion and 8 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 19 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 61 sites in France, Belgium, Germany, Italy, Netherlands and 4 more countries. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 May 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 48 (time frame: Baseline, Week 48). 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 NCT00934544, which also lists 7 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 19 Aug 2019.

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