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Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized TrialSofosbuvir Plus Velpatasvir for Patients With HCV Infection

Stephen Pianko, MD, PhD; Steven L. Flamm, MD; Mitchell L. Shiffman, MD; Sonal Kumar, MD; Simone I. Strasser, MD; Gregory J. Dore, MD; John McNally, PhD; Diana M. Brainard, MD; Lingling Han, PhD; Brian Doehle, PhD; Erik Mogalian, PhD; John G. McHutchison, MD; Mordechai Rabinovitz, MD; William J. Towner, MD; Edward J. Gane, MD; Catherine A.M. Stedman, MD; K. Rajender Reddy, MD; and Stuart K. Roberts, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 10 November 2015.


From Monash Health and Monash University, Clayton, Victoria, Australia; Northwestern University, Chicago, Illinois; Liver Institute of Virginia, Richmond, Virginia; Weill Cornell Medical College, New York, New York; Royal Prince Alfred Hospital and University of Sydney, Camperdown, New South Wales, Australia; Kirby Institute, University of New South Wales, and St. Vincent's Hospital, Sydney, New South Wales, Australia; Gilead Sciences, Foster City, California; University of Pittsburgh, Pittsburgh, Pennsylvania; Kaiser Permanente Medical Center, Los Angeles, California; Auckland Clinical Studies, Auckland, New Zealand; Christchurch Clinical Studies Trust and University of Otago, Christchurch, New Zealand; University of Pennsylvania, Philadelphia, Pennsylvania; and Alfred Health and Monash University, Melbourne, Victoria, Australia.

Acknowledgment: The authors thank the staff and patients who participated in the study. Laila Guzadhur, PhD, from Niche Science and Technology (Richmond-Upon-Thames, London, United Kingdom), provided writing and editorial support during development of this manuscript (these services were paid for by Gilead Sciences). Editorial assistance was provided by David McNeel of Gilead Sciences.

Grant Support: By Gilead Sciences.

Disclosures: Dr. Pianko reports personal fees from Gilead Sciences, Roche Diagnostics, and AbbVie during the conduct of the study; other from Gilead Sciences, Bristol-Myers Squibb, AbbVie, and Merck during the conduct of the study; and personal fees and nonfinancial support from Gilead Sciences outside the submitted work. Dr. Flamm reports personal fees from Gilead Sciences, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, and Merck and grants from Gilead Sciences, Bristol-Myers Squibb, AbbVie, and Janssen Pharmaceuticals outside the submitted work. Dr. Shiffman reports grants from Gilead Sciences during the conduct of the study; grants from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Conatus, Galectin, Gilead Sciences, Intercept, Lumena, and Merck outside the submitted work; and personal fees from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen Pharmaceuticals, and Merck outside the submitted work. Dr. Kumar reports personal fees from Gilead Sciences outside the submitted work. Dr. Strasser reports personal fees from Gilead Sciences outside the submitted work. Dr. Dore reports grants from AbbVie, Merck, Bristol-Myers Squibb, Janssen Pharmaceuticals, and Roche Diagnostics; personal fees from Gilead Sciences, AbbVie, Merck, Bristol-Myers Squibb, Janssen Pharmaceuticals, Roche Diagnostics, and GlaxoSmithKline; and nonfinancial support from Gilead, AbbVie, Merck, Bristol-Myers Squibb, and Roche Diagnostics outside the submitted work. Dr. McNally is an employee and stockholder of Gilead Sciences. Dr. Brainard reports other from Gilead Sciences outside the submitted work. Dr. Doehle reports personal fees from Gilead Sciences during the conduct of the study. Dr. Mogalian reports other from Gilead Sciences during the conduct of the study. Dr. McHutchison reports other from Gilead Sciences during the conduct of the study. Dr. Towner reports grants from Gilead during the conduct of the study and grants from Bristol-Myers Squibb, ViiV, and Merck outside the submitted work. Dr. Gane reports personal fees from Gilead Speakers Bureau and Gilead Advisors' Meeting outside the submitted work. Dr. Stedman reports nonfinancial support from Gilead Sciences during the conduct of the study and personal fees and nonfinancial support from Gilead Sciences, AbbVie, and Merck outside the submitted work. Dr. Reddy reports grants and personal fees from Gilead Sciences during the conduct of the study; personal fees from AbbVie, Merck, Janssen Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, UpToDate, and ViralEd outside the submitted work; grants from AbbVie, Merck, Janssen Pharmaceuticals, and Bristol-Myers Squibb outside the submitted work. Dr. Roberts reports other from Gilead Sciences, Bristol-Myers Squibb, Merck, and AbbVie outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1014.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol: See Supplement. Statistical code and data set: Not available.

Requests for Single Reprints: Stephen Pianko, MD, PhD, Monash Health, 10 Ancora Imparo Way, Monash University, Victoria 3800 Australia; e-mail, spianko@geds.com.au.

Current Author Addresses: Dr. Pianko: Monash Health, 10 Ancora Imparo Way, Monash University, Victoria 3800, Australia.

Dr. Flamm: Kovler Organ Transplantation Center, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611.

Dr. Shiffman: Liver Institute of Virginia, Bon Secours Health System, 5855 Bremo Road, Suite 509, Richmond, VA 23226.

Dr. Kumar: Director of Clinical Hepatology, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021.

Dr. Strasser: University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown, North South Wales 2050, Australia.

Dr. Dore: Head, Viral Hepatitis Clinical Research Program, Kirby Institute, University of North South Wales Australia, Wallace Wurth Building, Sydney, North South Wales 2052 Australia.

Drs. McNally, Brainard, Han, Doehle, Mogalian, and McHutchison: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404.

Dr. Rabinovitz: Professor of Medicine, Division of Gastroenterology and Hepatology, University of Pittsburgh, Kaufmann Building, 3471 Fifth Avenue, Suite 916, Pittsburgh, PA 15213.

Dr. Towner: Department of Infectious Diseases, Kaiser Permanente Los Angeles Medical Center, 1505 North Edgemont Street, Los Angeles, CA 90027.

Dr. Gane: New Zealand Liver Transplant Unit, Level 15 Support Building, Auckland City Hospital, Park Road, Auckland 1142, New Zealand.

Dr. Stedman: Christchurch Clinical Studies and University of Otago, Christchurch, Riccarton Avenue, Christchurch 8011, New Zealand.

Dr. Reddy: Viral Hepatitis Center, University of Pennsylvania, 2 Dulles, Liver Transplant Office, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Roberts: Department of Gastroenterology, Alfred Health, 99 Commercial Road, PO Box 315 Prahran, Victoria 3181, Australia.

Author Contributions: Conception and design: J. McNally, D.M. Brainard, E. Mogalian, J.G. McHutchison.

Analysis and interpretation of the data: S. Pianko, M.L. Shiffman, S.I. Strasser, G.J. Dore, J. McNally, D.M. Brainard, L. Han, B. Doehle, E. Mogalian, E.J. Gane, S.K. Roberts.

Drafting of the article: S. Pianko, J. McNally, W.J. Towner, S.K. Roberts.

Critical revision of the article for important intellectual content: S. Pianko, S.L. Flamm, S. Kumar, S.I. Strasser, D.M. Brainard, B. Doehle, M. Rabinovitz, W.J. Towner, E.J. Gane, C.A.M. Stedman, K.R. Reddy, S.K. Roberts.

Final approval of the article: S. Pianko, S.L. Flamm, M.L. Shiffman, S. Kumar, S.I. Strasser, G.J. Dore, J. McNally, D.M. Brainard, L. Han, B. Doehle, E. Mogalian, J.G. McHutchison, M. Rabinovitz, W.J. Towner, E.J. Gane, C.A.M. Stedman, K. Rajender Reddy, S.K. Roberts.

Provision of study materials or patients: S. Pianko, M.L. Shiffman, S.I. Strasser, G.J. Dore, W.J. Towner, C.A.M. Stedman, S.K. Roberts.

Statistical expertise: L. Han.

Collection and assembly of data: S. Pianko, M.L. Shiffman, G.J. Dore, J. McNally, E. Mogalian, M. Rabinovitz, E.J. Gane, C.A.M. Stedman.


Ann Intern Med. 2015;163(11):809-817. doi:10.7326/M15-1014
Text Size: A A A

Background: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed.

Objective: To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients.

Design: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01909804)

Setting: 58 sites in Australia, New Zealand, and the United States.

Patients: Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3).

Intervention: All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin.

Measurements: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12).

Results: In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea.

Limitation: Treatment assignments were not blinded, and no inferential statistics were planned.

Conclusion: Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12 weeks was well-tolerated and highly effective in treatment-experienced patients with genotype 1 or 3 HCV infection.

Primary Funding Source: Gilead Sciences.

Figures

Grahic Jump Location
Figure.

Study flow diagram.

Patients in groups 9 to 12 were enrolled after patients in groups 1 to 8 had completed the trial and were assessed for efficacy. HCV = hepatitis C virus; RBV = ribavirin; SOF = sofosbuvir; VEL = velpatasvir.

Grahic Jump Location

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Discrepancies between pre-specified and reported outcomes in Pianko et al
Posted on December 8, 2015
Henry Drysdale, Eirion Slade, Ben Goldacre
University of Oxford
Conflict of Interest: None Declared
Dear Editor,

Your recent publication Pianko et al [1] reports outcomes that are different to those initially registered [2].

There were 2 pre-specified primary outcomes, of which one is reported in the paper; while one is not sufficiently defined to assess whether or not it was reported. There were also 3 pre-specified secondary outcomes, of which 2 are not reported anywhere in the publication; while one is not sufficiently well specified that its reporting can be assessed. In addition, the paper reports 5 novel outcomes that are not pre-specified, without declaring them as such.

Annals of Internal Medicine has endorsed the CONSORT guidelines on best practice in trial reporting [3]. In order to reduce the risk of selective outcome reporting, CONSORT includes a commitment that all pre-specified primary and secondary outcomes should be reported; and that, where new outcomes are reported, it should be made clear that these were added at a later date, with an explanation of when and for what reason.

This letter has been sent as part of the COMPare project [4]. We aim to review all trials published from now in a sample of top journals, including Annals of Internal Medicine. Where outcomes have been incorrectly reported we are writing letters to correct the record, and to audit the extent of this problem, in the hope that this will reduce its prevalence. We are maintaining a website at COMPare-Trials.org where we will be posting the submission date and publication date of this letter, alongside a summary of the data on each trial and journal. We hope that you will publish this letter so that those using the results of this trial to inform decision-making are aware of the discrepancies.

Yours faithfully,

Henry Drysdale, Eirion Slade, and Ben Goldacre on behalf of the COMPare project team.


[1] Pianko S et al, Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection, Ann Intern Med., published online first at www.annals.org on 10 November 2015.

[2] Trial registry entry: https://clinicaltrials.gov/ct2/show/NCT01909804

[3] Moher D et al, CONSORT 2010 Explanation and Elaboration: updated
guidelines for reporting parallel group randomised trials, BMJ 2010; 340:c869.

[4] COMPare project website www.COMPare-Trials.org
COMPare Project
Posted on December 15, 2015
The Editors
Annals of Internal Medicine
Conflict of Interest: None Declared
Please see http://annals.org/article.aspx?articleid=2478526 for the Editors' summary of the COMPare Project’s methods.

Though we share COMPare’s overarching goals to assure the validity and reporting quality of biomedical studies, we do not agree with their approach. Until the COMPare Project’s methodology is modified to provide a more accurate, complete and nuanced evaluation of published trial reports, we caution readers and the research community against considering COMPare’s assessments as an accurate reflection of the quality of the conduct or reporting of clinical trials.

Given our ongoing concerns about COMPare's review methods, we do not believe that COMPare's comments on Pianko et al (Ann Intern Med. 2015; 163:809-817) merit a response.



Concerning statements on outcome switching from Annals' Editors
Posted on February 1, 2016
Henry Drysdale, Ben Goldacre, Carl Heneghan and Kamal Mahtani on behalf of the COMPare team
Centre for Evidence-Based Medicine, University of Oxford
Conflict of Interest: None Declared
We have been checking all trials in five top journals for outcome switching. In keeping with our commitment to open science all our raw underlying data can be reviewed in full at www.COMPare-trials.org, alongside our assessment of each individual pre-specified outcome on every trial, including the above trial by Pianko et al [1].

Our findings on the prevalence of outcome switching are consistent with previous published work [2] and therefore cannot be regarded as exceptional. We have added only one component to previous work: where others have published overall prevalence figures, we are posting specific details of misreporting by each individual trialist and journal. This is to correct the public record, and to use accountability to drive progress around ongoing and widespread misreporting of trial results.

The response from the editors mentioned above contains concerning misunderstandings on the pre-specification and correct reporting of clinical trial outcomes. However the Annals editors have declined to publish a full response from us. We have responded in full to their comment at COMPare-trials.org/blog [3], but here outline some key issues.

1. The editors argue our coding is unfair because we ignore protocols that are either unpublished or published after a trial began. These protocols cannot be an adequate source of pre-specified outcomes. The editors repeatedly make arguments that rely on “pre-specified” outcomes being extracted from documents dated after the trial began.

2. The editors incorrectly claim that we do not allow for legitimate changes to trial protocols after trial commencement. This is untrue, as we have repeatedly pointed out to the Annals editors: we regard such changes as completely normal, but changes must be declared in the trial report, to alert the reader to the statistical implications. This is what CONSORT requires.

3. The editors say registry information is often poor quality, with outcomes poorly pre-specified. The purpose of registers is to prospectively define key information on each clinical trial, including its outcomes, so that this can be assessed against results publications, to spot discrepancies and omissions. Journals could help by requiring trialists to ensure that outcomes in trial registries and protocols are properly pre-specified. Where registry entries are of very poor quality, and this is the only source of pre-specified outcomes from before the trial, we suggest the trial report should explain that the outcomes were inadequately pre-specified, that outcome switching is therefore hard to assess, and that the risk of false-positive results is consequently increased.

We are confident that Annals is committed to improving reporting standards and hope that Annals will engage substantively on this issue.

Henry Drysdale, Ben Goldacre, Carl Heneghan and Kamal Mahtani on behalf of the COMPare team

[1] Pianko S et al, Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection, Ann Intern Med., published online first at www.annals.org on 10 November 2015.

[2] Jones CW, Keil LG, Holland WC, Caughey MC, Platts-Mills TF. Comparison of registered and published outcomes in randomized controlled trials: a systematic review. BMC Med. 2015;13:282.

[3] COMPare blog post: http://compare-trials.org/blog/where-does-annals-of-internal-medicine-stand-on-outcome-switching-a-detailed-response/, last accessed 01/02/2016.
Pianko Clarification
Posted on March 29, 2016
The Editors
Annals of Internal Medicine
Conflict of Interest: None Declared
The wording in an Annals’ response (2nd comment to this article) was unclear and we wish to clarify it. The phrase, “…we do not believe that COMPare’s comments on Pianko et al merit response”, meant that we did not believe that COMPare’s comments merited a correction to the article, not that the authors would not be asked to respond. Annals has forwarded all of COMPare’s comments to trial authors and several have responded to date (1,2).
1. MacPherson H. Alexander technique lessons or acupuncture sessions for persons with chronic neck pain. Ann Intern Med2016. 164:376. doi:10.7326/L15-0632
2. www.annals.org/article.aspx?articleid=2468806&resultClick=3
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