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出境医 / 临床实验 / Combination Treatment of NAs and Peg IFN α-2b for Hepatitis B Related, Compensatory Cirrhosis Patients

Combination Treatment of NAs and Peg IFN α-2b for Hepatitis B Related, Compensatory Cirrhosis Patients

Study Description
Brief Summary:

The study aims to demonstrate that whether treatment of nucleoside （acid）analogues (NAs) plus pegylated interferon (Peg IFN) α-2b for those NAs treated, low level of HBsAg, hepatitis B related compensatory cirrhosis patients will result in higher HBsAg clearance rate and reduce the risk of liver cancer. The investigators plan to enroll about 84 hepatitis B related compensatory cirrhosis patients, who have received NAs treatment more than 1 year with the level of HBsAg <1000IU/ml. These participants will be devided into 2 groups. Group A will receive the treatment of NAs plus Peg IFNα-2b. Group B will be treated with NAs as before enrollment. The participants in both groups will be followed up for 96 weeks.

The primary endpoint is to compare the clearance rate of HBsAg between two groups. The secondary endpoint includes: (1) comparing the incidence of liver cancer during the 96 weeks follow-up, (2) comparing adverse side effects between the 2 groups. (3) comparing the virological and biochemical responses between the 2 groups.


Condition or disease Intervention/treatment Phase
Cirrhosis of Liver Due to Hepatitis B (Disorder) Drug: pegylated interferon (Peg IFN)α-2b Drug: Nucleoside （acid）analogue (NAs) Phase 2

Detailed Description:

Clearance of hepatitis B virus surface antigen (HBsAg) is considered to be the ultimate therapeutic goal for hepatitis B patients, for it is related with low incidence of fibrosis and liver cancer. The investigators' previous study show that nucleoside （acid）analogues (NAs) treated, non-cirrhosis hepatitis B patients switched to /or combined with pegylated interferon (Peg IFN)α-2b could obtain a higher HBsAg clearance rate. Hence, the investigators' hypothesis is that treatment of NAs plus Peg IFNα-2b for those NAs treated, low level of HBsAg, hepatitis B related compensatory cirrhosis patients result in higher HBsAg clearance rate and reduce the risk of liver cancer.

The investigators plan to enroll about 84 hepatitis B related compensatory cirrhosis patients, who have received NAs treatment more than 1 year with the level of HBsAg <1000IU/ml. These participants will be devided into 2 groups according to their wishes. Group A will receive the treatment of NAs (patients previously treated with telbivudine will be changed to entecavir) plus Peg IFNα-2b （180ug per week, the dose will be changed to 135ug or 90ug per week during the treatment if patients could not tolerate the side effects of Peg IFNα-2b）. Peg IFNα-2b treatment will be performed until HBsAg <0.05IU/ml, with a maximum duration of 48 weeks. Group B will be treated with NAs as before enrollment. The participants in both groups will be followed up for 96 weeks.

The primary endpoint is to compare the clearance rate of HBsAg between two groups. The secondary endpoint includes: (1) comparing the incidence of liver cancer during the 96 weeks follow-up, (2) comparing adverse side effects, such as ascites, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome between the 2 groups. (3) comparing the virological and biochemical responses between the 2 groups.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination Treatment of Nucleoside （Acid）Analogue (NAs) and Pegylated Interferon α-2b for NAs Treated, Hepatitis B Related, Compensatory Cirrhosis Patients With Low Level Hepatitis b Virus Surface Antigen (HBsAg)
Actual Study Start Date : June 17, 2019
Estimated Primary Completion Date : May 30, 2022
Estimated Study Completion Date : May 30, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: NAs+Peg IFN Group
NAs+Peg IFN Group will receive the treatment of NAs (patients previously treated with telbivudine will be changed to entecavir) plus pegylated interferon (Peg IFN)α-2b.
 Drug: pegylated interferon (Peg IFN)α-2b
Participants in NAs+Peg IFN Group will be treated by Peg IFNα-2b （180ug per week, the dose will be changed to 135ug or 90ug per week during the treatment if patients could not tolerate the side effects of Peg IFNα-2b). Peg IFNα-2b treatment will be performed until HBsAg <0.05IU/ml, with a maximum duration of 48 weeks.
Other Name: Pi Gebin

Drug: Nucleoside （acid）analogue (NAs)
Both of NAs Group and NAs+Peg IFN Group will be treated with NAs as before enrollment.
Other Name: Boludine
NAs Group
NAs Group will be treated with NAs as before enrollment.
 Drug: Nucleoside （acid）analogue (NAs)
Both of NAs Group and NAs+Peg IFN Group will be treated with NAs as before enrollment.
Other Name: Boludine
Outcome Measures
Primary Outcome Measures :
  1. The clearance rate of HBsAg for both groups during 96 weeks. [ Time Frame: 96 weeks ]
    The clearance rate of HBsAg will be compared between 2 groups.


Secondary Outcome Measures :
  1. The incidence rate of liver cancer for both groups during 96 weeks [ Time Frame: 96 weeks ]
    The incidence of liver cancer will be compared between 2 groups.

  2. Occurance rate of adverse side effects in both groups [ Time Frame: 96 weeks ]
    Adverse side effects, such as ascites, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome will be compared between 2 groups

  3. The change of liver functions in both groups [ Time Frame: 96 weeks ]
    The levels of alanine transaminase, glutamic-oxalacetic transaminase, albumin, total bilirubin, INR will be compared between the 2 groups.

  4. The change of blood routine test indexes in both groups [ Time Frame: 96 weeks ]
    The levels of WBC, Hb, PLT will be compared between the 2 groups.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged 16-65 years old; Clinical diagnosis of compensatory cirrhosis; Child-Pugh grade A; Positive serum hepatitis B surface antigen (HBsAg); HBsAg titer < 1000IU/ml; Treated by nucleoside （acid）analogues (NAs) more than 1 year; HBV DNA <20 IU/ml; Negative serum hepatitis B e antigen (HBeAg); 15 minutes retention rate of indocyanine green <10%; The blood routine examination: 4×10e9/L<WBC<10×10e9/L、100×10e9/L<PLT<300×10e9/L.

Exclusion Criteria:

  • Treated by interferon within half a year; Drug induce liver diseases; Autoimmune liver diseases; Liver diseases caused by metabolic factors; Superinfection with hepatitis A, C, D, E viruses; Infected by HIV virus; Severe respiratory diseases; Severe circulatory diseases, ; Severe digestive diseases; Severe neurological diseases; Need for immunosuppressive therapy for other diseases; Need for radiotherapy/chemotherapy for other diseases; Thyroid diseases; Rheumatic diseases; Malignant tumors; Severe varicose esophageal and gastric fundus veins; Mental or psychological disorders; Alcohol or drug abusers (average alcohol consumption >40g/d for men, >20g/d for women); With contraindications to interferon therapy; Pregnancy or having pregnancy plan in 3 years; Lactation; Can not comply with the study protocol; Fail to sign the informed consent; Other conditions that are not suitable for enrollment determined by researchers.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Bingliang Lin, Doctor 86-020-85253165 lamikin@126.com
Contact: Junfeng Chen, Master 86-020-85253165 mountainchen@139.com

Locations
Layout table for location information
China, Guangdong
Third Affliated Hospital of Sun Yat-sen University Recruiting
Guangzhou, Guangdong, China, 510630
Contact: Lin Bingliang, MD    86-20-85253165    lamikin@126.com   
Sponsors and Collaborators
Sun Yat-sen University
Investigators
Layout table for investigator information
Principal Investigator: Bingliang Lin, Doctor Third Affiliated Hospital, Sun Yat-Sen University
Tracking Information
First Submitted Date  ICMJE May 21, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date June 20, 2019
Actual Study Start Date  ICMJE June 17, 2019
Estimated Primary Completion Date May 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2019) 		The clearance rate of HBsAg for both groups during 96 weeks. [ Time Frame: 96 weeks ]
The clearance rate of HBsAg will be compared between 2 groups.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2019)
  • The incidence rate of liver cancer for both groups during 96 weeks [ Time Frame: 96 weeks ]
    The incidence of liver cancer will be compared between 2 groups.
  • Occurance rate of adverse side effects in both groups [ Time Frame: 96 weeks ]
    Adverse side effects, such as ascites, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome will be compared between 2 groups
  • The change of liver functions in both groups [ Time Frame: 96 weeks ]
    The levels of alanine transaminase, glutamic-oxalacetic transaminase, albumin, total bilirubin, INR will be compared between the 2 groups.
  • The change of blood routine test indexes in both groups [ Time Frame: 96 weeks ]
    The levels of WBC, Hb, PLT will be compared between the 2 groups.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Treatment of NAs and Peg IFN α-2b for Hepatitis B Related, Compensatory Cirrhosis Patients
Official Title  ICMJE Combination Treatment of Nucleoside （Acid）Analogue (NAs) and Pegylated Interferon α-2b for NAs Treated, Hepatitis B Related, Compensatory Cirrhosis Patients With Low Level Hepatitis b Virus Surface Antigen (HBsAg)
Brief Summary

The study aims to demonstrate that whether treatment of nucleoside （acid）analogues (NAs) plus pegylated interferon (Peg IFN) α-2b for those NAs treated, low level of HBsAg, hepatitis B related compensatory cirrhosis patients will result in higher HBsAg clearance rate and reduce the risk of liver cancer. The investigators plan to enroll about 84 hepatitis B related compensatory cirrhosis patients, who have received NAs treatment more than 1 year with the level of HBsAg <1000IU/ml. These participants will be devided into 2 groups. Group A will receive the treatment of NAs plus Peg IFNα-2b. Group B will be treated with NAs as before enrollment. The participants in both groups will be followed up for 96 weeks.

The primary endpoint is to compare the clearance rate of HBsAg between two groups. The secondary endpoint includes: (1) comparing the incidence of liver cancer during the 96 weeks follow-up, (2) comparing adverse side effects between the 2 groups. (3) comparing the virological and biochemical responses between the 2 groups.
Detailed Description

Clearance of hepatitis B virus surface antigen (HBsAg) is considered to be the ultimate therapeutic goal for hepatitis B patients, for it is related with low incidence of fibrosis and liver cancer. The investigators' previous study show that nucleoside （acid）analogues (NAs) treated, non-cirrhosis hepatitis B patients switched to /or combined with pegylated interferon (Peg IFN)α-2b could obtain a higher HBsAg clearance rate. Hence, the investigators' hypothesis is that treatment of NAs plus Peg IFNα-2b for those NAs treated, low level of HBsAg, hepatitis B related compensatory cirrhosis patients result in higher HBsAg clearance rate and reduce the risk of liver cancer.

The investigators plan to enroll about 84 hepatitis B related compensatory cirrhosis patients, who have received NAs treatment more than 1 year with the level of HBsAg <1000IU/ml. These participants will be devided into 2 groups according to their wishes. Group A will receive the treatment of NAs (patients previously treated with telbivudine will be changed to entecavir) plus Peg IFNα-2b （180ug per week, the dose will be changed to 135ug or 90ug per week during the treatment if patients could not tolerate the side effects of Peg IFNα-2b）. Peg IFNα-2b treatment will be performed until HBsAg <0.05IU/ml, with a maximum duration of 48 weeks. Group B will be treated with NAs as before enrollment. The participants in both groups will be followed up for 96 weeks.

The primary endpoint is to compare the clearance rate of HBsAg between two groups. The secondary endpoint includes: (1) comparing the incidence of liver cancer during the 96 weeks follow-up, (2) comparing adverse side effects, such as ascites, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome between the 2 groups. (3) comparing the virological and biochemical responses between the 2 groups.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cirrhosis of Liver Due to Hepatitis B (Disorder)
Intervention  ICMJE
  • Drug: pegylated interferon (Peg IFN)α-2b
    Participants in NAs+Peg IFN Group will be treated by Peg IFNα-2b （180ug per week, the dose will be changed to 135ug or 90ug per week during the treatment if patients could not tolerate the side effects of Peg IFNα-2b). Peg IFNα-2b treatment will be performed until HBsAg <0.05IU/ml, with a maximum duration of 48 weeks.
    Other Name: Pi Gebin
  • Drug: Nucleoside （acid）analogue (NAs)
    Both of NAs Group and NAs+Peg IFN Group will be treated with NAs as before enrollment.
    Other Name: Boludine
Study Arms  ICMJE
  • Experimental: NAs+Peg IFN Group
    NAs+Peg IFN Group will receive the treatment of NAs (patients previously treated with telbivudine will be changed to entecavir) plus pegylated interferon (Peg IFN)α-2b.
    Interventions:
    • Drug: pegylated interferon (Peg IFN)α-2b
    • Drug: Nucleoside （acid）analogue (NAs)
  • NAs Group
    NAs Group will be treated with NAs as before enrollment.
    Intervention: Drug: Nucleoside （acid）analogue (NAs)
Publications *
  • Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008 Feb;48(2):335-52. Epub 2007 Dec 4. Review.
  • Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. Erratum in: Hepatology. 2007 Jun;45(6):1347.
  • Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009 Feb 14;373(9663):582-92. doi: 10.1016/S0140-6736(09)60207-5.
  • Thompson AJ, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, Slavin J, Bowden S, Gane EJ, Abbott W, Lau GK, Lewin SR, Visvanathan K, Desmond PV, Locarnini SA. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology. 2010 Jun;51(6):1933-44. doi: 10.1002/hep.23571.
  • Nguyen T, Thompson AJ, Bowden S, Croagh C, Bell S, Desmond PV, Levy M, Locarnini SA. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol. 2010 Apr;52(4):508-13. doi: 10.1016/j.jhep.2010.01.007. Epub 2010 Feb 16.
  • Liu J, Lee MH, Batrla-Utermann R, Jen CL, Iloeje UH, Lu SN, Wang LY, You SL, Hsiao CK, Yang HI, Chen CJ. A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection. J Hepatol. 2013 May;58(5):853-60. doi: 10.1016/j.jhep.2012.12.006. Epub 2012 Dec 13.
  • Tseng TC, Liu CJ, Su TH, Wang CC, Chen CL, Chen PJ, Chen DS, Kao JH. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology. 2011 Aug;141(2):517-25, 525.e1-2. doi: 10.1053/j.gastro.2011.04.046. Epub 2011 Apr 28.
  • Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1001-10.
  • Hou JL, Gao ZL, Xie Q, Zhang JM, Sheng JF, Cheng J, Chen CW, Mao Q, Zhao W, Ren H, Tan DM, Niu JQ, Chen SJ, Pan C, Tang H, Wang H, Mao YM, Jia JD, Ning Q, Xu M, Wu SM, Li J, Zhang XX, Ji Y, Dong J, Li J. Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial. J Viral Hepat. 2015 Feb;22(2):85-93. doi: 10.1111/jvh.12313. Epub 2014 Sep 22.
  • Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, Dauvergne A, Cardoso AC, Asselah T, Nicolas-Chanoine MH, Vidaud M, Valla D, Bedossa P, Marcellin P. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol. 2009 Jun;50(6):1084-92. doi: 10.1016/j.jhep.2009.01.016. Epub 2009 Mar 9.
  • Dietary effects on diurnal variation in lipogenesis. Nutr Rev. 1987 May;45(5):157-8.
  • Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol. 2013 Apr;58(4):676-83. doi: 10.1016/j.jhep.2012.11.039. Epub 2012 Dec 3.
  • European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012 Jul;57(1):167-85. doi: 10.1016/j.jhep.2012.02.010. Epub 2012 Mar 20. Erratum in: J Hepatol. 2013 Jan;58(1):201. Janssen, Harry [corrected to Janssen, Harry L A].
  • Buster EH, Flink HJ, Cakaloglu Y, Simon K, Trojan J, Tabak F, So TM, Feinman SV, Mach T, Akarca US, Schutten M, Tielemans W, van Vuuren AJ, Hansen BE, Janssen HL. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008 Aug;135(2):459-67. doi: 10.1053/j.gastro.2008.05.031. Epub 2008 May 15.
  • Moucari R, Boyer N, Ripault MP, Castelnau C, Mackiewicz V, Dauvergne A, Valla D, Vidaud M, Chanoine MH, Marcellin P. Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients. J Viral Hepat. 2011 Aug;18(8):580-6. doi: 10.1111/j.1365-2893.2010.01332.x. Epub 2010 May 17.
  • Sarin SK, Kumar M, Kumar R, Kazim SN, Guptan RC, Sakhuja P, Sharma BC. Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol. 2005 Nov;100(11):2463-71.
  • Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol. 2014 Oct;61(4):777-84. doi: 10.1016/j.jhep.2014.05.044. Epub 2014 Jun 7.
  • Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1997 Nov;26(5):1338-42.
  • Ikeda K, Kobayashi M, Saitoh S, Someya T, Hosaka T, Akuta N, Suzuki Y, Suzuki F, Tsubota A, Arase Y, Kumada H. Significance of hepatitis B virus DNA clearance and early prediction of hepatocellular carcinogenesis in patients with cirrhosis undergoing interferon therapy: long-term follow up of a pilot study. J Gastroenterol Hepatol. 2005 Jan;20(1):95-102.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 28, 2019) 		84
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 30, 2024
Estimated Primary Completion Date May 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Aged 16-65 years old; Clinical diagnosis of compensatory cirrhosis; Child-Pugh grade A; Positive serum hepatitis B surface antigen (HBsAg); HBsAg titer < 1000IU/ml; Treated by nucleoside （acid）analogues (NAs) more than 1 year; HBV DNA <20 IU/ml; Negative serum hepatitis B e antigen (HBeAg); 15 minutes retention rate of indocyanine green <10%; The blood routine examination: 4×10e9/L<WBC<10×10e9/L、100×10e9/L<PLT<300×10e9/L.

Exclusion Criteria:

  • Treated by interferon within half a year; Drug induce liver diseases; Autoimmune liver diseases; Liver diseases caused by metabolic factors; Superinfection with hepatitis A, C, D, E viruses; Infected by HIV virus; Severe respiratory diseases; Severe circulatory diseases, ; Severe digestive diseases; Severe neurological diseases; Need for immunosuppressive therapy for other diseases; Need for radiotherapy/chemotherapy for other diseases; Thyroid diseases; Rheumatic diseases; Malignant tumors; Severe varicose esophageal and gastric fundus veins; Mental or psychological disorders; Alcohol or drug abusers (average alcohol consumption >40g/d for men, >20g/d for women); With contraindications to interferon therapy; Pregnancy or having pregnancy plan in 3 years; Lactation; Can not comply with the study protocol; Fail to sign the informed consent; Other conditions that are not suitable for enrollment determined by researchers.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bingliang Lin, Doctor 86-020-85253165 lamikin@126.com
Contact: Junfeng Chen, Master 86-020-85253165 mountainchen@139.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03969017
Other Study ID Numbers  ICMJE I-CURE VI STUDY
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Lin Bingliang, Sun Yat-sen University
Study Sponsor  ICMJE Sun Yat-sen University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bingliang Lin, Doctor Third Affiliated Hospital, Sun Yat-Sen University
PRS Account Sun Yat-sen University
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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